The Diabetic Retinopathy
Clinical Research Network
Short-term Evaluation of Combination
Corticosteroid+Anti-VEGF Treatment for
Persistent Central-Involved DME Following
Anti-VEGF Therapy in Pseudophakic Eyes
Raj Maturi, MD
1
Background: The Problem
 52% of Protocol I ranibizumab eyes didn’t
achieve ≥2 vision-line improvement, and more
than 40% did not have resolution of retinal
thickening (<250 µm) at year 2.
 Protocol I data suggest that eyes that remain
edematous at 6 months and 1 year following
ranibizumab treatment have been consistently
thickened throughout the treatment period.
 21% percent of ranibizumab eyes still had
retinal thickness ≥ 300 μm, with vision of 20/32
or worse at 1 year.
• 39% had persistent CST
≥300 μm during year 1
2
Studies have shown the benefits of
intravitreal steroids for DME
 Protocol I, pseudophakic subgroup had a
visual gain similar to the Ranibizumab
treated groups
 FAME study of intravitreal fluocinolone
demonstrated benefits over 3 years
 MEAD study results show benefit of Ozurdex
over three year treatment period
Cataracts and IOP rise are issues
Dexamethasone May Help
Study
Design
Dutra,
Ophthalmologica
2013
Retrospect.
Review
Pacella,
Clin Ophthalmol.
2013
Single center
uncontrolled
prospective
study
Zucchiatti,
Ophthalmologica
2012
Retrospec.
interventional
study
Maturi, et al. 2013
ASRS talk
(submitted, 2014)
Prospective
controlled
#
Eyes
58
20
9
40
Setting
Summary
Decrease in foveal
“Refractory” thickness and
DME
increase in VA at 3
and 6 mo.
DME ≥275
μm with
“previous”
anti-VEGF
Improve in ret.
thickness and VA 1-3
months then decline
through 6 months
Improvement in VA
“Persistent” and ret. Thickness
DME
maintained through
4th month
DME – 88%
with
previous
Avastin
Edema much less in
combo group.
4
Rationale
 There is a need for alternative or
additional treatments due to incomplete
response to ranibizumab in about ½ the eyes.
 Protocol I data showed that the pseudophakic
subgroup achieved the same results as
ranibizumab at 2 yrs (this was not a prespecified
subgroup, however).
 As intravitreal steroids have been shown to have
a positive effect on DME in some eyes, despite
safety issues, and might add benefit in eyes that
are already receiving anti-VEGF, where benefits
might outweigh risks.
5
Objectives
 To assess short-term effects of combination
steroid+anti-VEGF therapy on OCT retinal
thickness and visual acuity in comparison with
that of continued anti-VEGF therapy alone in
pseudophakic eyes with persistent DME and
visual acuity impairment despite previous antiVEGF treatment.
 To provide more information needed for future
conduct of a definitive phase III clinical trial.
6
Rationale for a Phase II Trial
 Currently, there are limited data on combination
steroid+anti-VEGF injections for DME
 A large treatment effect on pseudophakic eyes is
needed before considering combination therapy
as a long-term treatment in eyes at risk for
development of cataract
 Before embarking on a phase III study, we need:
• To determine whether the conduct of a phase III trial
has merit based on anatomic and functional outcomes
• To estimate recruitment potential of a phase III trial
• To assess safety of combination steroid+anti-VEGF in
eyes with persistent DME, removing confounding of
cataract and cataract surgery
7
Study Drugs
Dexamethasone
(OZURDEX®)
 Sustained-release
biodegradable polymer
matrix that provides 700
μg of preservative-free
dexamethasone
 FDA-approved for
noninfectious post.
uveitis and macular
edema due to retinal vein
occlusion
 Provided by Allergan Inc.
Ranibizumab 0.3mg
(LUCENTIS®)
 Anti-human VEGF
monoclonal antibody
 FDA-approved for
treatment of wet AMD,
macular edema following
RVO, and DME
 Provided by Genentech
Inc.
8
Dexamethasone
 Decreases inflammation by suppression of neutrophil
migration, decreased production of inflammatory
mediators, and reversal of increased capillary permeability,
and suppresses normal immune response*
 Onset of action*
• BRVO/CRVO: Improvement observed in 20% to 30% of
patients within first 2 months following intravitreal
injection
 Duration of effect*
• BRVO/CRVO: 1-3 months (following onset of
improvement)
 Absorption*
• Systemic levels negligible in majority of patients ≤90
days following implant
* AccessPharmacy: McGraw-Hill Global Education
9
Dexamethasone
 Size: 0.45 mm in diameter, and 6.5 mm in
length
 Administered through a single-use 22 gauge
injection system
 Common adverse events include*:
•
•
•
•
•
Cataract (nuclear, cortical, PSC) (22%)
Conjunctival hemorrhage (21%),
Increased IOP (15%)
Reduced VA (10%)
Vitreous hemorrhage (10%)
 Rare reported adverse events
• Migration to ant. chamber
• Endophthalmitis
 DRCR.net investigators’ experience
• 88% have performed Dex. implant in clinical
practice; of the 12% who haven't, 75% have
performed a training Dex implant (pig or cadaver
eye)
* Callanan et al; Ozurdex PLACID Study Group: Ophthalmology May 2012
10
METHODS
11
Study Design
Phase II, multicenter, controlled,
participant-masked, clinical trial
Duration of Follow-up
Run-in Phase
12 Weeks
Purpose
To ensure that enrolled
eyes truly have
“persistent DME” with
decreased visual
acuity despite prior
anti-VEGF therapy.
Randomized Phase
24 Weeks
12
Study Overview
SHM
SHM
VGF
VGF
Week
0
VGF
Week
4
VGF
Week
8
VGF
Week
12
VGF
Week
16
Week
20
Week
24
Group A: Sham + Ranibizumab
VGF
VGF
Week 0
Week
4
VGF
Week
8
Week
12
Group B: Dexamethasone+ Ranibizumab
Enrollment
Week
0
VGF
Dex
Run-In Phase (3 months)
Assess
Eligibility For
Randomization
Week
4
VGF
Week
8
VGF
Week
12
VGF
Week
16
VGF
Week
20
Week
24
VGF
Dex
Randomization Phase (6 months)
13
Study Eye
Both eyes can be enrolled if eligible for
the run-in phase
Both eyes can be randomized if criteria
met for randomization
Two eyes from the same participant will
be randomized to different treatment
arms
14
Study Sample Size
A minimum of 75 study eyes in each group
(from approximately 62 participants)
15
Major Eligibility Criteria
 Age ≥18 years
 Type 1 or type 2 diabetes
 At least 1 eye meeting study eye eligibility
criteria
 No history of chronic renal failure requiring
dialysis or kidney transplant
 BP <180/110
 No history of cardiac event
or stroke within 1 month
prior to enrollment
16
Major Study Eye Eligibility Criteria
 Pseudophakic
 At least 6 injections of anti-VEGF drugs (aflibercept,
bevacizumab, or ranibizumab) within the prior 36
weeks (9 months)
 Visual acuity letter score ≤78 and ≥24 (20/32 to 20/320)
 Central-involved DME on clinical exam
 OCT CSF thickness within 8 days of enrollment
 ≥340 on Zeiss Cirrus
 ≥360 on Zeiss Stratus
 No macular laser or PRP within 4 months or
anticipated need for PRP in next 6 months
 No previous history of glaucoma or steroid intraocular
pressure response in either eye
17
Other Study Eye Exclusion
Criteria
 Substantial posterior capsule opacity likely to be
decreasing visual acuity by 3 lines or more
 History of major ocular surgery within 4 months of
enrollment or anticipated within 6 in study, or any
history of vitrectomy
 History of cataract extraction within 6 months or YAG
capsulotomy within 2 mo prior to enrollment
 IOP ≥25 mmHg or history of open angle glaucoma
 History of herpetic ocular infection
 Sutured PC-IOL with ruptured post. capsule
 Exam evidence of toxoplasmosis or pseudoexfoliation
18
Non-Study Eye Criteria
 In subjects with only one study eye, the following
must be met in the fellow non-study eye:
• IOP <25 mm Hg
• No history of open-angle glaucoma
• No history of steroid-induced IOP elevation that
required IOP-lowering treatment
• No exam evidence of pseudoexfoliation
19
Enrollment Testing Procedures
 E-ETDRS visual acuity testing at 3 meters in
each eye
• within 8 days prior to enrollment
• Includes protocol refraction prior to VA testing
 OCT on study eye
• within 8 days prior to enrollment and at least 21 days
after any prior intravitreal anti-VEGF treatment
 Ocular examination on each eye
• including slit lamp, measurement of intraocular
pressure, lens assessment, and dilated
ophthalmoscopy (within 8 days prior to enrollment)
 Measurement of blood pressure
20
 Overview
Run-In Phase
• All enrolled eyes are required to complete a 12-week runin phase, where they receive 3 additional anti-VEGF
injections
 Objective
• To ensure that enrolled eyes truly have “persistent DME”
despite prior anti-VEGF therapy when given up to 3
injections within the controlled environment of a study
 Visit Schedule
• 4 weeks (±1 week)
• 8 weeks (±1 week)
• 12 weeks (±1 week) – Randomization visit
 A minimum of 21 days required between visits
21
Run-in Phase Visits
(4 and 8-week visit)
Procedures
 E-ETDRS visual acuity testing in each eye,
including protocol refraction in the study eye
 OCT on study eye
 Ocular examination on study eye
• including slit lamp, measurement of intraocular
pressure, lens assessment, and dilated
ophthalmoscopy
22
Treatment During Run-in Phase
 All study eyes will receive an injection of
ranibizumab 0.3 mg at enrollment, 4 weeks, and
8 weeks.
 Injections must be at least 21 days apart.
 If an eye experienced adverse effects from a
prior injection during the run-in phase
precluding future injections or additional
injections are otherwise contraindicated
according to the investigator (e.g. DME is no
longer present), the eye will not continue in the
study
23
Randomization
 At end of run-in phase, study eye(s) are randomized if:
• All 3 run-in visits and injections completed within ±10
days of the target visit date
o website will force completion of final status form if,
at any run-in visit, the participant comes in past the
allowable window or the injection is missed
• Randomization visit is no more than 5 weeks from 8week visit
• Has been ≥21 days since prior study injection
• VA letter score ≤78 and ≥24 (20/32 to 20/320)
• Definite central-involved DME on clinical exam
• Definition of “persistent DME” is met
• Confirmation that no exclusion criteria for enrollment
have developed/occurred during run-in phase
 If above are not met, study eyes exit the study
24
Persistent DME at End
of Run-in Phase
CSF thickness on OCT meeting either one
of the following two criteria:
• 1) ≥ 440 µm Zeiss Cirrus OR ≥ 460 µm on
Heidelberg Spectralis
OR
• 2) Zeiss Cirrus [340 - 439 μm] or
Heidelberg Spectralis [360 - 459 μm]
AND has not decreased from the prior
(8-week) visit by 10% or more
25
Randomization Visit Procedures
 E-ETDRS visual acuity (including protocol
refraction) in each eye on day of randomization
 OCT on study eye (on day of randomization)
 Ocular examination on each eye
• including slit lamp, measurement of intraocular
pressure, lens assessment, and dilated
ophthalmoscopy (on day of randomization)
 HbA1c
 Measurement of blood pressure
26
Study Treatment Groups
 Participants with one study eye
• Group A: Sham + intravitreal ranibizumab
• Group B: Intravitreal dexamethasone + intravitreal
ranibizumab
 Participants with two study eyes (both eyes are
eligible at the time of randomization):
• One eye randomly receives Group A, and the other
eye receives Group B
 Randomization will be stratified by VA and OCT
CSF thickness improvement during run-in phase
27
Treatment On Day of
Randomization
 The ranibizumab injection must be given on the
day of randomization.
 The sham or dexamethasone injection will be
given within 0-8 days of the ranibizumab
injection.
 If the injections are given consecutively on the
same day,
• Group A: Give Sham injection first
• Group B: Give Ranibizumab injection first
 Dexamethasone injection is NEVER given first
28
Post-Randomization Treatment
Evaluate VA and OCT at each protocol visit
VA ≥84 (20/20 or Better)
AND
OCT CSF thickness <
Cirrus: 290 ♀/ 305 ♂
Spectralis: 305 ♀/ 320 ♂
NO Protocol
Injection(s)
VA <84 (worse than 20/20)
OR
OCT CSF thickness ≥
Cirrus: 290 ♀/ 305 ♂
Spectralis: 305 ♀/ 320 ♂
Give Protocol
Injection(s)
* Retreatment at investigator’s discretion if AE occurs from prior
injection * Non-protocol treatment for DME should not be given
29
Injections
Group A: Sham + Ranibizumab
SHM
VGF
Rand
SHM
VGF
Week
4
VGF
Week
8
Within
0- 8 days
of each
other
Rand
VGF
Dex
VGF
VGF
Week
12
VGF
Week
16
Week
20
Week
24
Week
16
Week
20
Week
24
Within
0- 8 days
of each
other
Week
4
VGF
Week
8
VGF
Week
12
VGF
VGF
VGF
Dex
Group B: Dexamethasone + Ranibizumab
30
About Treatment….
If combination injections were not given at
the 12-week (post random.) for any reason,
combination injections should be given at
the first visit at which retreatment criteria
for injections are met (16- or 20-week visit)
Treatment at the 24 week visit is at
investigator discretion.
The Protocol Chair’s approval must be
obtained before treating the study eye with
any DME treatment that is different from
31
the treatment detailed in the protocol.
Order of Combination Injections
Must be Given 0 to 8 Days of Each Other
Group A
(Ranibizumab
alone)
SHAM FIRST
RANIBIZUMAB
Group B
(Combination)
RANIBIZUMAB
DEXAMETHASONE
Group A
(Ranibizumab
alone)
Random. day:
RANIBIZUMAB
Day 1-8:
SHAM
Group B
(Combination)
Random. day:
RANIBIZUMAB
Day 1-8:
DEXAMETHASONE
If the participant returns after a protocol visit specifically
to receive a study injection, testing prior to the injection
is at investigator discretion.
32
OCT Machines
Only the following spectral domain
machines are permitted
• Zeiss Cirrus
• Heidelberg Spectralis
Time domain machines are not
permitted
Same machine as baseline
(randomization) should be used in
follow-up visits
33
Efficacy Outcomes at 24 Weeks
 Primary:
• Mean change in visual acuity letter score adjusted for
baseline (randomization)
 Secondary:
• Visual Acuity
o % of eyes with ≥10 and ≥15 letter increase or decrease
o Area under the curve (AUC) from baseline
• OCT
o Change in CSF thickness adjusted for baseline
o % ≥2 logOCT step gain or loss in CSF
o CSF thickness < spectral-domain value equivalent to 250
microns on Zeiss Stratus
o AUC from baseline
• Diabetic Retinopathy worsening or improvement on clinical
exam
34
Safety Outcomes
Injected
Related
 Increased IOP
 Endophthalmitis
 Retinal
Detachment
 Intraocular
Hemorrhage
 Wound
problems
Ocular
Drug-Related
 Increased IOP
 IOP-lowering
treatment
 Migration of
Ozurdex to
anterior
chamber
Systemic
Drug-Related
 Cardiovascular
 Cerebrovascular
35
Study Challenges
Recruitment
• 25% of all protocol T eyes were
pseudophakic at baseline
• About 40% of ranibizumab eyes still have
macular edema (≥300 µm) after 7 injections
• Projected 7 participants recruited/month
oRecruitment: 18 months
 Safety
• Combination injection in one or two eyes
36
The Diabetic Retinopathy
Clinical Research Network
Thank you
37