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  

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

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

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

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 + 10.5-12.5 letters, 2mg q8wk + 10.7 letters, laser + 0.2 – 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

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

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

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

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

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

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

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

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

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?

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

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

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

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