A Randomized Controlled Trial Evaluating Edema and ROM Using Negative Pressure Therapy Over Closed Incisions and Surrounding Soft Tissue Versus Standard Surgical Dressings in Bilateral Total Knee Arthroplasty: A Pilot Study
Phase: NA
Conditions: Surgical Wound, Bilateral Total Knee Arthroplasty, Wounds and Injuries, Joint Diseases, Musculoskeletal Diseases, Edema Leg, Joint Pain, Arthritis Knee
Sponsor: Solventum US LLC

 
A Randomized Controlled Trial Evaluating Edema and ROM Using 
Negative Pressure Therapy Over Closed Incisions and Surrounding 
Soft Tissue Versus Standard Surgical Dressings in Bilateral Total Knee 
Arthroplasty: A Pilot Study (The ENABLE Trial) 
 
NCT Number 
 
NCT04712019 
Protocol Date 
07 December 2020 
 






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ARandomizedControlledTrialEvaluatingEdemaandROMUsing
NegativePressureTherapyOverClosedIncisionsandSurrounding
SoftTissueVersusStandardSurgicalDressingsinBilateralTotalKnee
Arthroplasty:APilotStudy(TheENABLETrial)

PROTOCOL
NUMBER

KCI.PREVENA.RESTOR.ARTHRO.2019.01
SPONSOR
KCIManufacturingUnlimitedCompany
25/28NorthWallQuay
Dublin1
Ireland
PROTOCOL
VERSION/DATE
Version2.0,07December2020

ConfidentialityStatement:ThisdocumentisaconfidentialcommunicationofKCIManufacturingUnlimited
Company.Acceptanceofthisdocumentconstitutestheagreementbytherecipientthatnounpublished
information contained herein will be published or disclosed without the prior written approval of KCI
ManufacturingUnlimitedCompany.ThisdocumentmaybedisclosedtoappropriateInstitutionalReview
Boards(IRBs)/EthicsCommittees(ECs)solongastheyarerequestedtomaintainitsconfidentiality.





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StudySynopsis
TITLE:
ARandomizedControlledTrialEvaluatingEdemaand
ROMUsingNegativePressureTherapyOverClosed
IncisionsandSurroundingSoftTissueVersusStandard
SurgicalDressingsinBilateralTotalKneeArthroplasty:A
PilotStudy(TheENABLETrial)
PROTOCOL
NUMBER:
KCI.PREVENA.RESTOR.ARTHRO.2019.01
TYPEANDPHASE:
Post-market,prospective,randomized,controlled
STUDY
PRODUCT(S):
PREVENA RESTORTM Incision Management System with
PREVENARESTORARTHRO•FORMTMDressing
vs.
Standardsilver-containingdressing
STUDY
OBJECTIVE(S):
Theprimaryobjectiveofthisstudyistocomparetheeffectsof
the
PREVENA
RESTOR
ARTHRO•FORM™
Incision
Management System to standard silver-containing dressings
on lower limb swelling after bilateral primary total knee
arthroplasty.
STUDYDESIGN:
Thisisarandomized,controlled,prospective,global,
multicenterstudyperformedatapproximately10sites.
PRIMARY
ENDPOINT:
The primary endpoint is the percent change in lower limb
volume, as calculated based on manual circumference
measurements, 5-7 days after bilateral TKA when using the
PREVENARESTORARTHRO•FORM™IncisionManagement
Systemcomparedtothecontrol.
SECONDARY
ENDPOINTS:
Thesecondaryendpointsareasfollows:
· Percent change in lower limb volume, as calculated
based on manual circumference measurements, from
baselinetovisits4,5,and6
· Percentchangeincircumferencesfrombaselinetovisits
3-6thataremeasuredat:
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o 10cmabovethecenterofthepatella
o atthecenterofthepatella
o 10cmbelowthecenterofthepatella
o attheankle;1cmabovethemedialmalleolus
· Changeinkneeflexionanglefrombaselinetovisits3-6
· Changeinkneeextensionanglefrombaselinetovisits
3-6
· Change of total ROM degrees, defined asthe flexion
angleminustheextensionangle,frombaselinetovisits
3-6
· TheincidenceofSSCsbyvisits5and6
· Scarcosmesisassessmentatvisits3-6
· Theaveragepainineachleginthelast24hours,using
anNPRS(numericalpainratingscale)of0-10(dailyfor
4weekspost-surgery,thenweeklyforweeks5-12)
· Theworstpainineachleginthelast24hours,usingan
NPRS of 0-10 (daily for 4 weeks post-surgery, then
weeklyforweeks5-12).
SAFETY
ENDPOINT:
TheSafetyEndpointisthesubjectincidenceofAdverseEvents
andSeriousAdverseEvents,includingsubsequentemergency
departmentvisitsorsubsequenthospitalizations/interventions
foreitherknee.
NUMBEROF
SUBJECTS
PLANNEDAND
DURATIONOF
PARTICIPATION:
Approximately52subjectswillparticipateinthisstudy.Thetotal
durationofparticipationmayincludeupto42daysofscreening,
dayofsurgery,andupto13weekspost-surgery.
Totaldurationofparticipationwillbeupto134days.
NUMBEROF
STUDYSITES:
Thiswillbeamulticenterstudyconductedatapproximately10
studysites.
INCLUSION
CRITERIA:
Thesubject:
· is at least 22 years of age on the date of informed
consent.
·
canindependentlyprovideinformedconsent.
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· requiresandisscheduledtoundergoasimultaneous,
bilateral,primaryTKA.
· is willing and physically capable of undergoing a
simultaneous, bilateral, primary TKA with or without
replacementofthepatella.
· iswillingandabletoreturnforallscheduledstudyvisits.
EXCLUSION
CRITERIA:
Thesubject:
· ispregnantorlactating.
· hassignsofaninfectionintheareaofeitherkneeorhas
signsofasystemicinfectionatthetimeofsurgery.
·
isachronicopioiduser,definedpertheCDCguidelines
asopioidusefor>3months,atthetimeofenrollment.
· hasacurrentdiagnosisoflymphedemaineitherleg.
· hassigns,symptoms,oracurrentdiagnosisofvenous
insufficiency in either leg, as determined by the
investigator'sreviewofthesubject'smedicalhistory.
· hasahistoryofclottingdisorderorpriorhistoryofdeep
veinthrombosis
· willundergoaunilateralTKA.
· willundergoastaged,bilateralTKA.
· hashadpreviouskneereplacementsurgery.
· hasreceivedacorticosteroidinjectionintoeitherknee
within30daysofsurgery.
· undergoesasimultaneous,bilateralTKAwithaplanned
differentincisiontypeoneachknee(eg,midlineincision
vs.medialparapatellarincision).
· hasknownsensitivitytothestudyproductcomponents
(drapeand/ordressingmaterialsindirectcontactwith
theclosedincisionorskin).
· hasknownsensitivitytosilver.
· isenrolledinanotherinterventionalclinicalstudy.
· hasskincancerlocalizedatorinproximitytotheincision
site.
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· does not have access to an electronic device
(smartphone, iPad, or computer) on a daily basis to
completeonlineassessments.
· hascondition(s)that,intheopinionoftheinvestigator,
cause the subject to be an overall health risk that is
unsuitableforthesurgery.
· hascondition(s)that,intheopinionoftheinvestigator,
will impact study endpoints (eg, hemophilia or
autoimmunedisorders)ortheabilitytocomplywithstudy
procedures.
Intra-opCriteria
Thesubject:
· does not receive a “total” knee replacement for first
knee.Forexample,apartialoruni-compartmentalknee
replacementisperformed
· hasasurgicalincisionthatwouldprecludeplacementof
eitherdressingontotheknee
· hasaTKAresultinginamuscleflap
STUDY
EVALUATION/VISIT
SCHEDULE:
The duration of study participation for each subject is as
follows:
· ScreeningPeriod:upto42days(Day-42toDay0)
· DayofSurgery–Bilateral,primaryTKAprocedures
· TreatmentPeriod:2weeks(12-14days,butnolonger
than14days),withdressingchangeandassessmentat
1week(5-7days)
· Follow-up:6weeks(±1week)and12weeks(±1week)
aftersurgery
Themaximumparticipationdurationpersubjectisupto134
days.
SAMPLESIZEAND
STATISTICAL
METHODOLOGY:
SampleSizeDetermination
Pichonnaz et al measured the limb volume utilizing the
truncated cone method.1 The mean volume percentage
differencefrombaselinetoDay8post-surgerywas11.9%,with
astandarddeviationof8.2%atDay8.In2016,Pichonnazetal
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usedthesamemethodtoevaluatethelowerlimbvolumeand
themeanpercentagedifferencefrombaselinetopostoperative
Day7was15.3%,withastandarddeviationof6.5%atDay7.2
Assuminginourstudythecontrolgrouphasapercentchange
of 13.6% in volume from baseline to post-surgery Day 5-7,
whilethePREVENARESTORgrouphasapercentchangeof
8%inthesameperiod,giventhestandarddeviationis9.2%in
bothgroups, a totalof 52 subjects (assuming15% dropout
rate)areneededtoachieve80%powerbasedonatwo-sample
t-testwithatypeIerrorrateof0.05.
AnalysisSets
Thefollowinganalysissetswillbeused:
· Intention-to-treat(ITT)AnalysisSet –TheITTSetwill
consistofallrandomizedsubjects.Subjects/Kneeswill
be analyzed according to the treatment allocated at
randomizationforthatparticularknee(rightorleft)
o Intheeventeachtreatmentisallocatedtoaknee
differentthanthattowhichtheywererandomized,
the subject/knee will be counted under the
treatment received as long as the subject
receiveseachtreatmentonce(onetreatmentper
knee).
o Intheeventsubjectsreceivethesametreatment
inbothknees,eachkneewillbecountedoncein
each unique treatment group according to the
treatmentallocatedaspertherandomizationand
will not be counted twice under the same
treatmentgroup.
· Per-Protocol(PP)AnalysisSet–ThePPSetwillinclude
allsubjectsand/orkneesintheITTAnalysisSetwithno
disqualifyingprotocoldeviation(s)thatwouldimpactthe
interpretationoftheprimaryendpoint.Thedisqualifying
protocoldeviation(s)forexclusionfromthissetwillbe
definedanddocumentedpriortodatabaselock.
· Safety Analysis Set – The Safety Analysis Set will
consistof allsubjects and/orknees thatreceivedany
studytreatment-relatedprocedures.Subjects/Kneeswill
beanalyzedaccordingtothetreatmentreceivedineach
knee.
AnalysisMethods
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A general linear mixed model repeated measures analysis
(MMRM) will be used to analyze the primary endpoint with
covariates: site, study visit, treatment, knee side (left/right),
baselinelowerlimbvolume,baselineBMIcategory(<30kg/m2,
≥30kg/m2),andtreatmentbystudyvisit.




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SIGNATUREPAGE


Approvedby:_________________________ 
Date:_______________
RonaldP.Silverman,MD,FACS
ChiefMedicalOfficer
3MMedicalSolutionsDivision,HealthCareBusinessGroup

Approvedby:_________________________ 
Date:_______________
JaneHart
VicePresident,GlobalClinicalResearch



3MHealthCareBusinessGroup


Approvedby:_________________________ 
Date:_______________


AnnaKuang,MD,MBA,FACS


GlobalMedicalDirector


3MMedicalSolutionsDivision,HealthCareBusinessGroup

Approvedby:_________________________
Date:_______________
BrendanCasey
RegulatoryAffairsManager
3MMedicalSolutionsDivision,HealthCareBusinessGroup

Approvedby:_________________________
Date:_______________


YeniNieves-Malloure,MS


Director,GlobalBiomedicalOperations


3MHealthCareBusinessGroup


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PRINCIPALINVESTIGATORACKNOWLEDGEMENTOFPROTOCOL
IconfirmthatIhavereadtheprotocolentitled:“ARandomizedControlledTrialEvaluating
Edema and ROM Using Negative Pressure Therapy Over Closed Incisions and
Surrounding Soft Tissue Versus Standard Surgical Dressings in Bilateral Total Knee
Arthroplasty:APilotStudy(TheENABLETrial)”Version2.0,dated07December2020.I
understand theprotocolandagree to conductthestudy accordingto theprocedures
thereininaccordancewithapplicablelocalgovernmentregulations,institutionalresearch
policiesandprocedures,theInternationalCouncilforHarmonisationprinciplesofGood
Clinical Practice, and in the spirit of the Declaration of Helsinki concerning medical
researchinhumans.

SiteName:__________________________________Site#:___________________

PrincipalInvestigatorName:____________________________________________

Signature:__________________________________Date:___________________



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ABBREVIATIONS
3D
three-dimensional
ASLR
activestraightlegraising
AUC
areaundercurve
AE
adverseevent
BMI
BodyMassIndex
CFR
CodeofFederalRegulations
ciNPT
closedincisionnegativepressuretherapy
cm
Centimeter
CRF
casereportform
CSR
ClinicalStudyReport
eCRF
electroniccasereportform
EC
EthicsCommittee
ED
emergencydepartment
GCP
goodclinicalpractice
hCG
humanchorionicgonadotropin
HIPAA
HealthInsurancePortabilityandAccountabilityAct
ICF
informedconsentform
IDE
investigationaldeviceexemption
IFU
instructionsforUse
IRB
InstitutionalReviewBoard
ITT
intention-to-treat
KCI
KineticConceptsIncorporated
KSKSS KneeSocietyKneeScoringSystem
ml
Milliliter
mmHg
millimetersofmercury
NPRS
numericalpainratingscale
PHI
personalhealthinformation
PRO
patient-reportedoutcome
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QoL
qualityoflife
RCT
randomized,controlledtrial
ROC
receiveroperatingcharacteristics
ROM
rangeofmotion
SAE
seriousadverseevent
SAP
statisticalanalysisplan
SOC
standardofcare
SSC
surgicalsitecomplication
SSI
surgicalsiteinfection
UADE
unanticipatedadversedeviceeffect
USA
UnitedStatesofAmerica
TEAE
treatment-emergentadverseevent
THA
totalhiparthroplasty
TKA
totalkneearthroplasty


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TABLEOFCONTENTS
1. INTRODUCTION...................................................................................................................................16
1.1.
BACKGROUND..............................................................................................................................16
1.1.1. OverviewofTKA....................................................................................................................16
1.1.2. PostoperativeSurgicalIncisionManagementFollowingTKA...............................................17
1.1.2.1.
Silver-containingdressings
17
1.1.2.2.
Closedincisionnegativepressuretherapy18
1.2.
RATIONALEFORSTUDYINGTHESPECIFICPOPULATION/CONDITION................................................19
1.3.
RATIONALEFORSTUDYDESIGN....................................................................................................20
1.4.
STUDYPRODUCTS.......................................................................................................................20
1.4.1. PREVENARESTORARTHRO•FORM™System................................................................21
1.4.2. RegulatoryStatus–UnitedStates........................................................................................22
1.4.3. RegulatoryStatus–Australia................................................................................................23
2. STUDYOBJECTIVES...........................................................................................................................24
3. STUDYDESIGN....................................................................................................................................24
3.1.
DESIGNSUMMARY.......................................................................................................................24
3.1.1. PREVENARESTORARTHRO•FORM™Dressing..............................................................25
3.1.2. Standardsilver-containingdressing......................................................................................25
3.1.3. DurationofStudyParticipation..............................................................................................25
3.2.
PRIMARYENDPOINT.....................................................................................................................25
3.3.
SECONDARYENDPOINTS..............................................................................................................26
3.4.
EXPLORATORYENDPOINTS...........................................................................................................26
3.5.
HEALTHECONOMICENDPOINTS....................................................................................................27
3.6.
SAFETYENDPOINT.......................................................................................................................27
4. STUDYPROCEDURESANDASSESSMENTS...................................................................................27
4.1.
INFORMEDCONSENT....................................................................................................................27
4.2.
INCLUSION/EXCLUSION.................................................................................................................29
4.2.1. InclusionCriteria....................................................................................................................29
4.2.2. ExclusionCriteria...................................................................................................................29
4.2.3. Intra-OperativeExclusionCriteria.........................................................................................30
4.3.
PREMATURESTUDYTERMINATION................................................................................................31
4.3.1. BySponsor............................................................................................................................31
4.3.2. ByIRB/EC.............................................................................................................................32
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4.4.
SUBJECTWITHDRAWALORTERMINATION......................................................................................32
4.4.1. ReasonsforWithdrawalorTermination................................................................................32
4.4.2. HandlingofWithdrawalorTermination.................................................................................32
4.5.
DEMOGRAPHICSANDSUBJECTCHARACTERISTICS.........................................................................33
4.6.
MEDICALANDSURGICALHISTORY................................................................................................33
4.7.
LABORATORYASSESSMENTFORPREGNANCY...............................................................................33
4.8.
RANDOMIZATIONANDSUBJECTNUMBERING..................................................................................34
4.9.
LOWERLIMBVOLUME...................................................................................................................34
4.10.
KNEERANGEOFMOTION.............................................................................................................35
4.11.
PATIENTREPORTEDOUTCOMES(PRO)ASSESSMENT:KNEESOCIETYKNEESCORINGSYSTEM
(KSKSS)..................................................................................................................................................36
4.12.
PAINASSESSMENTS.....................................................................................................................37
4.13.
SURGICALPROCEDURESANDASSESSMENTS................................................................................37
4.13.1. BilateralTKAProcedure........................................................................................................37
4.13.2. ApplicationofDressings........................................................................................................38
4.13.2.1.
ciNPT
38
4.13.2.2.
Standardsilver-containingdressings
38
4.14.
TREATMENTREMOVAL.................................................................................................................39
4.14.1. PREVENARESTORARTHRO•FORM™Dressing..............................................................39
4.14.2. Standardsilver-containingdressing......................................................................................39
4.15.
POST-OPERATIVEASSESSMENTS.................................................................................................39
4.15.1. SurgicalSiteComplications...................................................................................................39
4.15.2. ScarCosmesisAssessment..................................................................................................40
4.15.3. StraightLegRaises...............................................................................................................40
4.15.4. HealthEconomicsAssessment.............................................................................................40
4.16.
CONCOMITANTMEDICATIONS.......................................................................................................41
4.17.
PROHIBITEDPROCEDURESANDTREATMENTS...............................................................................41
4.18.
ENDOFSTUDY............................................................................................................................42
5. VISITSCHEDULEANDDESCRIPTIONOFSTUDYVISITS...............................................................43
5.1.
SCHEDULEOFVISITS...................................................................................................................43
5.2.
DESCRIPTIONOFSTUDYVISITS....................................................................................................45
5.2.1. Screening/Days-42to0.......................................................................................................45
5.2.2. DayofSurgery/Pre-op/Day0................................................................................................45
5.2.3. DayofSurgery/Intra-op/Day0...............................................................................................45
5.2.4. DayofSurgery/Post-op/Day1...............................................................................................46
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5.2.5. Mid-Treatment/Days5-7......................................................................................................46
5.2.6. EndofTreatment/Days12-14.............................................................................................46
5.2.7. Follow-upVisits-Midterm/Days35-49andLongTerm/Days77-91..................................47
5.2.8. UnscheduledVisits................................................................................................................48
6. RISKSASSOCIATEDWITHSTUDYPARTICIPATION.......................................................................49
7. SAFETYANDADVERSEEVENTS......................................................................................................50
7.1.
DEFINITIONS................................................................................................................................50
7.1.1. AdverseEvent(AE)...............................................................................................................50
7.1.2. SeriousAdverseEvent(SAE)...............................................................................................50
7.2.
CLASSIFICATION...........................................................................................................................51
7.2.1. RelationshiptoStudyTreatment...........................................................................................51
7.2.2. Severity..................................................................................................................................51
7.3.
AEREPORTINGPROCEDURES......................................................................................................52
7.4.
AECOLLECTION/REPORTINGPERIOD...........................................................................................52
7.5.
SAEREPORTINGTOSPONSOR.....................................................................................................52
7.6.
UADEREPORTING-UNANTICIPATEDADVERSEDEVICEEFFECT(UADE).......................................52
7.7.
FOLLOW-UPPERIODFORONGOINGAES.......................................................................................53
8. STATISTICALCONSIDERATIONS......................................................................................................53
8.1.
ANALYSISSETS............................................................................................................................53
8.2.
PLANNEDANALYSISANDDATASUMMARIES...................................................................................54
8.2.1. GeneralAnalysisTechniques................................................................................................54
8.2.2. SubjectDisposition................................................................................................................55
8.2.3. DemographicandBaselineCharacteristics..........................................................................55
8.2.4. AnalysisofPrimaryEndpoint................................................................................................55
8.2.4.1.
SensitivityAnalysesofPrimaryendpoint 56
8.2.5. AnalysisofSecondaryEndpoints..........................................................................................57
8.2.6. ExploratoryAnalyses.............................................................................................................58
8.2.7. AnalysisofSafetyEndpoint...................................................................................................59
8.3.
ADDITIONALSTATISTICALDETAILS................................................................................................59
8.3.1. SampleSizeDetermination...................................................................................................59
8.3.2. Randomization.......................................................................................................................60
8.4.
OPEN-LABELSTUDYREPORTINGRESULTS...................................................................................60
8.5.
INTERIMANALYSIS.......................................................................................................................60
8.6.
STATISTICALANALYSISPLANANDCHANGESINANALYSES.............................................................60
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9. HANDLINGOFSTUDYPRODUCTS...................................................................................................61
10.DATAHANDLINGANDRECORDKEEPING......................................................................................61
10.1.
INVESTIGATOR/STUDYSITETRAINING...........................................................................................61
10.2.
ELECTRONICCASEREPORTFORM(ECRF)ANDSOURCEDOCUMENTS..........................................61
10.3.
MONITORINGOFSTUDYDATA.......................................................................................................62
10.4.
DATAHANDLING..........................................................................................................................62
10.5.
RECORDSRETENTION..................................................................................................................62
11.ADMINISTRATIVEREQUIREMENTS..................................................................................................63
11.1.
GOODCLINICALPRACTICE(GCP)................................................................................................63
11.2.
ETHICALCONSIDERATIONS...........................................................................................................63
11.3.
SUBJECTINFORMEDCONSENT.....................................................................................................63
11.4.
CONFIDENTIALITY.........................................................................................................................63
11.5.
CLINICALTRIALREGISTRATION.....................................................................................................64
11.6.
AUDITINGANDINSPECTING...........................................................................................................64
12.PUBLICATIONPLAN............................................................................................................................64
13.REFERENCES......................................................................................................................................64



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1.INTRODUCTION
Total knee arthroplasty (TKA), which is the third most common surgical procedure
performedintheUnitedStatesofAmerica(USA),3isperformedtoprovidepainrelief,
restorejointfunction,andprovidejointstabilityanddurability.4Enhancedrecoveryafter
TKA is focused on pain management and return to ambulation.5 Therefore, primary
postoperativegoalsforTKAsinvolvemitigatingpostoperativeswelling(ie,increasedlimb
volumeresultingfromfluidaccumulation)andreestablishingadequaterangeofmotion
(ROM), including knee flexion and extension. Previous studies have shown that
postoperativelimbvolumeincreasesapproximately15%fromthetimeofsurgerytopost-
surgicalDay7or8.1;2ROMinitiallydeclinesfollowingTKAandthenimprovesforaperiod
beforeplateauing.6;7Forexample,onestudyshowedthatthepostoperativekneeflexion
anglesimprovedforupto12months,butflexionangleimprovementslowedbetweensix
monthsand12monthsat119degrees(119o)and123o,respectively.6Anotherstudy
showedimprovementinpostoperativekneeflexionangleplateauingafterapproximately
threemonthsat112o.7Thisprotocolisdesignedtoassesswhetherpostoperativesurgical
incisionmanagementmodalitiesdifferentiallyaffectlowerlimbswellingfollowingTKA.
The effects of postoperative surgical incision management modalities on knee ROM
followingTKAwillalsobeevaluated.
1.1. Background
1.1.1.
OverviewofTKA
ThestandardincisiontypeforTKA,alsoknownastotalkneereplacement,iseithera
midlineincisionoramedialparapatellarincision.However,otherincisiontypesmaybe
necessaryforpatientswithat-riskincisionsduetolocalcauses(eg,previousincision
present)orgeneralcauses(eg,prolongedcorticosteroiduseordiabetesmellitus).8The
goaloftheseincisionsistoprovideadequatespaceforthereplacementofadamaged
kneejointwithanartificialjoint,orprosthesis.4;9Themostcommonkneeprosthesisis
non-constrained,wherebythepatient'sligamentsandmusclesstabilizetheprosthesis;
however, prostheses can also be semi-constrained (patient ligaments removed and
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prosthesis provides some stability) or fully constrained, or "hinged".9 During the
procedure,thepatella,ifnotreplaced,mayormaynotberesurfaced,andligamentous
releases may be required for adequate balance.4 Options for holding the knee
replacement prosthesis in place include cementing the prosthesis to the bones with
polymethylmethacrylate, non-cementing procedures that allow bone growth into the
prosthesis,orhybridfixationthatcombinescementedandnon-cementedprocedures.4;9
Afterplacingtheprosthesis,allowingcementtodry(ifapplicable),andcopioussaline
lavagetoremoveanydebris,thewoundisclosedinlayers,startingwiththeretinaculum,
thenthefatandsubcutaneoustissue,andfinallytheskin.4Althoughwoundclosureof
kneesinflexionhasrecentlybeensuggestedtoleadtofavorableclinicaloutcomes,there
isnotcurrentlyenoughevidencetodeterminewhetheranyspecificdegreeofflexionused
duringclosureimpactsROMorotherclinicaloutcomes.10
1.1.2.
PostoperativeSurgicalIncisionManagementFollowingTKA
ThefocusofpostoperativesurgicalincisionmanagementforTKAsandothersurgical
procedureshasbeentoreducesurgicalsitecomplications(SSCs),includingsurgicalsite
infections(SSIs)–SSIshavebeenreportedasthethirdmostcommoncauseofnon-
revisionreoperationsinpatientsthathadundergoneapreviousTKA,accountingfor12%
ofnon-revisionreoperation.11Thisfocusstemsfrompatientswithpost-TKASSCshaving
a significantly increased probabilityof subsequent major surgeries anda significantly
increasedprobabilityofdeepinfectionwhencomparedtopatientswithoutSSCs.12Two
classesofpostoperativesurgicalincisionmanagementmodalities have recentlybeen
demonstratedtolowerSSCsinpatientsundergoingTKAswhencomparedtostandard
surgical dressings: silver-containing dressings and closed incision negative pressure
therapy(ciNPT).
1.1.2.1. Silver-containingdressings
Silverhasbeenincorporated(eg,bound,coated,orimpregnated)intovarioustypesof
dressings,includingbutnotlimitedtopolyethylenemeshdressings,charcoaldressings,
hydrofiber dressings, and hydrocolloid dressings.13 These silver-containing dressings
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haveantibacterialeffectsbydeliveringsilverionstothewoundorincisionsite,andthe
antimicrobialefficacyofthedressingscanbeinfluencedbythesilvercontentandthe
dressingformation.13Inapreviousrandomized,controlledtrial(RCT)andacase-control
study of joint arthroplasties, including TKAs, the use of silver-containing dressings
resultedinsignificantlyfewerSSCsandgreaterpatientsatisfactionwhencomparedto
dressingsthatdidnotcontainsilver.14;15Similarly,anRCTcomparingsilver-containing
dressingstodressingswithoutsilverafterclosureofminimallyinvasiveTKAsreported
significantlylongerweartimes,lowernumberofdressingchanges,higherpatientcomfort,
andgreatereaseofusewhenusingthesilver-containingdressing.16
1.1.2.2. Closedincisionnegativepressuretherapy
Incisional negative pressure therapy, which was introduced in 200617, involves the
applicationofnegativepressurewoundtherapyonclean,post-surgicallyclosedincisions.
Based on early results of incisional negative pressure therapy, a second-generation
closed incision negative pressure therapy (ciNPT) system (PREVENA™ Incision
ManagementSystem)wasreleasedin2010toenhancethepostoperativerehabilitation
process.18;19Sinceitsinitialrelease,ameta-analysisofRCTsassessingSSIs,including
anRCTconcerningtotalhiparthroplasties(THAs)andTKAs,revealedahighlysignificant
effectinfavorofciNPTwhencomparedtotraditionaldressingssuchassterilegauze,
absorbent dressings, or silver-containing dressings.20 Similarly, a meta-analysis of
comparativestudiesassessingSSIsinlowerextremitysurgeries,includingTHAsand
TKAs,showedahighlysignificanteffectinfavorofciNPTwhencomparedtotraditional
dressings.20Aretrospective,comparativestudyreportedthatarthroplastypatients(THA
orTKA) treated with ciNPThad significantly fewer SSCs when compared to patients
treatedwithsilver-containingdressingsafterclosure;however,theincidenceofSSCsin
low-riskpatients(ariskfactorscore<2)didnotsignificantlydifferbetweenthosetreated
withciNPTorsilver-containingdressings.21
Twostudies,includingasmallRCT22,havecomparedtheeffectivenessofciNPTwith
conventionaldrydressingsinpreventingSSCsafterTKAs,andneitherstudyfounda
statistically significant difference between treatments with respect to the incidence of
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SSCs.22;23However,intheRCT,patient-reportedQualityofLife(QoL)scoresforwound
leakageandwoundprotectionweresignificantlybetterforpatientstreatedwithciNPT
comparedtothosetreatedwithconventionaldrydressings.22
In2019,thePREVENARESTOR™IncisionManagementSystem,whichincorporatesall
thekeydesignelementsofPREVENA™Therapy(ie,utilizesanegativepressuretherapy
unit,withfluidcollectioncanister,thatdelivers-125mmHgandadressingcomposedof
open reticulated foam and wicking skin interface layer), was released. This system
containsuniquelyshapeddressingsthataredesignedforvariousincisiontypes(linear,
non-linear,intersectingand/ormultipleincisions)andvariousanatomicallocations,such
asarticulatingjoints.ThePREVENARESTORTMDressingscoveralargerareaofthesoft
tissuesurroundingthesurgicalsite.
1.2. RationaleforStudyingtheSpecificPopulation/Condition
AmplelegstrengthandROMofthekneejoint,alongwithsufficientROMofthehipand
anklejoints,enablenormalambulationandotherdailylivingactivities(eg,gettinginto
andoutofbathtubsandtyingshoelaces),withmorestrengthandhigherdegreesofROM
beingnecessaryformoreadvancedmovements(eg,crouchingwithorwithoutrotation).24
Previousstudieshaveshownthatchangesinkneeextensionstrengthandkneeflexion
ROMaresignificantlycorrelatedwithpatientambulation(eg,changesingaitspeed)after
TKA,andkneeswellingpost-TKAhasbeensignificantlycorrelatedwithreducedknee
extensionstrength.25Swellingofthelowerlimbcanalsobeanindicatorofmoreserious
healthissuessuchasdeepveinthrombosisorjointeffusion/haemarthrosis,whichare
conditionsthatwouldpotentiallyrequirehospitalreadmittance26,andlastly,swellingof
thelowerlimblastingbeyond1weekanddifficultywithdailylivingactivitieshavebeen
significantlycorrelatedwithpatientdissatisfactionafterTKAs.27
AmajorgoalforhealthcarepractitionersfollowingTKAistomitigateswellingandrestore
knee ROM and leg strength. Postoperative outcomes after TKA can be positively
impactedbyperi-operativeinterventions,andthereisagrowinginterestintheuseof
modernwounddressingsaspartofenhancedrecovery.28;29AlthoughciNPTmanages
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theenvironmentofclosedsurgicalincisions,inpart,byreducingedema,therehavebeen
limited studies assessing the effects of ciNPT on postoperative swelling or other
postoperativeoutcomes(eg,kneeROM)thatimpactenhancedrecoverygoalsafterTKA.
1.3. RationaleforStudyDesign
Tohavethehighestpossiblelevelofevidence,aprospective,multi-centerRCTwasthe
studydesignchosen.Silver-containingdressingswereselectedasthecomparatorsince
theyareroutinelyusedforthemanagementofclosedincisionsafterTKA,andthereare
several studies concerning the effectiveness of silver-containing dressings for the
preventionofSSCsafterTKAs(seeSection1.1.2.1).Asimultaneous,bilateralprocedure
wasalsochosenforthestudydesign,whichreducesthenumberofpatientsneededfor
thestudyandreducestheintraindividualvariability.Thistypeofprocedurealsoexposes
thesubjectstolessanesthesiaandhasfewerdayshospitalized,althoughtherearesome
risks reported of certain cardiopulmonary complications (eg, cardiac arrhythmia or
pulmonary embolism) when compared to unilateral TKAs.30 The proposed study is
designedtoevaluatedifferencesinlowerlimbswelling,asmeasuredvolumetrically,in
subjectsundergoing simultaneous,bilateral TKA when ciNPT is used tomanagethe
closedincisionandsurroundingsofttissue,ascomparedtosilver-containingdressings.
Itishypothesized that ciNPT will mitigatepost-surgicallowerlimbswelling after TKA
surgery.Thefollow-upperiodof6-12weeks,withanassessmentoflowerlimbswelling
asearlyas5-7daysaftersurgery,wasselectedduetopublishedstudiesshowingthat
lower limb swelling occurs within 2-8 days after TKA surgery1 and that knee ROM
improvesafterTKAbutcanbeginplateauingat3monthsinsomecases(seeSection
1).6;7
1.4. StudyProducts
Thefollowingdevicesanddressingswillbethetherapiesforthetwotreatmentgroups:
· PREVENARESTORARTHRO•FORM™System(Table1),including:
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o The PREVENA PLUS™ 125 Therapy Unit – 14 Day, which delivers
continuousnegativepressureat-125mmHgthroughthedressingtothe
incisionsiteforupto14days.
o ThePREVENAPLUS™150mLCanister,whereexudatefromtheincision
iscollectedandstored.
o The PREVENA™ Patch Strips, which may be used to help seal leaks
aroundthedressing.
o AnyPREVENAARTHRO•FORM™Dressing
· Anysilver-containingdressing
1.4.1.
PREVENARESTORARTHRO•FORM™System
The PREVENA RESTOR ARTHRO•FORM™ System, which incorporates all the
functionalelementsofciNPT,containsuniquelyshapeddressingsthataredesignedto
facilitateanatomicaladaptabilitybetterandtoexpandtheciNPTcoverageareatohelp
manage the incision over a larger soft tissue envelope. The dressings contain the
followingcomponents(Table1):
· apolyurethanefilmshellthatencapsulatesthefoambolsterandinterfacelayer
· apolyurethaneetherfoambolsterthatcoverstheinterfacelayer
· apolyesterfabricinterfacelayerthatwicksfluidfromtheskinsurface
· ahydrocolloidthatoutlinestheperimeteroftheinterfacelayertohelpsecurethe
dressingtotheskinandminimizeleaks
· apolyurethanefilmwithacrylicadhesive,whichprovidesadhesionofthedressing
totheskinsurroundingtheclosedincision


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Table1:PREVENARESTORARTHRO•FORM™IncisionManagementSystem.
Name/Description
Picture/Diagram
PREVENA
RESTOR
ARTHRO•FORM™
System
· PREVENAPLUS™125TherapyUnit-14
Day
· PREVENA RESTOR ARTHRO•FORM™
Dressing

PREVENAPLUS™150mlCanister

PREVENA
RESTOR
ARTHRO•FORM™
DressingComponents
1. Polyurethanefilmshell
2. Polyurethaneetherfoam
3. Polyesterfabricinterfacelayer
4. Hydrocolloid
5. Polyurethanefilmwithacrylicadhesive

1.4.2.
RegulatoryStatus–UnitedStates
ThePREVENARESTOR™IncisionManagementSystemisa510(k)–cleared,ClassII
device(K181507)withthefollowingindicationforuse.
ThePREVENARESTOR™IncisionManagementSystemisintendedtomanagethe
environmentofsurgicalincisionsthatcontinuetodrainfollowingsuturedorstapled
closurebymaintainingaclosedenvironmentandremovingexudateviatheapplication
ofnegativepressurewoundtherapy.
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ForthosekneesofsubjectsinthisstudythatarerandomizedintotheTreatmentarm,the
PREVENARESTORARTHRO•FORM™IncisionManagementSystemwillbeapplied
usingthe PREVENA PLUS™ 125 TherapyUnit (14-day) and aPREVENARESTOR
ARTHRO•FORM™Dressing.
Forthisstudy,thePREVENARESTOR™IncisionManagementSystemwillbeusedin
accordancewithitsclearedlabelingandindicationsforuseandis,therefore,exemptfrom
theinvestigationaldeviceexemptions(IDE)regulationbecauseitmeetstheconditions
foranexemptinvestigationasprovidedin21CFR812.2(c)(2).Thesystem’sindications,
contraindications,warnings,precautions,andinstructionscanbefoundinthePREVENA
RESTOR™IncisionManagementSystemInstructionsforUse(IFU)document.
1.4.3.
RegulatoryStatus–Australia
ThePREVENARESTOR™IncisionManagementSystemisaClassIIadevicelicensed
underARTG318254withthefollowingindicationforuse.

The PREVENA RESTOR™ Incision Management System is intended to manage the
environment of closed surgical incisions and surrounding intact skin in patients at risk for
developing post-operative complications, such as infection, by maintaining a closed
environmentviatheapplicationofanegativepressurewoundtherapysystemtotheincision.
ThePREVENARESTOR™IncisionDressingskininterfacelayerwithsilverreducesmicrobial
colonizationinthefabric.
ForthosekneesofsubjectsinthisstudythatarerandomizedintotheTreatmentarm,the
PREVENARESTORARTHRO•FORM™IncisionManagementSystemwillbeapplied
usingthe PREVENA PLUS™ 125 Therapy Unit (14-day) and aPREVENARESTOR
ARTHRO•FORM™Dressing.
Forthisstudy,thePREVENARESTOR™IncisionManagementSystemwillbeusedin
accordancewithitsclearedlabelingandindicationsforuse.Thesystem’sindications,
contraindications,warnings,precautions,andinstructionscanbefoundinthePREVENA
RESTOR™IncisionManagementSystemInstructionsforUse(IFU)document.
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2.STUDYOBJECTIVES
TheprimaryobjectiveofthisstudyistocomparetheeffectsofthePREVENARESTOR
ARTHRO•FORM™IncisionManagementSystemtostandardsilver-containingdressings
onlowerlimbswellingafterbilateralprimarytotalkneearthroplasty.
3.STUDYDESIGN
3.1. DesignSummary
Thisrandomized,controlled,prospective,global,multicenterstudywillenroll subjects
undergoingsimultaneous,bilateral,primaryTKA.Thestudywillenrollapproximately52
subjects(104randomizedknees)fromapproximately10sites.Eachenrolledsubjectwill
receiveciNPTaftersurgeryforoneknee,andtheotherkneewillreceiveastandardsilver-
containingpost-surgicaldressing.
ThekneerandomizedtotheciNPTtreatmentarmwillreceiveaPREVENARESTOR
ARTHRO•FORM™DressinginconjunctionwiththePREVENAPLUS™125Therapy
Unit for a duration of 12 to 14 days post-surgery, with a change of the PREVENA
RESTORARTHRO•FORM™Dressingat5-7days.
ThekneerandomizedtotheSOCtreatmentarmwillreceiveastandardsilver-containing
dressingfor12-14dayswithadressingchange andassessmentat5-7days.Silver-
containingdressingsshouldbechangedpertheproductIFUorasdeemednecessaryby
the investigator or investigator-designated attending physician during the 12-14 day
treatmentperiod.
SubjectswillbeseenduringScreening(nomorethan42daysbeforeTKA),ontheday
ofsurgery,oneweekaftersurgery(aminimumof5daystoamaximumof7days),at2
weeksaftersurgery(aminimumof12daystoamaximumof14dayspost-surgery),ata
6-weekfollow-upvisit(day35to49),andata12-weekfollow-upvisit(day77to91).
Subjectsmayparticipateinadditionalunscheduledvisitsasrequiredduringthestudyif
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evaluationofeitherkneeisrequired.Unscheduledvisitsmaybeinitiatedbyeitherthe
investigatororthesubject.
3.1.1.
PREVENARESTORARTHRO•FORM™Dressing
Closed incision NPT will be applied to theclean, closed surgical wound immediately
followingclosureandrandomization.ThedressingwillbeappliedonDay0andchanged
onpost-surgicalDay5-7.ClosedincisionNPTwillbediscontinued,andthedressingwill
beremovedbyDay14.
3.1.2.
Standardsilver-containingdressing
Standardsilver-containingdressingswillbeappliedtotheclean,closedsurgicalwound
immediatelyfollowingclosureandrandomization.ThedressingwillbeappliedonDay0
and changed on Day 7 or as deemed necessary by the investigator (or investigator
designee).Ifsubsequentdressingsareapplied,thefinaldressingmustberemovedby
Day14.
3.1.3.
DurationofStudyParticipation
Thedurationofstudyparticipationforeachsubjectisasfollows:
· ScreeningPeriod:upto42days(Day-42toDay0)
· DayofSurgery-BilateralTKAprocedures
· TreatmentPeriod:2weeks(12-14days,butnolongerthan14days),withdressing
changeandassessmentat1week(5-7days)
· Follow-up:6weeks(±1week)and12weeks(±1week)afterbilateralTKA
Themaximumparticipationdurationpersubjectisupto134days.
3.2. PrimaryEndpoint
Theprimaryendpointisthepercentchangeinlowerlimbvolume,ascalculatedbasedon
manual circumference measurements, 5-7 days after bilateral TKA when using the
PREVENARESTORARTHRO•FORM™IncisionManagementSystemcomparedtothe
control.
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3.3. SecondaryEndpoints
Thesecondaryendpointsareasfollows:
· Percent change in lower limb volume, as calculated based on manual
circumferencemeasurements,frombaselinetovisits4,5,and6
· Percentchangeincircumferencesfrombaselinetovisits3-6thataremeasured
at:
o 10cmabovethecenterofthepatella
o atthecenterofthepatella
o 10cmbelowthecenterofthepatella
o attheankle;1cmabovethemedialmalleolus
· Changeinkneeflexionanglefrombaselinetovisits3-6
· Changeinkneeextensionanglefrombaselinetovisits3-6
· ChangeoftotalROMdegrees,definedastheflexionangleminustheextension
angle,frombaselinetovisits3-6
· TheincidenceofSSCsbyvisits5and6
· Scarcosmesisassessmentatvisits3-6
· Theaveragepainineachleginthelast24hours,usinganNPRS(numericalpain
ratingscale)of0-10(dailyfor4weekspost-surgery,thenweeklyforweeks5-12)
· Theworstpainineachleginthelast24hours,usinganNPRSof0-10(dailyfor4
weekspost-surgery,thenweeklyforweeks5-12).
3.4. ExploratoryEndpoints
Theexploratoryendpointsareasfollows:
· the percent change in lower limb volume, as calculated based on three-
dimensional(3D)imaging,frombaselinetovisits3-6
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· Knee-relatedQoLquestionnaire(newKneeSocietyKneeScoringSystem)atvisits
4,5,and6
· Abilitytoperformastraightlegraiseatvisits4,5,and6
Additional exploratory endpoints may be added and will be detailed in the statistical
analysisplan(SAP).
3.5. HealthEconomicEndpoints
Thehealtheconomicendpointsareasfollows:
· Totallengthofhospitalization
· Subsequentemergencydepartment(ED)visitsrelatedtoeitherkneeandreason
(eg,edemaorpain)
· Subsequenthospitalizationrelatedtoeitherkneeandreason(eg,edemaorpain)
· Subsequent clinic visits (unscheduled) related to either knee and reason (eg,
edemaorpain).
Additionalhealtheconomicendpointsmaybeaddedandwillbedetailedinthestatistical
analysisplan(SAP).
3.6. SafetyEndpoint
TheSafetyEndpointistheincidenceofAdverseEventsandSeriousAdverseEvents,
including
subsequent
emergency
department
visits
or
subsequent
hospitalizations/interventionsforeitherknee.
4.STUDYPROCEDURESANDASSESSMENTS
4.1. InformedConsent
The investigator, or designee, will discuss the purpose of this study with potential
subjects.EachindividualwillreviewtheInformedConsentForm(ICF)approvedbythe
localInstitutionalReviewBoard(IRB)orEthicsCommittee(EC).TheICFmustbesigned
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according to IRB/EC requirements before the subject can undergo any study-related
procedures.Informedconsentwillbeobtainedundertheseconditions:
· Subjectsmustbemadeawareofthepurposeofthestudyandthepotentialrisks
andbenefitsknownorthatcanbereasonablypredictedorexpectedinlanguage
thatisunderstandabletothesubject.
· Subjectsmustbegiventheopportunitytoasktheinvestigatorquestionsandmust
beprovidedtimetoconsiderparticipationinthestudy.
· ICFswillbewritteninamannerthatisnon-technicalandunderstandabletothe
subject.
· Subjectswillnotbeledtobelievethattheyarewaivingtheirlegalrightstorelease
the investigator, sponsor, study site, or any of their agents from liability for
negligence.
· SubjectswillbeaskedtosignanddatetheICFindicatingtheirinformedconsent
toparticipateinthestudy.
· Theinvestigator’sresponsibilitiesduringtheICFprocessinclude:
o screeningoutpotentialsubjectswhomaynotbeableorwillingtocomplywith
thestudyprotocol.
o discussingwithpotentialsubjectstoensuretheyunderstandthepurposeofthe
study,thestudyproceduresthatwillberequired,andtherisksandbenefits
knownorthatcanbereasonablypredictedorexpected.
o answeringallquestionsfrompotentialsubjects.
o ensuring that subjects have signed the ICF before undergoing any study-
relatedassessments.
o confirmingthatthestudy-siterepresentativeperformingtheinformedconsent
processhassignedtheinformedconsentform,ifrequired.
o ensuringthateachsubjectreceivesacopyofthesignedICF.
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4.2. Inclusion/Exclusion
Inordertobeconsideredforrandomization,asubjectmustmeetalleligibilitycriteriaand
beassessednomorethan42daysbeforesurgery.Subjectswhodonotmeetalleligibility
criteriawillnotbeeligibleforrandomization,willdiscontinuefromthestudy,andwillbe
considered a screen failure. Inclusion and exclusion criteria will be reconfirmed
immediatelypriortosurgeryifvisit1andvisit2areondifferentdates.
4.2.1.
InclusionCriteria
Thesubject:
· isatleast22yearsofageonthedateofinformedconsent.
· canindependentlyprovideinformedconsent.
· requiresandisscheduledtoundergoasimultaneous,bilateral,primaryTKA.
· iswillingandphysicallycapableofundergoingasimultaneous,bilateral,primary
TKAwithorwithoutreplacementofthepatella.
· iswillingandabletoreturnforallscheduledstudyvisits.
4.2.2.
ExclusionCriteria
Thesubject:
· ispregnantorlactating.
· hassignsofaninfectionintheareaofeitherkneeorhassignsofasystemic
infectionatthetimeofsurgery.
· is a chronic opioiduser, defined per the CDCguidelines as opioiduse for >3
months,atthetimeofenrollment.
· hasacurrentdiagnosisoflymphedemaineitherleg
· hassigns,symptoms,oracurrentdiagnosisofvenousinsufficiencyineitherleg,
asdeterminedbytheinvestigator'sreviewofthesubject'smedicalhistory.
· hasahistoryofclottingdisorderorpriorhistoryofdeepveinthrombosis
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· willundergoaunilateralTKA
· willundergoastaged,bilateralTKA
· hasreceivedacorticosteroidinjectionintoeitherkneewithin30daysofsurgery
· undergoesasimultaneous,bilateralTKAwithaplanneddifferentincisiontypeon
eachknee(eg,midlineincisionvs.medialparapatellarincision).
· hasknownsensitivitytothe study product components(drape and/or dressing
materialsindirectcontactwiththeclosedincisionorskin).
· hasknownsensitivitytosilver.
· isenrolledinanotherinterventionalclinicalstudy.
· hasskincancerlocalizedatorinproximitytotheincisionsite.
· doesnothaveaccesstoanelectronicdevice(smartphone,iPad,orcomputer)on
adailybasistocompleteonlineassessments.
· hascondition(s)that,intheopinionoftheinvestigator,causethesubjecttobean
overallhealthriskthatisunsuitableforthesurgery.
· hascondition(s)that,intheopinionoftheinvestigator,willimpactstudyendpoints
(eg, hemophilia or autoimmune disorders) or the ability to comply with study
procedures.
4.2.3.
Intra-OperativeExclusionCriteria
Randomizationoccursimmediatelyaftercompletionofthefirsttotalkneearthroplasty
surgery.Priortorandomization,thefollowingcriteriashouldbeassessedtodetermineif
randomizationshouldoccurorthesubjectbecomesascreenfailure.
Thesubject:
· doesnotreceivea“total”kneereplacementforfirstknee.Forexample,apartialor
uni-compartmentalkneereplacementisperformed
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· hasasurgicalincisionthatwouldprecludeplacementofeitherdressingontothe
knee
· hasaTKAresultinginamuscleflap
4.3. PrematureStudyTermination
Ifthestudyisterminatedprematurelyorsuspended,studysubjectsandtheIRB/ECwill
beinformedpromptlyandprovidedwiththereason(s)fortheterminationorsuspension
bythesponsororbytheinvestigator.Ifapplicable,regulatoryauthoritiesandthepersonal
physiciansofthesubjectswillalsobeinformed.
4.3.1.
BySponsor
Thesponsorreservestherighttodiscontinuetheclinicalstudyforbusinessorethical
reasonsatanytime,suchas,butnotlimitedto:
· Informationregardingthestudyproductcausesdoubtastothebenefit/riskratio.
· Changesinmedicalpracticelimitutilityofthedataobtainedfromthestudy.
Thesponsorreservestherighttoterminateastudyatasiteatanytime,includingbutnot
limitedtoanyofthefollowingreasons:
· Investigator(s) lack of compliance with the approved study protocol, lack of
oversight, and/or not following applicable regulatory or IRB/EC guidelines in
conductingthestudy
· Incidence or severity of AEs indicates a potential health hazard or poses an
unreasonablerisktothestudyparticipants
· Subjectenrollmentisunsatisfactory
· Fraudormisconduct
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4.3.2.
ByIRB/EC
The IRB/EC may choose to discontinue the study at the site for which they granted
approval.IftheIRB/ECdiscontinuesthestudy,theinvestigatorwillreportawithdrawalof
IRB/ECapprovaltothestudysponsorwithinfive(5)workingdays.
4.4. SubjectWithdrawalorTermination
4.4.1.
ReasonsforWithdrawalorTermination
Subjectsmaywithdrawfromparticipationinthestudyatanytimeuponrequest.
Theinvestigatormaychoosetoterminatetheparticipationofasubjectfromthestudy
withorwithouttheirconsentforanyofthefollowingreasons:
· Adverseevents
· Noncompliance
· Foranyreasonthatmay,intheopinionoftheinvestigator,negativelyaffectthe
safetyorwell-beingofthesubject
Subjectswiththefollowingsurgicaloutcomeswillbewithdrawnfromthestudy.
· SubjectdoesnotundergoabilateralTKAprocedure
· Subjectdoesnotreceivea“total”kneereplacementforeachknee.Forexample,
apartialoruni-compartmentalkneereplacementisperformedononeorbothsides
· Subjecthasasurgicalincisionthatprecludesplacementofeitherdressingonto
theappropriatelyrandomizedknee
· SubjecthasaTKAresultinginamuscleflap
Aninvestigatormustterminateparticipationofasubjectfromthestudyforanyofthe
reasonsindicatedinsection4.17.
4.4.2.
HandlingofWithdrawalorTermination
Everyeffortshouldbemadetocompleteassessmentsrequiredfortheprimaryendpoint
andsafetyendpointspriortothesubjectwithdrawal.
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Forsubjectswhoarelosttofollow-up,theinvestigatorwillmakeattemptstocollectat
leastthevitalstatus(eg,whetherthesubjectisalive)beforeformallywithdrawingthe
subject from the study. Prior to considering a subject lost to follow-up, at least two
documentedattemptsshouldbemadetocontactthesubjectthroughallavailableroutes,
andacertifiedlettershouldbesenttothepermanentaddressonfile.
Oncethesubjectwithdrawsfromthestudy,bothkneeswillbeconsideredwithdrawn.A
subjectmaynotwithdrawonlyonekneefromthestudy.Nofurtherstudyevaluationswill
beperformed,andnoadditionaldatawillbecollected.Theinvestigatormayretainand
continuetouseanydatacollectedbeforewithdrawal.Thesubjectwillnotbereplaced.
If for any reason the subject is withdrawn by the investigator from this study, the
investigatorwillinformthesubjectandthesponsor.
4.5. DemographicsandSubjectCharacteristics
The following demographic data and subject characteristics will be collected and
documentedafterthesubjectsignstheICF:
· Age
· Sex
· Race/Ethnicity
· Vitalsigns(height/weight)
· Comorbidities
4.6. MedicalandSurgicalHistory
The research staff will collect medical and surgical history for each subject. If the
screeningvisitandsurgeryoccurondifferentdays,themedicalandsurgicalhistorywill
beupdated(ifchangeshaveoccurred)atthesurgicalvisit.
4.7. LaboratoryAssessmentforPregnancy
Serum or urine assessment for human chorionic gonadotropin (hCG) to determine
pregnancystatusinfemale subjectsofchild-bearingpotentialwillbeconducted. This
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assessment will need to be captured on the day of surgery. Ifthe pregnancy test is
positive, the subjectwillnotbeeligiblefor thestudyandwillbeconsideredascreen
failure.Womenwhohavehaddocumentedsurgicalsterilizationbyamedicallyaccepted
method (eg, tubal ligation, hysterectomy, or oophorectomy) or are post-menopausal,
definedasnothavingmenstruationfor>12months,willbeexcludedfromthislaboratory
assessment.
4.8. RandomizationandSubjectNumbering
Consented subjects will be assigned a unique subject identifier. Study data will be
reportedaccordingtothisuniquesubjectidentifier.
Subjectswhosatisfyallinclusioncriteriaandnoneoftheexclusioncriteriawillbeeligible
forrandomization,whichwilloccuruponclosureofthefirstkneeinthebilateralprocedure.
Randomizationofeachkneetothetreatmentarmorthecontrolarmwillbecentralized,
electronic,andweb-based.
Ifascreenedsubjectdoesnotmeetallinclusioncriteriaormeetsanyexclusioncriteria,
thesubjectwillbeconsideredascreenfailure.
4.9. LowerLimbVolume
Lowerlimbvolumeforeachlegwillbecalculatedusingtwodifferentmethods.Thefirst
willbethePartialFrustumModelmethod31,usingmeasurementsofcircumferencetaken
aboveandbelowthepatella.Thecircumferencesofeachlimbwillbemeasuredatthe
centerofthepatella,every5cmfromthecenterofthepatellato15cmsuperiortothe
patella(ie,3measurements),every5cmfromthecenterofthepatellato20-30cminferior
tothepatella(ie,nolessthan4butnomorethan6measurements).Additionally,the
circumference 1 cm above the superior edge of the medial malleolus will also be
measured for each leg; however, the measurement taken 1 cm above themalleolus
shouldnotoverlapwiththemostinferiormeasurementtakenbelowthepatella.Therewill
beatotalof nine(9)to 11measurementsperleg. Thevolumeofeachlegsegment
(betweentwomeasuresofcircumference)willthenbecalculatedusingaformulafora
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truncatedcone,andthesumofallsegmentswillthenbecalculatedtodeterminelower
limbvolume.
Thesecondmethodforcalculatinglowerlimbvolumewillutilizeamobile3Dimaging
system(LymphaTech)thatcombinesaninfrareddepthsensorwithatabletcomputer
using proprietary software. 3D imaging will be performed by the investigator or
investigatordesigneeaccordingtotheUserGuidedocumentationthataccompaniesthe
tabletcomputerthatisprovidedtotheinvestigators.Briefly,thesubjectwillstandwith
theirfeetshoulder-widthapartonaflatsurfacewithanapproximately1meterradiusof
freespaceonallsides.Theinvestigatorwillthenscanbothlegsbyslowlywalkingaround
thesubjectwhilekeepingthecamerapointedatthesubjectandmovingthecameraup
anddowntocapturea3Drendering(ie,image)oftheentiretyofbothlegs.Duringthe
scan,thesubjectshouldremainasstillaspossible,andthelowerlimbsshouldbefreeof
anymaterialsthatwilldistorttheimage(eg,clothingcoveringthearea).Oncethe3D
renderingisobtainedandinspectedforquality,lowerlimbvolumewillbecalculatedusing
scanmeasurementsfromthemid-thightotheankleofeachleg,excludingtheglutealfold
regionofeachleg,theheel/ankleregionofeachleg,andthefeet.
4.10.KneeRangeofMotion
ROMisthefullmovementofthejoint,measuredasanincreasedordecreasedangle(ie,
degrees)betweenthebonesofthelimbatthejoint.ROMforthekneeincludesflexion
(bending) and extension (straightening). A completely straight knee will have a joint
measureof0ºwhileafullybentknee(withoutcrouching)willhaveabout135ºofflexion.
Forthisstudy,theflexionandextensionanglesofeachkneewillbecapturedusinga
goniometerwiththesubjectlyingflat,inthesupineposition.ROMwillbecalculatedas
the difference between the flexion angle and the extension angle. Both active ROM,
wherebythesubjectflexesandextendsthejointwithoutassistance,andpassiveROM,
wherebytheinvestigatororinvestigatordesigneeflexesandextendsthejoint,willbe
captured.
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4.11.PatientReportedOutcomes(PRO)Assessment:KneeSocietyKneeScoring
System(KSKSS)
The KSKSS is a validated system that combines an objective physician-derived
componentwithasubjectivepatient-derivedcomponenttoevaluatepainrelief,functional
abilities, satisfaction and fulfillment of expectations. The score prioritizes the patient
perspective to better track patient expectations, satisfaction, and activity levels. Two
variationsoftheformexist:apreoperativeevaluationcompletedpriortosurgeryanda
postoperativeevaluationadministratedaftersurgery.32
Aside from a section on demographics, the questionnaire is divided into 4 scoring
sections:
1. Objectivecomponentsconsistingof:
· Alignment
· Instability
· JointMotion
· Symptoms
2. Patientexpectations
3. Patientsatisfaction
4. Functionalcomponentsconsistingof:
· WalkingandStanding
· StandardActivities
· AdvancedActivities
· DiscretionaryActivities
Inthisstudy,eachkneewillbeindependentlyscoredusingtheKSKSS.
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4.12.PainAssessments
Painwillbecaptureddailyforthefirst4weekspost-surgeryandthenweeklyforweeks
5-12.Inaddition,abaselinepainassessmentassociatedwitheachkneewillbecaptured
atscreeningandrecordedbytheinvestigatororinvestigatordesignee.Aftersurgery,the
painassociatedwitheachlegwillbeelectronicallyrecordedusinganePROsystemas
part of the EDC. Subjects will receive reminders (eg, phone calls, e-mails, orePRO
system reminders) to log-in by computer or use an app to complete their pain
assessments.
Forallpainassessments,subjectswillevaluatetheiraveragepainandtheirworstpain
associatedwitheachlegfortheprevious24hrperiodusingthenumericalpainratingscale
(NPRS),whichrangesfrom0(nopain)to10(extremelypainful).
4.13.SurgicalProceduresandAssessments
4.13.1.
BilateralTKAProcedure
Thesurgicalprocedurewillbeperformedinaccordancewiththeinvestigator’sstandard
practice;however,theincisiontypeforeachkneeshouldbethesame.Forthemethodof
closure,typessuchassutures,staples,steri-strips,andskinglueareallowed;however,
skinclosureusinganytypeofplasticclosuredevice(eg,Ziplinesutures)isrestricted.The
followinginformationregardingtheTKAprocedurewillbedocumented:
· Orderofkneesurgery(rightvs.left)
· Administrationoftranexamicacidpreoperativelyorintraoperatively
· Surgicalapproach
· MethodofClosure(eachknee)
· Lengthofincision
· Anesthesiastartandstoptime
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4.13.2.
ApplicationofDressings
4.13.2.1.ciNPT
ForthekneerandomizedtoreceiveciNPT,aPREVENARESTORARTHRO•FORM™
Dressingwillbeappliedovertheclosedincisionimmediatelyafterincisionclosureand
cleansingoftheapplicationsite.Anysurgicaldrainsmustberoutedundertheskinbeyond
thedressingboundaryandfunctionindependentlyfromtheciNPT.Thedressingsshould
notbeliftedorprematurelyremovedafterapplicationforreasonsotherthanthoserelated
tothedevice,suchasamalfunctionorleakalarm.Ifthedressingisliftedforanyreason,
anewdressingmustbeapplied;donotre-adherethesamedressing.Forthedeliveryof
negative pressure, a PREVENA PLUSTM 125 Therapy Unit will be attached to the
dressingtubing,andciNPTwillbeinitiatedintheoperatingroom.Ifthedressingleaks
and a seal cannot be maintained, replacement of the PREVENA RESTOR
ARTHRO•FORM™Dressingisacceptableandwillbedocumented.Intheeventthatthe
therapyunitmalfunctionsatanytimeduringtreatment,areplacementunitmaybeused.
Thedressing will be appliedon Day0andchangedonpost-surgicalDay 5-7.When
removingthedressing,itshouldalwaysberemovedparallel/in-linewiththeincisionand
neveracrosstheincisionline.Afterchangingthedressing,ciNPTwillbereappliedforthe
remainderofthetreatmentperioduntil12-14daysoftreatmentarecompleted.Treatment
removalisaddressedinSection4.14.1.
4.13.2.2.Standardsilver-containingdressings
Forthekneerandomizedtothecontrolarm,asilver-containingdressingwillbeapplied
overtheclosedincisionimmediatelyafterincisionclosureandcleansingoftheapplication
site. Silver-containing dressings will be applied following the product IFU, and the
dressingmaybereplacedasneededthroughoutthetreatmentperiodaccordingtothe
IFU.Ataminimum,thedressingwillberemovedandchangedattheDay5-7visit.After
re-applicationofthesilvercontainingdressingattheDay5-7visit,treatmentwillcontinue
until12-14daysoftreatmentarecompleted.TreatmentremovalisaddressedinSection
4.14.2.
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4.14.TreatmentRemoval
4.14.1.
PREVENARESTORARTHRO•FORM™Dressing
AllsubjectsshouldreceiveciNPTontheappropriatelyrandomizedkneeforadurationof
12-14 days post-surgery. Closed incision negative pressure therapy (ciNPT) will be
discontinued no later than 14 days after surgery, and the PREVENA RESTOR
ARTHRO•FORM™
Dressing
will
be
removed.
The
PREVENA
RESTOR
ARTHRO•FORM™ Dressing should be removed parallel/in-line with the incision and
neveracrosstheincisionline.Ifasubsequentdressingisrequired,agauzedressingmay
beused.
4.14.2.
Standardsilver-containingdressing
All subjectsshould receive astandardsilver-containingdressingon theappropriately
randomizedkneeforadurationof12-14dayspost-surgery.Ifasubsequentdressingis
required,agauzedressingmaybeused.
4.15.Post-OperativeAssessments
Itisrecommendedthatallpost-operativeassessmentsoccurduringtheafternoon(local
time), if possible, to control for time-of-day effects on the primary and secondary
endpoints.Thetimeofdayforeachpostoperativevisitwillberecorded.Inaddition,itis
recommended that subjects do not undergo physical therapy activities on the day of
follow-up visits before completing assessments in order to achieve more accurate
measuresofswelling,rangeofmotion,andstraight-leg-raisetests.IfPTistooccuron
thesamedayofafollow-upvisit,itisrecommendedthatitoccursafterthevisit.
4.15.1.
SurgicalSiteComplications
Theinvestigatorwillexaminebothlegsandbothincisionsofthesubjectforanyevidence
ofsurgicalsite complications.SSCswillbeassessedinthefollowingcategories,and
interventionstoresolvetheSSCwillbecaptured:
· SuperficialorDeepIncisionalSurgicalSiteInfection(SSI)
· Fullthicknessskindehiscence
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· Seromaorhematomarequiringdrainageorsurgery
· Skinnecrosis
· ContinueddrainagedeterminedbyanInvestigator’svisualinspectionofthe
incisionaftercompletionofthestudytreatmentperiodandremovalofthestudy
treatmentdressing.
· Othercomplicationthatrequiresintervention
o Investigatorwilldefinetypeofcomplication
4.15.2.
ScarCosmesisAssessment
Theassessmentsofscarqualityinthisstudywillbeperformedbytheinvestigatoror
investigator-designatedphysicianforeachkneeusingtheManchesterScarScale.33This
visualanalogscaleincludesclinicalassessmentofthescarcolor,contour,texture,and
distortion.
4.15.3.
StraightLegRaises
Assessments of active straight leg raising (ASLR), which is used to evaluate pain
provocationandtheabilitytoloadthequadricepsmuscleafterTKA,willbeperformed
independentlyforeachleginthisstudy.Whilelyingflatinasupinepositiononafirm
surface(eg,anexamtable),subjectswillbeaskedtoraisetheirleg20cmoffoftheflat
surfacewithoutanyassistance.Theabilitytoperformthestraightlegraisewillbescored
foreachlegusingasix-pointscalepreviouslydescribedbyMensetal:0=notdifficultat
all;1=minimallydifficult;2=somewhatdifficult;3=fairlydifficult;4=verydifficult;5=
unabletodo.34
4.15.4.
HealthEconomicsAssessment
Informationrelatedtoadditionalhospitaladmissions,procedures,emergencyroomvisits
and/orfollow-upcareafterthesubject’sTKAduringthestudyperiodwillbedocumented
atallpost-surgeryvisits,includingunscheduledvisits.Datatobecollectedwillinclude:
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· Hospitaladmissionsrelatedtoeitherkneesincepreviousstudyvisit(thekneethat
causedtheadmissionwillbedocumented)
o Ifadmitted,lengthofthehospitalstay
o Proceduresperformedoneitherknee
o Medicationsusedtotreatthecauseofadmission(ie,theknee)
· Emergency Department (ED) visits related to either knee since previous visit
(specifywhichkneenecessitatedEDvisit)
o Proceduresperformedrelatedtoeitherknee
o Medicationsusedtotreatthecauseofadmission(ie,theknee)
4.16.ConcomitantMedications
Concomitantmedicationswillbecollectedfromthetimeoftreatmentapplicationthrough
theendofthestudy.Themedicationname,startdate,enddate,andindicationwillbe
reported.
Medicationsrequiredtobereportedinclude:
· Medicationsrequiredtotreatpre-existinghealthconditionsthatareactiveduring
thestudyperiod
· Diuretics
· Anticoagulants(eg,tranexamicacid,acetylsalicylicacid,anti-thromboticagents,
etc)
· Steroids
· Medicationsusedtotreatadverseevents
· Allmedicationsthatareusedasprophylacticagent(s)
4.17.ProhibitedProceduresandTreatments
Skinclosureusinganytypeofplasticclosuredevice(eg,Ziplinesutures)isrestrictedin
thisstudy. Inaddition, re-application of ciNPT using a PREVENA ARTHRO•FORM™
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DressingoranyotherPREVENA™Dressingisprohibitedafterthetreatmentperiod.For
thecontrolarm, silver-containing dressingsshouldbe removednolater than14 after
surgery,andre-applicationofanysilver-containingdressingpastpost-operativeDay14
isprohibited.
SubjectswhoundergoasubsequentsurgeryinvolvingtheinitialTKAwithinthe12weeks
mustwithdrawfromthestudypriortothesubsequentprocedure.
SubjectswhoareinneedofaTKArevisiononeitherkneewithinthe12weeksofthe
originalstudyproceduremustwithdrawfromthestudypriortothesubsequentprocedure.
Cross-over therapy is not permitted during the study. Subjects receiving cross-over
therapyaftercompletingtheoriginalstudytreatmentoneitherknee(ie,therapyfromthe
arm in which each knee was not initially treated)must withdrawfrom thestudy. The
reasonforwithdrawalwillbedocumented.
4.18.EndofStudy
Subjectsmaywithdraworbediscontinuedfromthisstudyatanytime(Section4.4.1).
Theinvestigatormaydiscontinueasubject’sstudyparticipationiftheinvestigatorfeelsit
isinthebestinterestofthesubject.

ThefollowinginformationwillbedocumentedattheEndofStudy:
· Lastdayofstudyparticipation
· Completionstatus–Didthesubjectcompletethestudy(Yes/No)?
· Reasonforstudydiscontinuation
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5.VISITSCHEDULEANDDESCRIPTIONOFSTUDYVISITS
5.1. ScheduleofVisits
ProcedureDescription
Visit1
Visit2
Visit3
Visit4
Visit5
Visit6
Unscheduled
Screening
DayofSurgery
Mid-
Treatment
Follow-up
EndofTreatment
MidtermFollow-up
LongTerm
Follow-up


Pre-Op
Intra-Op
Post-Op





VisitWindows
Day-42to
0
Day0
Day0
Day1
Day5-7
Day12-14
Day35-49
Day77-91

InformedConsent
X








Inclusion/Exclusion
Criteria
X
X1







Demographicsand
SubjectCharacteristics
X
X1







MedicalandSurgical
History
X
X1







KneeSocietyKnee
Score
X



X
X
X
X
X
LowerLimbVolume–
Circumference
measurements(manual
and3D)

X


X
X
X
X
X
RangeofMotion

X


X
X
X
X
X
PainAssessment

X

X4




X
LaboratoryAssessment
forPregnancy

X2







BilateralTKAProcedure


X






Intra-opexclusion
criteria


X






Randomization


X3






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ProcedureDescription
Visit1
Visit2
Visit3
Visit4
Visit5
Visit6
Unscheduled
Screening
DayofSurgery
Mid-
Treatment
Follow-up
EndofTreatment
MidtermFollow-up
LongTerm
Follow-up


Pre-Op
Intra-Op
Post-Op





VisitWindows
Day-42to
0
Day0
Day0
Day1
Day5-7
Day12-14
Day35-49
Day77-91

Applicationof
Treatment


X






ConcomitantMedication


X
X
X
X
X
X
X
AdverseEvents


X
X
X
X
X
X
X
RemovalofStudy
Treatment




X5
X



Scarcosmesis
assessment




X
X
X
X
X
StraightLegraises




X
X
X
X
X
HealthEconomic
Assessments




X
X
X
X
X
SSCAssessments




X
X
X
X
X
EndofStudy







X
X6

1Ifvisit1andvisit2occurondifferentdays,assessmentswillbereviewedandupdatedifchangeshaveoccurred.
2Forwomenofchild-bearingpotential
3Uponsurgicalclosureof1stTKAbutbeforeinitiating2ndTKAonthecontralateralknee.
4Dailypost-oppaincollectionwillstartthedayfollowingbilateralTKAbyePRO.
5Dressingswillberemoved,andanewdressingplacedafterassessmentscompleted.
6Ifthesubjectiswithdrawnearly.

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5.2. DescriptionofStudyVisits
5.2.1.
Screening/Days-42to0
Thefollowingproceduresandassessmentswillbeperformedanddocumentedinthe
subject’smedicalrecords/sourcenotes:
· Informedconsent
· Inclusionandexclusioncriteria
· Demographicsandsubjectcharacteristics
· Medicalandsurgicalhistory
· KSKSS(foreachknee)
5.2.2.
DayofSurgery/Pre-op/Day0
Thefollowingproceduresandassessmentswillbeperformedanddocumented:
· Inclusionandexclusioncriteriaconfirmationimmediatelypriortorandomization
· Demographics and subject characteristics update, if the Screening visit and
surgeryoccurondifferentdays
· Medicalandsurgicalhistoryupdate,iftheScreeningvisitandsurgeryoccuron
differentdays
· Laboratoryassessmentforpregnancy
· Lowerlimbvolume(foreachleg),beforesurgery
· RangeofMotion(foreachknee),beforesurgery
· Painassessment
5.2.3.
DayofSurgery/Intra-op/Day0
· BilateralTKA
· Intraoperativeexclusioncriteria
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· Randomization
· Applicationoftreatment
· Concomitantmedications
· AEassessmentandseriousadverseevent(SAE)reportingafterrandomization
5.2.4.
DayofSurgery/Post-op/Day1
· eProaccessgrantedpost-opDay1forpainassessments
· Concomitantmedications
· AEassessmentandseriousadverseevent(SAE)
5.2.5.
Mid-Treatment/Days5-7
Thefollowingproceduresandassessmentswillbeperformedanddocumented:
· Dressingchange/removalofthedressing
· Lowerlimbvolume(foreachknee)bymeasuringlowerlimbcircumferences
· KSKSS(foreachknee)
· RangeofMotion(foreachknee)
· Scarcosmesisassessment(foreachknee)
· Straightlegraises(foreachleg)
· SSCassessment(foreachknee)
· ConcomitantMedications
· AEassessmentandSAEreporting
· HealthEconomicsassessments
5.2.6.
EndofTreatment/Days12-14
Thefollowingproceduresandassessmentswillbeperformedanddocumented:
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· RemovalofDressing
· Lowerlimbvolume(foreachknee)bymeasuringlowerlimbcircumferences
· KSKSS(foreachknee)
· RangeofMotion(foreachknee)
· Scarcosmesisassessment(foreachknee)
· Straightlegraises(foreachleg)
· SSCassessment(foreachknee)
· ConcomitantMedications
· AEassessmentandSAEreporting
· HealthEconomicsassessments
5.2.7.
Follow-upVisits-Midterm/Days35-49andLongTerm/Days77-91
Thefollowingproceduresandassessmentswillbeperformedanddocumented:
· Lowerlimbvolume(foreachknee)bymeasuringlowerlimbcircumferences
· KSKSS(foreachknee)
· RangeofMotion(foreachknee)
· Scarcosmesisassessment(foreachknee)
· Straightlegraises(foreachleg)
· SSCassessment(foreachknee)
· ConcomitantMedications
· AEassessmentandSAEreporting
· HealthEconomicsassessments
· EndofStudy,afterlongtermfollow-up
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5.2.8.
UnscheduledVisits
Outsideofscheduledstudyvisits,ifthesubjectneedstobeassessedbytheinvestigator
foranyreasonrelatedtoeitherknee,thefollowingproceduresandassessmentswillbe
performedanddocumentedinthesubject’smedicalrecords/sourcenotes:
· Lowerlimbvolume(foreachknee)bymeasuringlowerlimbcircumferences
· KSKSS(foreachknee)
· RangeofMotion(foreachknee)
· Scarcosmesisassessment(foreachknee)
· Straightlegraises(foreachleg)
· SSCassessment(foreachknee)
· Painassessment
· Concomitantmedications
· AEassessmentandSAEreporting
· HealthEconomics
· Endofstudy,ifasubjectiswithdrawnearly


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6.RISKSASSOCIATEDWITHSTUDYPARTICIPATION
Participationintheclinicalinvestigationpresentslowriskstosubjects.Somerisksare
generalizedandarelistedbelow:

Risks
Disorders/Conditions
Skin and Subcutaneous
Tissue
· Epidermal(skin)stripping
· Contusion(bruising)
· Maceration
· Minorsofttissuedamage
· Localcutaneousreaction(i.e.,redness,rash,significantpruritis,urticaria)
· Minorbleeding
· Pain
Other
·Bleeding complications (associated with the surgical procedure,
concomitanttherapy,andco-morbidities)
·Localizedinfection
·Exposurerelatedinfection
·First-degreeburn(ifthedevicegetswarm)
·Minordesiccation(duetodressingleak)
·Moderate soft tissue damage (i.e., due to trip hazard, tubing
entanglement)
·Deteriorationofthewound(duetolackofvisibilityofincisionsitethrough
dressing)
·Physicaldiscomfort



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7.SAFETYANDADVERSEEVENTS
7.1. Definitions
7.1.1.
AdverseEvent(AE)
Any untoward medical occurrence, unintended disease or injury, or untoward clinical
signs(includingclinicallysignificantabnormallaboratoryfindings)insubjects,usersor
otherpersons,whetherornotrelatedtotheinvestigationalmedicaldevice.
7.1.2.
SeriousAdverseEvent(SAE)
AnAEisconsideredseriousifitresultsinanyofthefollowingoutcomes:
· Death
· Life-threatening
· Hospitalization(initialorprolonged)
· Persistentorsignificantincapacityorsubstantialdisruptionoftheabilitytoconduct
normallifefunctions
· Congenitalanomaly/birthdefect
· Requiredinterventiontopreventpermanentimpairmentordamage
· Otherimportantmedicaleventsmaybeconsideredserious when,basedupon
appropriatemedicaljudgment,theymayjeopardizethesubjectandmayrequire
medical or surgical intervention to prevent one of the outcomes listed in this
definition.
Anyplannedhospitalizationforapre-existingcondition,oraprocedurerequiredbythe
protocol,withoutseriousdeteriorationinhealth,isnotconsideredanSAE.
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7.2. Classification






7.2.1.
RelationshiptoStudyTreatment
TheinvestigatorwillassesstherelationshipoftheAEas:
· Relatedtothestudyproduct:anyAEforwhichthereisareasonablepossibility
that the study product caused the AE. The sponsor will review all SAEs for
expectedness.
· NotRelatedtothestudyproduct:whenitisdeterminedthatthereisnorelationship
betweentheAEandtheuseofthestudyproduct.
7.2.2.
Severity
Theinvestigatorwillassignseverityas:
· Mild–asymptomaticormildsymptoms;clinicalordiagnosticobservationsonly;
nointerventionindicated
· Moderate–minimal,local,ornon-invasiveinterventionindicated
· Severe–medicallysignificantbutnotimmediatelylife-threatening;hospitalization
orprolongationofhospitalizationindicated;disabling
AdverseEvent
(AE)
Serious?=YES
CompleteSAE
report
CompleteAEin
clinicaldatabase
Serious?=NO
CompleteAEin
clinicaldatabase
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7.3. AEReportingProcedures
Theinvestigatorisresponsibleformonitoringthesafetyofallsubjectsenrolledinthe
studyandreportingAEsasdescribedinthisprotocol.
7.4. AECollection/ReportingPeriod
The AE collection/reporting period will begin after the subject has been randomized.
InvestigatorsshouldassessforAEsateachvisit.Inaddition,studysubjectsshouldbe
instructedtoreportanyAEthattheyexperiencetotheinvestigator.
All AEs, regardless of perceived relationship to study product, will be reported and
documented in a timely manner. In addition, the worsening of a medical condition
previouslyreportedinthemedicalhistoryshouldalsoberecordedasanAE.
TheAEdescriptionwillincludethenatureoftheexperience(AEterm),thestartdate,the
end date, the severity of each sign or symptom, the seriousness of the event or
experience,relationshiptostudytreatment,thecourseofactiontaken,andtheoutcome
oftheexperience.ItwillbeindicatediftheAEcausedthesubjecttobediscontinuedfrom
thestudy.
7.5. SAEReportingtoSponsor
TheSAEcollection/reportingperiodwillbeginafterthesubjecthasbeenrandomized.
SAEswillbereportedviathesponsor’sSAEReportForm.Thisformshouldbecompleted
bytheinvestigator,ordesignee,andsubmitted(faxoremail)tothesponsorwithin24
hoursoftheinvestigatorbecomingawareoftheevent.Thesponsor’sSAEe-mailinbox
isavailableforSAEreporting24hoursperdayandismonitoredduringnormalbusiness
hours.
7.6. UADEReporting-UnanticipatedAdverseDeviceEffect(UADE)
AUADEisanySAEonhealthorsafetyoranylife-threateningproblemordeathcaused
by, or associated with, a device, if that effect, problem, or death was not previously
identified in nature, severity, or degree of incidence in the investigational plan or
application(includingasupplementaryplanorapplication),oranyotherunanticipated
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seriousproblemassociatedwithadevicethatrelatestotherights,safety,orwelfareof
subjects.
ThesponsorwillimmediatelyconductanevaluationofthereceivedSAEstodetermine
whethertheeventmeetstheUADEdefinition.IftheeventisdeterminedtobeaUADE,
sponsorwillreporttheresultsoftheevaluationtoallregulatoryagenciesoverseeingthe
projectandtoparticipatinginvestigators.
If the sponsor determines that the event presentsan unreasonable risk to the study
subjects,thesponsorwillterminateallclinicalstudiesorpartsofstudiespresentingrisk
assoonaspossible.
7.7. Follow-upPeriodforOngoingAEs
Treatment-relatedAEs(seriousandnon-serious)thatareongoingatthefinalstudyvisit
willbefollowedupto30daystoassessresolutionorstabilization.AllunrelatedAEswill
beconsideredclosedatthetimethesubjectcompletesparticipationinthestudy.
8.STATISTICALCONSIDERATIONS
8.1. AnalysisSets
Thefollowinganalysissetswillbeused:
· Intention-to-treat(ITT)AnalysisSet–TheITTSetwillconsistofallrandomized
subjects.Subjects/Kneeswillbeanalyzedaccordingtothetreatmentallocatedat
randomizationforthatparticularknee(rightorleft)
o Intheeventeachtreatmentisallocatedtoakneedifferentthanwhatthey
wererandomizedto,thesubject/kneewillbecountedunderthetreatment
received as long as the subjects receives each treatment once (one
treatmentperknee).
o Intheeventsubjectsreceivethesametreatmentinbothknees,eachknee
will be counted once in each unique treatment group according to the
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treatmentallocatedaspertherandomizationandwillnotbecountedtwice
underthesametreatmentgroup.
· Per-Protocol(PP)AnalysisSet–ThePPSetwillincludeallsubjectsand/or
kneesintheITTAnalysisSetwithnodisqualifyingprotocoldeviation(s)that
wouldimpacttheinterpretationoftheprimaryendpoint.Thedisqualifying
protocoldeviation(s)forexclusionfromthissetwillbedefinedanddocumented
priortothefinaldatabaselock.
· SafetyAnalysisSet–TheSafetyAnalysisSetwillconsistofallsubjectsand/or
kneesthatreceivedanyonstudytreatment-relatedprocedures.Subjects/Knees
willbeanalyzedaccordingtothetreatmentreceivedineachknee.
8.2. PlannedAnalysisandDataSummaries
8.2.1.
GeneralAnalysisTechniques
In general, summaries of endpoints will consist of descriptive statistics. Data will be
summarizedbytreatmentgroup,overalland/orbyvisit,ifapplicable.Duetoeachsubject
servingastheirowncontrolandreceivingbothtreatments(onetreatmentperknee),the
same subjects will be counted once within each treatment group according to the
treatmentreceivedand/orrandomizedinforeachknee.Subjectswhoonlyhaveoneknee
treated will only be counted in the treatment group that the knee received. Data
processing,tabulationofdescriptivestatistics,andanygraphicalrepresentationswillbe
performedprimarilyusing SAS(release9.4orhigher).Iftheuseofothersoftwareis
warranted,detailswillbeincludedintheclinicalstudyreport(CSR).
Summariesofcontinuousvariableswilldisplaythenumberofsubjectsand/orkneeswith
availabledata(n),themean,median,standarddeviation,minimum,andmaximumvalues
ateachtimepoint.Forcategoricalvariables, thenumberandpercentageofsubjects
and/orkneesthatareineachcategorywillbeprovided.Thedenominatorforpercentages
willbeallrelevantsubjectsand/orkneesinaparticularanalysis,includingthoseforwhom
dataarenotreportedormissing.
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Formalstatisticaltestingwillbeconductedutilizingtwo-sidedtestsatasignificancelevel
of0.05.Corresponding95%confidenceintervals(CIs)willbepresentedforappropriate
endpoints.
Additionalanalysestocharacterizethesafetyand/orefficacymaybeconducted.These
additional analyses will be included in the Statistical Analysis Plan. Any ad hoc
summaries/analyses conducted after database lock will be included in the CSR and
labeledasadhoc.
8.2.2.
SubjectDisposition
Summariesofdispositionwillbetabulatedbytreatmentgroupandoverall.Ataminimum,
thefollowingsummariescontainingthenumberofsubjectsandpercentageofsubjects
willbeincludedforsubjects:
· Includedeachanalysisset
· Providedinformedconsent
· Randomizedandtreated
· Discontinued early from the study for any reason, along with the reason for
discontinuation(ifthereasonisanAE,thesystemorganclassandpreferredterm)
· Completedthestudyasplanned
Subjectdispositionalsowillbedescribedinaflowchart(CONSORTdiagram).
8.2.3.
DemographicandBaselineCharacteristics
Demographiccharacteristics(eg,age,sex,race,andethnicity),baselinecharacteristics,
andotherdiseasecharacteristicsmaybesummarizedbytreatmentarmandoverall.
8.2.4.
AnalysisofPrimaryEndpoint
Theprimaryendpointisthepercentchangeinlowerlimbvolume,ascalculatedbasedon
manualcircumferencemeasurements,5-7daysaftertotalkneearthroplasty(TKA)when
using the PREVENA RESTOR ARTHRO•FORM™ Incision Management System
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compared to the control. The lower limb volume is calculated using the Frustum
formula35;36:
 =	 
() + 
 +  · () ℎ
3
whereandarethecircumferencesoftwoconsecutivesectionsalongthelimb,and
ℎisthelengthoftheintervalbetweenthetwomeasurementsonthelimb.Thelowerlimb
volumeisdeterminedbycalculatingthesumofthevolumesofallsections.Thepercent
changeofthelowerlimbvolumeisdefinedasthedifferenceoflowerlimbvolumefrom
baseline(pre-op)topostoperativeDay5-7,dividedbythebaselinemeasurementoflower
limbvolume,multipliedby100.
A general linear mixed model repeated measures analysis (MMRM) will be used to
analyze the primary endpoint with covariates: site, study visit, treatment, knee side
(left/right),baselinelowerlimbvolume,baselineBMIcategory(<30kg/m2,≥30kg/m2),
andtreatmentbystudyvisit.Kneesidewillserveasarepeated-measurefactortoaccount
forthecorrelationsbetweenleftkneeandrightkneeonthesamesubject,andthesubject
variablewillalsobespecifiedtoidentifythoseobservationsthataretobecorrelated.Raw
means,LSMeans,including95%confidenceintervals,willbepresentedbytreatment
group.TheITTanalysissetwillbeusedfortheprimaryanalysis.
8.2.4.1. SensitivityAnalysesofPrimaryendpoint
· TheprimaryanalysiswillberepeatedonthePer-Protocolanalysisset.
· The primary analysis will be repeated on the ITT analysis set to explore the
following covariate: treatment, site, visit, baseline lower limb volume, surgical
approach,andlengthofincisions.
· Additionalsensitivityanalysesmaybeconductedtoexploreothercharacteristics
that may impact the lower limb volume. All analyses will be outlined in the
StatisticalAnalysisPlan.
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8.2.5.
AnalysisofSecondaryEndpoints
AllsecondaryendpointswillbesummarizedbytreatmentgroupontheITTpopulation.
Raw means and changes from baseline will be displayed by treatment group, as
appropriate.
Thefollowingcontinuousendpoints:
· Percent change in lower limb volume, as calculated based on manual
circumferencemeasurements,frombaselinetovisits4,5,and6
· Percentchangeincircumferencesfrombaselinetovisits3-6thataremeasured
at:
o 10cmabovethecenterofthepatella
o atthecenterofthepatella
o 10cmbelowthecenterofthepatella
o attheankle;1cmabovethemedialmalleolus
· Changeofkneeflexionanglefrombaselinetovisits3-6
· Changeofkneeextensionanglefrombaselinetovisits3-6
ChangeoftotalROMdegrees,definedastheflexionangleminustheextensionangle,
frombaselineto visits3-6willbeanalyzedusingamixed modelrepeated measures
analysis (MMRM) with the same covariates outlined in the primary analysis. General
linearmixedmodelsand/orpairedt-testsateachweekmayalsobeperformed.
The average pain and worst pain in each leg in the last 24 hours using an NPRS
(numericalpain ratingscale)of0-10(dailyfor4 weekspost-surgery,then weeklyfor
weeks5-12)willbeanalyzedinthefollowingtwoways:
· AnAUC,orareaunderthereceiveroperatingcharacteristics(ROC)curve,will
becalculatedfordailypainscoresforeachkneeusingagenerallinearmixed
modelwithsite,treatment,andkneeside(left/right)includedinthemodelas
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covariateswhileadjustingforcorrelationsfromthewithin-subjectcomparisons
overtime.AmodelwithanAUCofatleast0.70willbeconsideredadequate.37
· Weekly pain scores (average pain scores for each week (weeks 1-4) and
reportedweeklypainscores(weeks5-12)willbeanalyzedusinganMMRM
with site, week, treatment, knee side (left/right), and treatment by week
includedinthemodelascovariateswhileadjustingforcorrelationsfromthe
within-subjectcomparisonsovertime.Thecovariancestructurewillbeselected
based on the lowest Akaike Information Criterion value. Raw means, LS
Means, including 95% confidence intervals, will be presented by treatment
group.
AChi-square,McNemar's,orFisher’stestasappropriatewillbeusedto analyzethe
followingendpoints:
· TheincidenceofSSCsbyvisits5and6
· Scarcosmesisassessmentatvisits3-6
AdditionaldetailswillbespecifiedintheStatisticalAnalysisPlan.
8.2.6.
ExploratoryAnalyses
Theexploratoryendpointsareasfollows:
· the percent change in lower limb volume, as calculated based on three-
dimensional(3D)imaging,frombaselinetovisits3-6
· Knee-relatedQoLquestionnaire(newKneeSocietyKneeScoringSystem)atvisits
4,5,and6
· Abilitytoperformastraightlegraiseatvisits4,5,and6
Anyadditionalexploratoryendpointsandallexploratoryendpointanalyseswillbeoutlined
intheSAP.Becausetheanalysesareexploratory,noadjustmentwillbemadeformultiple
comparisons.
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8.2.7.
AnalysisofSafetyEndpoint
AllsafetyresultswillbepresentedbasedontheSafetyAnalysisSet.AllTEAEswillbe
summarized by treatment arm. Subject incidence of TEAEs will be summarized by
treatmentarmandbyMedDRA(Version23orhigher)systemorganclassandpreferred
term.Foreachcodedmedicalterm,theproportionofsubjectswhoexperienceatleast
onetreatment-emergent:
· adverseevent(s);
· adverseevent(s)relatedtotreatment
· seriousadverseevent(s);
· seriousadverseevent(s)relatedtotreatment
· adverseevent(s)byseverity(mild,moderate,severe);
· adverseevent(s)leadingtotreatment/studydiscontinuation,or
· serious adverse event(s) leading to treatment/study discontinuation will be
reported.
Alistingofdeath(s),subjectswhodiedofanycauseduringthestudy,willbepresented.
8.3. AdditionalStatisticalDetails
8.3.1.
SampleSizeDetermination
Pichonnazetalmeasuredthelimbvolumeutilizingthetruncatedconemethod.Themean
volumepercentagedifferencefrombaselinetoDay8post-surgerywas11.9%,witha
standarddeviationof8.2%atDay8.1In2016,Pichonnazetalusedthesamemethodto
evaluatethelowerlimbvolumeandthemeanpercentagedifferencefrombaselineto
postoperativeDay7was15.3%,withastandarddeviationof6.5%atDay7.2Assuming
inourstudythecontrolgrouphasapercentchangeof13.6%involumefrombaselineto
post-surgeryDay6-8,whilethePREVENARESTORgroupholdsapercentchangeof
8%inthesameperiod,giventhestandarddeviationis9.2%inbothgroups,atotalof52
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subjects(assuming15%dropoutrate)areneededtoachieve80%powerbasedona
two-samplet-testwithatypeIerrorrateof0.05.
8.3.2.
Randomization
Allsubjectswhomeetallinclusioncriteriaandnoexclusioncriteriawillberandomizedin
a1:1ratiotoreceivethePREVENARESTORARTHRO•FORM™IncisionManagement
Systemorthecontrolineitherrightorleftknee.Eachsubjectwillreceivebothtreatments
(onetreatmentperknee).Arandomizationschedule,includingrandomizationnumbers
andtreatmentassignments,willbegeneratedandmaintainedcentrallyintheweb-based
clinicaldatabasemanagementsystem.Oncerandomized,asubject’sassignmentcannot
bealteredorchanged;asubjectshouldnotberandomizedtwice.Therandomization
schedulewillbekeptblindtoanypersonwhoisinvolvedinthedailyoperationsofthe
study.Itwillonlybeaccessibletothestudybiostatisticianswhogenerateandreviewthe
schedule,andthevendor’steammembers(ifanEDCvendorisutilized)whoareinvolved
inreviewingthescheduleanduploadingtheschedule.
8.4. Open-LabelStudyReportingResults
Allprecautionswillbetakentoavoidintroducinganyformofbiasduringtheconductof
thestudy.Whilethestudyisongoing,summarystatisticsbytreatmentarmsacrossall
sitesmaybelimitedtoasmallgroupnotinvolvedinthedailyoperationsofthestudy.
Treatmentarmsmaybemaskedinthesummaryreportsoroutputs(tables,listings,and
figures)ifneeded.Summarystatisticsduringtheconductofthestudywillnotbeshared
withinvestigatorsandclinicalsites.Uponstudycompletion,thefullresultswillbeshared
withallinvestigatorsandclinicalsites.
8.5. InterimAnalysis
Nointerimanalysisisplannedforthisstudy.
8.6. StatisticalAnalysisPlanandChangesinAnalyses
AStatisticalAnalysisPlan(SAP)containingfulldetailsofthestatisticalanalysesand
executionwillbepreparedforthisstudy.TheSAP(SAP)willbefinalizedpriortolocking
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thestudydatabaseandthefinalanalysis.Anychangesfromtheplannedanalysesin
thisprotocolorSAPwillbenotedintheClinicalStudyReport(CSR).
9.HANDLINGOFSTUDYPRODUCTS
Study product receipt, use, dispensation, destruction, and return records will be
maintainedthroughoutthestudy.
Uponreceiptofproduct, theinvestigatorordesigneewillinventorytheshipment and
immediatelynotifythesponsorifthestudyproductorotherstudysuppliesaremissing.
The monitor will verify that study product documentation is maintained appropriately
duringmonitoringvisits.
Atthecompletionofthestudy,therewillbeafinalreconciliationofstudyproductshipped,
used,andunused.Anyunusedstudyproductandassociatedsupplieswillbereturnedto
thesponsor.
10.DATAHANDLINGANDRECORDKEEPING
10.1.Investigator/StudySiteTraining
Theinvestigatorandsitestaffwillbetrainedontheprotocol,thestudyproducts,andany
specializedprocedurespriortoenrollingsubjectsintothestudy.Thesponsorwillprovide
support to site staff for any questions or concerns related to study products and
procedures.Thesponsorwillnothaveanyinfluenceonsubjectmedicalcare.
10.2.ElectronicCaseReportForm(eCRF)andSourceDocuments
Sourcedocumentsincludeallinformationinoriginalrecords,certifiedcopiesoforiginal
records,observations,orotheractivitiesnecessaryforthereconstructionandevaluation
ofthestudy.Allsourcedocumentsshouldbecompletedintheirentiretyinaneat,legible
mannertoensureaccurateinterpretationofthedata.
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Datafromsourcedocumentsofeachsubjectwillbeenteredintothesubject’selectronic
casereportform(eCRF).GuidanceforeCRFcompletionwillbeprovidedandreviewed
withthesitestaffpriortoreceivingstudyproduct.
10.3.MonitoringofStudyData
ThedatawillbeenteredintotheclinicalstudydatabasebyInvestigativesitestaffand
verifiedforaccuracybyasponsorrepresentative.Theinvestigatorwillallowaccessto
theirclinicalstudyrecordsforperiodicon-sitemonitoringvisitsbyadesignatedsponsor
representative,withtheunderstandingthattherepresentativeisboundbyprofessional
secrecyandwillnotdiscloseasubject’sidentityorpersonalmedicalinformation.The
representativewillrevieweCRFsforcompletenessduringon-sitemonitoringvisits,and
aftertheeCRFsaresubmitted;anydiscrepancieswillberesolvedwiththeinvestigatoror
designee,asappropriate.
10.4.DataHandling
The sponsoris responsible for compilation and verification of the clinical study data,
retention of the clinical study database, performance of statistical analysis, and
preparationoftheCSR.
10.5.RecordsRetention
Thestudysitewillmaintainallstudydocumentationandinstitutemeasurestopreventthe
accidentalorprematuredestructionofanydataand/ordocumentsrelatedtothestudy.
After formal discontinuation or completion of the study, the investigator will retain all
clinicalstudydocumentationforaminimumoftwo(2)yearsfromthedatetheinvestigation
is terminated or completed or in accordance with the regulations in effect for the
jurisdictionwherethesiteislocated.Theinvestigatorwillcontactthesponsorpriortothe
destructionofanystudyrecords.
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11.ADMINISTRATIVEREQUIREMENTS
11.1.GoodClinicalPractice(GCP)
Thisstudyistobeconductedaccordingtoapplicablenationalregulationswherethestudy
isbeingconducted,internationalstandardsofgoodclinicalpractice(GCP)suchasthe
InternationalCouncilforHarmonisationguidelines,andinstitutionalresearchpoliciesand
procedures.
11.2.EthicalConsiderations
This study will be conducted in accordance with ethical principles founded in the
Declaration of Helsinki. Approving IRB/ECs will be provided all relevant study
documentationtosafeguardtherights,safety,andwell-beingofsubjectsasmandated.
ParticipatinginvestigatorswillobtainIRB/ECapprovalofthestudypriortoinitiationat
theirsites.Theprotocol,IFUs,informedconsent,writteninformationgiventosubjects,
safetyupdates,andanyrevisionstothesedocumentswillbeprovidedtotheIRB/ECby
theinvestigator.
11.3.SubjectInformedConsent
Writteninformedconsentwillbeobtainedfromapotentialsubjectafterthestudyhas
beenfullyexplainedandpriortotheconductofanystudy-relatedprocedures.Obtaining
informed consent is a process that must be documented in compliance with GCP,
IRB/EC,andotherapplicableregulatoryrequirements.Theinvestigatorisresponsiblefor
continuinganopenconversationwiththesubjectabouttheircontinuedparticipationinthe
study. The sponsor will conduct periodic monitoring to ensure informed consent is
obtainedforeachsubjectpriortoanystudyprocedures.
11.4.Confidentiality
Information collected about subjects during the study will be kept confidential and
managedaccordingtotherequirementsoftheIRB/EC,HealthInsurancePortabilityand
AccountabilityActof1996(HIPAA),andanyadditionalrequirementsasrequiredbythe
country/regulatoryagencywherethestudyistakingplace.
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IntheeventthatasubjectrevokesanauthorizationtocollectorusePersonalHealth
Information(PHI),theinvestigatorretainstheabilitytouseallinformationcollectedprior
totherevocationofsubjectauthorization.
11.5.ClinicalTrialRegistration
Adescriptionofthisstudywillbeavailableonhttp://www.ClinicalTrials.govandanyother
designatedpublicstudyregistryasrequiredbyapplicablelocalandfederalregulations.
The description of the study that is made available will not include information that
identifiessubjects.Atmost,thewebsitewillincludeasummaryoftheresultsofthestudy
andwillbeavailableforpublicreviewatanytime.Ifrequired,thestudymayalsobelisted
onadditionalclinicaltrialwebsitesasrequiredbythecountry/regulatoryagency.
11.6.AuditingandInspecting
Participationasaninvestigatorinthisstudyimpliesacceptanceofpotentialinspectionby
government regulatory authorities and applicable compliance and quality assurance
offices.
Theinvestigatorwillpermitstudy-relatedmonitoring,audits,andinspectionsofallstudy-
related documents (eg, source documents, regulatory documents, data collection
instruments, study data) by the IRB/EC, sponsor or its designee, and government
regulatorybodies.
12.PUBLICATIONPLAN
Thepublicationpolicyforthisstudywillbeaddressedinaseparateagreement.
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