1. The Diabetic Retinopathy Clinical Research Network
Intravitreous Anti-VEGF Treatment for Prevention of Vision Threatening Diabetic Retinopathy in Eyes at High Risk
Investigator Training Slides 2.0
[Protocol version 1.0] 1

2. Background
Eyes with severe NPDR are at high risk for DR worsening and subsequent VA loss
52% develop PDR over 1 year
60% develop PDR with HRC over next 5 years 2

3. Background
No clear treatment mandate for severe NPDR although some eyes may benefit from early PRP
Deferred Scatter
Risk of Severe Visual Loss or Vx
Type 2
Early Scatter
10%
Type 1 5%
Type 2
P=0.43
P=0.0001 0% 1 2 3 4 5
Years
P (Interaction) =
Ferris F. Early photocoagulation in patients with either type I or type II diabetes. Trans Am Ophthalmol Soc. 1996;94:

4. More Recent Data: DRCR.net Trial Laser Groups (DME at baseline)

5. DRCR.net Protocol I: Comparison to Anti-VEGF Treated Eyes
Add “N” for each bar

6. RISE/RIDE: Risk of PDR Outcomes in Sham vs Ranibizumab Groups
Time to First Progression to PDR Outcome
3 fold higher risk in sham group
Months
Cumulative probabilities calculated using the Kaplan-Meier method. Progression was defined by (1) progression from NPDR (DR severity level < 60) at baseline to PDR (DR severity level  60) at a later time point, (2) need for PRP laser, (3) vitreous hemorrhage (AE or slit lamp grade 0 at baseline to > 0 at a later time point, (4) cases identified by ophthalmoscopy, (5) vitrectomy, (6) iris neovascularization AE, or (7) retinal neovascularization AE. 1 month = 30 days. AE, adverse event; PRP, panretinal photocoagulation.

7. Proportion of Patients Requiring PRP Proportion of patients
From Baseline to Week 100
VIVID
VISTA
Proportion of patients
Please spell out IAI
133
136
135
154
155
152
PRP: Panretinal Photocoagulation
IAI: Intravitreal Aflibercept Injection 7

8. DME Development
Eyes with severe NPDR and no CI-DME at baseline are also at risk for developing DME requiring anti-VEGF treatment
15% in ETDRS developed CI-DME on photos by 2 years
DRCR.net Protocol R included eyes with non-CI DME and any level of retinopathy and 14% developed CI-DME on OCT or required treatment by 1 year
Edits

9. Primary Objective To determine safety and efficacy of
prompt anti-VEGF versus observation in eyes presenting with severe NPDR and no CI-DME for prevention of vision threatening outcomes
Observation (sham injections)
Intravitreous anti-VEGF
NMB edits; did I define VA loss correctly?
CRS - Fine
Primary outcome: Proportion of eyes that develop PDR/PDR-related outcomes or center-involved DME causing visual acuity loss at 2 years 9

10. Follow-Up and Treatment Overview
Total duration: 4 years
Primary outcome: 2 years for anatomic outcome – if anatomic benefit through 2 years, continue follow-up through 4 years to determine if VA benefit too
Visits at 1, 2, and 4 months; every 4 months thereafter
Injections (intravitreous or sham) required at each of the above visits through 2 years
Thereafter, evaluate at each visit for retreatment:
If eye is “Mild NPDR” or better, defer injection
If “Moderate NPDR” or worse, injection is required

11. Composite Primary Outcome: Part 1 – PDR
Development of NV within the 7 modified ETDRS fields on fundus photography or FA, confirmed by Reading Center
NVI, NVA, or NVG on clinical exam
Traction retinal detachment, vitreous hemorrhage, or pre-retinal hemorrhage presumed to be from PDR, documented on fundus photography or FA
PRP, anti-VEGF, or vitrectomy for PDR, images should be obtained prior to treatment 11

12. Composite Primary Outcome: Part 2 – DME
Center-involved DME on clinical exam with ≥10% increase in central subfield thickness from baseline and visual acuity loss, defined as:
1) at least 10 letter VA loss at a single visit, or
2) 5 to 9 letter VA loss at 2-consecutive visits, presumed to be from DME
Treatment for DME performed without meeting above criteria (protocol deviation)
Note: An eye will be considered to have met the primary outcome if any one of the above PDR or DME criteria are met

13. Outcome Estimates Anti-VEGF group Observation (Sham) group
Based on Protocol I and RIDE/RISE data, we estimate ~ 15% of eyes in this study that receive the study anti-VEGF regimen will develop PDR/DME outcome.
Observation (Sham) group
Based on available data from Protocols A, B, I, we estimate ~ 30% of eyes in this study that receive no treatment will develop PDR/DME outcome.
SAMPLE SIZE  386 eyes (193 per group)

14. Long-Term Objectives
If there is a clinically important difference identified among the treatment groups for the primary outcome at 2 years, the study will also evaluate whether increased chance of prevention of PDR/DME with anti-VEGF at 2 years results in long-term beneficial visual outcomes at 4 years.

15. Rationale
The application of anti-VEGF therapy earlier in the course of disease could help to reduce future potential treatment burden in patients, at the same time resulting in similar or better long-term visual acuity outcomes.
If this study demonstrates that anti-VEGF treatment is effective and safe in the setting of severe NPDR, a new strategy to prevent vision-threatening complications will be available for patients.

16. Major Inclusion/Exclusion Criteria in Study Eye
Severe NPDR (ETDRS level 53) according to investigator
4-2-1 rule
Severe hemorrhages in at least 4 quadrants, or
Definite venous beading in at least 2 quadrants, or
Moderate IRMA in at least 1 quadrant
VA letter score 20/25 or better
No CI-DME using standard OCT thresholds
No history of DME/DR treatment in prior 12 months and <4 prior injections at any time
No prior PRP 16

17. Determining Eligibility Using Standard Photos
“All 4 midperipheral quadrants show severe hemorrhages or microaneurysms (at least as great as Standard photograph 2a, approximately 20 dot and blot hemorrhages”
Link to “Standard photograph 2a” will be available on website

18. Standard Photos
OR “At least 2 fields of definite venous beading in the midperipheral quadrants, at least as severe as Standard photograph 6A”
Link to “Standard photograph 6a” will be available on website

19. Standard Photos
OR “At least 1 field of moderate intraretinal microvascular abnormalities (IRMA) in the midperipheral quadrants, at least as severe as Standard photograph 8A”
Link to “Standard photograph 8a” will be available on website

20. Website Tools
NPDR definition provided
Links to standard photos

21. DR Level Confirmation
At Screening Visit, investigator must confirm eye has severe NPDR on photos and no PDR within the 7-modified ETDRS fields on FA or clinical exam
The FA and photos must be uploaded immediately for Reading Center grading
The Reading Center will confirm eligibility prior to randomization
Expected turnaround within 1 week
If eligible, the Randomization Visit must occur within 35 days of Screening Visit

22. Use of Wide-Field Imaging for FA
UWF color photos will not be permitted
For FA, sites should use OPTOS if available at baseline
Presence of NV outside of the 7-modified ETDRS fields will NOT be an exclusion.
If a new OPTOS machine is obtained during follow-up, FA images should then be taken for ALL participants going forward
Peripheral NV outside the 7 modified ETDRS fields will not meet the primary outcome and generally should not be treated unless high risk
Note: Heidelberg UWF device not permitted at this time

23. Randomization Reminder
Before submitting the Randomization Visit, the investigator MUST
Confirm eligibility
Confirm patient’s willingness to accept either assignment and to complete all treatment/follow-up
Be available to perform the injection (intravitreous or sham) THAT DAY
Educate patient with a thorough ICF process so that they understand:
Time commitment
Treatment requirements

24. Assessment Visits First 2 Years: Injections given at every visit
Baseline (0)
Month 1
Month 2
Month 4
Month 8
Month 12
Month 16
Month 20
Month 24
Month 28
Month 32
Month 36
Month 40
Month 44
Final Visit (48M)
First 2 Years: Injections given at every visit
≥2 Years: Injections given if worse than mild NPDR

25. When are photos/FA required?
At 4-month visit and annually
Reading Center will perform a masked assessment of whether primary endpoint has been met
If initiating PDR or DME treatment and primary endpoint not previously confirmed by RC at one of the time points above
Note: Images will not be sent as soon as early NV detected
There is concern with unmasked investigators detecting NV earlier in the sham group than in the anti-VEGF group, this approach is intended to minimize such potential bias
To document TRD, VH, or PRH for primary endpoint

26. Intravitreous Injection Procedure
Two individuals must confirm the study eye and drug number against the printout or website
Mark the eye for injection
Apply topical anesthetic
Subconjunctival anesthetic may only be given if topical anesthetic is not sufficient to minimize discomfort
Place the lid speculum
Apply povidone iodine directly over and surrounding the injection site
DRCR.net injections must NOT be given without the use of povidone iodine in any circumstance
Pre- and post-injection topical antibiotics should NOT be used (prior discussion with Protocol Chair or her designate will be required prior to use)

27. Endophthalmitis Rates by Antibiotic Use
24,052*
Intravitreal Injections
(2,596 eyes) 9
Cases of
Endophthalmitis
6 (0.06%)
With
Topical Antibiotics
3 (0.02%)
Without
Topical Antibiotics
P = 0.19
*Excluding injections given without povidone iodine (13 injections in 2 eyes)

28. Evolution of Antibiotic Use in DRCR.net Over Time
NMB edits
If you are in the 34% and are planning to participate in this protocol and still are uncomfortable omitting antibiotics, please discuss with Network leadership

29. Intravitreal Injections without Povidone-Iodine
Povidone-Iodine Use
24,065
Intravitreal Injections
(2,598 eyes)
Povidone-Iodine MUST be used
13 injections (2 eyes)
without Povidone-Iodine
(protocol violation)
100% of eyes developed
endophthalmitis

30. Sham Injection Procedure
Same procedure as intravitreous injection, including:
Confirming/marking the study eye
Apply topical anesthetic (subconj should not be used)
Place the lid speculum
Apply povidone iodine directly over and surrounding the injection site (allowing sufficient time for the povidone iodine to dry)
Sham injections must NOT be given without the use of povidone iodine in any circumstance
A syringe without a needle will be used, with the hub pressed against the conjunctival surface to simulate the force of an actual injection

31. Successful Sham Masking
In DRCR.net Protocol I, participants with 1 study eye (N = 423)
The majority receiving sham thought they were receiving real injections
Participant Response to type of injections
Sham Group
Ranibizumab Groups
IVT Group
Always Real
72%
88-90%
55%
Sometimes real
/sometimes sham
18%
7-12%
44%
Always Sham
10%
0-4% 1%

32. Bilateral Injections 2 study injections One non-study injection
Perform all required injection procedures on the right eye first before initiating any pre-injection prep of the left eye.
Study drug for the left eye should not be in the room before completing all right eye injection procedures.
One non-study injection
Perform all required injection procedures on the study eye before initiating any pre-injection prep of the non-study eye.
Study drug for the non-study eye should not be in the room before completing all study eye injection procedures.

33. PDR/DME Treatment During Follow-Up
It is expected that many eyes will require PDR or DME treatment at some point during follow-up
~15% to 30% in the first 2 years are estimated to meet PDR/DME endpoint
Standardizing the criteria to treat and the treatment itself will allow us to better evaluate long-term visual acuity outcomes for the two treatment strategies (prevention vs. observe and treat)

34. PDR Treatment Criteria
Treatment for PDR must not be given unless:
The eye has high-risk characteristics:
NVD greater than standard photograph 10A
(1/4 to 1/3 disc area) or
Any NVD with pre-retinal or vitreous hemorrhage
NVE greater than ½ disc area with pre-retinal or vitreous hemorrhage
The eye has VH requiring treatment that is presumed to be from PDR

35. PDR Treatment Criteria
If high-risk criteria not met, RC confirmation of the primary endpoint (NV within 7-modified fields) should be obtained prior to initiating treatment whenever possible.
Treatment for NVE outside of the 7 modified fields without the presence of pre-retinal or vitreous hemorrhage is discouraged.
If the investigator believes treatment for peripheral NV is necessary, protocol chair review is required.

36. Treatment for PDR
PDR treatment will include intravitreous anti-VEGF using DRCR.net Protocol S algorithm
3 q4-week injections
Then each eye will be categorized into one of the following 5 scenarios:
Category
Injection
PRP
Resolved
At investigator discretion No
Improved from last injection
Required
Stable
Required 1st 2 times stable; then at investigator discretion
Not fully treated (worsening)
Failure/Futility
Yes
Failure= one of the following:
1. NV worse than at baseline and at least 4 study injections have been given over the previous 4 months.   OR
 2. New or worsened NV of the angle
 3. definite worsening of NV at least 1 day after the last injection that the investigator believes is likely to lead to substantial vision loss if PRP is not performed within 1 week. (approval required for PRP)
Futility criteria = NV at 1.5 years or later follow-up that is equal to or greater than the extent of the NV present at baseline and at least 5 study injections performed over the preceding 6 months. (approval required for PRP) 

37. DME Criteria and Treatment
Treatment for CI-DME must not be given until the primary endpoint for DME has been met:
CI-DME on clinical exam with ≥10% increase in central subfield thickness from baseline and:
1) at least 10 letter VA loss at a single visit, or
2) 5 to 9 letter VA loss at 2 consecutive visits.
Once the above endpoint has been met, must use DRCR.net Anti-VEGF Regimen for DME:
Continue q4w injections as long as there is improvement or worsening
No injection if stable after 2 consecutive injections and either “success” or >24w from initial injection
Resume injection if worsen after withholding injection

38. PDR/DME Treatment Visits
Once PDR or DME treatment is initiated, visits are every 4 weeks for first 6 months and then follow-up can be extended if injections no longer needed
Assessment Visits must still be completed on schedule
Baseline (0)
Month 1
Month 2
Month 4
Month 8
Month 12
Month 16
Month 20
1st PDR Injection
Month 21
Month 22
Month 23
Month 24
Month 25
Month 26
Month 27
Month 28
Month 32

39. DRCR.net Website
Like all DRCR.net trials, the website will help guide you through follow-up, including:
Assessing eligibility (standard photos provided)
Assessing primary outcome (reminders when imaging is needed)
Criteria to initiate treatment PDR or DME
Retreatment criteria once initiated
Visit schedule

40. Complete the Visit Form
A treatment message will display for each indication (prevention, PDR, DME)
The investigator must make a treatment determination based on all messages
A second individual should confirm that the treatment planned is not contrary to the messages
An injection of aflibercept in the left eye must be given at this visit.
An injection of Aflibercept should not be given for PDR at this visit since criteria to initiate anti-VEGF injections for PDR have not been met.
An injection of Aflibercept should not be given in the left eye for DME at this visit since criteria to initiate anti-VEGF injections for DME have not been met.

41. Complete the Visit Form
You will then indicate whether an injection is planned AND the indication
If PDR or DME is entered as an indication for the first time, the eye will have met that outcome and the retreatment protocol for PDR or DME will be initiated
It is extremely important that these questions are answered accurately

42. Treatment Message Questions
Retreatment calculation depends on correct data entry
Prior missed visits/missing data could also impact the calculations
If at any time, you do not believe the message is correct or you wish to deviate, CONTACT US!
An injection of Aflibercept should not be given for PDR at this visit since criteria to initiate anti-VEGF injections for PDR have not been met.
An injection of Aflibercept should not be given in the left eye for DME at this visit since criteria to initiate anti-VEGF injections for DME have not been met.

43. The Diabetic Retinopathy Clinical Research Network
Only YOU can prevent vision loss! 43