Transcript Protocol T - Jaeb Center for Health Research

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
I have the following financial interests or relationships to disclose:
•
•
•
•
•
Allergan: S
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):
o
•
•
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 centralinvolved 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
Follow-up Schedule
Baseline to
1 Year
• Visits every 4 weeks
• Primary outcome at 1 year
Optional Visit 2-3
Days after
1st, 2nd or 3rd visit
• Urine sample
• Blood pressure (another BP
measurement will be taken at the first
4 week visit after the optional 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 nonstudy 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?
YES
No injection (if after 20-wk visit**);
return in 4 weeks
DME change* on
OCT or VA from last
injection?
YES
Re-inject and return in 4
weeks
*OCT change: >10% CSF
*VA change: >5 letters
**If before 24-wk visit:
Re-inject if OCT >250 or VA <20/20
YES
DME Worsens or
Recurs?
NO
Return in 4 weeks, or after 1 year, double return
interval up to 16 weeks
Case Example 1
Week
0
4
8
12
16
20
24
28
32
36
40
OCT
631
550
550
410
390
380
385
375
420
300
249
VA
44
249
20/80 20/80 20/50 20/32 20/32 20/32 20/32 20/32 20/32 20/20 20/20 20/20
Category --
I
I
I
St
A-VEGF
Laser**
St
St
St
Deferred
Required due
to
improvement
Required
1st time
stable
2nd time
stable
but <24w
W
I
Su
52
48
Su
255
20/20
St
Deferred
Required
Required 1st
due to
time
worsening
success
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
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
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:
o
o
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