ORIGINALARTICLE Useofapurifiedreconstitutedbilayermatrixinthe managementofchronicdiabeticfootulcersimproves patientoutcomesvsstandardofcare:Resultsofa prospectiverandomisedcontrolledmulti-centreclinical trial DavidG.Armstrong 1 |DennisP.Orgill 2 |RobertD.Galiano 3 | PaulM.Glat 4 |JarrodP.Kaufman 5 |MarissaJ.Carter 6 | LawrenceA.DiDomenico 7 |CharlesM.Zelen 2 1 DivisionofSurgery,KeckSchoolof Medicine,UniversityofSouthern California,LosAngeles,California,USA 2 ProfessionalEducationandResearch Institute,Roanoke,Virginia,USA 3 DivisionofPlasticSurgery,Feinberg SchoolofMedicine,Northwestern University,Chicago,Illinois,USA 4 SurgeryandPediatrics,DrexelUniversity CollegeofMedicine,St.Christopher's HospitalforChildren,Philadelphia, Pennsylvania,USA 5 DepartmentofSurgery,Temple UniversitySchoolofMedicineand McGowanInstituteforRegenerative Medicine,UniversityofPittsburgh, Pittsburgh,Pennsylvania,USA 6 StrategicSolutions,Inc.,Bozeman, Montana,USA 7 LowerExtremityInstituteforResearch andTherapy,Youngstown,Ohio,USA Correspondence CharlesM.Zelen,DPM,FACFAS, MedicalDirector,ProfessionalEducation andResearchInstitute,Inc.222Walnut Avenue,Roanoke,VA24016,USA. Email:cmzelen@periedu.com Abstract Diabeticfootinfectionscontinuetobeamajorchallengeforhealthcaredelivery systems.Followingencouragingresultsfromapilotstudyusinganovelpurified reconstitutedbilayermatrix(PRBM)totreatchronicdiabeticfootulcers(DFUs), wedesignedaprospective,multi-centrerandomisedtrialcomparingoutcomes ofPRBMat12weekscomparedwithastandardofcare(SOC)usingacollagen alginatedressing.Theprimaryendpointwaspercentageofwoundsclosedafter 12weeks.Secondaryoutcomesincludedassessmentsofcomplications,healing time,qualityoflife,andcosttoclosure.Fortypatientswereincludedinan intent-to-treat(ITT)andper-protocol(PP)analysis,with39completingthestudy protocol(n = 19PRBM,n = 20SOC).WoundstreatedwithPRBMweresignifi- cantlymorelikelytoclosethanwoundstreatedwithSOC(ITT:85%vs30%, P = .0004,PP:94%vs30%P = .00008),healedsignificantlyfaster(mean37days vs67daysforSOC,P = .002),andachievedameanwoundareareduction within12weeksof96%vs8.9%forSOC.Noadverseevents(AEs)directly relatedtoPRBMtreatmentwerereported.MeanPRBMcostofhealingwas $1731.UseofPRBMwassafeandeffectivefortreatmentofchronicDFUs. KEYWORDS advancedwoundcare,advancedwoundmatrix,diabeticfootulcers,standardofcare, woundhealing KeyMessages • patientswithnon-healingDFUsrandomisedtotreatmentwithanadvanced woundmatrix,PRBM,demonstratedasignificantlyimprovedhealingrate Received:23July2021Revised:14October2021Accepted:20October2021 DOI:10.1111/iwj.13715 ThisisanopenaccessarticleunderthetermsoftheCreativeCommonsAttribution-NonCommercial-NoDerivsLicense,whichpermitsuseanddistributioninany medium,providedtheoriginalworkisproperlycited,theuseisnon-commercialandnomodificationsoradaptationsaremade. ©2022TheAuthors.InternationalWoundJournalpublishedbyMedicalhelplines.comInc(3M)andJohnWiley&SonsLtd. IntWoundJ.2022;1 – 13.wileyonlinelibrary.com/journal/iwj1Fundinginformation Thisstudywassupportedbyaresearch grantfromGeistlichPharmaAG(002). andshortertimetohealcomparedwithpatientsrandomisedtostandardof caretreatmentovera12-weekperiod • themeanPRBMproductcosttoclosurewas$1731perhealedwound • PRBMdemonstratedastaticallysignificantimprovementinpercentarea reductionover12weeksvsstandardofcare 1|INTRODUCTION TheprevalenceofdiabetesintheUnitedStatescontinues torise,withthediseasenowaffecting34.2million,with anestimatedadditional84millionatriskofprogressingto diabetesinthecomingyears. 1 Thelifetimeincidenceof DFUsamongdiabeticsis19%to34%,withrecurrentulcer- ationreportedasapproximately40%at1yearand60%at 3years. 2 Managementischallengingandassociatedwith substantialsocio-economicburdenapproaching$40billion annuallyindirectcosts. 3 Approximately70%ofDFUs resolvewithstandardwoundcaretherapies.However,the naturalhealingcascadeisarrestedintheremaining30%, whichultimatelybecomechronicwounds. 4,5 Patientswith chronicwoundstypicallysufferlossoffunction,recurrent infection,andsignificantmorbidity. 6 Amputationsare reportedinupto20%ofcaseswithanassociatedmortality of70%at5yearspost-amputation. 2 Successfultreatment ofnon-healingwoundsischallengingandnotgenerally accomplishedusinga ‘ onesizefitsall ’ approach.Often, multipletherapiesoveranextendedcoursearenecessary toachievecompleteclosure. 7 Ongoingfocusondevelopmentofnewmodalitiesto improvediabeticwoundhealinghasproducednumerous advancedbiomaterials.Presently,76commercially availableskinsubstitutesforchronicwoundsare recognisedbytheCentersforMedicare&MedicaidSer- vices(CMS). 8 Themajorityareextracellularmatrix (ECM)graftsderivedfromhumanandanimaltissues. Whetherproducedfromallogeneicorxenogeneic sources,decellularisedgraftspurporttopreservethe essentialECMstructureandbiochemicalfunctionsfor woundhealing.Numerousproductshavebeendescribed ascapableofenhancingchronicwoundhealing,however onlyalimitednumberhavebeenrigorouslystudied. Recently,anovelporcine-derived,purifiedrec- onstitutedbilayerwoundmatrix(PRBM,Geistlich Derma-Gide,GeistlichPharmaAG,Switzerland)was evaluatedinaseriesof10patientswithchronicDFUs andwasfoundtosafelysupportrapidhealingin90%of woundsatarelativelylowproductcosttoachieveclo- sure. 9 PRBMisprocessedusingproprietaryextraction andpurificationmethodstoremovecells,lipids,unde- siredproteins,andantigensandalsotoinactivatepoten- tialviruses.Thepurified,tissue-derivedcomponentsare reconstitutedintoanon-cross-linked3-dimensional bilayerECMwithastructuresimilartohumandermis 9,10 (Figure1).Ininvitroexperiments,PRBMsupportedthe attachment,proliferation,andmigrationoffibroblasts andkeratinocytes,thebindingofgrowthfactors,andthe FIGURE1Purifiedreconstituted bilayermatrix(PRBM).(A)Theimageof PRBMinitsdrystateand(B)inits hydratedstate.TheporesofPRBMallows drainageofwoundfluid,uptoninetimes ofitsownmass.(C)Scanningelectron micrographofcrosssectionofPRBM.The electronmicroscopyimageshowsthe bilayerstructureofthePRBM.Theupper compactlayerismoredenselypacked formingabarriertomicrobeentryandto lossofwoundfluid,anditguides reepithelialisation.Thelowerporouslayer mimicsdermisandprovidesastructure forcellularingrowth 2ARMSTRONG ETAL .modulationofexcessiveMMPstypicallyfoundinthe chronicwoundmicroenvironment. 10 Followingtheseinitialclinicalandbench-topassess- ments,arandomisedtrialtocomparethesafety,effec- tiveness,andcostofPRBMvsstandardofcare(SOC)was performed. 2|METHODS 2.1|Studydesign Amulti-centre,prospective,parallel-group,randomised, controlledtrial(RCT)evaluatingtreatmentoffull-thick- ness,non-infectednon-ischaemic(WagnerGrade1/Uni- versityofTexas1A)DFUswithPRBMorSOCwas approvedbyWesternIRB(Protocol#20190130)andcon- ductedincompliancewithUnitedStatesFDAandISO standardsandinconformancewiththeethicalguidelines oftheDeclarationofHelsinki.Thetrialwasperformedat multiplespecialtywoundcarecentresbetweenFebruary 2019andSeptember2020.Table1summarisestheproto- colschedule.Patientswereprovidedwrittenconsent priortoanystudy-relatedactivities. TABLE1Studyprotocolschedule Wk1-2screeningphase • Informedconsent,inclusion/exclusioncriteriaassessment • Medicalhistoryandphysical,vitalsignsandlabs • Assessmentofdiabeticwounds;DFUhistory • Assessmentofcurrentwoundtherapies • 10-pointmonofilamenttest • X-ray • ABI,SPP,TCOMTBImeasurementorarterialDopplerstudy • PatientcompletesWound-QoLandpainassessment • Selectionofindexulcer;measurementofsurfaceareaand digitalimaging • IndexUlcerAssessmentofexudateandinfection • TreatmentofindexulcerwithSOCprotocol • Woundimprovementover14d • Confirmeligibilitytocontinueenrolmentintostudy Wk3-14treatmentphase • Medicalhistoryandphysical,vitalsignsandbloodsugar • Assessmentofanyadverseevents • Painandneuropathyassessments • Indexulcerassessment(exudateandinfection),cleaningand debridement • Measurementofsurfacearea,depth,anddigitalimagingof indexulcer • Assessmentofoffloading • Randomisation(wk3) IfrandomisedtoSOC:ApplySOCtherapywithFibracol andouterdressing IfRandomisedtoPRBM:ApplySOCtherapywithPRBM andouterdressing • Weeklyassessmentofindexulcer,measurement,cleaning, debridement,andrepeatdressings(wk4-14) Ifindexulcerishealed,nofurthertreatment Aftersixtreatmentvisits,ifwound<50%healed, treatmentphaseended;treatmentfailure Wk15-16:endofstudy/confirmationvisit • Medicalhistoryandphysicalvitalsignsandlabs/bloodsugar • Assessmentofanyadverseevents • Assessmentofoffloading • Assessmentofindexulcer(exudateandinfection);complete epithelializationorifwoundhasre-opened • Measurementofsurfaceareaanddigitalimagingofindex ulcer • Assessmentofinfection • Cleaning,debridement,anddressingofindexulcerif applicable • PatientcompletesWound-QoLandpainassessment TABLE2Studyinclusionandexclusioncriteria InclusioncriteriaExclusioncriteria • Age18orolder • Type1ortype2diabetes • DFUWagnerGrade1 • Noclinicalsignsof infection • Studyulcerpresent >4wkunresponsiveto SOCpriortoscreening visit • Studyulcersize ≥ 1.0cm 2 and<25cm 2 • Serumcreatinine <3.0mg/dLand HbA1c<12% • Otherulcers,ifpresenton thesamefoot,are>2cm distantfromthestudy ulcer • Adequatecirculationto theaffectedfoot:TCOM orSPPof ≥ 30mmHg,or ABIbetween0.7and1.3 within3moofscreening orbiphasicDopplerof dorsalispedisand posteriortibialvesselsat theleveloftheankleor TBIof>0.6 • Offloadingoftargetulcer ≥ 14dpriorto randomisation • Ableandwillingto provideconsentand complywithweeklyvisits • Ulcer(s)deemedtobe causedbyconditionsother thandiabetes • Knownorsuspected malignancyofindexulcer • Indexwoundduration>1y • PatientstakingCOX-2 inhibitors,immunesystem modulators • Patientsonany investigationaldrug(s)or therapeuticdevice(s) within30d • Historyofradiationatthe ulcersiteorrequirementof chemotherapy • Osteomyelitisoftheaffected footwithin30dpriorto randomisation. • Diabeteswithpoor metaboliccontrol (HbA1c>12.0)within90d ofrandomisation • End-stagerenaldisease • Woundsimproving>20% over14drun-inwith standardofcaretreatment andoffloadingpriorto randomisationvisit • Historyofpooradherence withmedicaltreatmentor inabilitytocompletestudy ARMSTRONG ETAL .32.2|Treatments 2.2.1|Purifiedreconstitutedbilayermatrix Sterile,shelf-stablePRBM(GeistlichDerma-Gide;Wolhusen Switzerland)wasprovidedinindividualdrypackagingin sizesfrom1.1to12cm 2 .PRBMwasmanuallytrimmedto matchthesizeofeachwoundandplaceddrywiththeporous lowerlayerfacingdown,directlyontothewoundbed,all- owingforuptakeofwoundfluids.IfthePRBMwasnot completelyhydratedbywoundfluid,sterilesalinewasadded forcompletehydration,allowingthegrafttoconformtothe woundbedbeforeapplicationofaroutinetopicaldressing. 2.3|Standardofcare(SOC) Amoisture-retentive,conformablecollagenalginatedress- ing(FIBRACOLPlusDressing,KCI,SanAntonio,TX) wastheprimarywounddressingintheSOCstudyarm. Thisdressinghasbeenrigorouslytestedwithfavourable resultsandwaschosenasawell-known,clinically acceptedSOCproductreadilyavailableinwoundclinics. 11 2.4|Studyendpoints Theprimarystudyendpointwasacomparisonofwound closureratesat12weeks.Secondaryendpointsincluded comparisonsoftimetohealat6and12weeks,percent- agewoundareareductionat6and12weeks,and patient-reportedqualityoflifeoutcomes.Costtoclosure wascalculatedforPRBMbasedonproductlistpricesand thetotalnumberandsizeofgraftsused. 2.5|Patientscreening Afterobtaininginformedconsent,participantswere screenedovera14-dayrun-inperiodtodetermine FIGURE2Consortflowdiagram 4ARMSTRONG ETAL .eligibilityaccordingtoinclusionandexclusioncriteria (Table2).Therun-inprecededrandomisationtoelimi- natethosepatientsinwhomashortcourseofroutine therapywoulddemonstrateeffectivenessasmeasuredby a>20%reductioninwoundarea.Areviewofeach patient'smedicalhistoryandacompletephysicalexami- nationwereperformedincludingvisualassessmentofall footulcerswithattentiontosignsofinfection.Theindex ulcerwasselected,imaged,andmeasuredforareaand depth.Allwoundsweremanagedduringrun-inusinga standardprotocolincludingcleaning,appropriatesharp debridement,infectionmanagement,dressing,and offloadingusingadiabeticoffloadingbootorwhenthe patient'sfootcouldnotbeaccommodatedwiththe offloadingboot,atotalcontactcastwasused.Subjects wereinstructedtokeepthewoundsitedryandinformed ontheimportanceofoffloading.Theyreceivededucation oninfectionindicatorsandaskedtocontacttheclinic withconcerns.Patientscompletedthewoundquality-of- life(Wound-QoL)questionnaire 12,13 andscoredtheir painintensityonascaleof0to10usingavisualana- loguescale(VAS).Afterfailingsufficientprogressduring the2-weekrun-inperiod,subjecteligibilitywasrecon- firmed,andalleligiblepatientsproceededto randomisation. 2.6|Randomisationandmeasuresto minimisebias SubjectswererandomisedtoeitherthePRBMArmor SOCarm.Toassureabalancedrandomisation,envelopes werecreatedwitharandomallocationsequenceinblock sizesof10.Woundassessmentatconclusionoftreatment TABLE3Patientcharacteristics VariablePRBMSOC P value Age(years)59.3(13.35)66.5(11.26).073 Race Caucasian20(100)19(95)1.0 AfricanAmerican0(0)1(5) Gender Male13(65)12(60).74 Female7(35)8(40) BMI33.0(7.68)31.8(7.14).49 Smoking.072 Never8(40)12(60) Former8(40)8(40) Current4(20)0(0) HbA1c(screening)7.2(1.20)6.9(1.83).19 HbA1c(endstudy) a 6.7(1.17)6.6(1.71).92 Creatinine1.1(0.51)1.2(0.39).27 Bloodglucose160(57.47)174(71.0).51 Historyofsignificantfootdeformities9(45)6(30).33 AgewhenfirstDFUappeared(years)52.3(12.77)60.3(10.80).037 PriorDFUcount4.7(3.48)6.1(5.29).63 HistoryofDFUrecurrence13(65)12(60).74 Amputation.35 Minor(1)5(25)1(5) Major(1)1(5)1(5) Both(1)0(0)1(5) OtherconcurrentDFUs(atscreening)3(15)4(20).68 Note:Subject-relateddemographics.Categoricalvariablesreportedasnumbersandpercentagesin parentheses;continuousvariablesreportedasmeansandSDintheparenthesis. a Conditionalstatisticalpowerusingbetacurveparameters(mean/SD)toestimateaMann-Whitney approximationwithbootstrap:95%-99%. ARMSTRONG ETAL .5wasperformedbyaclinician,otherthantheinvestigator, whowasblindedtothetreatment.Additionally,confir- mationofwoundhealingwasoverseenbyanindepen- dentadjudicationcommitteeofexperts. 2.7|Treatmentphase Regardlessofthestudyarm,woundsweremanaged withacceptedroutineSOCpractices,includingweekly TABLE4Wound-relatedcharacteristics VariablePRBMSOC P value Woundarea(cm 2 ) a 2.5(2.16)3.5(2.85).21 Median:1.7;IQR:1.4Median:3.0;IQR:3.8 Initialdepth(mm) a .18 <215(75)11(55) ≥ 25(25)9(45) Woundage(weeks) a 12.1(8.21) Median:9;IQR:8 15.6(12.92) Median:8;IQR:17 .74 Plantarlocation14(70)14(70)1.0 Woundposition.74 Lateral7(35)8(40) Medial13(65)12(60) Woundlocation.34 Toe5(25)2(10) Forefoot4(20)7(35) Midfoot9(45)6(30) Heel1(5)4(20) Ankle1(5)1(5) Offloadingdurationatscreening(weeks)11.6(11.09)18.7(23.77).67 Mean%oftimewoundoffloadedduringstudy83.5(13.56)84.7(9.32).89 Note:Summaryofwound-relatedcharacteristics.Categoricalvariablesarereportedasnumbersandpercentagesinparentheses,continuousvariablesare reportedasmeansandSDinparentheses.Forcontinuousvariablesthatarerelativelynon-normalindistribution(eg,woundarea),mediansandinterquartile rangesandIQRareincluded. a Atrandomisation. FIGURE3Kaplan-Meier plotofprobabilityofwound healingbytreatmentgroup. Unadjustedtimedepictedafter randomisation.Censormarks indicatesubjectexitpriorto 12weeks.Asuperiorhealing trajectoryisdemonstratedinthe PRBMtreatmentgroupwitha divergenceapparentafterabout 1week 6ARMSTRONG ETAL .sharpdebridementasindicated.Patientsrandomised toPRBMarmweretreatedwithaPRBMgraftfollowed byasiliconenon-adherentdressing(AdapticTouch, 3M/KCIMinneapolis,MNorequivalent),andthose randomisedtoSOCarmweretreatedwithcalcium alginatedressing(FIBRACOLPlus).Allwounds receivedanouterdressingcomprisedofapadded 3-layerdressing(Dynaflex,3M/KCIMinneapolis,MN orequivalent). Studyvisitswereperformedweeklyuntileithercom- pletehealingoftheindexulcerorfor12weeks,which- evercamefirst.Ateachvisit,thesubject'soverall health,glucosecontrol,andoffloadingwereassessed, andclosureoftheindexulcerwasgaugedbyablinded investigator.Iftheindexulcerwasnotcompletely reepithelialised,thewoundwasevaluatedforsignsof infection,cleaned,imaged,andmeasured.Whenthe indexulcerwasdeemedtobe100%reepithelialised,fur- thertreatmentceased,andthepatientwasscheduled fortwoconsecutivevisits1weekapart.Finalwound areameasurementandconclusiveimagingwereper- formed,andpatientscompletedtheWound-QoLques- tionnaireatthefinalvisit.Subjectswhoseindexulcer didnotimproveby50%after6weeksweredesignated perprotocolasatreatmentfailureandwereallowedto receivealternativetreatmentsoutsideofthestudy. DetailsspecifictoPRBMincludingtrimmedsizeand handlingcharacteristicswerenoted.Anyadverseevents (AEs)wereidentified,investigated,andmanagedas clinicallyappropriate.Suspectedwoundinfectionwas diagnosedviawoundswabs,andappropriatesystemic antibioticswereprescribed.Topicalantibioticswere contraindicatedperprotocol. 2.8|Samplesizeandstatisticalanalysis Accordingtoaprioripoweranalysis,usinganeffectsize of0.45andapowerof0.8,thesamplesizeforeacharm required20patients.Powercalculationsfortheprimary endpointwerebasedonatwo-sidedZ-testwithpooled variance.Theprimaryendpointwasevaluatedusingan intent-to-treat(ITT)analysisofallrandomisedpatients. AFisherexacttestwasusedfortheprimaryoutcome whiletimetohealwithin6and12weekswasanalysed usingKaplan-Meierlog-ranktest.Theprimaryandsec- ondaryendpointsweretestedhierarchicallyinaconfir- matorymannerwhilealogisticregressionwasperformed asexploratoryanalysisiftheprimaryendpointwassig- nificant.Otherendpointsassessedinanexploratoryman- nerincluded:12-weekpercentareareduction(PAR), Wound-QoL,painscorechangesfrombaselineto 12weeks,andtotalcostoftreatmentuntilclosure.Statis- ticaltestsweretwo-sidedandperformedatasignificance thresholdof.05.Statisticalanalysiswasperformedusing SPSSStatistics27(IBM,Armonk,NY). 3|RESULTS Forty-sixpatientswerescreened,with40randomisedto treatmentwitheitherPRBMorSOC(Figure2).One patientinthePRBMarmwaswithdrawnatweek11and excludedfromPP(perprotocol)analysisbecauseofan SAErequiringhospitalisation,whiletwootherswerealso excludedfromPPanalysisbecauseofmissedscheduled treatmentvisits.IntheSOCArm,10subjectsexhibited poorwoundhealingtrajectories(<50%areareduction FIGURE4Weeklypercent woundareareductionby treatmentgroup.Weeklymean percentreductionofulcer surfaceareabytreatmentgroup. After1week,healing trajectoriesdivergeconsiderably, withPRBM-treatedwounds demonstratinggreater,more rapidareareductioncompared towoundstreatedwithSOC alone ARMSTRONG ETAL .7aftersixtreatments)andwere,therefore,designatedper protocolastreatmentfailure.OneSOCpatientwitha healedwoundat6weekspresentedattheconfirmation visit(week8)withevidenceofwoundreopeningandwas designatedasatreatmentfailure. Thestudycohortwasrepresentativeofthediabetic populationattheinvestigationalsites,withthetypical rangeofcomorbidities.Patientdemographicsandwound characteristicswerewellbalancedbetweenthetwoarms (Tables3and4).Theonlystatisticaldifferencebetween thegroupswasthatpatientsrandomisedtoPRBM reportedalowerageatfirstDFUoccurrence. Woundclosureratewassignificantlyhigherinthe PRBMarmthantheSOCarm. UsinganITTapproach,after12weeksoftreatment, thePRBMarmhad85%(17/20)ofulcershealedcom- paredwith30%(6/20)intheSOCarm(P<.001)withall patientsanalysed.Whenevaluatedperprotocol(PP),the PRBMarmdemonstrated94%(16/17)woundclosure comparedwith30%(6/20)intheSOCArm(P<.001).In FIGURE5PhotosdepictingrepresentativePRBMwoundhealingcourse.Representativecasesdepictingthetimeprogressionofwound healingfollowingtreatmentwithPRBM.Patient1:76-year-oldfemaleBMI33.7presentedwith1.4cm 2 DFUpresentfor12weeks.Aftertwo PRBMtreatmentsthewoundareadecreasedover90%,and,followingthethirdtreatment,theulcerwasconfirmedtobefullyhealed (4-weekvisit).Patient2:65-year-oldfemaleBMI27.4presentedwitha2-cm 2 DFUpresentfor8weeks.AftertheinitialPRBMtreatmentthe woundareahaddecreasedbyover90%,andaftertwotreatmentswasconfirmedtobefullyhealed(3-weekvisit).Patient3:73-year-oldmale BMI32.5presentedwitha5.12-cm 2 DFUpresentfor20weeks.AfterthreePRBMtreatments,thewoundareahaddecreasedbyover54%, andaftersixtreatments,thewoundareawasconfirmedtobefullyhealed(7-weekvisit) 8ARMSTRONG ETAL .additiontothemaineffectvariable,severaladditional variableswereevaluatedinregressionmodelsusingpar- tialfactorialapproach,includingthevariables,initial woundareaanddepth,offloadingdurationatscreening, andwoundareaatrandomisation.Allcomponents excepttreatmentwerenotsignificant.Accordingly, adjustmentforothercovariateswasunnecessary.A Kaplan-Meierplotofhealingprobability(Figure3)illus- tratesearlydivergenceafter1week,withPRBMshowing higherlikelihoodofclosure.Anoddsratio(OR)is definedastherelativeratioofasuccessfuloutcomefor onetreatmentmodalitycomparedwithanother.At 12weeks,thecalculatedORforPRBMtreatmentcom- paredwithSOCalonewas13(95%CI:2.8-63). Ulcershealedsignificantlyfasterwhentreatedwith PRBM.Onaverage,PRBM-treatedwoundshealed completelyin37days(95%CI:26-48,median21days)vs completehealingintheSOCgroupaveraging67days (P = .002;95%CI:55-78,medianinestimable).AKaplan- Meierplotofhealingprobabilitywithin12weeksillustrates earlyandmaintaineddivergenceinhealingprobability betweengroups(Figure2),withPRBMshowinghigher probabilityofclosure.Analysisoftimetohealwithin 6weeksshowedasignificantdifferencebetweenstudy arms,withthePRBM-treatedwoundshealinginameanof 28days(95%CI:22-35)comparedwithameanof39.9days (95%CI:38-42)forwoundsintheSOCarm(P = .002). HealingrateinthePRBMarmatthe6-weekmid-study pointwas65%comparedwith20%intheSOCarm. Themeanpercentareareduction(PAR)at6and 12weeksforwoundstreatedwithPRBMwas95%(SD: 8%)and96%(SD:10%),respectively,comparedwith24% (SD:82)and9.8%(SD:89%)forwoundsintheSOC group.Conditionalpowertestingshowsthisdifferenceto bestatisticallysignificant.AsdepictedinFigure4,the PARvaluesdemonstrateconsiderabledivergencein healingtrajectoriesatapproximately1week,with PRBM-treatedwoundsexperiencingmorerapidarea reduction.Figure5depictsrepresentativehealingcourses ofwoundstreatedwithPRBM. Theinvestigatorsevaluatedthewoundqualityoflife (Wound-QoL)andpatientsinthePRBMarmreporteda TABLE5ResultsofRCTsevaluatingperformanceofadvancedbiomaterialforchronicDFUs Description6-wkhealing12-wkhealing Meancostto closure($US)Refs Purifiedrefinedbilayermatrix(PRBM); purifiedporcineECM 65%PRBMvs20% SOC ITT:85%PRBMvs30% SOC $1731Current study PP:94%PRBMvs30% SOC Acellularsinglelayer — dehydratedhuman amnion-chorionmembrane(dHACM) NotassessedITT:70%dHACMvs 50%SOC $NA27 PP:81%dHACMvs55% SOC ITT:97%dHACMvs 51%SOC $279829 Asepticallyprocesseddehydratedhuman amnionandchorionallograft(dHACA) 70%dHACAvs15% SOC ITT:85%dHACAvs25% SOC $140021 ITT:85%dHACAvs33% SOC $177122,23 Asepticallyprocessedhumanreticular dermaltissue(HR-ADM) 65%HR-ADMvs5% SOC ITT:80%HR-ADMvs 20%SOC $147528 68%HR-ADMvs 15%SOC ITT:80%HR-ADMvs 30%SOC $120030 Dehydratedhumanumbilicalcord allograft(dHUC) NotassessedITT:70%dHUCvs48% SOC $325131 PP:81%dHUCvs54% SOC Tri-layerporcine,smallintestinal- submucosacollagenscaffold(SIS) NotassessedITT:54%SISvs32% SOC $301920,32 Note:SummaryofsimilarlydesignedRCTsevaluatingadvancedbiomaterialsvsstandardofcare(SOC)fortreatmentofchronicdiabeticfootulcers(DFUs). Abbreviations:ITT,intent-to-treatanalysis;PP,per-protocolanalysis. ARMSTRONG ETAL .9Next >