1. Laser-Ranibizumab-Triamcinolone for DME Study DRCR.net Protocol I
Michael J. Elman, M.D.
Protocol Chair

2. Protocol Summary Study Objective
To Evaluate safety and efficacy of the following in eyes with center-involved DME
intravitreal anti-VEGF treatment in combination with prompt focal laser
intravitreal anti-VEGF treatment with deferred focal laser
intravitreal corticosteroids in combination with prompt focal laser 2

3. Protocol Summary Major Eligibility Criteria
Age >=18 years.
Type 1 or type 2 diabetes
Center involved DME responsible for VA of 20/32 or worse
OCT central subfield thickness >250µ 3

4. Protocol Summary Sample Size
Minimum of 842 eyes
Subjects may have one or two study eyes.
701 subjects assuming 20% have 2 study eyes 4

5. Protocol Summary Treatment Groups
Randomization to one of the following 4 groups:
Group A: Sham injection + focal laser
Group B: 0.5 mg injection of intravitreal Ranibizumab + focal laser
Group C: 0.5 mg injection of intravitreal Ranibizumab + deferred focal laser
Group D: 4 mg injection of intravitreal Triamcinolone + focal laser 5

6. Protocol Summary Efficacy Outcomes
Primary Outcome:
VA at 1 year
Secondary Outcomes:
Change in OCT CSF and retinal volume
# of injections in first year 6

7. Protocol Summary Main Safety Outcomes
Injected-related:
Endophthalmitis, retinal detachment
Ocular drug-related:
Inflammation, cataract, cataract surgery, increased IOP, glaucoma medications, glaucoma surgery
Systemic drug-related:
Cardiovascular events 7

8. Protocol Summary Follow-up Schedule
First Year
Visits every 4 weeks
Second and Third Years
Visit schedule depends on treatment group
If failure met, visits occur every 4 months regardless of trt group 8

9. Retreatment Criteria: Injections During Follow-Up
Group A - sham
Groups B and C - ranibizumab
Group D - Triamcinolone injection is given if one has not been given in the prior 15 weeks; otherwise a sham injection is given. 9

10. Retreatment Criteria Through 12-Week Visit
Everyone gets an injection (Drug or Sham)
Visual acuity score does not matter
OCT score does not matter
Injection can only be skipped if an adverse event occurs
Rationale: ensures that enough treatment is given to accurately assess efficacy 10

11. Retreatment Criteria for Injection at 16 and 20-week Visits
VA letter score >=84 or OCT < 250:
Can defer injection
VA letter score <84 (worse than 20/20) AND OCT > 250:
Give injection
Rationale: Ensures that eyes assigned to triamcinolone with vision less than 20/20 will receive at least 2 injections. 11

12. Retreatment Criteria for Injection 24 to 48 Week Visit
Eyes are assigned to 1 of 4 categories:
VA letter score >=84 (20/20 or better) or OCT <250:
Decision to reinject at investigator discretion
Evidence of improvement at any visit since the last non-sham injection (or baseline for group A):
An injection is given 12

13. Retreatment Criteria for Injection 24 to 48 Week Visit
Failure criteria (next slide) not met, and no improvement at any visit since the last non-sham injection (or baseline for group A):
Decision to reinject is at investigator discretion. 13

14. Retreatment Criteria for Injection 24 to 48 Week Visit
Failure defined as:
VA letter score 10 or more worse than baseline, OCT CSF >=250 microns, DME present on clinical exam that is the cause of the visual loss, complete laser given AND ≥13w since last laser treatment with no improvement since the last laser treatment
The eye can be treated at investigator discretion. 14

15. Retreatment Criteria: Focal Photocoagulation
In general, focal photocoagulation will be given 3 to 10 days later following each injection unless one of the following is present:
Focal laser given in the previous 13 weeks
Maximal focal laser has already been given
The central subfield thickness is <250 microns and there is no edema threatening the fovea 15

16. Retreatment Criteria for Laser
Group C – Laser Deferred
No focal photocoagulation before 24 weeks
At the 24-week or later visit, if there is no evidence of improvement from the last 2 consecutive injections and the investigator believes that macular edema is present for which focal photocoagulation is indicated, the eye should receive focal photocoagulation. 16

17. Retreatment Criteria at and after 52-Week Visit
Subjects are unmasked to treatment grp
Eyes assigned to Sham and Triamcinolone groups start every 16 wk visits and discontinue sham injections
Eyes assigned to ranibizumab continue every 4 week visits unless injections are deferred due to success or no improvement – visits then move to 8 or 16 wk intervals 17

18. Retreatment Criteria at and after 52-Week Visit
Failure/futility defined as:
VA letter score <84, OCT CSF >=250 microns, DME present on clinical exam that is the cause of the visual loss, complete laser given AND either 1) ≥13w since last laser treatment with no improvement since the last laser treatment and VA 10 or more worse than baseline OR 2) ≥ 29w since last laser with no improvement since the last laser treatment
The eye can be treated at investigator discretion.