The Diabetic Retinopathy Clinical Research NetworkThe Diabetic Retinopathy

Clinical Research Network

Treatment for Central-involved DME in Eyes with Very Good Visual Acuity

Presenter: Carl W. Baker, MD

11

OCT CSF = 358

ETDRS VA Letter Score = 83

(20/25)

OCT CSF = 358

ETDRS VA Letter Score = 83

(20/25)

22

Clinical QuestionClinical QuestionWhat is the best treatment strategy for eyes with

central-involved (CI) DME and good visual acuity?Possible treatment approaches in clinical

practice:• Initiate intravitreal anti-VEGF promptly• Initiate focal/grid laser promptly

o If VA worsens, begin anti-VEGF

• Observeo If DME worsening on OCT, begin anti-VEGF or lasero If VA worsens, begin anti-VEGF

33

What do we already know?What do we already know?

In Protocol I, ranibizumab + deferred or prompt laser for CI-DME provided VA outcomes superior to prompt focal/grid laser alone• Only eyes with VA letter score ≤78 (20/32 or

worse) were enrolled• Anti-VEGF has not been evaluated in eyes that

have CI-DME with VA 20/25 or better

44

What do we already know?What do we already know?

In ETDRS – 20/25 or better eyes with CI-DME that lost 5 or more letters at 2 years

o Focal laser 27% oObservation 40%

• OCT not available to closely follow improvement or worsening of DME

• Clinical characteristics of the cohort may have changed since the time of ETDRS

• Deferred Anti-VEGF as a rescue treatment not evaluated as part of treatment approach

55

Available 2 Year Data SummaryAvailable 2 Year Data Summary

66

ETDRSFocal

ETDRSObservation

Protocol I Ranibizumab

+ Deferred Laser

Eyes with VA ≥20/25 or better at baseline

VA = 20/32 at baseline

N = 118 N = 246 N = 28

Visual Acuity Decrease by Letter Score of 5 or More

27% 40% 4%

Visual Acuity Decrease by Letter Score of 10 or More

13% 25% 0

VA Change from Baseline

Median (25th , 75th) -1 (-5, 2) -3 (-10, 1) 5 (1, 9)

ETDRS and Protocol I Data*: Percent with VA loss ≥ 5 lettersETDRS and Protocol I Data*:

Percent with VA loss ≥ 5 letters

77*ETDRS study eyes with CI-DME and VA 20/25 or better at baseline. Protocol I study eyes with CI-DME and VA = 20/32 at baseline

0

5

10

15

20

25

30

35

40

45

0 4 8 12 18 20 24

Perc

en

t

Months

ETDRS Laser Group

ETDRS Observation Only

DRCR.net I Ranibizumab+deferred laser N= 231

N= 110

N= 237

N= 113

N= 246

N= 118

N = 28 N = 26

Study QuestionsStudy Questions In eyes with good VA, is deferring anti-VEGF similar,

better, or worse than prompt anti-VEGF for long-term visual acuity outcomes?• If similar or better, how long can you defer anti-

VEGF?• What % never need anti-VEGF?

If deferring anti-VEGF, is it better to observe or give focal/grid laser?• Does one provide better VA outcomes?• Does one allow for fewer anti-VEGF injections?

88

Study QuestionsStudy Questions

If prompt anti-VEGF is better, does it have enough of a benefit to warrant risks of repeated intravitreal injections?• How many injections are needed to maintain

20/20 vision?• Are fewer injections needed in the long run

than if you wait until after VA or OCT decline to initiate anti-VEGF?

99

1010

Prompt laser + deferred anti-VEGF

Observation + deferred anti-VEGF

At least one eye meeting all of the following criteria:• Central-involved DME on OCT (Cirrus/Spectralis only)*

• VA letter score 20/25 or better*

• Minimal prior treatment for DME **

Prompt anti-VEGF

Study DesignStudy DesignRandomized, multi-center clinical trial

Primary outcome: Proportion of eyes that have lost ≥5 letters of VA at 2 years

Primary outcome: Proportion of eyes that have lost ≥5 letters of VA at 2 years

*Confirmed at 2 visits (screening and randomization 1-28 days apart)**No more than 1 laser and/or 4 injections, at least 12 months ago

Outcome MeasuresOutcome MeasuresPrimary Outcome

% with VA loss of ≥ 5 letters at 2 years

Secondary Outcomes Mean change in VA letter score % with at least 10 and 15 letter VA gain/loss Visual acuity area under the curve Mean change in OCT CSF thickness % with 1 or 2 log step gain or loss on OCT Number of injections/lasers performed Worsening/improvement of DR severity level Low contrast visual acuity Safety outcomes 11

Treatment Groups:Prompt Anti-VEGF

Treatment Groups:Prompt Anti-VEGF

Treatment Group Description: • Intravitreal anti-VEGF (2.0 mg aflibercept) at

randomization • DRCR.net retreatment criteria during follow-up

Rationale:• Protocol I and other studies have demonstrated

that anti-VEGF is well-tolerated and more effective than laser alone in increasing vision gain and decreasing vision loss in patients with CI DME, but this benefit has not been established in eyes that have good vision despite the presence of CI DME

12

Treatment Groups:Prompt Laser + Deferred Anti-VEGF

Treatment Groups:Prompt Laser + Deferred Anti-VEGF

Treatment Group Description: • Focal/grid laser at randomization• Anti-VEGF only initiated if protocol criteria met

Rationale: • The initial use of focal/grid laser could offer

advantages over starting treatment with anti-VEGF in terms of reducing adverse events associated with intravitreal injections as well as fewer treatments given over time with potentially less frequent follow-up

13

Treatment Groups:Observation + Deferred Anti-VEGF

Treatment Groups:Observation + Deferred Anti-VEGF

Treatment Group Description: • Observation• Anti-VEGF only initiated if protocol criteria met (to be

discussed)

Rationale: • Deferral of immediate treatment might result in

decreased inconvenience, adverse events and costs associated with anti-VEGF treatments that are performed as often as once a month while potentially preserving vision in eyes with CI DME with good vision

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Major Eligibility CriteriaMajor Eligibility Criteria Type 1 or 2 diabetes Study Eye:

• Central-involved DME on clinical exam, confirmed on OCT at two consecutive visits (1-28 days apart)

• VA letter score >79 (~20/25 or better) at two consecutive visits (1-28 days apart)

• The investigator is comfortable with the eye being randomized to any of the three treatment groups

• Minimal history of prior DME treatmento No more than 1 laser, 4 injections at least 12 months ago

Non-study eye:• Investigator must be willing to use (or switch to using)

study aflibercept on the non-study eye if needed

15

VA and OCT VariabilityVA and OCT Variability

There is inherent measurement variability There may also be day to day actual variability,

particularly in patients with diabetes Two separate measurements are required to confirm

the eye truly has good vision with DME• Randomization criteria slightly relaxed for OCT central

subfield thickness (~5% less than screening cutoff), however investigator must still confirm DME on clinical exam

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Major Exclusion CriteriaMajor Exclusion Criteria Systemic

• History of chronic renal failure requiring dialysis or kidney transplant• Initiation of intensive insulin treatment (a pump or multiple daily

injections) within 4 months prior to randomization or plans to do so in the next 4 months

• BP > 180/110

Study eye• Macular edema not due to DME (eyes with thickening due to ERM, prior

cataract surgery or other non-DME reason should not be enrolled)• PRP in last 4 months or anticipated in next 6 months• History of intravitreal anti-VEGF for an ocular condition other than DME

in last 6 months or anticipated in next 6 months

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OCT CSF = 400

VA Letter Score = 89

ERM present

OCT CSF = 400

VA Letter Score = 89

ERM present

1818

EXCLUDED

Baseline Testing ProceduresBaseline Testing Procedures Visual acuity and OCT eligibility must be confirmed

at 2 visits within 1 to 28 days Screening Visit

• Refraction followed by E-ETDRS visual acuity testing using the refraction obtained in the study eye

• OCT in the study eye oCirrus and Spectralis only

• Ocular exam may be done to rule out exclusions; however, data collection and official eligibility assessment occurs at randomization

• Fundus photography may be done at screening or randomization

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Baseline Testing ProceduresBaseline Testing Procedures Randomization Visit

• Refraction followed by E-ETDRS visual acuity testing using the refraction obtained in both eyes

• Low-contrast visual acuity in the study eye (select sites)

• OCT in the study eye

• Ocular exam in both eyes

• Fundus photographs in the study eye (if not done at screening visit)

• Measurement of blood pressure

• HbA1c

o The same lab or DCA Vantage must be used at baseline and follow-up

2020

FA Sub-studyFA Sub-study Certification – each investigator will indicate whether

they routinely perform FA prior to focal/grid laser and whether they would be willing to collect FA in this study

Randomization Visit – For investigators who indicate FA will be collected• FA will be obtained on all participants at baseline

Follow-up Visits – For investigator who indicate FA will be collected• FA will be obtained at following prior to repeat focal/grid

treatment for eyes randomized to laser group

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Randomization FormRandomization Form Before submitting, investigator MUST

• Confirm eligibility• Confirm patient’s willingness to accept any of the treatment

assignments and to complete all treatment/follow-upo This is particularly important in this study since the

treatment approaches are so varied (no treatment vs injection in the eye)

o Investigator is responsible for making sure patient has been properly informed of potential risks/benefits via consent process

• Be available to perform whatever the randomized treatment is THAT DAY as applicable

2222

RandomizationRandomization Approximately 702 study eyes (one per participant)

assigned to one of the three treatment groups Stratified by site and fellow-eye DME treatment

• If the fellow eye is being seen more frequently than the study eye, it may influence the number of treatments performed in the study eye

• Rather than excluding patients that are already receiving DME treatment in the non-study eye, this will be used as a stratification factor during randomization

2323

Follow-Up ScheduleFollow-Up Schedule Total follow-up through 2 years Visit schedule will vary by treatment group and

disease progression• Prompt anti-VEGF group: visits every 4 weeks through 24

weeks, then every 4 to 16 weeks depending on whether injections are being given

• Deferred groups (observation and laser groups): visits at 8 and 16 weeks, then every 16 weeks unless vision and/or OCT are worsening or anti-VEGF is initiated (visits every 4, 8 or 16 weeks depending on disease progression and treatment)

All participants will have visits at 1 and 2 years

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Follow-up TestingFollow-up TestingAll Protocol Visits: Protocol refraction in the study eye followed by E-ETDRS

VA testing in each eye OCT on the study eye (same device as at baseline) Ocular exam on the study eye at each visit and on the non-

study eye only if study anti-VEGF treatment has been given

Additional Annual Visit Procedures: Non-study eye refraction prior to visual acuity Low-contrast visual acuity (at select sites) Fundus photography in the study eye HbA1c (also at 16 weeks)

• The same lab or DCA Vantage that was used at baseline should be used

Criteria for Initiating Anti-VEGF in Deferred Groups

Criteria for Initiating Anti-VEGF in Deferred Groups

Visual acuity worsening of at least 10 letters at one visit or 5 to 9 letters at 2 consecutive visits• If VA loss of 5 to 9 letters, subject is seen in 4 (±2) weeks to check for

continued vision loss• Requiring a second confirmation visit for 5 to 9 letter loss will

minimize initiation of treatment unnecessarily due to measurement error or other variability

• Delaying treatment for 2 to 6 weeks is not likely to be harmful to the participant

OCT worsening alone will not warrant anti-VEGF• However, subject will be seen more frequently to check for vision loss

and delaying treatment in this case is not likely to be harmful to the participant

2626

Retreatment Criteria Once Anti-VEGF Initiated

(either at baseline or when criteria met)

Retreatment Criteria Once Anti-VEGF Initiated

(either at baseline or when criteria met)

2727

Improving on OCT or VA Inject

• Improving = OCT CSF thickness decreased by ≥ 10% or VA letter score improved by ≥ 5

Worsening on OCT or VA Inject

• Worsening = OCT CSF thickness increased by >10% or VA letter score decreased by >5

Stable: not improving or worsening on OCT or VA Inject unless stable since last 2 injections OR it is before 24-wk visit and OCT is > machine-specific threshold (250 µm equivalent) or VA worse than 20/20

An eye will be considered a “failure” if after 24 weeks of anti-VEGF and at least 13 weeks since “complete” laser has been given, DME is still present on OCT and clinical exam, VA letter score is ≥ 10 letters worse than baseline at 2 consecutive visits and there has been no improvement from prior injections or laser

Once “failure” is met, treatment is at investigator discretion

Principles of DRCR.net DME Intravitreal Anti-VEGF Treatment

Principles of DRCR.net DME Intravitreal Anti-VEGF Treatment

If the investigator’s desired treatment plan deviates from the retreatment protocol, the Protocol Chair or designee must be contacted prior to deviating from retreatment protocol, including:• Desire to defer an injection when injection

indicated by protocol• Desire to inject when injection should be

deferred per protocol

Principles of DRCR.net DME Intravitreal Anti-VEGF Treatment

Principles of DRCR.net DME Intravitreal Anti-VEGF Treatment

Injection Preparation RemindersInjection Preparation Reminders Two individuals must confirm the study eye and drug

number against the printout or website Mark the eye for injection Apply topical anesthetic Place the lid speculum Apply povidone iodine directly over and surrounding the

injection site (allowing sufficient time for the povidone iodine to dry)• DRCR.net injections must NOT be given without the use of

povidone iodine in any circumstance

Pre- and post-injection topical antibiotics can be applied at the discretion of the investigator

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Focal/Grid Laser Treatment Criteria after Anti-VEGF initiated

Focal/Grid Laser Treatment Criteria after Anti-VEGF initiated

Once anti-VEGF is initiated, laser can be added at investigator discretion if:• ≥24 weeks since first anti-VEGF injection• OCT CSF is ≥machine-specific threshold or there

is edema threatening the fovea AND• The eye has not improved on OCT or VA compared

with either of the last two consecutive injections

After 24 weeks, if OCT or VA are worsening from the last two injections, laser should be given

Focal/Grid Laser Re-TreatmentFocal/Grid Laser Re-TreatmentOnce focal/grid laser has been initiated (either

at baseline for laser group or when criteria are met), retreatment with laser will be performed unless one of the following is present:• Laser has been given in <13 weeks• The OCT CSF is < machine-specific threshold (250

micron equivalent) and there is no edema threatening the fovea

• Complete focal/grid laser has been given • The OCT or VA has improved since last laser

Complete the Visit InstructionsComplete the Visit Instructions

3333

Because the eye is stable for only one visit or is worsening since the last visit, an injection of Aflibercept in the right eye must be given at this visit.

Focal/grid photocoagulation should not be performed at this visit.

Intravitreal Anti-VEGF Treatment in the Non-study Eye

Intravitreal Anti-VEGF Treatment in the Non-study Eye

If the non-study eye is treated for any condition which requires treatment with an anti-VEGF agent, study aflibercept must be used

The DRCR.net CC will provide drug for the non-study eye

If non-study eye and study eye will be injected on the same day, the study eye must be injected first

Use of Intravitreal Anti-VEGF in the Study Eye for Non-DME TxUse of Intravitreal Anti-VEGF in the Study Eye for Non-DME Tx

Use of study aflibercept for an FDA approved indication other than DME is at investigator discretion

Any off-label use of anti-VEGF for an ocular condition other than DME (e.g. PDR, vitreous hemorrhage) will require discussion with and approval by the protocol chair or designee

Study aflibercept must be used for any anti-VEGF treatment in the study eye

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Case Example: Prompt Anti-VEGF GroupCase Example: Prompt Anti-VEGF Group4 8 12 16 20 24 28 360Week

OCT

VA

I = improved: OCT CSF decreased by >10% or VA LS improved by >5W= worsened: OCT CSF increased by >10% or VA LS worsened by >5St = stable: did not improve or worsen (according to above definitions)Su = success: stable (according to above definition) AND visual acuity letter score >84 (~20/20) and OCT CSF <250µ or SD equivalent

300 245 249 242 245 249 275 245 245 247 245

20/25

20/20 20/20

20/20

20/20 20/20 20/32

20/20 20/20

20/20

20/20

A-VEGF

Laser

Category

32 40 44 48

-- I Su Su SuSu W Su

249

20/20 Su

249

20/20 Su Su

Required due to

improvement

Deferred while Success

Required due to

worseningRequired 1st

time success

I

Required due to

improvement

Required 1st time success

Su

Deferred while Success

Case Example: Laser+Def Anti-VEGFCase Example: Laser+Def Anti-VEGF8 16 360Week

OCT

VA

I = improved: OCT CSF decreased by >10% or VA LS improved by >5W= worsened: OCT CSF increased by >10% or VA LS worsened by >5St = stable: did not improve or worsen (according to above definitions)Su = success: stable (according to above definition) AND visual acuity letter score >84 (~20/20) and OCT CSF <250µ or SD equivalent

300 275 275 325 325 255

20/25

20/25

20/25

20/32

20/32

20/20

A-VEGF

Laser

Category

32 40 44 48

--

260

20/20

255

20/20

St St

Return in 4 weeks to re-

check VAVA still

decreased; initiate anti-

VEGF

-- -- -- -- I

Required 1st time stable 2nd time

stable but <24w

Case Example: Observe+Def Anti-VEGFCase Example: Observe+Def Anti-VEGF8 16 360Week

OCT

VA

I = improved: OCT CSF decreased by >10% or VA LS improved by >5W= worsened: OCT CSF increased by >10% or VA LS worsened by >5St = stable: did not improve or worsen (according to above definitions)Su = success: stable (according to above definition) AND visual acuity letter score >84 (~20/20) and OCT CSF <250µ or SD equivalent

300 325 400 300 260 250

20/25

20/25

20/25

20/25

20/25

20/20

A-VEGF

Laser

Category

32 40 44 48

--

260

20/20

255

20/20

St St

> 10% worsening on OCT; return in

8 weeks

-- -- I I I

Required 1st time stable Defer 2nd

time stable ≥24w

400

20/40

24

--

325

20/32

28

I

VA decreased 10 letters;

initiate anti-VEGF

Inject due to improvement

Observational PhaseObservational Phase Objective

• To collect additional data on the natural history of eyes with good VA and DME (when the RCT is declined)

Summary• Potential participants who are not ready/willing to be

randomized but meet certain criteria can enroll

• Collect data every 4 months while the eye is being observed

• Follow-up will continue until…

o The eye is randomized

o Treatment is given outside of the study OR

o The patient reaches 2 years from enrollment

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Enter RCT or Observational Phase?Enter RCT or Observational Phase?

Screening Visit (OCT/VA)

Randomize Ready/Eligible to Randomize?

Eligible Observational

PhaseNo

Yes

Yes

Yes

No

Ready/ Eligible to Randomize?

Completed

Receive DME Trt

Observational Phase Follow-up

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Stay Out of Trouble: Use the Computer!

Stay Out of Trouble: Use the Computer!

All visits must be entered in real time!• Menu includes required exams and

visit reminders.• Forms include visit specific

instructions (i.e. required on study eye only or both eyes)

DME treatment and visit schedule are determined for you!

Contact CC prior to any deviations from protocol treatment

***CRITICAL***Investigator AND Coordinator Role Enrolling the Correct Participants

***CRITICAL***Investigator AND Coordinator Role Enrolling the Correct Participants

Educate patient with a thorough ICF process so that they understand:• Time commitment• Treatment requirements

Assess likelihood that patient will adhere to protocolListen to the coordinatorVerify patient has reliable means of transportation to

study siteConsider travel distance and patient’s other health

conditions

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Certification Requirements Certification Requirements Site Specific• IRB approval of protocol and ICF• Contract addendum

Investigator• Completed 1572

• Protocol Q+A (80% correct or higher)• Protocol acceptance form• Protocol review teleconference w/in 2 months• Investigator brochure acknowledgment (PI only)• Competing studies form

Coordinator Requirements • Completed mock informed consent with

investigator