1. The Diabetic Retinopathy Clinical Research Network
DRCR.net Prompt PRP vs Ranibizumab+Deferred PRP for PDR Study
Jeffrey G. Gross, M.D. – Protocol Chair
Supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services EY14231, EY14229, EY018817 

2. Background
Current treatment for PDR is panretinal photocoagulation (PRP)
Inherently destructive
Adverse effects on visual function
Some eyes with PDR+DME now receive anti-VEGF as standard care for DME
Would initial treatment of PDR with intravitreal anti-VEGF delay or prevent need for PRP? 2

3. Study Objective and Treatment Groups
To determine if visual acuity outcomes at 2 years in eyes with PDR (with or without concurrent DME) that receive anti-VEGF therapy with deferred PRP are non-inferior to those in eyes that receive prompt PRP therapy.
(Note: Study ranibizumab may be given as needed for DME using Protocol I retreatment as guidelines.)
Prompt PRP
0.5mg ranibizumab with deferred PRP 3

4. Important Secondary Objectives (assuming visual acuity outcomes are non-inferior)
Compare visual function outcomes (including Humphrey visual field testing and study participant self-reports of visual function)
Determine percent of eyes not requiring PRP when intravitreal anti-VEGF is given in the absence of prompt PRP
Compare safety outcomes
Perform cost effectiveness analysis 4

5. Sample Size Minimum of 380 eyes
Subjects may have one or two study eyes
316 participants assuming 20% have two study eyes 5

6. Major Inclusion Criteria
Age ≥ 18 years
Type 1 or 2 diabetes
PDR for which PRP is planned but in the investigator’s opinion can be deferred for at least 4 weeks if an intravitreal anti-VEGF injection is given
Visual acuity (Snellen equivalent) 20/320 or better
Note: eyes with or without DME may be enrolled 6

7. Major Exclusion Criteria
Systemic
Significant renal disease
BP > 180/110
Cardiac event or stroke within 4 months
Study eye
Prior PRP
Tractional retinal detachment involving the macula
NV of the angle
History of intravitreal anti-VEGF within past 2 months
History of corticosteriod in the past 4 months

8. Testing Procedures – Undilated within 14 days of randomization
Questionnaires (except in participants with two study eyes)
NEI-VFQ, UAB-LLQ, WPAI, and TTO
Humphrey visual field testing (30-2 and 60-4) – dilation may be needed depending on pupil size
Required at sites with certified HVF equipment

9. Testing Procedures – Undilated Day of Randomization
E-ETDRS best-corrected visual acuity in each eye
Binocular E-ETDRS using the participant’s everyday glasses or contacts
IOP in the study eye

10. Testing Procedures - Dilated
OCT of study eye (within 8 days)
Fundus photographs of study eye (within 21 days)
If NV is not captured on 7F or 4W, additional fields should be taken to capture NV
This is documented on protocol specific form
Ocular exam in both eyes (day of randomization)

11. PRP Treatment
Prompt PRP group receives 1200 to 1600 burns initiated on day of randomization (or within 14 days of baseline if injection for DME given) and completed within 8 weeks.
Anti-VEGF+Deferred PRP may receive PRP only if failure/futility criteria are met
Protocol chair approval MUST be obtained before PRP is given in some cases of failure/futility 11

12. Follow-up Schedule Assessment Visits every 16 weeks in both groups
PDR Treatment Visits every 4 weeks (deferred PRP group only)…interval may only be extended if PRP is given
Baseline to
1 Year
Assessment Visits every 16 weeks in both groups
PDR Treatment Visit every 4-16w (deferred PRP group only)…interval is extended if injections for PDR continually deferred
Primary outcome visit at 2 years
1 Year to
3 Years
JKS- presenter should note that additional visits may be scheduled as standard care for DME treatment. (or may want to put this on slide)
4 to 5
Years
Annual visits for data collection only
Treatment as part of usual care

13. Non-Annual Testing Procedures
E-ETDRS best-corrected visual acuity in both eyes
Ocular exam and IOP in the study eye (extended ophthalmoscopy in deferred PRP group)
OCT only if eye
1) has initiated DME treatment,
2) will be evaluated for initial DME treatment, or
3)10 letter unexplained loss since last visit.
Fundus photography only if PRP will be initiated in an eye assigned to IVR+deferred PRP
WPAI questionnaire at 16-week interval visits (except in OU participants)

14. Annual Testing Procedures
Binocular E-ETDRS using the participant’s everyday glasses or contacts
Questionnaires (except in OU participants)
NEI-VFQ, UAB-LLQ, WPAI, and TTO
May be completed at home prior to visit (within 14 days)
Fundus photography
Humphrey visual field testing (30-2 and 60-4)
Required at sites with certified HVF equipment

15. Anti-VEGF Injections for PDR (Deferred PRP Group)
Injections every 4 weeks through 12- week visit
NV status does not matter
Injection can only be skipped if an adverse event occurs
If at anytime the investigator thinks PRP is needed within 1 week to avoid substantial vision loss, PRP may be given once protocol chair approval obtained 15

16. Injection Retreatment Criteria for PDR (Deferred PRP Group)
Starting at the 16-week visit, each eye will be categorized into one of the following 5 groups:
1. Resolved
NV of the retina, disc, and iris/angle* is absent.
Decision to re-inject is at investigator discretion. PRP should not be given.
*if angle is examined 16

17. Injection Retreatment Criteria for PDR (Deferred PRP Group)
2. Improved
NV of the retina, disc, or iris/angle* still persists, but there is evidence of “improvement” since the last visit.
“Improvement” defined as a decrease in the size of NV or diminished density of NV
An injection is given. PRP should not be given.
*if angle is examined 17

18. Injection Retreatment Criteria for PDR (Deferred PRP Group)
3. Stable
NV of the retina, disc, and iris/angle* is clinically unchanged since the last visit.
Once the eye meets criteria for stability, at least 2 more injections must be given, each one month apart.  Further reinjection is then at investigator discretion as long as the eye remains stable.  PRP should not be given. 
*if angle is examined 18

19. Injection Retreatment Criteria for PDR (Deferred PRP Group)
4. Not fully treated
Failure/futility criteria not met and recurrent or worsening NV of the retina, disc, or iris is present in an eye that has had fewer than 4 injections over the previous 4 months or there is vitreous or preretinal hemorrhage precluding assessment. 
An injection is given.  PRP should not be given.  19

20. Injection Retreatment Criteria for PDR (Deferred PRP Group)
5. Failure/futility
One of the following criteria are met:
NV worse than last visit such that it is greater in extent than baseline and at least 4 injections given over previous 4 months
NV of the angle
PRP needed within 1 week to avoid substantial vision loss and protocol chair approval obtained
Persistent NV after 1.5 years of follow-up despite anti-VEGF and protocol chair approval obtained
Decision to re-inject is at investigator discretion.  PRP may be given. 20

21. Follow-Up Treatment for DME
If DME develops during follow-up, treatment is at investigator discretion using study ranibizumab and/or focal/grid laser with Protocol I retreatment criteria as guidelines
Additional follow-up visits for DME retreatment are at the discretion of the investigator (not part of visit schedule) 21