1. The Diabetic Retinopathy Clinical Research Network
Treatment for Central-involved DME in Eyes with Very Good Visual Acuity
Presenter: Carl W. Baker, MD

2. OCT CSF = 358 ETDRS VA Letter Score = 83 (20/25)

3. Clinical Question
What 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
If VA worsens, begin anti-VEGF
Observe
If DME worsening on OCT, begin anti-VEGF or laser

4. 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

5. What do we already know?
In ETDRS – 20/25 or better eyes with CI-DME that lost 5 or more letters at 2 years
Focal laser  27%
Observation  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

6. Available 2 Year Data Summary
ETDRS
Focal
Observation
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%
VA Change from Baseline
Median (25th , 75th)
-1 (-5, 2)
-3 (-10, 1)
5 (1, 9)
NMB - Out of curiosity and teaching of our investigators; could we make another slide that shows what happens in the PRP arm of this cohort in the ETDRS – since so many retina specialists want to do PRP for persistent DME

7. ETDRS and Protocol I Data*: Percent with VA loss ≥ 5 letters
*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

8. Study 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?

9. Study 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?

10. Study Design Randomized, multi-center clinical trial
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*
No prior treatment for DME
Prompt
anti-VEGF
Prompt laser + deferred anti-VEGF
Observation + deferred anti-VEGF
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)

11. Outcome Measures Primary Outcome Secondary Outcomes
% 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

12. 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 ranibizumab 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

13. Treatment Groups: Prompt Laser + Deferred Anti-VEGF
Treatment Group Description:
Focal/grid laser at randomization
Anti-VEGF only initiated if protocol criteria met (to be discussed)
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

14. 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 14

15. Outcome Estimates Prompt anti-VEGF group Deferred anti-VEGF groups
Based on Protocol I data, we estimate ~ 5% of eyes in this study that receive prompt anti-VEGF treatment will lose ≥5 letters.
Deferred anti-VEGF groups
In protocol I, ~50% of eyes that were 20/32 at baseline (with or without prior laser) gained ≥5 letters at 2 years. Therefore, approximately half of the eyes in the deferred groups that lose ≥5 letters by 2 years would regain the 5 letters after anti-VEGF therapy.
Using ETDRS data for the estimate of % with ≥5 letter loss and taking into account that ~50% will regain vision after anti-VEGF, we estimate ~ 10% in the laser group and ~17% in the observation group will have ≥5 letter loss

16. Major 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
No history of prior DME treatment
Non-study eye:
Investigator must be willing to use (or switch to using) study aflibercept on the non-study eye if needed 16

17. VA 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

18. OCT and VA Minimizing misclassification
Requiring two separate measures of VA and OCT on two separate days will minimize the chances of classifying an eye as having DME with good VA, when the eye actually has poorer vision or no DME
Reducing regression to the mean effect
Using an average of the two measurements as the “baseline” will provide a truer measure of the real VA/OCT thickness at the start of the study making assessments of change (e.g. outcome) more accurate

19. Major 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 or anticipated need for intravitreal anti-VEGF for an ocular condition other than DME

20. OCT CSF = 400 VA Letter Score = 89 ERM present
EXCLUDED

21. Baseline 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
Spectral domain preferred (Cirrus and Spectralis only) but Stratus allowed if SD unavailable
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

22. Baseline 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
The same lab or DCA Vantage must be used at baseline and follow-up

23. FA 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

24. Randomization Form Before submitting, investigator MUST
Confirm eligibility
Confirm patient’s willingness to accept any of the treatment assignments and to complete all treatment/follow-up
This is particularly important in this study since the treatment approaches are so varied (no treatment vs injection in the eye)
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

25. Randomization
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

26. Follow-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

27. Follow-up Testing All 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

28. 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

29. Retreatment Criteria Once Anti-VEGF Initiated (either at baseline or when criteria met)
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 then inject only if before 24-wk visit when OCT is >250 µm or VA worse than 20/20

30. Principles of DRCR.net DME Intravitreal Anti-VEGF Treatment Are you sure the eye is stable?
When eye is stable after at least 2 consecutive injections and OCT CSF is <250 µm and VA is 20/20 or better  Defer injection
When eye is stable after at least 2 consecutive injections and OCT CSF is ≥250 µm or VA is worse than 20/20:
Prior to the 24-week visit  Inject
≥ 24-week visit  Defer injection

31. Principles of DRCR.net DME Intravitreal Anti-VEGF Treatment
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

32. 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

33. Injection 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

34. 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 ≥250 µm (or SD equivalent) 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
Edema threatening the fovea is defined as edema within 500 microns of the foveal center or edema associated with lipid within 500 microns of the foveal center or ≥ 1 disc area of edema the posterior edge of which is within 1 disc diameter of the foveal center

35. Focal/Grid Laser Re-Treatment
Once 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 <250 and there is no edema threatening the fovea
Complete focal/grid laser has been given already
The OCT or VA has improved since the last laser
NMB - What about no treatable lesions (e.g., all leaks are wihtin 500 microns and the VA is 20/20?)

36. Complete the Visit Instructions
Because the eye is stable for only one visit or is worsening sine 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.

37. 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

38. Use 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

39. Case Example: Prompt Anti-VEGF Group
Week 4 8 12 16 20 24 28 32 36 40 44 48
OCT
300
245
249
242
245
249
275
245
245
247
249
249
245 VA
20/25
20/20
20/20
20/20
20/20
20/20
20/32
20/20
20/20
20/20
20/20
20/20
20/20
Category -- I Su Su Su Su W I Su Su Su Su Su
A-VEGF
Laser
Deferred while Success
Deferred while Success
Required due to worsening
Required due to improvement
Required 1st time success
Required 1st time success
NMB: Add and 36-week individually; then can be grouped
Required due to improvement
I = improved: OCT CSF decreased by >10% or VA LS improved by >5
W= worsened: OCT CSF increased by >10% or VA LS worsened by >5
St = 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

40. Case Example: Laser+Def Anti-VEGF
Week 8 16 32 36 40 44 48
OCT
300
275
275
325
325
260
255
255 VA
20/25
20/25
20/25
20/32
20/32
20/20
20/20
20/20
Category -- -- -- -- -- I St St
A-VEGF
Laser
Return in 4 weeks to re-check VA
Required 1st time stable
VA still decreased; initiate anti-VEGF
2nd time stable but <24w
I = improved: OCT CSF decreased by >10% or VA LS improved by >5
W= worsened: OCT CSF increased by >10% or VA LS worsened by >5
St = 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

41. Case Example: Observe+Def Anti-VEGF
Week 8 16 24 28 32 36 40 44 48
OCT
300
325
400
400
325
300
260
260
255
250 VA
20/25
20/25
20/25
20/40
20/32
20/25
20/25
20/20
20/20
20/20
Category -- -- -- -- I I I I St St
A-VEGF
Laser
> 10% worsening on OCT; return in 8 weeks
Inject due to improvement
Required 1st time stable
VA decreased 10 letters; initiate anti-VEGF
Defer 2nd time stable ≥24w
I = improved: OCT CSF decreased by >10% or VA LS improved by >5
W= worsened: OCT CSF increased by >10% or VA LS worsened by >5
St = 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

42. 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

43. ***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 protocol
Listen to the coordinator
Verify patient has reliable means of transportation to study site
Consider travel distance and patient’s other health conditions

44. Timeline to Start
Enrollment anticipated to begin last week in October

45. 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

46. Time to complete enrollment Enrollment Completed /
Recruitment Timeline
Sample Size = 702 participants
# subjects per site
Time to complete enrollment
Enrollment Completed /
2 Year F/U completed
1 per month
10 months
Aug 2014 / Aug 2016
1 every other month
20 months
June 2015 / June 2017
1 per quarter
30 months
Apr 2016 / Apr 2018
*Based on ~70 participating sites