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Lenze et al. - 2020 - Efficacy and application of a novel topical anaest

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PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. E cacyandapplicationofanoveltopicalanaestheticwoundformulationfortreatingcattlewithFoot-and-Mouthdisease:a eldtrialinCameroonSevidzemLenze1,JacquesMavoungou1,KongBurinyuy1,KoumbaArmel1,SimonDickmu1,JamesYoung2,PeterThomson3,andPeterWindsor21A liationnotavailable2UniversityofSydney3SchoolofLifeandEnvironmentalSciencesSeptember16,2020AbstractRecently,awounddressingformulation,(Tri-Solfen®,MedicalEthicsPtyLtd,Australia;TS)registeredforuseinruminanthusbandryinAustralia,wasregisteredforFoot-and-MouthDisease(FMD)therapyinlargeruminantsinLaos,followingclinicalobservationsofimprovedwelfareandhealingfollowingtreatmentofFMDlesions.InNovember2019,anFMDoutbreakinCameroonprovidedanopportunityfora eldtrial,comparingclinicalresponsesandrecoveriestotreatmentsonasampleofcattle(n=36)comprisingthreeequalgroupsofanimals(n=12),comparingresponsestothreetreatments:(i)theapplicationtolesionsofTS,(ii)theadministrationofparenteraloxytetrayclinecommonlyusedforFMDinCameroon;and(iii)anuntreatedcontrolgroup(C).Appetitescores,lesionhealingscores,andchangesindimensionsoflesions,wererecordedovera15-daystudyperiod.CattletreatedwithTSachievedbothsuperiorappetiteandlesionhealingscoreswithmorerapidreductionindimensionsoflesionsthanothergroups.FarmerobservationsindicatedtheTStreatmentgrouphadamorerapidreturntoeatingwithcessationofexcessivesalivation,andmorerapidreturnofmobility(walking)withabsenceofovertlameness.The ndingsindicatethatalthoughmortalityisusuallylowinFMDoutbreaks,thediseaseisadebilitatingandpainfuldisorderwithnegativeanimalwelfareimpactsthatshouldbeaddressed.AllfarmersexpressedtheirdesirethattheproductbemadeavailableforuseintheirregionandmodellingindicatesthatTStherapyimposesnoadditional nancialburdenonfarmers,withthetreatmentlikelytobeprovidedatasimilarorreducedcosttocurrenttreatmentchoices.Asuseofantibioticsfortreatmentofaviraldiseasepotentiallyincreasespressuresfordevelopmentofantimicrobialresistanceandresiduesinthefoodchain,TSasanalternativenon-antimicrobialtherapyshouldbepromotedforwideruseinFMDoutbreaks.INTRODUCTIONCameroon,withapopulationofalmost28millionpeople,islocatedincentralAfrica,borderingtheGulfofGuinea.Itisakeytransitlink,sharingborderswithsixcountries:Nigeria,Chad,CentralAfricanRepublic,RepublicofCongoandEquatorialGuinea.Thegrossdomesticproduct(GDP)percapitaofCameroonisestimatedatUSD3,700(CIA,2017).Theapproximately7.1millioncattleinCameroonaresusceptibletoregularoutbreaksfromFoot-and-MouthDisease(FMD),andendemicdiseaseinmuchofAfrica.WithnopreventivecontrolprogramsinplaceandnoaccesstocommercialFMDvaccination,farmersarefocusedontreatmentchoicesfora ectedcattle,withantibioticsand/ortraditionaltherapiescommonlyusedandprolongedperiodsforanimalstorecover.FMDisamostimportantglobalviralpathogenofartiodactylfarmedandwildlifeanimals.Thediseaseischaracterisedbylesionsinandaroundthemouthandfeet(Fakhrul-Islametal.,2016).Globally,there1 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. aresevenpoolsofcirculatingFMDvirusesrecognised.EachpoolrepresentsindependentlycirculatingandevolvingFMDvirus(FMDV)genotypes(Russo,2018).Withinthepools,cyclesofemergenceandspreadoccurthatusuallya ectmultiplecountriesintheregion.Intheabsenceofspeci candlaboratory-con rmedreports,itshouldbeassumedthattheprevalentserotypesarecontinuouslycirculatinginpartsofthepoolareaandwouldbedetectedifsu cientsurveillancewasinplace(Russo,2018).CameroonsitsintheWest/CentralAfricanregiondesignatedasPool5.FMDcauseshugeeconomiclossesinCameroon,withestimationofthetotalannualcostofFMDmanagementatUSD112million(FAO,2015).OfthesevenFMDVserotypes,four(O,A,SAT1&SAT2)occurinCameroon(Ludietal.,2016;Sevidzemetal.,2019b;Ehiziboloetal.,2019).ThereisnomassvaccinationprogramforFMDandnocommercialFMDvaccinesareavailableinCameroon(Bertrametal.,2018).Apilottrialusingcommercialtrivalentvaccine(Aftovax®)wasconductedin2015inNgaoundere,withobservationsthatclinicalinfectionofFMDappearedtohavebeenprevented,althoughpersistentinfectionoccurred.CattleownersinCameroonroutinelymanagethediseaseusingarangeoftherapies,includinganti-inammatorypreparations,antibioticsandtraditionalformulations(Sevidzemetal.,2019a).Intheabsenceofstrategicpreventivecontrolprograms,thereareurgentneedsforalternativeFMDmana-gementoptionsforendemicFMD-infectedcountries,includingCameroon.Witha ordableande caciousvaccinecandidatesformanagingFMDunlikelyinthenearfuture,thereviewandrationalizingofFMDtherapiesisadvisable.Severaltopicaltreatmentswithethno-veterinaryandrecognizedveterinarypharma-ceuticalshavebeenexaminedinFMDendemicsettingsinAfrica(Gakuyaetal.,2011;Misketal.,2015;Fakhrul-Islametal.,2016;Al-Lethieetal.,2018).However,thewidespreaduseofparenteralantibioticsforFMDglobally,includingnumerouscountriesinAfricaandCamerooninparticular,presentsantimicrobialresistance(AMR)andpotentialfoodsafetyresiduerisksthatneedtobeaddressed.Recently,anAustralianwounddressingformulation,Tri-Solfen®(MedicalEthicsPtyLtd,Australia;TS)registeredforuseincattleandsmallruminanthusbandryinAustraliaandNewZealand,wasregisteredforFMDtherapyinlargeruminantsinLaosinsoutheastAsia(Windsoretal.,2020).Thewoundandlesiondressingformulationcontainstwolocalanaesthetics(lignocaineandbupivacaine),adrenalinandcetramideinagelmatrixthatcreatesabarriere ect,numbingthepainoflesions,rapidlyreducingtheirinfectivity,andhasteninghealing,potentiallyreducingtheweightlossina ectedindividuals(Windsoretal.,2020).Ifmadeavailableforpurchaseandadministrationbyfarmers,thisproductcouldprovideaviablealternativeapproachformanagingFMDinCameroon,otherAfricancountriesanddevelopingcountriesglobally.Thisformulationo ersnumerousadvantagesovercurrenttherapiesasitprovidese caciouspainreliefandmorerapidhealingofwoundsandlesions(Windsoretal.,2016;RobertsandWindsor,2019;Windsoretal.,2020).Further,withapHof~2.7,andcontainingtheantisepticcetrimide,itpotentiallyhasviricidalimpactsandanti-bacterialpropertiesrespectively,avoidingtheneedforothertreatments,includingantibiotics(Windsoretal,2020).InNovember2019,TSwasprovidedtotheCameroonresearchteamfortrialsduringFMDoutbreaksincattle.Thisreportdescribesa eldtrialinCameroonaimedatevaluatingthee cacyofthistherapyforFMDlesionmanagement,particularlyforenhancingrecoveryandwoundhealing,comparingtheclinicalresponsestothemostcommonlyusedandavailableantimicrobialtherapycurrentlyinuse.IfTSisproventobease caciousforFMDinthiscurrentstudyasitappearedtobeon rstuseinLaosasdescribed(Windsoretal.,2020),itislikelythattheproductcouldo eranimportantinnovationforimprovingFMDlesiontreatment,potentiallyglobally,withreducedanimalwelfareburdens,risksofAMRissuesandpossibly,increasedtransboundarydiseasereportingandsurveillance.MATERIALSANDMETHODSTriallocationanddesignThisclinicaltrialwasconductedbetweenthe5thofNovemberandthe5thofDecember2019inNgaoundereII,NgaoundereIIIandMartapsubdivisionsintheVinaDivisionoftheAdamawaplateau.Around40%ofthecattlepopulationofCameroonislocatedintheAdamawaregion(MINEPIA,2013).Ngaoundereisthe2 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. capitaloftheAdamawaregion,withgeo-referencedcoordinatesbetween6°40'0"and7°30'0"northlatitudeandbetween13°20'0"and14°10'0"'eastlongitude(Fig.1).AnFMDoutbreakinthemunicipalitiesofNgaoundereII,NgaoundereIIIandMartapwasadvisedtotheleadauthorbya eldtechnicianinNgaoundereonthe4thofNovember2019.Thefollowingday,theoutbreakareaswereaccessed,andthetreatmenttrialscommencedimmediately.Twoteamsoftwomemberseachwereformedtoenableanimaltreatmentsandfollow-upofthetreatedcases.Participatingfarmswereselectedfollowingdemonstrationofownerwillingnesstoparticipate,andincluded:Hor eMayanga,Borongo,TchabalBaouroandMbidjoro.TheGPSdataofallfarmswasrecorded.AsMoore-Oxy®(manufacturedinChina;MO)wasthereferenceantibioticcommonlyusedbyfarmerstomanageclinicalFMDinthestudyarea,itwasdecidedtocomparethee cacyofthisformulationonthehealingofFMDlesionswiththatofTS.AsMOisadministeredintra-muscularlyandTSisadministeredtopically,oneachfarm,threeanimalswerematchedbyageandbreed,withsimilarFMDclinicalpresenta-tions;withonetreatedwithMO,onewithTSandthethirdleftuntreated.Thiscreated12setsofcattleforthiscomparativeclinicaltrialonthedi erentfarms. Figure1:Mapsshowingthestudysites(NgaoundereII,NgaoundereIIIandMartap)M1:Mbidjoro1,M2:Mbidjoro2,T1:TchabalBaouro1,T2:TchabalBaouro2,T3:TchabalBaouro3,T4:Tchabal4,T5:Tchabal5,T6:Tchabal6,B:Borongo,H1:Hor eMayanga1,H2:Hor eMayanga2,H3:Hor eMayanga3.TreatmentApplicationsTheclinicaltreatmenttrialwasconductedon`fresh'FMDlesions,containingintactvesiclesorrecentlyrupturedvesicles.AnimalstreatedwithTShadlesionsliberallysprayedwith2mloftheproduct,asperlabelinstructions.AnimalstreatedwithMOreceivedanintra-muscularinjectionoftheproduct,alsoatdosesperlabelinstructions.Clinicalresponseobservationswerenoted,includinganyimprovementsincapacityandabilityoftheanimaltowalkandeat.Thefollowingsemi-quantitativeclinicalmeasurementsweremade:Lesionhealingscore(LHS)onascaleof1to4(adaptedfromAl-Lethieetal.,2018)Appetitescore(AS)onascaleof1to4(fromAl-Lethieetal.,2018)3 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. Lesionsize(cm):healingoflesionswasmeasuredquantitativelyinthe eldusinga30-cmruler,every3daysfromdayzero(D0)throughday15(D15),withlesionsphotographedusingandroidmobilephones.FarmerObservationsThefarmerswererequestedtoprovidetheirobservationsforeachanimalforeachtreatmentgroup,withthefollowinginformationrecorded:Numberofdaysuntilcattlemobility(walking)returnedNumberofdayscattlewerenoteatingNumberofdayscattlecontinuedtosalivateNumberofdaysdisplayedlamenessNumberofdaysrequiredforcattletoreturntograzingTreatmentcostmodelThecostsoftreatmentswereestimatedandusedtodevelopacost-bene tmodelenablingcomparisonoftherapiesthatcouldassistdecisionsforbothindividualfarmersandpublichealthpolicymakersonFMDoutbreakmanagement.StatisticalAnalysesOrdinalscaleanalysisBoththelesionhealingscoresandtheappetitescoreswererecordedonafour-pointordinalscale,notaquantitativescale,soappropriateordinalcategoricalmethodswererequiredforthisanalysis(Agresti,2002).Inaddition,walkingwasalsomodelledonathree-pointordinalscale:(1:immobile;2:walkingwithdi culty;3:walkingnormally).Anordinallogisticmixedmodelwas ttedtoeachdatasetwith xede ectsforTreatment,Day,BreedandAge(covariate),andarandome ectfortheindividualAnimalID.ATreatment×Dayinteractionwasincludedineachofthemodels,toallowforadi erentshapedtimecourseforeachtreatment.Notethatthe ttedmodelreturnedasetofmodel-basedprobabilitiesofobtainingeachpossiblescore(1through4,or1through3),fortheparticularcombinationoftermsinthemodel.Themodelwas ttedusingtheclmmfunctionintheordinalpackageofR(Christensen,2019),andprobabilityestimatesobtainedusingtheemmeans(Lenth,2020)andRVAideMemoire(Herv e,2020)packagesinR.BinarydataanalysisThestatusofcattlebeingonpastureandcattlesalivating(Yes=1,No=0)arebinaryoutcomes,andforthis,binarylogisticmixedmodelswereusedtoanalysethesedata.Asabove, xede ectsforTreatment,Day,Treatment×Day,Age,BreedandSex,andarandome ectforAnimalIDwereincludedinthemodel.Themodelwas ttedusingtheglmerfunctioninthelme4packageofR(Batesetal.,2015),andmodel-basedmeansobtainedusingtheemmeanspackage.QuantitativedataanalysisLesionsize(cm)wasanalysedusingalinearmixedmodel,with xede ectsforTreatment,Day,Treatment×Day,Age,BreedandSex,andarandome ectforAnimalID.Model ttingwasviathelmerfunctioninthelme4,andmodel-basedmeansobtainedusingtheemmeanspackage.Eventdurationdata(numberofdaysthatcattleareimmobile,walkwithdi culty,walknormally,onpasture,andsalivating)wereanalysedusinglinearmodelswith xede ectsforTreatment,Age,BreedandSex.Duetothepositiveskew,aloge(y+1)transformationwasapplied.However,withthelargenumberof`zero'durations,hypothesistestingwasconductedwithpermutationtestsratherthanF-tests,usingtheaovpermfunctioninthepermucopackage(Frossard&Renaud,2019)inR.RESULTS4 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. Ofthe12farmersenrolledintothe15-daytreatmenttrialwiththreematched-cattle,eachreceivingadi erenttreatment,theageandbreedofthecattlerecruitedintoeachtreatmentgrouparepresented(Table1).Table1.Ageandbreedofcattlerecruitedintoeachtreatmentgroup. TreatmentgroupTreatmentgroupTreatmentgroup VariableMoore-Oxy®Tri-Solfen®ControlOverallAverageage(yr)3.743.33.7Agerange(yr)2to52to82to52to8BreedcountGoudali991028Holstein1113WhiteFulani1214RedFulani1001Total12121236 LesionhealingscoresTherewasahighlysigni cantTreatment×Dayinteraction(P=3.4×10{7),indicatingdi eringlesionhealingscoretimecoursesacrossthethreetreatmentgroups.Model-basedlesionscoreprobabilitiesaredisplayed(Figure2).Whilecontrolcattlemaintainedthepresenceoferosions/ulcers(ascoreof1),recoverieswereobservedinthetwotreatmentgroups.FromDay9onwards,cattletreatedwithTShadsigni cantlyhigherlesionhealingscoresthanthoseonMO(Day9:P=0.025;Day12:P=0.016;Day15:P=0.0008).Noneoftheothertermshadasigni cantassociationwithlesionhealingscore:Age:P=0.464;Breed:P=0.311;Sex:P=0.376.5 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. Figure2.Model-basedprobabilitiesofobtaininglesionhealingscores1through4acrossthesixstudydays,forthethreetreatmentgroups.AppetitescoresAgain,therewasahighlysigni cantTreatment×Dayinteraction(P=2.0×10{6)forappetitescore,indicatingtreatmente ectswerechangingoverthestudyperiod.Model-basedappetitescoreprobabilitiesaredisplayed(Figure3).Mostcontrolcattlehadnoappetiteoverthewholestudyperiod(scoreof1).However,thetwotreatmentgroupshadhighappetitescoresonDay0,lowonDay3,thenprogressivelyincreasingappetitescoresafterthat.FromDay9onwards,cattletreatedwithTShadsigni cantlyhigherhealingscoresthanthoseonMO(Day9:P=0.025;Day12:P=0.016;Day15:P=0.0008).AfterDay0,therewerenosigni cantdi erencesinappetitescorebetweenMOandTStreatedcattle(allP>0.10).NeitherAge(P=0.810),Breed(P=0.524),norSex(P=0.324)hadasigni cante ectinappetitescore.6 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. Figure3.Model-basedprobabilitiesofobtainingappetitescores1through4acrossthesixstudydays,forthethreetreatmentgroups.LesionsizeTherewasahighlysigni cantTreatment×Dayinteraction(P<2×10{16)forlesionsize(Figure4),indicatingdi erentratesofhealingacrossthethreegroups.Initially,therewerenosigni cantdi erencesinmeanwoundsizesamongstthethreegroups(allP>0.25).WhilemeanwoundsizeincreasesforControlcattle,theyreducedforthetwotreatmentgroups,withthoseintheTStreatmentreducingatafasterrate(di erencesweresigni cantfromDay9,allP<0.01).Therewasnosigni cante ectofAge(P=0.454),Breed(P=0.225),norSex(P=0.374)onlesionsize.7 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. Figure4.Model-basedmeanlesionsize(cm)acrossthesixstudydays,forthethreetreatmentgroups.Shadedareasare±1standarderrorofthemean.WalkingWhenwalkingisconsideredasanordinalscore(Immobile<Withdi culty<Normal),therewasahighlysigni cantTreatment×Dayinteraction(P=1.8×10{13).Initially(Day0),therewerenodi erencesinwalkingscoresbetweenthethreegroups(allP>0.15)and.somecattleremained`Immobile'or`Withdi culty'throughoutthestudyperiod(Figure5).However,walkingimprovedforthetwotreatmentgroups,particularlyfortheTStreatmentgroup.However,thedi erencesbetweenthesetwogroupsneverreachedthresholdsigni cance(allP>0.05).Therewerenosigni cante ectsofotherfactorsonwalking(Age:P=0.583;Breed:P=0.9012;Sex:P=0.778).8 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. Figure5.Model-basedprobabilitiesofobtainingwalkingscoresof`Immobile',`Withdi culty'and`Normal'acrossthesixstudydays,forthethreetreatmentgroups.Anadditionalanalysiswasconductedtocomparethenumberofdaysthatcattleareimmobile,numberofdaystheywalkwithdi culty,andnumberofdaystheywalknormally(Table2).Inallcases,thesedurationsdi eredsigni cantlybetweenthethreetreatmentgroups(allP<0.01).Controlcattlehadasigni cantlylongerperiodofimmobilitycomparedwiththetwotreatmentgroups(bothP<0.005).Table2.Analysisofthenumberofdaysthatcattleareimmobile,numberofdayswalkingwithdi culty,andnumberofdayswalkingnormally WalkingVariableP-valueControlMoore-Oxy®Tri-Solfen® ImmobileTreatment0.0022.47A±1.390.05B±0.350.00B±0.30Age0.942Breed0.590Sex0.268WithTreatment0.0098.27A±4.953.49AB±2.000.70B±0.85Di cultyAge0.471Breed0.875Sex0.724NormalTreatment0.0000.60A±0.402.72B±0.787.18C±1.92Age0.221Breed0.1179 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. WalkingVariableP-valueControlMoore-Oxy®Tri-Solfen® Sex0.033 A,B,C:Meanssharingthesamesuperscriptarenotsigni cantlydi erent(P>0.05).TS-treatedcattlehadasigni cantlyshorterperiodofwalkingwithdi cultycomparedwithControlcattle(P=0.0022),andalsohadsigni cantlylongerperiodwalkingnormallycomparedwithbothControlandMO-treatedcattle(bothP<0.005).Notethattherewerenoe ectsofAge,Breed,notSexonthethreedurations,withtheexceptionofSexondurationofnormalwalking(P=0.033)withmalecattlehavingmeanduration3.72±1.14days,comparedwithfemaledurationof1.82days.TimeonPastureTherewasahighlysigni cantTreatment×Dayinteractionforpresenceofcattleonpasture(P=1.5×10{6).ItwasapparentthatControlcattlebasicallyneverreturnedontopastureduringthetrial(Figure6).However,forthetwotreatmentgroups,afterinitiallynonebeingonpasture,allwereonpasturebyDay6.AlthoughTSshowedafasterreturntopasturethanMO,itwasnotpossibletoformallytestthis.Therewerenosigni cante ectsofAge(P=0.791)norSex(P=0.661)ontheprobabilityofbeingonpasture;therewassomeevidenceofbreeddi erences(P=0.023),butbreedestimatescouldnotberelieduponbecauseofsmallnumberinsomebreeds. Figure6.Model-basedprobabilitiesofcattlebeingonpastureacrossthesixstudydays,forthethreetreatmentgroups.Shadedareasare±1standarderrorofthemean(whereavailable).10 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. Theresultsofanadditionalanalysistocomparethenumberofdaysthatcattleareonpastureisdisplayed(Table3).Asinthepreviousanalysis,nosigni cante ectsofTreatment,norAge,BreedorSexweredetected(allP>0.4).However,consistentwiththepreviousanalysis,thetwotreatmentgroupsspentmoretimeonpasture.Table3.Analysisofthenumberofdaysthatcattlearesalivating. VariableP-valueControlMoore-Oxy®Tri-Solfen® Treatment0.1461.59A±0.820.49A±0.390.56A±0.46Age0.171Breed0.537Sex0.500 A:Meanssharingthesamesuperscriptarenotsigni cantlydi erent(P>0.05).Salivation Figure7.Model-basedprobabilitiesofcattlesalivatingacrossthesixstudydays,forthethreetreatmentgroups.Therewasnosigni cantTreatment×Dayinteractionforoccurrenceofsalivation(P=0.496),norwasthereanoverallmaine ectofTreatment(P=0.401).Model-basedprobabilitiesofsalivatingareshown(Figure7).However,frominitialhighratesofsalivating,therewasasigni cantdeclineoverthestudyperiod(P=11 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. 6.4×10{12),withanapparentfasterrateofdeclineforthetwotreatmentgroupscomparedwiththecontrolgroup.Therewerenosigni cante ectsofAge(P=0.619),Breed(P=0.096)norSex(P=1.000)oninstancesofsalivation.Theresultsoftheanalysistocomparethenumberofdaysthatcattlearesalivatingisdisplayed(Table4).Asinthepreviousanalysis,nosigni cante ectsofTreatment,norAge,BreedorSexweredetected(allP>0.1).However,consistentwiththepreviousanalysis,thetwotreatmentgroupsspentlesstimesalivating.Table4.Analysisofthenumberofdaysthatcattlearesalivating. VariableP-valueControlMoore-Oxy®Tri-Solfen® Treatment0.1461.59A±0.820.49A±0.390.56A±0.46Age0.171Breed0.537Sex0.500 A:Meanssharingthesamesuperscriptarenotsigni cantlydi erent(P>0.05).CostoftherapymodelThetreatmenttypesandcostsforFMDtherapyinCameroonwereestimated,enablingamodeltosupporttherapydecisionsforbothindividualfarmersandpublichealthpolicymakers(Table5).Withasingletreatmentof1mlperlesionforTS,atUSD0.50perml,thecostoftreatmentperanimalisestimatedbetweenUSD1.50-2.50.Table5.Treatmenttypesusedbyfarmers,applicationmethod,daysoftreatmentandestimateddailyandtotalcosts. TreatmentchoiceApplicationEst.cost/day(USD)TreatmentdaysEst.cost/animal(USD) Moore-OxyInjection0.8532.55ProcainepenicillinInjection0.1730.51Oxytet30%Injection0.8532.55SurvidiumInjection0.8554.25Insecticide&PetrolTopical0.4272.94TraditionaldrugsTopical/oral0.5173.57OXYDOZER50Injection0.8532.55Tri-SolfenTopical/12.50 Moore-Oxy®hasa7daymilkWHPand21meatWHP.Tri-Solfen®hasarecommended4dayWHPformilkandmeatinLaoPDRDISCUSSIONThisstudyreportsthe rst eldtreatmenttrialusingTri-Solfen®asatherapyfortheclinicalmanagementofFMDinAfrica,comparingtheclinicale cacyofthisnoveltherapywiththecommonlyusedparenteralantibiotictreatmentMoore-Oxy®andanimalsremaininguntreated.Despitenecessarylimitationsduetoresourcesavailabilityonnumbersoffarmersandcattlerecruitedforthetrial,theresultsandallparticipants,considereditwasverysuccessful,withhighlevelsofappreciationbyparticipantsfortheirinvolvementandtheclearresultsobtained.LesionhealingscoresacrossthethreegroupsrevealedsuperiorresultsfortheTS-treatedcohortandalthoughtheMO-treatedcohortalsoachievedareasonablescore,theuntreatedcontrolanimalshadlesionspersisting12 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. forinexcessof2weeks.Althoughasubjectivemeasurement,thesescoresprovideausefulindicationofthehealingrateofFMDlesionsin eldconditionsinCameroon.Similarly,appetitescoreswerehighestintheTS-treatedcohort,indicatingthatthetreatmentsupportedtherapidreturnofappetite,evenafter3days.Superiorappetitescoresinthisgroupwererecordedateachdatacollectionbetweenday3andday15,withthecohortreceivingtreatmentwithMOalsohavingreasonableappetitescoresbetweendays3and15.Thecontrolcohortcattlehadpoorappetitescoresthroughout,indicatingappetiteremainspoorforinexcessof2weekswhenFMDremainsuntreated.Lesionsizewasmeasured(incm)atsixdatacollectionintervals,withtheFMDinfectedcattlelesionsizedecreasingrapidlyintheTS-treatedcohort.Byday6thiscohortwasperformingwellwithaveragelesionsizeat0.33cm,despitecommencinginthetrialwithhigheraveragelesionsize.Byday9,thelesionsintheTS-treatedcohorthadalmostentirelydisappeared,remainingat0cmthroughday12and15.Interestingly,thecontrolgroupaveragelesionsizeincreasedasthetrialprogressed.IntheMO-treatedcohort,theaveragelesionsizedecreaseduntilday12,whereitwasrecordedtoincreasefrom0.17cmto0.75cmatday15.Stageofinfectionmayhavea ectedthestudyhere,particularlyasthelesionsizeinthecontrolcohortwas0cmattrialonday0.Thefarmerobservationsofclinicalimpactsalsoprovidedinterestingresultswhichcouldbeusedasanimalwelfareindicatorsaswellasindicatorsofclinicalresponsetothetreatments.Themobilityofall12cattleintheTS-treatedcohortreturnedimmediately,suggestingthisisaveryusefultherapytoenablecattletowalkandgainaccesstowaterandfeed.IntheMO-treatedcohort,10oftheanimalsalsoimmediatelyreturnedtowalking.However,ofthecontrolgroup,only vehadimmediatemobilityandfouranimalsdidnotreturntowalkingevenbyday15.TherewasoneanimalintheMO-treatedcohortthatdidnotreturntomobilityuntilday12.Intotal,7/36(19.4%)cattlehadnotreturnedtomobilitybyday9,indicatingthatFMDisaseverediseaseasitrendersanimalsimmobileandthatalthoughFMDisconsideredalowmortalitydisease,theanimalwelfareimpactsareconsiderable.Asoralvesicularlesionscanhavesigni cantimpactsonanimalbehaviours,recordingthenumberofdaystheanimalswereanorexicwasconsideredimportant.Intotal,11/12cattleintheTS-treatedcohortwerereportedtobeeatingthesamedayastreatment(day0).Thiscomparedto9/12cattleintheMO-treatedcohort,withonly2/12inthecontrolcohort,with9/12oftheseuntreatedcattleremaininganorexicuntilday15.Further,salivationisacommonclinicalsignwithcattlewithvesiculardisease,consideredanovertindicatoroforallesionsandpresumablyoralpain.Inallthreecohortsthemajorityofcattlehadceasedsalivatingatday0,withtheTS-treatedcohortachieving11/12,MO-treatedcohort10/12andthecontrols8/12.Farmerreportsofvisiblelamenessoftrialcattleindicatedthat9/12cattleintheTS-treatedcohortceasedanylamenessatday0,comparedto5/12intheMO-treatedcohortand3/12inthecontrols.Byday6,nofurthercattleintheTS-treatedcohortshowedanylamenesscomparedto5/12cattleintheMO-treatedcohortstillshowinglamenessbydays12and15,withlamenessonlyceasingbyday15in9/12controlcattle.Forthequestionofhowmanydayspriortocattlereturningtograzing,mixedresultswererecorded.Inthecontrolcohort,9/12werereportedgrazingbyday0,with8/12intheTS-treatedcohortreturnedtograzingbyday3andall12/12intheMO-treatedcohortreturningtograzingbyday6.WhenaskedforabroadoverviewoftreatmentsappliedtoFMD,sixoptionswereprovided,includingantibioticformulations,traditionaldrugs,insecticidesandpetrol.Withoutspeculatingonthetherapeuticpotentialofeachtreatment,itdoesindicatethatfarmersandparaveterinariansareinclinedtotreata ectedanimalswithsomething.Thedataoncostsoftreatmentsuggestthereareonlyminimaldi erencesbetweentreatmentsandthatcostshouldnotbeanimpedimenttochangingoftreatmentchoice.Fieldstudiesinvolvinganimaltreatmentswithassessmentsofclinicalimpactsarechallengingandsubjecttopotentialbias,reectedinthelimitedpublishedliteratureonFMDtherapy.However,theresultsobtainedinthisstudydemonstratethesuperiorclinicale cacyofasingleapplicationtoFMDlesionsoftheTStopicalanaestheticwoundformulation.Theparticipatingfarmersreporteda100%appreciationfortheproductin13 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. thetreatmentofFMDandexpressedtheywerehappytohavethisproductavailableforuseintheregion.These ndingswereconsistentwiththosefromarecentlyreportedclinicalinvestigationofTStherapyforFMDinLaos(Windsoretal,2020)andreportsoftheuseofthisproductforFMDinothercountriesinAfrica,includingNiger,Nigeria,andKenya.ThisstudyinCameroonprovidesthequantitativeassessmentthatcon rmthatTSise caciousinhasteningclinicalrecoveries,immediatelyaddressingpainandinvokingmorerapidhealingofFMDlesions,asobservedqualitativelyinLaos(Windsoretal,2020).Asthisinnovationprovidessuperioranimalwelfareoutcomesforanimalssu eringfromFMD,withouttherisksofAMRthatarisefromthemoretypicaltherapiesinuseforFMDglobally,e ortstopromotethisnewtherapeuticapproachshouldbesupported.ACKNOWLEDGEMENTSWethankthepresidentofthecattlefarmersandthesub-divisionaldelegatesforlivestockofCameroonandparticularlythatofTchabalforsupportandhelpininformingfarmersaboutthistrial,andP.L.E.Bfor nancialsupport.WealsothanktheProgOncho eldlabfortheircooperationandstorageofsamples,plusthedriverandallteammembersfortheirpunctualityandtimededicatedtothiswork.ThesupportofMedical/AnimalEthicsCompanyforprovisionoftheproductisgratefullyacknowledged.ETHICSSTATEMENTTheauthorscon rmthattheethicalpoliciesofthejournalasnotedontheauthorsguidelinespage,havebeenadheredto.InadditiontofollowingcurrentproceduresonanimalandhumanethicsprocessesinCameroon,theauthorscommunicatedwiththeirAustraliancollaboratorstoensuretheycompliedwiththeNationalHealthandMedicalResearchCouncil's(NHMRC)NationalStatementonEthicalConductinHumanResearch(2007)andtheUniversitiesAustraliaAustralianCodefortheResponsibleConductofResearch.Thisincludedensuringthatallparticipantsprovidedverbalinformedconsentforthecollectionofanimalbloodsamples,tissues,farmerinterviewsandparticipationinvideosandimages,wherewrittenconsentwasunavailableduetofarmerilliteracy.AUTHORCONTRIBUTIONSPWandSLdesignedthestudyandPW,JYandPTprovidedanalyticalandwritingsupport.SLwithsupportfromJM,KB,KAandSD,performedthe eldtrialactivities.PTconductedthestatisticalanalysesandallauthorscontributedtothe naldraftofthemanuscript.CONFLICTOFINTERESTTheauthorsreportnoconictsofinterestinthiswork.StudiesevaluatingTri-Solfen®andothertherapiesforaversiveanimalhusbandryinterventionsoccurringpriortothisstudy,werefundedbyanAustralianResearchCouncilLinkageGrantfromtheAustraliangovernmentwith nancialcontributionsfromAnimalEthicsPtyLtdAustraliaandBayerAnimalHealthAustralia.However,thiscurrentstudydidnotreceivefundingfromeitherofthesecompanies,nordidtheyhavearoleinstudydesign,datacollectionandanalysis,decisiontopublish,orpreparationofthemanuscript.DATAAVAILABILITYSTATEMENTThedatathatsupportthe ndingsofthisstudyareavailablefromthecorrespondingauthoruponreasonablerequest.REFERENCESAgresti,A.(2002).CategoricalDataAnalysis(2nded.).NewYork:JohnWiley&Sons.AL-Lethie,A.,AL-Lethie,S.F.,El-Hawari,K.,El-Khabaz;A.S.,Elmeligy;E.,Khalphallah,A.,UsamaT.Mahmoud,U.T.(2018).EvaluationofClinicalRecoveryandHealingofOralLesionsby3di erentTherapeuticRegimensinCattlewithFootandMouthDisease(FMD).AssiutVeterinaryMedicineJournal,64(156),89-95.14 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. Bates,D,MaechlerM.,Bolker,B.,Walker,S.(2015).Fittinglinearmixed-e ectsmodelsusinglme4.JournalofStatisticalSoftware,67(1):1-48.doi:10.18637/jss.v067.i01Bertram,M.R.,Delgado,A.,Pauszek,S.J.,Smoliga,G.R.,Brito,B.,Stenfeldt,C.,Hartwig,E.J.,Jumbo,S.D.,Abdoulmoumini,M.,OlivaMarie,A.A.,Salhine,R.,Rodriguez,L.L.,Garabed,R.,Arzt,J.(2018).E ectofvaccinationoncattlesub-clinicallyinfectedwithFoot-and-MouthdiseasevirusinCameroon.Pre-ventiveVeterinaryMedicine,155,1{10.ChristensenRHB.2019.Ordinal:regressionmodelsforordinaldata.Rpackageversion2019.12-10.https://CRAN.R-project.org/package=ordinalEhizibolo,D.O.,Fish,H.,Brito,B.,Bertram,M.R.,Ardo,A.G.,Ularamu,H.G.,Lazarus,D.D.,Wungak,Y.S.,Nwosuh,C.I.,Smoliga,G.R.,Hartwig,E.J.,Pauszek,S.J.,Dickmu,S.,Abdoulkadiri,S.,Arzt,J.(2019).Re-emergenceofthenoveltopotypeoffootandmouthdiseasevirusserotypeSAT1inNigeriaandCameroon.GFRA2019Scienti cMeeting,Bangkok,ThailandOctober29-31.Fakhrul-Islam,K.M.,Jalal,M.S.,Podder,S.,Quader,M.N.,Sahidur-Rahman,M.,Dutta,A.,Mazum-der,S.(2016).ClinicalinvestigationoffootandmouthdiseaseofcattleinBatiaghataUpazillavete-rinaryhospital,Bangladesh.VeterinarySciences:ResearchandReviews.2(3):76-81.doi:10.17582/jour-nal.vsrr/2016.2.3.76.81FAO(2015).StrategicPlanfortheControlofFootandMouthDiseaseinCameroon.In:Towardsimprovingthecontroloftransboundaryanimaldiseasesoftradelivestock.Cameroon,FAO,OMC.MTF/CMR/034/STF.https://www.standardsfacility.org/information-session-cameroonFrossardm,J.,Renaud,O.(2019).permuco:Permutationtestsforregression,(repeatedmea-sures)ANOVA/ANCOVAandcomparisonofsignals.Rpackageversion1.1.0.https://CRAN.R-project.org/package=permucoGakuya,D.W.,Mulei,C.M.,Wekesa,S.B.(2011).UseofEthnoveterinaryremediesintheManagementofFootandMouthDiseaselesionsinaDairyHerd.AfricanJournalTraditionalandComplementaryAlternativeMedicine.8(2),165-169.Herv e,M.(2020).RVAideMemoire:testingandplottingproceduresforbiostatistics.Rpackageversion0.9-77.https://CRAN.R-project.org/package=RVAideMemoire.Lenth,R.(2020).emmeans:estimatedmarginalmeans,akaleast-squaresmeans.Rpackageversion1.4.7.https://CRAN.R-project.org/package=emmeans.Ludi,A.,Ahmed,Z.,Pomeroy,L.W.,Pauszek,S.J.,Smoliga,G.R.,Moritz,M.,Rodriguez,L.L.(2016).SerotypeDiversityofFoot-and-Mouth-DiseaseVirusinLivestockwithoutHistoryofVaccinationintheFarNorthRegionofCameroon.TransboundaryandEmergingDiseases,63(1),e27{e38.doi:10.1111/tbed.12227MINEPIA,`Minist eredel'Elevage,desP^echesetdesIndustriesAnimales',MINEPIAPolicyDocument.2013;29.Misk,N.A.,Misk,T.N.,Rateb,H.Z.(2015).AssessmentandTopicalTreatmentofLesionsofFootandMouthDiseaseinCattle.AssiutVeterinaryMedicineJournal,61,75-81.Roberts,C.D.,Windsor,P.A.(2019).Innovativepainmanagementsolutionsinanimalsmayprovideim-provedwoundpainreductionduringdebridementinhumans:Anopinioninformedbyveterinaryliterature.InternationalWoundJournal,16(4),968-973.doi:10.1111/iwj.13129Sevidzem,S.L.,Mavoungou,J.F.,Mintsa,N.R.(2019a).VeterinaryPharmaceuticalsSoldinCattleMarketsfortheManagementofFoot-and-MouthDiseaseandFliesinVinaDivision(Adamawa-Cameroon).JournalofDairyandVeterinaryScience,10(2),555782.doi:10.19080/JDVS.2019.10.5557820010Sevidzem,S.L.,Abdoulmoumini,M.,Jacques,F.M.,Ikoum,D.,Mohammadou,B.,Oumarou,L.,Hiol,V.D.,Rodrigue,M.N.,Zinga-Koumba,C.R.,Acapovi-Yao,G.L.,Simon,D.,Garabed,R.(2019b).Serolo-15 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. gicalEpidemiologyofFoot-and-mouthDiseaseamongSedentaryMixed-speciesHerdsinAdamawaRegion,Cameroon.JournalofAdvancesinMicrobiology,17(2):1-14.Stenfeldt,C.,Hartwig,E.J.,Smoliga,G.R.,Palinski,R.,Silva,E.B.,Bertram,M.R.,Fish,I.H.,Pauszek,S.J.,Arzt,J.(2018).Contactchallengeofcattlewithfoot-and-mouthdiseasevirusvalidatestheroleofthenasopharyngealepitheliumasthesiteofprimaryandpersistentinfection.mSphere3:e00493-18.doi:org/10.1128/mSphere.00493-18Tanya.(2015).Supporttowardsimprovingthecontroloftransboundaryanimaldiseasesoftradelivestock.Cameroon,FAO,OMC.MTF/CMR/034/STF.Pages7-21.Windsor,P.A.,Lomax,S.,White,P.(2016).Painmanagementforimprovedsmallruminantwelfare.SmallRuminantResearch,142:55-57.Windsor,P.A.,Earp,F.,MacPhillamy,I.,Khounsy,S.,Young,J.,Bush,R.D.(2020).Anewtopicalthe-rapyforFoot-and-mouthdiseaseaddressesanimalwelfareandotherissues.VeterinaryMedicine:ResearchReports.in-pressTable1.Ageandbreedofcattlerecruitedintoeachtreatmentgroup. TreatmentgroupTreatmentgroupTreatmentgroup VariableMoore-Oxy®Tri-Solfen®ControlOverallAverageage(yr)3.743.33.7Agerange(yr)2to52to82to52to8BreedcountGoudali991028Holstein1113WhiteFulani1214RedFulani1001Total12121236 Table2.Analysisofthenumberofdaysthatcattleareimmobile,numberofdayswalkingwithdi culty,andnumberofdayswalkingnormally WalkingVariableP-valueControlMooreOxy®Tri-Solfen® ImmobileTreatment0.0022.47A±1.390.05B±0.350.00B±0.30Age0.942Breed0.590Sex0.268WithTreatment0.0098.27A±4.953.49AB±2.000.70B±0.85Di cultyAge0.471Breed0.875Sex0.724NormalTreatment0.0000.60A±0.402.72B±0.787.18C±1.92Age0.221Breed0.117Sex0.033 A,B,C:Meanssharingthesamesuperscriptarenotsigni cantlydi erent(P>0.05).Table3.Analysisofthenumberofdaysthatcattlearesalivating.16 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. VariableP-valueControlMooreOxy®TriSolfen® Treatment0.1461.59A±0.820.49A±0.390.56A±0.46Age0.171Breed0.537Sex0.500 A:Meanssharingthesamesuperscriptarenotsigni cantlydi erent(P>0.05).Table4.Analysisofthenumberofdaysthatcattlearesalivating. VariableP-valueControlMooreOxy®TriSolfen® Treatment0.1461.59A±0.820.49A±0.390.56A±0.46Age0.171Breed0.537Sex0.500 A:Meanssharingthesamesuperscriptarenotsigni cantlydi erent(P>0.05).Table5.Treatmenttypesusedbyfarmers,applicationmethod,daysoftreatmentandestimateddailyandtotalcosts. TreatmentchoiceApplicationEst.cost/day(USD)TreatmentdaysEst.cost/animal(USD) Moore-OxyInjection0.8532.55ProcainepenicillinInjection0.1730.51Oxytet30%Injection0.8532.55SurvidiumInjection0.8554.25Insecticide&PetrolTopical0.4272.94TraditionaldrugsTopical/oral0.5173.57OXYDOZER50Injection0.8532.55Tri-SolfenTopical/12.50 Moore-Oxy®hasa7daymilkWHPand21meatWHP.Tri-Solfen®hasarecommended4dayWHPformilkandmeatinLaoPDRFigureLegendsFigure1:Mapsshowingthestudysites(NgaoundereII,NgaoundereIIIandMartap)M1:Mbidjoro1,M2:Mbidjoro2,T1:TchabalBaouro1,T2:TchabalBaouro2,T3:TchabalBaouro3,T4:Tchabal4,T5:Tchabal5,T6:Tchabal6,B:Borongo,H1:Hor eMayanga1,H2:Hor eMayanga2,H3:Hor eMayanga3.Figure2.Model-basedprobabilitiesofobtaininglesionhealingscores1through4acrossthesixstudydays,forthethreetreatmentgroups.Figure3.Model-basedprobabilitiesofobtainingappetitescores1through4acrossthesixstudydays,forthethreetreatmentgroups.Figure4.Model-basedmeanlesionsize(cm)acrossthesixstudydays,forthethreetreatmentgroups.Shadedareasare±1standarderrorofthemean.17 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. Figure5.Model-basedprobabilitiesofobtainingwalkingscoresof`Immobile',`Withdi culty'and`Normal'acrossthesixstudydays,forthethreetreatmentgroups.Figure6.Model-basedprobabilitiesofcattlebeingonpastureacrossthesixstudydays,forthethreetreatmentgroups.Shadedareasare±1standarderrorofthemean(whereavailable).Figure7.Model-basedprobabilitiesofcattlesalivatingacrossthesixstudydays,forthethreetreatmentgroups.Hosted leFMDCameroonTables140920.docxavailableathttps://authorea.com/users/359354/articles/481409-efficacy-and-application-of-a-novel-topical-anaesthetic-wound-formulation-for-treating-cattle-with-foot-and-mouth-disease-a-field-trial-in-cameroonHosted leFMDCameroonFigures140920.docxavailableathttps://authorea.com/users/359354/articles/481409-efficacy-and-application-of-a-novel-topical-anaesthetic-wound-formulation-for-treating-cattle-with-foot-and-mouth-disease-a-field-trial-in-cameroon18

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llrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. E cacyandapplicationofanoveltopicalanaestheticwoundformulationfortreatingcattlewithFoot-and-Mouthdisease:a eldtrialinCameroonSevidzemLenze1,JacquesMavoungou1,KongBurinyuy1,KoumbaArmel1,SimonDickmu1,JamesYoung2,PeterThomson3,andPeterWindsor21A liationnotavailable2UniversityofSydney3SchoolofLifeandEnvironmentalSciencesSeptember16,2020AbstractRecently,awounddressingformulation,(Tri-Solfen®,MedicalEthicsPtyLtd,Australia;TS)registeredforuseinruminanthusbandryinAustralia,wasregisteredforFoot-and-MouthDisease(FMD)therapyinlargeruminantsinLaos,followingclinicalobservationsofimprovedwelfareandhealingfollowingtreatmentofFMDlesions.InNovember2019,anFMDoutbreakinCameroonprovidedanopportunityfora eldtrial,comparingclinicalresponsesandrecoveriestotreatmentsonasampleofcattle(n=36)comprisingthreeequalgroupsofanimals(n=12),comparingresponsestothreetreatments:(i)theapplicationtolesionsofTS,(ii)theadministrationofparenteraloxytetrayclinecommonlyusedforFMDinCameroon;and(iii)anuntreatedcontrolgroup(C).Appetitescores,lesionhealingscores,andchangesindimensionsoflesions,wererecordedovera15-daystudyperiod.CattletreatedwithTSachievedbothsuperiorappetiteandlesionhealingscoreswithmorerapidreductionindimensionsoflesionsthanothergroups.FarmerobservationsindicatedtheTStreatmentgrouphadamorerapidreturntoeatingwithcessationofexcessivesalivation,andmorerapidreturnofmobility(walking)withabsenceofovertlameness.The ndingsindicatethatalthoughmortalityisusuallylowinFMDoutbreaks,thediseaseisadebilitatingandpainfuldisorderwithnegativeanimalwelfareimpactsthatshouldbeaddressed.AllfarmersexpressedtheirdesirethattheproductbemadeavailableforuseintheirregionandmodellingindicatesthatTStherapyimposesnoadditional nancialburdenonfarmers,withthetreatmentlikelytobeprovidedatasimilarorreducedcosttocurrenttreatmentchoices.Asuseofantibioticsfortreatmentofaviraldiseasepotentiallyincreasespressuresfordevelopmentofantimicrobialresistanceandresiduesinthefoodchain,TSasanalternativenon-antimicrobialtherapyshouldbepromotedforwideruseinFMDoutbreaks.INTRODUCTIONCameroon,withapopulationofalmost28millionpeople,islocatedincentralAfrica,borderingtheGulfofGuinea.Itisakeytransitlink,sharingborderswithsixcountries:Nigeria,Chad,CentralAfricanRepublic,RepublicofCongoandEquatorialGuinea.Thegrossdomesticproduct(GDP)percapitaofCameroonisestimatedatUSD3,700(CIA,2017).Theapproximately7.1millioncattleinCameroonaresusceptibletoregularoutbreaksfromFoot-and-MouthDisease(FMD),andendemicdiseaseinmuchofAfrica.WithnopreventivecontrolprogramsinplaceandnoaccesstocommercialFMDvaccination,farmersarefocusedontreatmentchoicesfora ectedcattle,withantibioticsand/ortraditionaltherapiescommonlyusedandprolongedperiodsforanimalstorecover.FMDisamostimportantglobalviralpathogenofartiodactylfarmedandwildlifeanimals.Thediseaseischaracterisedbylesionsinandaroundthemouthandfeet(Fakhrul-Islametal.,2016).Globally,there1

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appearedtohavebeenprevented,althoughpersistentinfectionoccurred.CattleownersinCameroonroutinelymanagethediseaseusingarangeoftherapies,includinganti-in ammatorypreparations,antibioticsandtraditionalformulations(Sevidzemetal.,2019a).Intheabsenceofstrategicpreventivecontrolprograms,thereareurgentneedsforalternativeFMDmana-gementoptionsforendemicFMD-infectedcountries,includingCameroon.Witha ordableande caciousvaccinecandidatesformanagingFMDunlikelyinthenearfuture,thereviewandrationalizingofFMDtherapiesisadvisable.Severaltopicaltreatmentswithethno-veterinaryandrecognizedveterinarypharma-ceuticalshavebeenexaminedinFMDendemicsettingsinAfrica(Gakuyaetal.,2011;Misketal.,2015;Fakhrul-Islametal.,2016;Al-Lethieetal.,2018).However,thewidespreaduseofparenteralantibioticsforFMDglobally,includingnumerouscountriesinAfricaandCamerooninparticular,presentsantimicrobialresistance(AMR)andpotentialfoodsafetyresiduerisksthatneedtobeaddressed.Recently,anAustralianwounddressingformulation,Tri-Solfen®(MedicalEthicsPtyLtd,Australia;TS)registeredforuseincattleandsmallruminanthusbandryinAustraliaandNewZealand,wasregisteredforFMDtherapyinlargeruminantsinLaosinsoutheastAsia(Windsoretal.,2020).Thewoundandlesiondressingformulationcontainstwolocalanaesthetics(lignocaineandbupivacaine),adrenalinandcetramideinagelmatrixthatcreatesabarriere ect,numbingthepainoflesions,rapidlyreducingtheirinfectivity,andhasteninghealing,potentiallyreducingtheweightlossina ectedindividuals(Windsoretal.,2020).Ifmadeavailableforpurchaseandadministrationbyfarmers,thisproductcouldprovideaviablealternativeapproachformanagingFMDinCameroon,otherAfricancountriesanddevelopingcountriesglobally.Thisformulationo ersnumerousadvantagesovercurrenttherapiesasitprovidese caciouspainreliefandmorerapidhealingofwoundsandlesions(Windsoretal.,2016;RobertsandWindsor,2019;Windsoretal.,2020).Further,withapHof~2.7,andcontainingtheantisepticcetrimide,itpotentiallyhasviricidalimpactsandanti-bacterialpropertiesrespectively,avoidingtheneedforothertreatments,includingantibiotics(Windsoretal,2020).InNovember2019,TSwasprovidedtotheCameroonresearchteamfortrialsduringFMDoutbreaksincattle.Thisreportdescribesa eldtrialinCameroonaimedatevaluatingthee cacyofthistherapyforFMDlesionmanagement,particularlyforenhancingrecoveryandwoundhealing,comparingtheclinicalresponsestothemostcommonlyusedandavailableantimicrobialtherapycurrentlyinuse.IfTSisproventobease caciousforFMDinthiscurrentstudyasitappearedtobeon rstuseinLaosasdescribed(Windsoretal.,2020),itislikelythattheproductcouldo eranimportantinnovationforimprovingFMDlesiontreatment,potentiallyglobally,withreducedanimalwelfareburdens,risksofAMRissuesandpossibly,increasedtransboundarydiseasereportingandsurveillance.MATERIALSANDMETHODSTriallocationanddesignThisclinicaltrialwasconductedbetweenthe5thofNovemberandthe5thofDecember2019inNgaoundereII,NgaoundereIIIandMartapsubdivisionsintheVinaDivisionoftheAdamawaplateau.Around40%ofthecattlepopulationofCameroonislocatedintheAdamawaregion(MINEPIA,2013).Ngaoundereisthe2

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nicalpresenta-tions;withonetreatedwithMO,onewithTSandthethirdleftuntreated.Thiscreated12setsofcattleforthiscomparativeclinicaltrialonthedi erentfarms. Figure1:Mapsshowingthestudysites(NgaoundereII,NgaoundereIIIandMartap)M1:Mbidjoro1,M2:Mbidjoro2,T1:TchabalBaouro1,T2:TchabalBaouro2,T3:TchabalBaouro3,T4:Tchabal4,T5:Tchabal5,T6:Tchabal6,B:Borongo,H1:Hor eMayanga1,H2:Hor eMayanga2,H3:Hor eMayanga3.TreatmentApplicationsTheclinicaltreatmenttrialwasconductedon`fresh'FMDlesions,containingintactvesiclesorrecentlyrupturedvesicles.AnimalstreatedwithTShadlesionsliberallysprayedwith2mloftheproduct,asperlabelinstructions.AnimalstreatedwithMOreceivedanintra-muscularinjectionoftheproduct,alsoatdosesperlabelinstructions.Clinicalresponseobservationswerenoted,includinganyimprovementsincapacityandabilityoftheanimaltowalkandeat.Thefollowingsemi-quantitativeclinicalmeasurementsweremade:Lesionhealingscore(LHS)onascaleof1to4(adaptedfromAl-Lethieetal.,2018)Appetitescore(AS)onascaleof1to4(fromAl-Lethieetal.,2018)3

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llrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. Lesionsize(cm):healingoflesionswasmeasuredquantitativelyinthe eldusinga30-cmruler,every3daysfromdayzero(D0)throughday15(D15),withlesionsphotographedusingandroidmobilephones.FarmerObservationsThefarmerswererequestedtoprovidetheirobservationsforeachanimalforeachtreatmentgroup,withthefollowinginformationrecorded:Numberofdaysuntilcattlemobility(walking)returnedNumberofdayscattlewerenoteatingNumberofdayscattlecontinuedtosalivateNumberofdaysdisplayedlamenessNumberofdaysrequiredforcattletoreturntograzingTreatmentcostmodelThecostsoftreatmentswereestimatedandusedtodevelopacost-bene tmodelenablingcomparisonoftherapiesthatcouldassistdecisionsforbothindividualfarmersandpublichealthpolicymakersonFMDoutbreakmanagement.StatisticalAnalysesOrdinalscaleanalysisBoththelesionhealingscoresandtheappetitescoreswererecordedonafour-pointordinalscale,notaquantitativescale,soappropriateordinalcategoricalmethodswererequiredforthisanalysis(Agresti,2002).Inaddition,walkingwasalsomodelledonathree-pointordinalscale:(1:immobile;2:walkingwithdi culty;3:walkingnormally).Anordinallogisticmixedmodelwas ttedtoeachdatasetwith xede ectsforTreatment,Day,BreedandAge(covariate),andarandome ectfortheindividualAnimalID.ATreatment×Dayinteractionwasincludedineachofthemodels,toallowforadi erentshapedtimecourseforeachtreatment.Notethatthe ttedmodelreturnedasetofmodel-basedprobabilitiesofobtainingeachpossiblescore(1through4,or1through3),fortheparticularcombinationoftermsinthemodel.Themodelwas ttedusingtheclmmfunctionintheordinalpackageofR(Christensen,2019),andprobabilityestimatesobtainedusingtheemmeans(Lenth,2020)andRVAideMemoire(Herv e,2020)packagesinR.BinarydataanalysisThestatusofcattlebeingonpastureandcattlesalivating(Yes=1,No=0)arebinaryoutcomes,andforthis,binarylogisticmixedmodelswereusedtoanalysethesedata.Asabove, xede ectsforTreatment,Day,Treatment×Day,Age,BreedandSex,andarandome ectforAnimalIDwereincludedinthemodel.Themodelwas ttedusingtheglmerfunctioninthelme4packageofR(Batesetal.,2015),andmodel-basedmeansobtainedusingtheemmeanspackage.QuantitativedataanalysisLesionsize(cm)wasanalysedusingalinearmixedmodel,with xede ectsforTreatment,Day,Treatment×Day,Age,BreedandSex,andarandome ectforAnimalID.Model ttingwasviathelmerfunctioninthelme4,andmodel-basedmeansobtainedusingtheemmeanspackage.Eventdurationdata(numberofdaysthatcattleareimmobile,walkwithdi culty,walknormally,onpasture,andsalivating)wereanalysedusinglinearmodelswith xede ectsforTreatment,Age,BreedandSex.Duetothepositiveskew,aloge(y+1)transformationwasapplied.However,withthelargenumberof`zero'durations,hypothesistestingwasconductedwithpermutationtestsratherthanF-tests,usingtheaovpermfunctioninthepermucopackage(Frossard&Renaud,2019)inR.RESULTS4

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(Day9:P=0.025;Day12:P=0.016;Day15:P=0.0008).Noneoftheothertermshadasigni cantassociationwithlesionhealingscore:Age:P=0.464;Breed:P=0.311;Sex:P=0.376.5 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. Figure2.Model-basedprobabilitiesofobtaininglesionhealingscores1through4acrossthesixstudydays,forthethreetreatmentgroups.AppetitescoresAgain,therewasahighlysigni cantTreatment×Dayinteraction(P=2.0×10{6)forappetitescore,indicatingtreatmente ectswerechangingoverthestudyperiod.Model-basedappetitescoreprobabilitiesaredisplayed(Figure3).Mostcontrolcattlehadnoappetiteoverthewholestudyperiod(scoreof1).However,thetwotreatmentgroupshadhighappetitescoresonDay0,lowonDay3,thenprogressivelyincreasingappetitescoresafterthat.FromDay9onwards,cattletreatedwithTShadsigni cantlyhigherhealingscoresthanthoseonMO(Day9:P=0.025;Day12:P=0.016;Day15:P=0.0008).AfterDay0,therewerenosigni cantdi erencesinappetitescorebetweenMOandTStreatedcattle(allP>0.10).NeitherAge(P=0.810),Breed(P=0.524),norSex(P=0.324)hadasigni cante ectinappetitescore.6

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di erencesinappetitescorebetweenMOandTStreatedcattle(allP>0.10).NeitherAge(P=0.810),Breed(P=0.524),norSex(P=0.324)hadasigni cante ectinappetitescore.6 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. Figure3.Model-basedprobabilitiesofobtainingappetitescores1through4acrossthesixstudydays,forthethreetreatmentgroups.LesionsizeTherewasahighlysigni cantTreatment×Dayinteraction(P<2×10{16)forlesionsize(Figure4),indicatingdi erentratesofhealingacrossthethreegroups.Initially,therewerenosigni cantdi erencesinmeanwoundsizesamongstthethreegroups(allP>0.25).WhilemeanwoundsizeincreasesforControlcattle,theyreducedforthetwotreatmentgroups,withthoseintheTStreatmentreducingatafasterrate(di erencesweresigni cantfromDay9,allP<0.01).Therewasnosigni cante ectofAge(P=0.454),Breed(P=0.225),norSex(P=0.374)onlesionsize.7

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reducingatafasterrate(di erencesweresigni cantfromDay9,allP<0.01).Therewasnosigni cante ectofAge(P=0.454),Breed(P=0.225),norSex(P=0.374)onlesionsize.7 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. Figure4.Model-basedmeanlesionsize(cm)acrossthesixstudydays,forthethreetreatmentgroups.Shadedareasare±1standarderrorofthemean.WalkingWhenwalkingisconsideredasanordinalscore(Immobile<Withdi culty<Normal),therewasahighlysigni cantTreatment×Dayinteraction(P=1.8×10{13).Initially(Day0),therewerenodi erencesinwalkingscoresbetweenthethreegroups(allP>0.15)and.somecattleremained`Immobile'or`Withdi culty'throughoutthestudyperiod(Figure5).However,walkingimprovedforthetwotreatmentgroups,particularlyfortheTStreatmentgroup.However,thedi erencesbetweenthesetwogroupsneverreachedthresholdsigni cance(allP>0.05).Therewerenosigni cante ectsofotherfactorsonwalking(Age:P=0.583;Breed:P=0.9012;Sex:P=0.778).8

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thesetwogroupsneverreachedthresholdsigni cance(allP>0.05).Therewerenosigni cante ectsofotherfactorsonwalking(Age:P=0.583;Breed:P=0.9012;Sex:P=0.778).8 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. Figure5.Model-basedprobabilitiesofobtainingwalkingscoresof`Immobile',`Withdi culty'and`Normal'acrossthesixstudydays,forthethreetreatmentgroups.Anadditionalanalysiswasconductedtocomparethenumberofdaysthatcattleareimmobile,numberofdaystheywalkwithdi culty,andnumberofdaystheywalknormally(Table2).Inallcases,thesedurationsdi eredsigni cantlybetweenthethreetreatmentgroups(allP<0.01).Controlcattlehadasigni cantlylongerperiodofimmobilitycomparedwiththetwotreatmentgroups(bothP<0.005).Table2.Analysisofthenumberofdaysthatcattleareimmobile,numberofdayswalkingwithdi culty,andnumberofdayswalkingnormally WalkingVariableP-valueControlMoore-Oxy®Tri-Solfen® ImmobileTreatment0.0022.47A±1.390.05B±0.350.00B±0.30Age0.942Breed0.590Sex0.268WithTreatment0.0098.27A±4.953.49AB±2.000.70B±0.85Di cultyAge0.471Breed0.875Sex0.724NormalTreatment0.0000.60A±0.402.72B±0.787.18C±1.92Age0.221Breed0.1179

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thTreatment0.0098.27A±4.953.49AB±2.000.70B±0.85Di cultyAge0.471Breed0.875Sex0.724NormalTreatment0.0000.60A±0.402.72B±0.787.18C±1.92Age0.221Breed0.1179 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. WalkingVariableP-valueControlMoore-Oxy®Tri-Solfen® Sex0.033 A,B,C:Meanssharingthesamesuperscriptarenotsigni cantlydi erent(P>0.05).TS-treatedcattlehadasigni cantlyshorterperiodofwalkingwithdi cultycomparedwithControlcattle(P=0.0022),andalsohadsigni cantlylongerperiodwalkingnormallycomparedwithbothControlandMO-treatedcattle(bothP<0.005).Notethattherewerenoe ectsofAge,Breed,notSexonthethreedurations,withtheexceptionofSexondurationofnormalwalking(P=0.033)withmalecattlehavingmeanduration3.72±1.14days,comparedwithfemaledurationof1.82days.TimeonPastureTherewasahighlysigni cantTreatment×Dayinteractionforpresenceofcattleonpasture(P=1.5×10{6).ItwasapparentthatControlcattlebasicallyneverreturnedontopastureduringthetrial(Figure6).However,forthetwotreatmentgroups,afterinitiallynonebeingonpasture,allwereonpasturebyDay6.AlthoughTSshowedafasterreturntopasturethanMO,itwasnotpossibletoformallytestthis.Therewerenosigni cante ectsofAge(P=0.791)norSex(P=0.661)ontheprobabilityofbeingonpasture;therewassomeevidenceofbreeddi erences(P=0.023),butbreedestimatescouldnotberelieduponbecauseofsmallnumberinsomebreeds. Figure6.Model-basedprobabilitiesofcattlebeingonpastureacrossthesixstudydays,forthethreetreatmentgroups.Shadedareasare±1standarderrorofthemean(whereavailable).10

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del-basedprobabilitiesofcattlebeingonpastureacrossthesixstudydays,forthethreetreatmentgroups.Shadedareasare±1standarderrorofthemean(whereavailable).10 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. Theresultsofanadditionalanalysistocomparethenumberofdaysthatcattleareonpastureisdisplayed(Table3).Asinthepreviousanalysis,nosigni cante ectsofTreatment,norAge,BreedorSexweredetected(allP>0.4).However,consistentwiththepreviousanalysis,thetwotreatmentgroupsspentmoretimeonpasture.Table3.Analysisofthenumberofdaysthatcattlearesalivating. VariableP-valueControlMoore-Oxy®Tri-Solfen® Treatment0.1461.59A±0.820.49A±0.390.56A±0.46Age0.171Breed0.537Sex0.500 A:Meanssharingthesamesuperscriptarenotsigni cantlydi erent(P>0.05).Salivation Figure7.Model-basedprobabilitiesofcattlesalivatingacrossthesixstudydays,forthethreetreatmentgroups.Therewasnosigni cantTreatment×Dayinteractionforoccurrenceofsalivation(P=0.496),norwasthereanoverallmaine ectofTreatment(P=0.401).Model-basedprobabilitiesofsalivatingareshown(Figure7).However,frominitialhighratesofsalivating,therewasasigni cantdeclineoverthestudyperiod(P=11

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5SurvidiumInjection0.8554.25Insecticide&PetrolTopical0.4272.94TraditionaldrugsTopical/oral0.5173.57OXYDOZER50Injection0.8532.55Tri-SolfenTopical/12.50 Moore-Oxy®hasa7daymilkWHPand21meatWHP.Tri-Solfen®hasarecommended4dayWHPformilkandmeatinLaoPDRDISCUSSIONThisstudyreportsthe rst eldtreatmenttrialusingTri-Solfen®asatherapyfortheclinicalmanagementofFMDinAfrica,comparingtheclinicale cacyofthisnoveltherapywiththecommonlyusedparenteralantibiotictreatmentMoore-Oxy®andanimalsremaininguntreated.Despitenecessarylimitationsduetoresourcesavailabilityonnumbersoffarmersandcattlerecruitedforthetrial,theresultsandallparticipants,considereditwasverysuccessful,withhighlevelsofappreciationbyparticipantsfortheirinvolvementandtheclearresultsobtained.LesionhealingscoresacrossthethreegroupsrevealedsuperiorresultsfortheTS-treatedcohortandalthoughtheMO-treatedcohortalsoachievedareasonablescore,theuntreatedcontrolanimalshadlesionspersisting12

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llrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. forinexcessof2weeks.Althoughasubjectivemeasurement,thesescoresprovideausefulindicationofthehealingrateofFMDlesionsin eldconditionsinCameroon.Similarly,appetitescoreswerehighestintheTS-treatedcohort,indicatingthatthetreatmentsupportedtherapidreturnofappetite,evenafter3days.Superiorappetitescoresinthisgroupwererecordedateachdatacollectionbetweenday3andday15,withthecohortreceivingtreatmentwithMOalsohavingreasonableappetitescoresbetweendays3and15.Thecontrolcohortcattlehadpoorappetitescoresthroughout,indicatingappetiteremainspoorforinexcessof2weekswhenFMDremainsuntreated.Lesionsizewasmeasured(incm)atsixdatacollectionintervals,withtheFMDinfectedcattlelesionsizedecreasingrapidlyintheTS-treatedcohort.Byday6thiscohortwasperformingwellwithaveragelesionsizeat0.33cm,despitecommencinginthetrialwithhigheraveragelesionsize.Byday9,thelesionsintheTS-treatedcohorthadalmostentirelydisappeared,remainingat0cmthroughday12and15.Interestingly,thecontrolgroupaveragelesionsizeincreasedasthetrialprogressed.IntheMO-treatedcohort,theaveragelesionsizedecreaseduntilday12,whereitwasrecordedtoincreasefrom0.17cmto0.75cmatday15.Stageofinfectionmayhavea ectedthestudyhere,particularlyasthelesionsizeinthecontrolcohortwas0cmattrialonday0.Thefarmerobservationsofclinicalimpactsalsoprovidedinterestingresultswhichcouldbeusedasanimalwelfareindicatorsaswellasindicatorsofclinicalresponsetothetreatments.Themobilityofall12cattleintheTS-treatedcohortreturnedimmediately,suggestingthisisaveryusefultherapytoenablecattletowalkandgainaccesstowaterandfeed.IntheMO-treatedcohort,10oftheanimalsalsoimmediatelyreturnedtowalking.However,ofthecontrolgroup,only vehadimmediatemobilityandfouranimalsdidnotreturntowalkingevenbyday15.TherewasoneanimalintheMO-treatedcohortthatdidnotreturntomobilityuntilday12.Intotal,7/36(19.4%)cattlehadnotreturnedtomobilitybyday9,indicatingthatFMDisaseverediseaseasitrendersanimalsimmobileandthatalthoughFMDisconsideredalowmortalitydisease,theanimalwelfareimpactsareconsiderable.Asoralvesicularlesionscanhavesigni cantimpactsonanimalbehaviours,recordingthenumberofdaystheanimalswereanorexicwasconsideredimportant.Intotal,11/12cattleintheTS-treatedcohortwerereportedtobeeatingthesamedayastreatment(day0).Thiscomparedto9/12cattleintheMO-treatedcohort,withonly2/12inthecontrolcohort,with9/12oftheseuntreatedcattleremaininganorexicuntilday15.Further,salivationisacommonclinicalsignwithcattlewithvesiculardisease,consideredanovertindicatoroforallesionsandpresumablyoralpain.Inallthreecohortsthemajorityofcattlehadceasedsalivatingatday0,withtheTS-treatedcohortachieving11/12,MO-treatedcohort10/12andthecontrols8/12.Farmerreportsofvisiblelamenessoftrialcattleindicatedthat9/12cattleintheTS-treatedcohortceasedanylamenessatday0,comparedto5/12intheMO-treatedcohortand3/12inthecontrols.Byday6,nofurthercattleintheTS-treatedcohortshowedanylamenesscomparedto5/12cattleintheMO-treatedcohortstillshowinglamenessbydays12and15,withlamenessonlyceasingbyday15in9/12controlcattle.Forthequestionofhowmanydayspriortocattlereturningtograzing,mixedresultswererecorded.Inthecontrolcohort,9/12werereportedgrazingbyday0,with8/12intheTS-treatedcohortreturnedtograzingbyday3andall12/12intheMO-treatedcohortreturningtograzingbyday6.WhenaskedforabroadoverviewoftreatmentsappliedtoFMD,sixoptionswereprovided,includingantibioticformulations,traditionaldrugs,insecticidesandpetrol.Withoutspeculatingonthetherapeuticpotentialofeachtreatment,itdoesindicatethatfarmersandparaveterinariansareinclinedtotreata ectedanimalswithsomething.Thedataoncostsoftreatmentsuggestthereareonlyminimaldi erencesbetweentreatmentsandthatcostshouldnotbeanimpedimenttochangingoftreatmentchoice.Fieldstudiesinvolvinganimaltreatmentswithassessmentsofclinicalimpactsarechallengingandsubjecttopotentialbias,re

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nimpedimenttochangingoftreatmentchoice.Fieldstudiesinvolvinganimaltreatmentswithassessmentsofclinicalimpactsarechallengingandsubjecttopotentialbias,re ectedinthelimitedpublishedliteratureonFMDtherapy.However,theresultsobtainedinthisstudydemonstratethesuperiorclinicale cacyofasingleapplicationtoFMDlesionsoftheTStopicalanaestheticwoundformulation.Theparticipatingfarmersreporteda100%appreciationfortheproductin13

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llrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. thetreatmentofFMDandexpressedtheywerehappytohavethisproductavailableforuseintheregion.These ndingswereconsistentwiththosefromarecentlyreportedclinicalinvestigationofTStherapyforFMDinLaos(Windsoretal,2020)andreportsoftheuseofthisproductforFMDinothercountriesinAfrica,includingNiger,Nigeria,andKenya.ThisstudyinCameroonprovidesthequantitativeassessmentthatcon rmthatTSise caciousinhasteningclinicalrecoveries,immediatelyaddressingpainandinvokingmorerapidhealingofFMDlesions,asobservedqualitativelyinLaos(Windsoretal,2020).Asthisinnovationprovidessuperioranimalwelfareoutcomesforanimalssu eringfromFMD,withouttherisksofAMRthatarisefromthemoretypicaltherapiesinuseforFMDglobally,e ortstopromotethisnewtherapeuticapproachshouldbesupported.ACKNOWLEDGEMENTSWethankthepresidentofthecattlefarmersandthesub-divisionaldelegatesforlivestockofCameroonandparticularlythatofTchabalforsupportandhelpininformingfarmersaboutthistrial,andP.L.E.Bfor nancialsupport.WealsothanktheProgOncho eldlabfortheircooperationandstorageofsamples,plusthedriverandallteammembersfortheirpunctualityandtimededicatedtothiswork.ThesupportofMedical/AnimalEthicsCompanyforprovisionoftheproductisgratefullyacknowledged.ETHICSSTATEMENTTheauthorscon rmthattheethicalpoliciesofthejournalasnotedontheauthorsguidelinespage,havebeenadheredto.InadditiontofollowingcurrentproceduresonanimalandhumanethicsprocessesinCameroon,theauthorscommunicatedwiththeirAustraliancollaboratorstoensuretheycompliedwiththeNationalHealthandMedicalResearchCouncil's(NHMRC)NationalStatementonEthicalConductinHumanResearch(2007)andtheUniversitiesAustraliaAustralianCodefortheResponsibleConductofResearch.Thisincludedensuringthatallparticipantsprovidedverbalinformedconsentforthecollectionofanimalbloodsamples,tissues,farmerinterviewsandparticipationinvideosandimages,wherewrittenconsentwasunavailableduetofarmerilliteracy.AUTHORCONTRIBUTIONSPWandSLdesignedthestudyandPW,JYandPTprovidedanalyticalandwritingsupport.SLwithsupportfromJM,KB,KAandSD,performedthe eldtrialactivities.PTconductedthestatisticalanalysesandallauthorscontributedtothe naldraftofthemanuscript.CONFLICTOFINTERESTTheauthorsreportnocon

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dthe eldtrialactivities.PTconductedthestatisticalanalysesandallauthorscontributedtothe naldraftofthemanuscript.CONFLICTOFINTERESTTheauthorsreportnocon ictsofinterestinthiswork.StudiesevaluatingTri-Solfen®andothertherapiesforaversiveanimalhusbandryinterventionsoccurringpriortothisstudy,werefundedbyanAustralianResearchCouncilLinkageGrantfromtheAustraliangovernmentwith nancialcontributionsfromAnimalEthicsPtyLtdAustraliaandBayerAnimalHealthAustralia.However,thiscurrentstudydidnotreceivefundingfromeitherofthesecompanies,nordidtheyhavearoleinstudydesign,datacollectionandanalysis,decisiontopublish,orpreparationofthemanuscript.DATAAVAILABILITYSTATEMENTThedatathatsupportthe ndingsofthisstudyareavailablefromthecorrespondingauthoruponreasonablerequest.REFERENCESAgresti,A.(2002).CategoricalDataAnalysis(2nded.).NewYork:JohnWiley&Sons.AL-Lethie,A.,AL-Lethie,S.F.,El-Hawari,K.,El-Khabaz;A.S.,Elmeligy;E.,Khalphallah,A.,UsamaT.Mahmoud,U.T.(2018).EvaluationofClinicalRecoveryandHealingofOralLesionsby3di erentTherapeuticRegimensinCattlewithFootandMouthDisease(FMD).AssiutVeterinaryMedicineJournal,64(156),89-95.14

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llrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. Bates,D,MaechlerM.,Bolker,B.,Walker,S.(2015).Fittinglinearmixed-e ectsmodelsusinglme4.JournalofStatisticalSoftware,67(1):1-48.doi:10.18637/jss.v067.i01Bertram,M.R.,Delgado,A.,Pauszek,S.J.,Smoliga,G.R.,Brito,B.,Stenfeldt,C.,Hartwig,E.J.,Jumbo,S.D.,Abdoulmoumini,M.,OlivaMarie,A.A.,Salhine,R.,Rodriguez,L.L.,Garabed,R.,Arzt,J.(2018).E ectofvaccinationoncattlesub-clinicallyinfectedwithFoot-and-MouthdiseasevirusinCameroon.Pre-ventiveVeterinaryMedicine,155,1{10.ChristensenRHB.2019.Ordinal:regressionmodelsforordinaldata.Rpackageversion2019.12-10.https://CRAN.R-project.org/package=ordinalEhizibolo,D.O.,Fish,H.,Brito,B.,Bertram,M.R.,Ardo,A.G.,Ularamu,H.G.,Lazarus,D.D.,Wungak,Y.S.,Nwosuh,C.I.,Smoliga,G.R.,Hartwig,E.J.,Pauszek,S.J.,Dickmu,S.,Abdoulkadiri,S.,Arzt,J.(2019).Re-emergenceofthenoveltopotypeoffootandmouthdiseasevirusserotypeSAT1inNigeriaandCameroon.GFRA2019Scienti cMeeting,Bangkok,ThailandOctober29-31.Fakhrul-Islam,K.M.,Jalal,M.S.,Podder,S.,Quader,M.N.,Sahidur-Rahman,M.,Dutta,A.,Mazum-der,S.(2016).ClinicalinvestigationoffootandmouthdiseaseofcattleinBatiaghataUpazillavete-rinaryhospital,Bangladesh.VeterinarySciences:ResearchandReviews.2(3):76-81.doi:10.17582/jour-nal.vsrr/2016.2.3.76.81FAO(2015).StrategicPlanfortheControlofFootandMouthDiseaseinCameroon.In:Towardsimprovingthecontroloftransboundaryanimaldiseasesoftradelivestock.Cameroon,FAO,OMC.MTF/CMR/034/STF.https://www.standardsfacility.org/information-session-cameroonFrossardm,J.,Renaud,O.(2019).permuco:Permutationtestsforregression,(repeatedmea-sures)ANOVA/ANCOVAandcomparisonofsignals.Rpackageversion1.1.0.https://CRAN.R-project.org/package=permucoGakuya,D.W.,Mulei,C.M.,Wekesa,S.B.(2011).UseofEthnoveterinaryremediesintheManagementofFootandMouthDiseaselesionsinaDairyHerd.AfricanJournalTraditionalandComplementaryAlternativeMedicine.8(2),165-169.Herv e,M.(2020).RVAideMemoire:testingandplottingproceduresforbiostatistics.Rpackageversion0.9-77.https://CRAN.R-project.org/package=RVAideMemoire.Lenth,R.(2020).emmeans:estimatedmarginalmeans,akaleast-squaresmeans.Rpackageversion1.4.7.https://CRAN.R-project.org/package=emmeans.Ludi,A.,Ahmed,Z.,Pomeroy,L.W.,Pauszek,S.J.,Smoliga,G.R.,Moritz,M.,Rodriguez,L.L.(2016).SerotypeDiversityofFoot-and-Mouth-DiseaseVirusinLivestockwithoutHistoryofVaccinationintheFarNorthRegionofCameroon.TransboundaryandEmergingDiseases,63(1),e27{e38.doi:10.1111/tbed.12227MINEPIA,`Minist eredel'Elevage,desP^echesetdesIndustriesAnimales',MINEPIAPolicyDocument.2013;29.Misk,N.A.,Misk,T.N.,Rateb,H.Z.(2015).AssessmentandTopicalTreatmentofLesionsofFootandMouthDiseaseinCattle.AssiutVeterinaryMedicineJournal,61,75-81.Roberts,C.D.,Windsor,P.A.(2019).Innovativepainmanagementsolutionsinanimalsmayprovideim-provedwoundpainreductionduringdebridementinhumans:Anopinioninformedbyveterinaryliterature.InternationalWoundJournal,16(4),968-973.doi:10.1111/iwj.13129Sevidzem,S.L.,Mavoungou,J.F.,Mintsa,N.R.(2019a).VeterinaryPharmaceuticalsSoldinCattleMarketsfortheManagementofFoot-and-MouthDiseaseandFliesinVinaDivision(Adamawa-Cameroon).JournalofDairyandVeterinaryScience,10(2),555782.doi:10.19080/JDVS.2019.10.5557820010Sevidzem,S.L.,Abdoulmoumini,M.,Jacques,F.M.,Ikoum,D.,Mohammadou,B.,Oumarou,L.,Hiol,V.D.,Rodrigue,M.N.,Zinga-Koumba,C.R.,Acapovi-Yao,G.L.,Simon,D.,Garabed,R.(2019b).Serolo-15

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ment0.0098.27A±4.953.49AB±2.000.70B±0.85Di cultyAge0.471Breed0.875Sex0.724NormalTreatment0.0000.60A±0.402.72B±0.787.18C±1.92Age0.221Breed0.117Sex0.033 A,B,C:Meanssharingthesamesuperscriptarenotsigni cantlydi erent(P>0.05).Table3.Analysisofthenumberofdaysthatcattlearesalivating.16

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PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. VariableP-valueControlMooreOxy®TriSolfen® Treatment0.1461.59A±0.820.49A±0.390.56A±0.46Age0.171Breed0.537Sex0.500 A:Meanssharingthesamesuperscriptarenotsigni cantlydi erent(P>0.05).Table4.Analysisofthenumberofdaysthatcattlearesalivating. VariableP-valueControlMooreOxy®TriSolfen® Treatment0.1461.59A±0.820.49A±0.390.56A±0.46Age0.171Breed0.537Sex0.500 A:Meanssharingthesamesuperscriptarenotsigni cantlydi erent(P>0.05).Table5.Treatmenttypesusedbyfarmers,applicationmethod,daysoftreatmentandestimateddailyandtotalcosts. TreatmentchoiceApplicationEst.cost/day(USD)TreatmentdaysEst.cost/animal(USD) Moore-OxyInjection0.8532.55ProcainepenicillinInjection0.1730.51Oxytet30%Injection0.8532.55SurvidiumInjection0.8554.25Insecticide&PetrolTopical0.4272.94TraditionaldrugsTopical/oral0.5173.57OXYDOZER50Injection0.8532.55Tri-SolfenTopical/12.50 Moore-Oxy®hasa7daymilkWHPand21meatWHP.Tri-Solfen®hasarecommended4dayWHPformilkandmeatinLaoPDRFigureLegendsFigure1:Mapsshowingthestudysites(NgaoundereII,NgaoundereIIIandMartap)M1:Mbidjoro1,M2:Mbidjoro2,T1:TchabalBaouro1,T2:TchabalBaouro2,T3:TchabalBaouro3,T4:Tchabal4,T5:Tchabal5,T6:Tchabal6,B:Borongo,H1:Hor eMayanga1,H2:Hor eMayanga2,H3:Hor eMayanga3.Figure2.Model-basedprobabilitiesofobtaininglesionhealingscores1through4acrossthesixstudydays,forthethreetreatmentgroups.Figure3.Model-basedprobabilitiesofobtainingappetitescores1through4acrossthesixstudydays,forthethreetreatmentgroups.Figure4.Model-basedmeanlesionsize(cm)acrossthesixstudydays,forthethreetreatmentgroups.Shadedareasare±1standarderrorofthemean.17

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hethreetreatmentgroups.Figure4.Model-basedmeanlesionsize(cm)acrossthesixstudydays,forthethreetreatmentgroups.Shadedareasare±1standarderrorofthemean.17 PostedonAuthorea16Sep2020|Thecopyrightholderistheauthor/funder.Allrightsreserved.Noreusewithoutpermission.|https://doi.org/10.22541/au.160029789.93744641|Thisapreprintandhasnotbeenpeerreviewed.Datamaybepreliminary. Figure5.Model-basedprobabilitiesofobtainingwalkingscoresof`Immobile',`Withdi culty'and`Normal'acrossthesixstudydays,forthethreetreatmentgroups.Figure6.Model-basedprobabilitiesofcattlebeingonpastureacrossthesixstudydays,forthethreetreatmentgroups.Shadedareasare±1standarderrorofthemean(whereavailable).Figure7.Model-basedprobabilitiesofcattlesalivatingacrossthesixstudydays,forthethreetreatmentgroups.Hosted leFMDCameroonTables140920.docxavailableathttps://authorea.com/users/359354/articles/481409-efficacy-and-application-of-a-novel-topical-anaesthetic-wound-formulation-for-treating-cattle-with-foot-and-mouth-disease-a-field-trial-in-cameroonHosted leFMDCameroonFigures140920.docxavailableathttps://authorea.com/users/359354/articles/481409-efficacy-and-application-of-a-novel-topical-anaesthetic-wound-formulation-for-treating-cattle-with-foot-and-mouth-disease-a-field-trial-in-cameroon18

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