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
Protocol Chair: Raj Maturi, MD
1
Background: Persistent DME
Experience from DRCR.net Protocol I
• 52% of ranibizumab eyes didn’t achieve
≥2 vision-line improvement
• ≥40% did not have resolution of retinal
thickening (<250 µm) at year 2
• Eyes that remain edematous at 6
months and 1 year following
ranibizumab treatment have been
consistently thickened
throughout the treatment
period.
2
Evidence from Clinical Trials of
Beneficial Effects of Intravitreal
Corticosteroids for DME
 DRCR.net Protocol I
• pseudophakic subgroup had a visual gain similar to
the Ranibizumab groups
 FAME study
• Fluocinolone Acetonide demonstrated benefits over 3
years
 MEAD study
• benefit of dexamethasone intravitreal implant over
three year treatment period
Cataract and IOP rise are issues
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.
4
Why This Study?
 To assess short-term effects of combination
corticosteroid+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.
5
Study Drugs
Dexamethasone
(OZURDEX®)
Ranibizumab 0.3mg
(LUCENTIS®)
 Sustained-release
polymer that provides
700 μg of
dexamethasone
 FDA-approved for uveitis
and macular edema due
to RVO, and for DME that
that have had (or will
imminently have)
cataract surgery
 Provided by Allergan Inc.
 Anti-human VEGF
monoclonal antibody
 FDA-approved for
treatment of wet AMD,
macular edema following
RVO, and DME
 Provided by Genentech
Inc.
6
METHODS
7
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)
8
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
9
Study Sample Size
A minimum of 75 study eyes in each group
(from approximately 62 participants)
10
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
11
Major Study Eye Eligibility Criteria
 Pseudophakic
 At least 3 injections of anti-VEGF drugs (aflibercept,
bevacizumab, or ranibizumab) within the prior 20
weeks (5 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
 Zeiss Cirrus: ≥290 in women; ≥305 in men
 Heidelberg Spectralis: ≥305 in women; ≥320 in men
 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
12
Other Important Study Eye
Exclusion Criteria
 History of cataract extraction within 6
months
 IOP ≥25 mmHg or history of open angle
glaucoma
 Sutured PC-IOL with ruptured post. capsule
13
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
14
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
15
 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
16
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 each injection is not given within window for
any reason (e.g. AE, DME resolution), the eye
will not continue in the study
17
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
• 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
18
Persistent DME at End
of Run-in Phase
CSF thickness on OCT meeting either
one of the following two gender- and
OCT machine-specific criteria:
• Zeiss Cirrus
o≥290 in women
o≥305 in men
• Heidelberg Spectralis
o≥305 in women
o≥320 in men
19
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
20
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
21
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
22
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
23
About Treatment….
If combination injections were not given at
the 12-week for any reason, combination
injections should be given at the first visit
at which retreatment criteria for injections
are met (16- or 20-week visits).
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
24
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.
25
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
26
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
27
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
28
The Diabetic Retinopathy
Clinical Research Network
Thank you
29