1. The Diabetic Retinopathy Clinical Research Network
Protocol T
Comparative Effectiveness Study of Aflibercept, Bevacizumab and Ranibizumab for DME

2. Background
Ranibizumab is safe, efficacious, and gives superior visual acuity results to laser for treating eyes with DME (e.g., Phase 3 trials of DRCR.net, RESTORE, RISE & RIDE)
However:
High cost can be a barrier to ranibizumab’s widespread use (~$2,000/dose) in the world
Bevacizumab is much less expensive but unknown if it is superior, equivalent, or inferior to ranibizumab
Also reasonable to investigate alternative anti-VEGF agents that are currently available

3. Alternative Anti-VEGF Drugs to Ranibizumab for DME
Bevacizumab is a good candidate for direct comparison
Closest molecular structure to ranibizumab
Costs less (~$50 to $100)
Widely available
Evidence suggests efficacy compared with laser (BOLT 2011)
Already widely used for DME

4. Alternative Anti-VEGF Drugs to Ranibizumab for DME
Aflibercept
Approved by FDA for treatment of AMD
Phase 2 DME results:
Baseline mean VA: 20/63 in aflibercept arms and 20/80 in laser arm
Eyes treated with aflibercept had greater mean improvement in VA at week 52 compared with eyes treated with macular laser (+9.7 to letters gained versus -1.3 letters) – DA VINCI, 2012
Unit dose similar to ranibizumab
Potential to decrease treatment burden: q4 wk x3 followed by q8 wk equivalent to q4 wk ranibizumab for CNV in AMD (VIEW 1 and VIEW 2) – Note: in CATT, ranibizumab PRN with q4 week OCT equivalent to q4 wk ranibizumab

5. Study Objective and Treatment Arms
To compare the efficacy and safety of (1) intravitreal aflibercept, (2) intravitreal bevacizumab, and (3) intravitreal ranibizumab when given to treat central-involved DME in eyes with visual acuity of 20/32 to 20/320.
2.0 mg
intravitreal aflibercept
1.25 mg intravitreal bevacizumab
0.3 mg intravitreal ranibizumab

6. Sample Size 660 eyes Participants can have only one study eye
If both eyes are eligible, and the patient and the investigator are willing to have either eye as the study eye:
The eye that never received anti-VEGF treatment should be randomized
If both eyes have previously received anti-VEGF treatment or both eyes have never received anti-VEGF treatment, then the study eye should be selected by the investigator and the participant

7. Major Inclusion Criteria
Age ≥18 years
Type 1 or 2 diabetes
Study eye:
Visual acuity (~Snellen equivalent) 20/32 or worse and 20/320 or better
Definite retinal thickening due to central-involved DME on clinical exam
OCT central subfield ≥ OCT-machine gender specific cut-off for definite central involved DME
Non-study eye:
Investigator must be willing to use (or switch to using) randomized anti-VEGF drug on the non-study eye if needed
For eligibility central subfield thickness on OCT must be:
Zeiss Stratus: ≥250;
Zeiss Cirrus and Optovue RTVue: Men ≥305; Women ≥290;
Heidelberg Spectralis: Men ≥ 320; Women ≥305

8. Major Exclusion Criteria
Systemic
Significant renal disease
BP > 180/110
Based on average of 3 measurements using DRCR.net provided BP device
MI, other acute cardiac event requiring hospitalization, stroke, TIA, or treatment for acute CHF within 4 months
Study eye
History of intravitreal anti-VEGF within past 12 months
Enrollment limited to a maximum of 25% of the planned sample size with any history of anti-VEGF treatment
History of DME treatment other than anti-VEGF (e.g., macular laser) within past 4 months
Macular edema not due to DME
PRP in last 4 months or anticipated in next 6 months

9. Baseline Testing E-ETDRS VA testing in each eye
OCT on the study eye (spectral domain preferred if available)
Ocular exam on each eye
Fundus photos in the study eye
Blood pressure measurement
Using study provided device
Laboratory testing:
Urine sample – sent to University of Minnesota
HbA1c – sent to University of Minnesota
Plasma sample (ancillary study) – sent to Fred Hutchinson Cancer Research Center

10. Optional Visit 2-3 Days after 1st, 2nd or 3rd visit
Follow-up Schedule
Baseline to
1 Year
Visits every 4 weeks
Primary outcome at 1 year
Urine sample
Blood pressure (another BP measurement will be taken at the first 4 week visit after the optional visit)
Optional Visit 2-3 Days after 1st, 2nd or 3rd visit
Visits every 4 to 16 weeks
Depends on disease status and treatment
1 Year to 2 Years

11. Follow-up Testing All Protocol Visits:
E-ETDRS VA testing in each eye including protocol refraction in the study 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 treatment planned
Additional Procedures at 1-year Visit Only:
Non-study eye refraction and ocular exam
Fundus photos in the study eye
Blood pressure measurement (3 measurements taken at the visit)
Urine sample collection
Plasma collection (also taken at the 4-week visit)

12. Principles of DRCR.net DME Treatment: Intravitreal Anti-VEGF
Improving on OCT or VA  Inject
Improving = OCT central subfield thickness decreased by ≥ 10% or VA letter score improved by ≥ 5
Worsening on OCT or VA  Inject
Worsening = OCT central subfield thickness increased by >10% or visual acuity letter score decreased by >5
Stable: not improving or worsening on OCT or VA  Inject unless stable since last 2 injections in which case inject only if before 24-wk visit when OCT is >250 µm and VA <20/20

13. Principles of DRCR.net DME Treatment: Intravitreal Anti-VEGF:
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

14. Focal/Grid Laser Treatment Criteria
Laser can be initiated only at or after the 24 week visit if:
OCT CSF is ≥250 µm or there is edema that is threatening* the fovea AND
The eye has not improved on OCT or VA compared with either of the last two consecutive injections
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
*Edema threatening the fovea is defined as edema within 500 µm of the foveal center or edema associated with lipid within 500 µm of the foveal center or ≥ 1 disc area of edema the posterior edge of which is within 1 disc diameter of the foveal center

15. Focal/Grid Laser Re-Treatment
Once focal/grid laser has been initiated, retreatment with focal/grid laser will be given unless one of the following is present:
Focal/grid 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

16. 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, the non-study eye must be treated with the same drug to which the study eye was randomized
The DRCR.net CC will provide drug for the non-study eye
For participants that have a study eye randomized to ranibizumab the non-study eye can receive one of the following:
0.5mg for treatment of conditions other than DME in the non-study eye
0.3mg for DME treatment in study eye and non-study eye

17. Referrals
Please consider any eyes with definite retinal thickening due to central-involved DME
Must be willing to be randomized to any of the three treatment groups and continue in the study for 2 years
Consenting/Enrollment/Randomization may be split into separate visits

18. Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net)
Dedicated to multicenter clinical research of diabetic retinopathy, macular edema and associated disorders. 18