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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
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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.
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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.
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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.
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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.
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METHODS
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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)
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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
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Study Sample Size
A minimum of 75 study eyes in each group
(from approximately 62 participants)
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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
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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
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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
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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
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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
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 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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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The Diabetic Retinopathy
Clinical Research Network
Thank you
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