Transcript The Diabetic Retinopathy Clinical Research Network Protocol T

The Diabetic Retinopathy Clinical
Research Network
Protocol T
Comparative Effectiveness Study of
Aflibercept, Bevacizumab and
Ranibizumab for DME
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Background
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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
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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
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Approved by FDA for treatment of AMD
Phase 2 DME results:
o
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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 +13.1 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
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
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:
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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 antiVEGF treatment, then the study eye should be
selected by the investigator and the participant
Major Inclusion Criteria
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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
Major Exclusion Criteria
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Systemic
• Significant renal disease
• BP > 180/110
o
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
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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
Baseline Testing
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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
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Using study provided device
Laboratory testing:
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Urine sample – sent to University of Minnesota
HbA1c – sent to University of Minnesota
Plasma sample (ancillary study) – sent to Fred
Hutchinson Cancer Research Center
Follow-up Schedule
Baseline to
1 Year
• Visits every 4 weeks
• Primary outcome at 1 year
Optional Visit 23 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 Testing
All Protocol Visits:
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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:
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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)
Principles of DRCR.net DME Treatment:
Intravitreal Anti-VEGF
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Improving on OCT or VA  Inject
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Worsening on OCT or VA  Inject
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Improving = OCT central subfield thickness
decreased by ≥ 10% or VA letter score improved
by ≥ 5
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 24wk visit when OCT is >250 µm and VA <20/20
Principles of DRCR.net DME
Treatment: Intravitreal Anti-VEGF:
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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
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When eye is stable after at least 2 consecutive
injections and OCT CSF is ≥250 µm or VA is
worse than 20/20:
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Prior to the 24-week visit  Inject
≥ 24-week visit  Defer injection
Focal/Grid Laser Treatment Criteria
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Laser can be initiated only at or after the 24
week visit if:
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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
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Once focal/grid laser has been initiated,
retreatment with focal/grid laser will be
given unless one of the following is
present:
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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
Intravitreal Anti-VEGF Treatment in
the Non-study Eye
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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 nonstudy eye
For participants that have a study eye randomized
to ranibizumab the non-study eye can receive one
of the following:
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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
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
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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.
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