1. The Diabetic Retinopathy Clinical Research Network
Protocol T
Comparative Effectiveness Study of Aflibercept, Bevacizumab and Ranibizumab for DME
John A. Wells, III MD for the Diabetic Retinopathy Clinical Research Network

2. Financial Disclosure S = Research support
I have the following financial interests or relationships to disclose:
Ampio Pharmaceuticals: S
DRCR Network: S
Genentech: S
Regeneron : S
S = Research support

3. 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

4. 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

5. Alternative Anti-VEGF Drugs to Ranibizumab for DME
Aflibercept
Approved by FDA for treatment of AMD
Phase 3 DME results (VIVID and VISTA):
Aflibercept 2mg q4wk letters, 2mg q8wk letters, laser – 1.2 letters gained
Unit dose volume similar to ranibizumab and bevacizumab
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

6. 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

7. Plasma Collection Ancillary Study: Collection and Processing
Approximately 5 mL of blood will be collected at: Baseline, 4-week visit, 1 year visit
Purpose: Compare changes in plasma concentrations of VEGF after intravitreal treatment with ranibizumab vs. bevacizumab vs. aflibercept
Previous studies have found lower levels of plasma VEGF in patients receiving bevacizumab versus ranibizumab
Secondary analysis: A participant can consent to allow the blood left over after the VEGF analysis to be used for future research

8. 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

9. Follow-up Schedule Visits every 4 weeks Primary outcome at 1 year
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
1 Year to 2 Years
Visits every 4 to 16 weeks
Depends on disease status and treatment

10. Follow-up Schedule – 2nd Year
Injection given
Next visit in 4 weeks
1st and 2nd time
an injection is
deferred
Next visit in 4 weeks
3rd consecutive
time an injection
is deferred
Next visit in 8 weeks
4th consecutive
time an injection
is deferred
Next visit in 16 weeks

11. Study Drug
All three drugs will be distributed by the Coordinating Center (CC) in unmasked numbered vials
Aflibercept: Provided to CC by Regeneron
Bevacizumab: Provided to CC in repackaged vials by a single compounding pharmacy at the University of Pennsylvania
Ranibizumab: Provided to CC by Genentech

12. Masking
Visual acuity testers and OCT technicians will be masked to treatment group at the annual visits
Study participants will be masked
May be unmasked if needed to discuss non-study eye anti-VEGF treatment
Investigators and coordinators will not be masked to treatment group assignment

13. Retreatment and Follow-up of CI DME with Anti-VEGF
Assessment 4 weeks after initial injection
No change for at least 2 injections? NO NO
YES
DME change* on OCT or VA from last injection?
No injection (if after 20-wk visit**); return in 4 weeks
DME Worsens or Recurs?
YES
Re-inject and return in 4 weeks
YES NO
*OCT change: >10% CSF
*VA change: >5 letters
**If before 24-wk visit:
Re-inject if OCT >250 or VA <20/20
Return in 4 weeks, or after 1 year, double return interval up to 16 weeks

14. Case Example 1
Week 4 8 12 16 20 24 28 32 36 40 44 48 52
OCT
631
550
550
410
390
380
385
375
420
300
249
249
255 VA
20/80
20/80
20/50
20/32
20/32
20/32
20/32
20/32
20/32
20/20
20/20
20/20
20/20
Category -- I I I St St St St W I Su Su St
A-VEGF
Deferred
Deferred
Laser**
Required due to improvement
Required due to worsening
Required 1st time success
Required 1st time stable
2nd time stable but <24w
Focal/grid laser added due to persistent DME with no 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 <250 µm or SD equivalent
Hide?

15. 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 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
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

16. Focal/Grid Laser Re-Treatment
Once focal/grid laser has been initiated, retreatment with focal/grid laser can be given if:
>13 weeks since last laser
The OCT CSF is >250 µm and there is edema threatening the fovea
Complete focal/grid laser has not been given
The OCT or VA have not improved since the last laser

17. 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

18. Recruitment (N = 660)
Original projected enrollment of ~35 per month would end in
March 2014