the diabetic retinopathy clinical research network 11
TRANSCRIPT
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The Diabetic Retinopathy Clinical Research NetworkThe Diabetic Retinopathy
Clinical Research Network
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Background: Persistent DMEBackground: Persistent DMEExperience 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
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
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RationaleRationale 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?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 anti-VEGF treatment.
To provide more information needed for future conduct of a definitive phase III clinical trial.
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Study DrugsStudy Drugs
Dexamethasone (OZURDEX®)
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.
Ranibizumab 0.3mg (LUCENTIS®)
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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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METHODSMETHODS
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Study OverviewStudy Overview
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VGF VGF VGF
Enrollment
SHM
VGF
Dex
VGF
VGF VGF VGF VGFVGF
VGF VGF VGF VGF VGF
SHM
Dex
Group A: Sham + Ranibizumab
Group B: Dexamethasone+ Ranibizumab
Run-In Phase (3 months) Randomization Phase (6 months)
Assess Eligibility For
Randomization
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Study EyeStudy 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 SizeStudy Sample Size
A minimum of 75 study eyes in each group
(from approximately 62 participants)
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Major Eligibility CriteriaMajor 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 CriteriaMajor 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
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 CriteriaNon-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 ProceduresEnrollment 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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Run-In PhaseRun-In Phase Overview
• All enrolled eyes are required to complete a 12-week run-in 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 PhaseTreatment 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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RandomizationRandomization 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 8-week 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
Persistent DME at End of Run-in Phase
CSF thickness on OCT meeting either one CSF thickness on OCT meeting either one of the following two gender- and OCT of the following two gender- and OCT machine-specific criteria: machine-specific criteria: • Zeiss Cirrus
o≥290 in womeno≥305 in men
• Heidelberg Spectraliso≥305 in womeno≥320 in men
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Randomization Visit ProceduresRandomization 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 GroupsStudy 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
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 TreatmentPost-Randomization Treatment
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Evaluate VA and OCT at each protocol visit
VA ≥84 (20/20 or Better)AND
OCT CSF thickness <Cirrus: 290 ♀/ 305 ♂
Spectralis: 305 ♀/ 320 ♂
VA <84 (worse than 20/20)OR
OCT CSF thickness ≥Cirrus: 290 ♀/ 305 ♂
Spectralis: 305 ♀/ 320 ♂
NO Protocol Injection(s)
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….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 the treatment detailed in the protocol.
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Order of Combination InjectionsOrder of Combination Injections
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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.
Must be Given 0 to 8 Days of Each OtherMust be Given 0 to 8 Days of Each Other
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OCT MachinesOCT MachinesOnly the following spectral domain
machines are permitted• Zeiss Cirrus
• Heidelberg Spectralis
Time domain machines are not permittedSame machine as baseline
(randomization) should be used in follow-up visits
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Efficacy Outcomes at 24 WeeksEfficacy 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 decreaseo Area under the curve (AUC) from baseline
• OCT o Change in CSF thickness adjusted for baseline o % ≥2 logOCT step gain or loss in CSFo CSF thickness < spectral-domain value equivalent to 250 microns on
Zeiss Stratuso AUC from baseline
• Diabetic Retinopathy worsening or improvement on clinical exam
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Safety OutcomesSafety OutcomesOcular
Drug-Related Increased IOP IOP-lowering
treatment Migration of
Ozurdex to anterior chamber
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InjectedRelated
Increased IOP Endophthalmitis Retinal
Detachment Intraocular
Hemorrhage Wound
problems
Systemic Drug-Related
Cardiovascular Cerebrovascular
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The Diabetic Retinopathy Clinical Research NetworkThe Diabetic Retinopathy
Clinical Research Network
Thank you
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