Efficacy and Safety of Intravitreal Aflibercept Treat-and-Extend for Macular Edema in Central Retinal Vein Occlusion: The CENTERA Study.

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ORIGINAL ARTICLE

Efﬁcacy and Safety of Intravitreal Aﬂibercept Treat-and-Extend for Macular Edema in Central

Retinal Vein Occlusion: the CENTERA Study

JEAN-FRANÇOISKOROBELNIK,MICHAELLARSEN,NICOLEETER,CLAREBAILEY,SEBASTIANWOLF, THOMASSCHMELTER,HELMUTALLMEIER,ANDVARUNCHAUDHARY

• PURPOSE: Toevaluatetheefficacyandsafetyofintrav- itreal aflibercept (IVT-AFL) treat-and-extenddosing in patientswithmacularedemasecondarytocentralretinal veinocclusion(CRVO).

• DESIGN: CENTERA (Evaluation of a Treat and Ex- tend Regimen of Intravitreal Aflibercept for Macular Edema Secondary to CRVO; NCT02800642) was an open-label,Phase4clinicalstudy.

• METHODS: Patientsreceived2mgofIVT-AFLatbase- lineandevery 4weeksthereafter,untildiseasestability criteriaweremet(oruntilweek20),atwhichpointtreat- mentintervalswereadjustedin2-weekincrementsbased onfunctionalandanatomicoutcomes.

• RESULTS: From baseline to week 76, 105 patients (65.6%) (P <.0001 [test against threshold of 40%]) gained ≥15 letters; and, during the treat-and-extend phase, 72 patients (45.0%) (P=0.8822 [test against thresholdof 50%]) achieveda meantreatment interval of ≥8 weeks. Alast and next planned treatmentinter- valof ≥8weekswas achievedby101patients(63.1%) andby108 patients(67.5%),respectively.Mean±SD best-correctedvisualacuityincreasedfrom51.9±16.8 lettersatbaselineto72.3±18.5lettersatweek76(mean change:+20.3±19.5letters),andcentralretinalthick- ness decreased from 759.9 ± 246.0 µm at baseline to 265.4±57.9µmatweek76(meanchange:−496.1±

AcceptedforpublicationJanuary28,2021.

Service d’Ophtalmologie,CentreHospitalier Universitaire(CHU) Bordeaux,France; BordeauxPopulationHealthResearchCenter,Team Lifelongexposureshealthandaging(LEHA),Univ.Bordeaux,Institut NationaldelaSanté etdelaRechercheMédicale(INSERM),Unité mixte derecherche(UMR),Bordeaux,France; Department ofOphthalmol- ogy,Rigshospitalet,UniversityofCopenhagen,Copenhagen,Denmark;

DepartmentofOphthalmology,UniversityofMuensterMedicalCenter, Muenster,Germany; BristolEyeHospital,Bristol,UnitedKingdom; De- partmentforOphthalmology,Inselspital,UniversityHospital,University ofBern,Bern,Switzerland; DepartmentofOphthalmology,BayerAG, Berlin,Germany; BayerConsumerCare(HA),AG,Basel,Switzerland;

HamiltonRegionalEyeInstitute,St.Joseph’sHealthcareHamilton,On- tario,Canada,andDepartmentofSurgery,McMasterUniversity,Hamil- ton,Ontario,Canada

InquiriestoJean-FrançoisKorobelnik,HôpitalPellegrin,CHUdeBor- deaux,PlaceAmélieRabaLéon,33000Bordeaux,France;e-mail:jean- francois.korobelnik@chu-bordeaux.fr

252.4µm).ThesafetyprofileofIVT-AFLwasconsistent withthatofpreviousstudies.

• CONCLUSIONS: Clinically meaningful improvements in functional and anatomic outcomes were achieved with IVT-AFL treat-and-extend dosing. Most patients achieved a last actual and last intended treatment in- terval of ≥8 weeks; therefore, treatment intervals may have been extended even further with a longer study duration. (Am J Ophthalmol 2021;227: 106–115.

This is an open access article under the CC BY-NC- ND license (http://creativecommons.org/licenses/by-nc- nd/4.0/))

Retinalveinocclusionisacommoncauseofvisionloss inpatientswithchronicmacularedema.¹Thereare3dif- ferenttypesofretinalveinocclusions,basedontheobstruc- tionsite:branchretinalveinocclusion,centralretinalvein occlusion (CRVO), and hemiretinal vein occlusion.² CRVOisanobstructionofthemainretinalveinatorposte- riortotheopticnervehead³;itaffectsbothmenandwomen andoccursmostcommonlyinpatientswhoare60yearsof ageorolder.²^,⁴AlthoughCRVOisusuallyunilateral,⁴ap- proximately7.8%ofpatientswithCRVOinoneeyealso haveRVOinthefelloweye.⁵CRVOleadstoimpairedve- nous drainage from the eye,which in turn mayresult in increased venous pressure,reducedarterialperfusion, and retinalischemia.Retinalnonperfusionleadstoanincrease in vascular endothelialgrowth factor(VEGF),which in- creasesvascularpermeabilityandcancausemacularedema, retinalhemorrhage,andneovascularization.⁶

Treatment of macular edema secondary to CRVO in- volves the administration of anti-VEGF agents, such as afliberceptandranibizumab,whichhavebecomethestan- dardofcare.Theefficacyandsafetyofintravitrealafliber- cept (IVT-AFL)were assessed in 2 pivotal Phase3 studies, COPERNICUS (NCT00943072)⁷^, ⁸ and GALILEO (VascularEndothelialGrowthFactor[VEGF]Trap-Eye:In- vestigationofEfficacyandSafetyinCentralRetinalVein Occlusion;NCT01012973),⁹^,¹⁰inwhichfindingsdemon-

THISISANOPENACCESSARTICLEUNDERTHECCBY-NC-NDLICENSE 0002-9394/$36.00

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stratedthatIVT-AFL was beneficialforthe treatmentof macularedemasecondarytoCRVO.Inthesestudies, the mean changefrom baseline to week24in best-corrected visual acuity (BCVA) was +17.3 and +18.0 letters for patients treated with IVT-AFL compared with −4.0and +3.3lettersinpatientswhoreceivedshaminjections,respectively.⁷^, ¹⁰ Thesestudiesdemonstratehow,if leftun- treated,patientswithmacularedemasecondarytoCRVO lose VA and have a poor prognosis. This was similarly shownintheCRUISEstudy(AStudyoftheEfficacyand Safety of Ranibizumab Injection in Patients With Mac- ular Edema Secondary to Central Retinal Vein Occlu- sion;NCT00485836),in which mean changefrom base- lineBCVAatmonth6was+12.7lettersand+14.9letters inthe0.3-mgand0.5-mgranibizumabgroups,respectively, and+0.8letters inthe shamgroup.¹¹ BoththeCOPER- NICUS and the GALILEO studies included pro re nata (PRN) dosing from week 24 oftreatment to investigate thepossibilityofextendingthetreatmentintervalbeyond 4 weeks.Posthoc assessmentofthedifferent dosingsub- groups demonstrated some de-stabilization of the disease withdosesadministeredPRN.Althoughthedeterioration seenduringthestudyperiodwasminor,possiblyduetothe regular monitoring schedule implementedin those trials, itislikelytoprogressovertheexpectedlonger-termtreat- mentdurationrequiredinthereal-worldsettingforpatients withmacularedemasecondarytoCRVO.

The Lucentis, Eylea, Avastin in Vein Occlusion (LEAVO) study (ISRCTN13623634) compared IVT- AFL,bevacizumab, and ranibizumabusingaPRN dosing regimenand introduced athreshold oftreatmentsuccess forsuspending treatment(>83Early TreatmentDiabetic Retinopathy Study [ETDRS] letters), which allowed a comparativeassessmentofthetreatmentburdenassociated with each treatmentarm.¹² Treatment with anyofthese 3 anti-VEGF agents resulted in improved and sustained VA when patients were monitored regularly and treated promptly(IVT-AFL:+15.1letters;ranibizumab:+12.5let- ters;andbevacizumab:+9.8lettersatweek100).Notably, IVT-AFLwasnon-inferiortoranibizumabatweek100.

PosthocanalysesofCOPERNICUSandGALILEOsup- portedtheimplementationofproactivetreatmentto pre- vent deteriorationof functionaland anatomic outcomes.

“Treatandextend” isaproactive,individualizeddosestrat- egywherebythepatientreceivesaninjectionateveryvisit.

Thetreatmentintervalisdecidedateveryvisitandisgradu- allyextendediffunctionalandanatomicstabilityaremain- tainedandshortenedifdeteriorationisobserved,tomini- mizetheriskofdiseaserecurrenceratherthaninresponseto it.¹³ Additionally,withtreat-and-extenddosingregimens, theneed forinterim monitoring is minimized,which re- ducesthenumber ofappointmentsperpatient andmini- mizestheneedformonitoringvisits.¹⁴Decreasingthenum- berofvisitsperpatientreducesthetreatmentburdenand theneedforschedulingvisits,thusbenefitingboththepa- tientandthehealthcareproviders.

To our knowledge, treat-and-extend dosing regimens havenotbeenevaluatedinlarge-scalestudiesofIVT-AFL forthetreatmentofmacularedemasecondaryto CRVO.

Therefore,theaimoftheCENTERA(EvaluationofaTreat andExtendRegimenofIntravitrealAfliberceptforMacu- larEdemaSecondarytoCRVO;NCT02800642)studywas toassesstheefficacyandsafetyofIVT-AFLadministeredin atreat-and-extenddosingregimeninpatientswithmacular edemasecondarytoCRVO.

METHODS

• STUDYDESIGN: CENTERA(NCT02800642)wasa76- week, multicenter, open-label, single-arm, Phase 4 study thatassessed theefficacyand safetyofIVT-AFLadminis- teredusingatreat-and-extenddosingregimenintreatment- naive patients with macular edema secondaryto CRVO.

CENTERA was conducted between June 2016 and July 2019at42studycentersinAustralia, Canada,Denmark, France,Germany,Italy,Spain,andtheUK,inaccordance with the Declaration of Helsinki and the International Council for Harmonisation guideline E6: Good Clinical Practice.Theprotocolandanyamendmentswerereviewed andapprovedbyeachstudysite’sIndependentEthicsCom- mitteeorInstitutionalReviewBoard(IRB)beforethestart ofthestudy.Thenameofeachstudysite’sIRBislistedin SupplementalTable1.Allenrolledpatientsprovidedwrit- teninformedconsent.

• PARTICIPANTS: Treatment-naive patients≥18years of age with center-involved macular edema secondary to CRVOfornolongerthan3monthswereenrolled.Patients were required to have a BCVA of73-24 ETDRS letters (Snellenequivalentof20/40-20/320)inthestudyeye.All patientswerescheduledtobetreatedwithIVT-AFLaspart ofroutineclinicalpractice,withtheintenttouseatreat- and-extendregimenaftertheinitialdose.Exclusioncriteria arelistedintheSupplementalmaterial.

• INTERVENTIONS: CENTERA was a single-arm study, and patients receivedtreatment at the discretion ofthe physician.Allpatientsreceived2-mgIVT-AFLinjections atbaselineandevery 4weeksuntildiseasestabilitycrite- riaweremetoruntilweek20,whicheveroccurredfirst(the initiationphaseofthetreatment).Startingatweek8,the re-treatmentintervalwasdetermined,andthefrequencyof injectionscouldbeadjustedby2-weekincrementstomain- tain stablefunctional and anatomicoutcomes (thetreat- and-extendphaseoftreatment).

Thestabilitycriteriawerenonewcystsfoundonoptical coherencetomography;BCVAwithina±5-letter“stability corridor” (definedasnomorethana5-lettergainasthelast orsecondtolastvisitandnomorethana5-letterlossfrom

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FIGURE1. Patientdisposition.Twopatientshadnopost-baselineassessmentsavailableandwerenotincludedinthefullanalysis set.AE=adverseevent;IVT-AFL=intravitrealaflibercept.

bestpreviousBCVAatanyvisit);andcentralretinalthick- ness(CRT)withina±20%“stabilitycorridor” (definedas nomorethan20%thicknessreductionasthelastorsecond tolastvisitandnomorethan20%thickeningfrombestpre- viousCRTatanyvisit).ValuesofBCVAandCRToutside those“stabilitycorridors” wereconsidered“improvements”

forhigherBCVAvaluesandlowerCRTvaluesand“dete- riorations” forlowerBCVAvaluesandhigherCRTvalues.

Fromweek8,ateverytreatmentvisit(andatweeks24, 52,and 76),thephysician determinedthestabilitystatus ofeachpatient, and thefollowing algorithmwasusedto determinethe re-treatmentinterval:if theconditionwas stable(allstabilitycriteriamet),thetreatmentintervalwas extendedby2 weeks.Iftheconditionwasimproving(no newcystsandimprovementinatleast1ofthediseaseac- tivitycriteria[BCVAorCRT]withtheotherimprovingor stable),thetreatmentintervalwasmaintained;andifthe conditionwasdeteriorating(newcystsand/ordeterioration inatleast1oftheotherdiseaseactivitycriteria[BCVAor CRT]),thetreatmentintervalwasreducedby2weeks.In- jectionswerenottobeadministeredmorefrequentlythan every4weeks(minimumre-treatmentinterval).

• STUDY ENDPOINTS: The pre-determined co-primary endpointsweretheproportionofpatientswhogained≥15 lettersfrombaselinetoweek76andtheproportionofpa- tientswithameantreatmentintervalof≥8weeksfromthe lastinitiationphasevisittoweek76.Theseendpointswere

metifsignificantly≥40%ofpatientsgained≥15lettersand ifsignificantly≥50%ofpatientshadameantreatmentin- tervalof≥8weeks.

Secondary endpoints includedmean change in BCVA andCRTfrombaselinetoweeks24,52,and76;thenum- berofinjectionsfrombaselinetoweek76;andthemean treatment intervalfrom baseline to week76.Otherend- pointsreportedincludedtheproportionofpatientswholost

<15letters.Thefollowingposthocanalyseswerealsocon- ducted:theproportionofpatientswhoachievedalastac- tual(definedasthelengthoftheintervalbeforestudyend [last])andlastintendedtreatmentinterval(definedasthe nextplannedinterval[nextplanned])of≥8weeksandthe proportionofpatientswhohad aBCVAof≥70lettersat allmandatorystudyvisits.Safety wasassessedthroughout the study period. Adverse events (AEs)were treatment- emergent iftheyoccurredorworsenedafter thefirstIVT- AFLdoseand,atmost,30daysafterthelastdose.AllAEs werereportedincasereportformsandcodedusingMedi- cal DictionaryforRegulatoryActivities,edition22.0.An adjudicationofAEsaccordingtotheAntiplateletTrialists’

Collaborationcriteriawasalsoperformed.

• STATISTICAL ANALYSIS: Study success required that a gainof≥15lettersatweek76wasreachedbysignificantly morethan40%ofpatientsandthatameantreatmentin- tervalof≥8weekswasreachedbysignificantlymorethan 50%ofpatientsduringthetreat-and-extendphase.Theex-

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act1-samplebinomialtestwasusedtoassesseachoftheco- primaryefficacyvariablesatasignificancelevelof5%(2- sidedtest)usingthefullanalysisset(FAS),and95%confidenceintervals(CIs)wereprovided.Asamplesizeof150 patientswascalculatedtoprovideapowerof≥90%tomeet bothco-primaryendpoints,assumingatrueprobabilityfor gaining≥15lettersof55%andatrueprobabilitytoreach ameantreatmentintervalof≥8weeksof65%.Allother variableswereanalyzedbydescriptivestatisticalmethods, andfrequencytablesweregeneratedforcategoricaldata.

Thesafetyanalysissetincludedallenrolledpatientswho receivedIVT-AFL.TheFASincludedallenrolledpatients whoreceivedIVT-AFL,hadabaselineBCVAassessment, and had at least 1 post-baseline BCVA assessment. The primary efficacy analysis was conducted using the FAS.

Theper-protocolset(PPS)includedall enrolledpatients whoreceivedIVT-AFL,had aBCVAassessmentatstudy baseline,had at least 1 BCVA assessmentatweek 24or later,anddidnothaveamajorprotocoldeviation.Theco- primaryefficacyvariablesensitivityanalysiswasconducted usingthePPS.Statisticalevaluationwasperformedusing StatisticalAnalysis Systemversion9.4software(SASIn- stitute,Cary,NorthCarolina,USA).

RESULTS

• PATIENTS:Ofthe244patientswhowereenrolled,162 completed screening and entered the treatment period.

Two patients had no post-baseline assessments available andwere notincludedin theFAS.Overall, 150 patients (92.6%) completed the study. The reasons for studydis- continuation were death (n=4), withdrawal by patient (n=3),AEs(n=2),physiciandecision(n=2),andlost tofollow-up (n=1).In total,147patientswereincluded inthePPS(Figure1).

Theoverallmean±SDagewas66.2±13.4years,and 60.0%ofpatientsweremale(Table1).Atbaseline,mean

±SDBCVAwas51.9±16.9lettersandCRTwas759.9± 246.0µm.

• TREATMENTEXPOSURE: Patientsreceivedamean5.3± 0.7(baselineto week 24), 3.9±1.3(weeks 24-52), and 3.0±1.3(weeks52-76)IVT-AFLinjections.Ofthosewho completedtreatment(n=150),themeantreatmentinter- valinthetreat-and-extendphasewas7.6±1.9weeks,and themeanlengthofthelastandnextplannedtreatmentin- tervalswere9.3±3.5weeksand9.7±3.8weeks,respectively.Overall,25.6%(n=41)and36.9%(n=59)ofpa- tientsachievedalastandanextplannedtreatmentinterval of≥12weeks,respectively.

• EFFICACY: Intotal,105patients(65.6%;95%CI,57.7- 72.9; P <.0001 [test against threshold of 40%]) gained

≥15lettersfrombaselinetoweek76.Overall,72patients (45.0%;95%CI,37.1-53.1;P=.8822[testagainstthresh-

old of50%]) achieved amean treatment interval of ≥8 weeksduringthetreat-and-extendphase.Additionally,101 patients(63.1%)achievedalastand108patients(67.5%) achievedanextplannedtreatmentintervalof≥8weeks.

Asensitivityanalysisofthecoprimaryefficacyvariables conducted using the PPS provided results similar to the primaryanalysisoftheFAS:98patients(66.7%;95%CI, 58.4-74.2)gained≥15lettersfrombaselinetoweek76and 70patients(47.6%;95%CI,39.3–56.0)achievedamean treatmentintervalof≥8weeksduringthetreat-and-extend phase.

Clinically meaningful improvements in mean BCVA wereobservedatallmandatoryvisits.Mean±SDBCVA was51.9±16.8lettersatbaselineand72.3±18.5letters atweek76(meanchange:+20.3±19.5letters)(Figure2).

Overall,112patients(70.0%gained≥15letters,and153 patients(95.6%)maintainedvision(<15lettersloss)from baseline to week76in theFAS (lastobservationcarried forward).CategoricalBCVAgainsandlossesfrombaseline toweek76areshowninSupplementalFigure1.

In aposthocanalysis oftheFAS,22patients(13.8%) hadabaselineBCVAof≥70letters(20/40Snellenequiv- alent), which increased to 107 patients (66.9%)at week 76(lastobservationcarried forward).Overall, 96patients (60.0%)includedintheFAShadaBCVAof≥70lettersat allmandatorystudyvisits(weeks24,52,and76).

Clinically meaningful improvements in mean CRT were observed atall mandatory visits. Mean± SDCRT decreased from759.9±246.0µmatbaselineto265.4± 57.9µmatweek76(meanchange:−496.1±252.4µm) (Figure3).

• SAFETY: Intotal,131patients(80.9%)reportedatleast 2treatment-emergentAEs(TEAEs)duringthestudy,and these TEAEs were predominantly mild or moderate in severity (Table 2).Overall, 90 patients(55.6%) reported ocularTEAEsinthestudyeye,themostcommonofwhich werereducedVA(24patients;14.8%),increasedintraoc- ular pressure (20 patients; 12.3%), conjunctival hemor- rhage (15 patients; 9.3%), and retinal ischemia (15 patients;9.3%).Nocasesofendophthalmitiswerereported.

AlistingofocularTEAEs≥1%inthestudyeyeisreported inSupplementalTable2.

Serious TEAEs were reported in 32 patients (19.8%), and 8 patients (4.9%)experienced seriousocular TEAEs in the study eye. One case of intraocular inflammation, iridocyclitis, and 1 case ofretinalartery occlusion(0.6%

each)wereassessedasseriousTEAEsrelatedtoIVT-AFL.

In total, there were 4 deaths reported; one patient had anAntiplateletTrialists’Collaborationevent(pulmonary embolism;thepatientalsoexperiencedalowerrespiratory tract infection and atrial flutter). The other 3 deaths reportedly were due to B-cell lymphoma, intestinal per- foration, and pneumonia (n=1 each).Two deaths were treatment-emergent, and none were assessed as being relatedtoIVT-AFL.

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TABLE1.PatientBaselineDemographicsandDisease Characteristics

Characteristic IVT-AFLN=160

Meanage,years(SD) 66.2(13.4)

Agerange,years,n(%)

18–64 62(38.8)

65–84 87(54.4)

≥85 11(6.9)

Sex,n(%)

Male 96(60.0)

Race,n(%)

White 152(95.0)

Asian 3(1.9)

Black 1(0.6)

Notreported 4(2.5)

MeanBVCAETDRSletters,(SD) 51.9(16.9)

MeanCRT,µm(SD)^a 759.9(246.0)

WeekssinceCRVOdiagnosis,n(%)^b

0 3(1.9)

1 35(22.3)

2 43(27.4)

3 21(13.4)

4 13(8.3)

5 8(5.1)

6 9(5.7)

7 5(3.2)

8 3(1.9)

9 3(1.9)

≥10 17(10.8)

Meanrefractionsphere,diopters(SD) 1.8(1.7) Capillarynon-perfusiononFA,n(%)

No 149(93.1)

Yes 11(6.9)

Locationofcapillarynon-perfusiononFA,n(%)

Q1,Q2,Q3,Q4 6(3.8)

Q2,Q3 3(1.9)

Q3 2(1.3)

Gonioscopy,n(%)

Normal 148(92.5)

Abnormal 9(5.6)

Missing 3(1.9)

an=158

bn=157.

Fullanalysisset.BVCA=best-correctedvisualacuity;CRT=centralreti- nalthickness;CRVO=centralretinalveinocclusion;ETDRS=EarlyTreat- ment Diabetic Retinopathy Study; FA=ﬂuorescein angiography; IVT- AF=intravitrealaﬂibercept;Q=quadrant;SD=standarddeviation.

DISCUSSION

CENTERAwasamong the first studiesto evaluate IVT- AFLadministeredinatreat-and-extenddosingregimenfor thetreatmentofmacularedemasecondarytoCRVOona relativelylargescale.

This study showed that IVT-AFL administered in a treat-and-extenddosingregimenimprovedfunctionaland anatomic outcomes in patients with macular edema sec- ondarytoCRVOover76weeks.Overall,66%ofpatients gained≥15lettersfrombaselinetoweek76;conversely,the proportionofpatientswhoachievedameantreatmentin- tervalof≥8 weeksbetweenthelastinitiation phasevisit

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FIGURE2. MeanchangeinBCVAfrombaselinetoweek76.Fullanalysisset;lastobservationcarriedforward.Errorbarsare 95%confidence intervals. BCVA=best-corrected visualacuity; ETDRS=Early Treatment DiabeticRetinopathy Study; IVT- AF=intravitrealaflibercept;SD=standarddeviation.

FIGURE3. MeanchangeinCRTfrombaselinetoweek76.Fullanalysisset;lastobservationcarriedforward.Errorbarsare95%

confidenceintervals.Changeatweek4,n=156;n=157atweek8;andn=158atweeks24,52,and72.CRT=centralretinal thickness;IVT-AFL=intravitrealaflibercept;SD=standarddeviation.

andweek76didnotreachstatisticalsignificance.Thero- bustnessoftheseresultswasfurtherdemonstratedinasen- sitivityanalysisofthePPS.

Althoughfewer thanhalf ofpatientsachieved amean treatmentintervalof≥8weeks,posthocanalysisdemon- stratedthat63%and68%ofpatientsachievedalastand nextplannedtreatmentintervalof≥8weeks,respectively.

Functional and anatomic improvements were achieved with amean of5 injections(baselineto week24), 4 injections(weeks24-52),and3injections(weeks52-76).As

expected with the treat-and-extend treatment paradigm, treatmentburden washighest duringtheinitiationphase and decreasedovertime.Thedownward trendin thein- tensityofthetreatmentpatternthroughtotheendofthe studyfurthersupportsthenotionthatameantreatmentin- tervalof≥8 weeksbetweenthelastinitiation phasevisit and week76mighthavebeenmetwiththeimplementa- tionofalongerobservationperiod.

ClinicallymeaningfulimprovementsinBCVAwereob- served atallmandatorystudyvisits, with ameanchange

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TABLE2.SafetyOverviewatWeek76

Numberofpatients(%)

IVT-AFL N=162

AnyAE 134(82.7)

AnyocularAE 103(63.6)

AnyTEAE 131(80.9)

AnyocularTEAE 98(60.5)

AnyocularTEAEinthestudyeye 90(55.6)

AnyocularTEAEinthefelloweye 56(34.6)

Anynon-ocularTEAE 106(65.4)

AnyTEAErelatedtostudydrug 6(3.7)

AnyTEAErelatedtoIVTinjectionprocedure 48(29.6)

AnyTEAErelatedtootherproceduresrequiredbytheprotocol 10(6.2) MaximumintensityforanyTEAE

Mild 41(25.3)

Moderate 70(43.2)

Severe 20(12.3)

OcularTEAEsinthestudyeye≥5%

Visualacuityreduced 24(14.8)

Increasedintraocularpressure 20(12.3)

Conjunctivalhemorrhage 15(9.3)

Retinalischemia 15(9.3)

Macularedema 10(6.2)

Foreignbodysensation 9(5.6)

Retinalhemorrhage 9(5.6)

Vitreousdetachment 9(5.6)

AnySAE 37(22.8)

Anytreatment-emergentSAE 32(19.8)

Anytreatment-emergentSAErelatedtostudydrug^a 2(1.2)

Anytreatment-emergentSAErelatedtoIVTinjection^aprocedure 2(1.2) Anytreatment-emergentSAEcausallyrelatedtootherproceduresrequiredbytheprotocol0

DiscontinuationofstudydrugduetoAEs 6(3.7)

DiscontinuationofstudydrugduetoTEAEs 2(1.2)

AnyAPTCevent 1(0.6)

Anydeaths 4(2.5)

Anytreatment-emergentdeaths 2(1.2)

aBothcaseswererelatedtostudydrugandIVTinjectionprocedure.

Safetyanalysisset.AE=adverseevent;APTC=Anti-PlateletTrialists’Collaboration;IVT=intravitreal;IVT- AFL=intravitrealaﬂibercept;SAE=seriousadverseevent;TEAE=treatment-emergentadverseevent.

from baseline of +20 letters at week 76. Results of a post hoc analysis showed that, by week 76, 67% of patients had a BCVA of ≥70 letters, which is a threshold formaintaining a driving license in many countries.

Clinicallymeaningfulimprovementsinanatomicoutcomes were also observed at all mandatory study visits, with a mean change in CRT of−496 µmat week 76.Most of the reduction in CRT was seen following the first IVT- AFLinjection(−462µmatweek4).Itisalsoworthnot- ing that73% of patients were treated within4 weeksof diagnosis. The safety profile of IVT-AFL was consistent with that in previousstudies.⁸^, ⁹ Notably, therewere no cases of endophthalmitis and only 1 case of intraocular inflammation.

The functional and anatomic outcomes achieved in CENTERA usinga treat-and-extend regimenare similar to those seenin otherstudies ofIVT-AFL with monthly orPRNdosing.⁸^,⁹^,¹²^,¹⁵ThemeanchangeinBCVAfrom baselinetoweek24was+20lettersinCENTERA,+17let- tersinCOPERNICUS,⁷ +18lettersinGALILEO,¹⁰ +19 lettersinSCORE-2:StudyofCOmparativeTreatmentsfor REtinalVeinOcclusion2,¹⁵and+13lettersinLEAVO.¹² The meanchange in CRTfrombaseline toweek 52was

−481µminCENTERA,−413µminCOPERNICUS,and

−424µmGALILEO⁸^,⁹.

MostpatientsintheCENTERAstudyhadnonischemic CRVO (93%). In the COPERNICUS⁷ and VIBRANT:

StudytoAssesstheClinicalEfficacyandSafetyofIntravit-

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realAfliberceptInjection(IAI;EYLEA®;BAY86-5321)in PatientsWithBranchRetinalVeinOcclusion¹⁶ studiesof IVT-AFL,asmallerproportionofpatientshadnonischemic disease,67.5%and60.4%,respectively.Inall3studies,patients showedimprovements in functional and anatomic outcomes,thereforeindicatingthatIVT-AFLtherapywas effectiveinpatientswithbothischemicandnonischemic CRVO.

The importance of differentiating fluid compartments isgainingincreasing attention in neovascularage-related macular degeneration (nAMD), whereby fluid compartments have been shown to have differential effects on functionaloutcomes.¹⁷ Itisfeasiblethattoleranceofanti- VEGF-resistantfluidinspecificcompartments(suchassub- retinalfluid)mayallowextensionofintervalswhilemain- taininggoodfunctionaloutcomes.However,theimpactof suchanapproachonthetreatmentofmacularedemasec- ondarytoCRVOhasyettobeexplored.Additionally,possi- blymoresothaninnAMD,thetreatmentburdeninCRVO significantlylessensovertimeasthediseaseappearstosta- blize moreeffectively,potentiallyenabling further exten- sionoftreatmentintervalsasthediseasestabilizes.

Further data, including those from the LEAVO study, suggestthatalowertreatmentintensitymayhaveadetri- mentalimpact onfunctional outcomes.Itis possiblethat thelowernumberofinjectionsthrough52weeksinLEAVO compared with those in CENTERA (approximately 7.0 vs.9.2injections,respectively)allowedforpersistentfluid and more recurrence.Initial monthly dosagesfor CRVO mayneedtobemoreprotractedthanthetypicaltreatment scheduleof3initialmonthlydosesinnAMD.

Publishedstudies,includingLEAVO,¹²havealsodemon- stratedthesuperiordurabilityofIVT-AFLcomparedwith ranibizumab,asshownbythelowermeannumberofinjec- tionsover100weekswith IVT-AFL(10.0vs. 11.8injec- tions,respectively).However,thevisiongainsinLEAVO at100weeks(+15lettersforIVT-AFL)werenotashigh asthosereportedinCENTERAat76weeks(+20letters), possiblysupportingtherequirementforproactivetreatment (suchastreat-and-extend)inpatientswithCRVO.

This studyhadanumber ofstrengths,including ahigh statistical power of ≥90%, inclusion of a broad range of baselinevisual function (73-24ETDRS letters;20/40- 20/320 Snellen equivalent)and early initiation of treatment.Limitationsofthisstudyarethatitwasasingle-arm studywithnoactivecomparator,thuspotentiallylimiting interpretationoftheresults.However,thesingle-armde- sign waschosen to evaluate the utilityof the treat-and- extend regimen in patients with CRVO, asthis regimen has notpreviously been analyzed in largeclinical studies withinthispatientpopulation.Furthermore,analysisofthe lastandnextplannedtreatmentintervalswasposthocin nature,whichlimitedinterpretationofthedata.

Overall, clinicallymeaningfuland significantimprove- mentsinfunctionalandanatomicoutcomeswereachieved withIVT-AFLadministeredusingatreat-and-extendregi- meninpatientswithmacularedemasecondarytoCRVO.

Treatmentintervalswerealsoextended,andmostpatients achievedalastandnextplannedtreatmentintervalof≥8 weeks.

All authorshavecompleted and submittedtheICMJE FormforDisclosureofPotentialConflictsofInterest and nonewerereported.

CENTERA(EvaluationofaTreatandExtendRegimenof Intravitreal Aflibercept forMacular EdemaSecondary to CRVO;NCT02800642)evaluatedtheefficacyandsafetyof intravitrealaflibercepttreat-and-extenddosinginpatients withmacularedemasecondarytocentralretinalveinocclu- sion.Overall,clinicallymeaningfulimprovementsinfunc- tional and anatomicoutcomes were achieved.Treatment intervalswereextended,andmostofthepatientsachieved last and next planned treatment intervals of ≥8 weeks.

These results support the use of intravitreal aflibercept treat-and-extenddosinginpatientswithmacularedemain centralretinalveinocclusionwithinclinicalpractice.

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FUNDING/SUPPORT:ThisstudywassponsoredbyBayerAG,Leverkusen,Germany.Medicalwritingandeditorialsupportforthepreparationofthis manuscriptwasfundedbyBayerConsumerCareAG,Switzerland.BayerAGparticipatedinthedesignandconductofthestudy;collection,management, analysis,andinterpretationofthedata;preparation,review,andapprovalofthemanuscript;anddecisiontosubmitthemanuscriptforpublication.

FINANCIALDISCLOSURES:J-FKisa:consultantforAlcon,Allergan,Bayer,Kanghong,Krys,NanoRetina,Novartis,NovoNordisk,Roche,Théa, andZeiss;MLhasservedasastudyinvestigatorandconsultant,andtheRigshospitalethasreceivedcompensationforclinicaltrials:AbbVie,Novartis, Bayer,NovoNordisk,Allergan,GlaxoSmithKline,SparkTherapeutics,Oculis,Biogen,AstraZeneca,andAcucela;NE:isaconsultantforRoche,Bayer, Novartis,andAllergan;andhasreceivedgrantsupportfromBayerandNovartis;CBisanadvisoryboardmemberandspeakerforBayer,Novartis,Alimera Sciences,andRoche;SWisaconsultantforAllergan,Bayer,HeidelbergEngineering,Novartis,Optos,Zeiss,andRoche;andhasreceivedgrantsupport fromHeidelbergEngineering;TSisanemployeeofBayerAG,Berlin,Germany;andownsstockinBayerAG;HAisanemployeeofBayerConsumerCare AG,Basel,Switzerland;VCisascientificadvisorforAlconLaboratories,BayerHealthcare,andNovartisPharmaAG;andhasreceivedgrantsupport fromAllergan,BayerHealthcare,andNovartisPharmaAG;J-FK,ML,NE,CB,SW,andVCareCENTERASteeringCommitteemembers.

Acknowledgments:Theauthorsthankthepatientsandinvestigatorswhoparticipatedinthestudy.Medicalwritingandeditorialsupportforthe preparationofthismanuscript,undertheguidanceoftheauthors,wasprovidedbyCharlotteHead,ApotheCom,UK,andwasfundedbyBayerConsumer CareAG,Switzerland.

AuthorContributions:Allauthorscontributedtotheconceptualizationofthestudydesign,datacuration,investigation,visualization,andprovided criticalreviewofthemanuscript.

Accesstodataanddataanalysis:AvailabilityofthedataunderlyingthispublicationwasdeterminedaccordingtoBayer’scommitmenttotheEuropean FederationofPharmaceuticalIndustriesandAssociations(EPFIA)/PharmaceuticalResearchandManufacturersofAmerica(PhRMA),Principlesfor ResponsibleClinicalTrialDataSharing.Thispertainstoscope,timepoint,andprocessofdataaccess.

Assuch,Bayercommitstosharing,uponrequestfromqualifiedscientificandmedicalresearchers,patient-levelclinicaltrialdata,study-levelclinical trialdata,andprotocolsfromclinicaltrialsinpatientsformedicinesandindicationsapprovedintheUnitedStates(US)andEuropeanUnion(EU)as necessaryforconductinglegitimateresearch.ThisappliestodataonnewmedicinesandindicationsthathavebeenapprovedbytheEUandUSregulatory agenciesonorafterJanuary1,2014.

Interestedresearcherscanusewww.clinicalstudydatarequest.comtorequestaccesstoanonymizedpatient-leveldataandsupportingdocumentsfrom clinicalstudiestoconductfurtherresearchthatcanhelpadvancemedicalscienceorimprovepatientcare.InformationontheBayercriteriaforlisting studiesandotherrelevantinformationisprovidedintheStudysponsorssectionoftheportal.

Dataaccesswillbegrantedtoanonymizedpatient-leveldata,protocolsandclinicalstudyreportsafterapprovalbyanindependentscientificreview panel.Bayerisnotinvolvedinthedecisionsmadebytheindependentreviewpanel.Bayerwilltakeallnecessarymeasurestoensurethatpatientprivacy issafeguarded.

CENTERAstudyinvestigators:Dr.JosepCallizo;Prof.GerdAuffarth;Dr.HuesnueBerk;Dr.Maria-AndreeaGamulescu;Dr.NicoleEter;Prof.Arthur Mueller;Dr.FanniMolnar;Prof.Dr.RainerGuthoff;Prof.MatusRehak;Dr.AmeliePielen;Prof.AlbertAugustin;Dr.HakanKaymak;Prof.Ulrich Kellner;Dr.ClareBailey;Dr.JigneshPatel;Dr.FaruqueGhanchi;Dr.AhmedKamal;Dr.SrilakshmiSharma;Dr.MagedHabib;Prof.Jean-François Korobelnik;Prof.CatherineCreuzot-Garcher;Prof.LaurentKodjikian;Prof.FedericoRicci;Prof.CesareMariotti;Prof.FrancescoBandello;Dr.Monica Varano;Prof.EdoardoMidena;Prof.GiovanniStaurenghi;Prof.MarcoNardi;Dr.IsaacAlarcónValero;Dr.Jose-JuanEscobarBarranco;Dr.Álvaro Fernandez-VegaSanz;Dr.LauraSararolsRamsay;Dr.MonicaAsencioDuran;Dr.CatalinaEsmeradoAppiani;Dr.LaurentLalonde;Dr.JohnGonder;

Dr.MichelGiunta;Dr.VarunChaudhary;Dr.MichaelFielden;Dr.SergeBourgault;Dr.KarimHammamji;Prof.MichaelLarsen;Prof.HenrikVorum;

Dr.JenniferArnold;Dr.AndrewChang;andDr.AlanLuckie.

SUPPLEMENTARY MATERIALS

Supplementarymaterialassociatedwiththisarticlecanbe found,intheonlineversion,atdoi:10.1016/j.ajo.2021.01.

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