The Diabetic Retinopathy Clinical Research NetworkThe Diabetic Retinopathy

Clinical Research Network

1111

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.

22

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

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.

44

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.

55

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®)

66

Anti-human VEGF monoclonal antibody

FDA-approved for treatment of wet AMD, macular edema following RVO, and DME

Provided by Genentech Inc.

METHODSMETHODS

77

Study OverviewStudy Overview

88

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

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

99

Study Sample SizeStudy Sample Size

A minimum of 75 study eyes in each group

(from approximately 62 participants)

1010

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

1111

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

1212

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

1313

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

1414

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

1515

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

1616

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

1717

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

1818

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

1919

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

2020

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

2121

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

2222

Post-Randomization TreatmentPost-Randomization Treatment

2323

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

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.

2424

Order of Combination InjectionsOrder of Combination Injections

2525

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

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

2626

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

2727

Safety OutcomesSafety OutcomesOcular

Drug-Related Increased IOP IOP-lowering

treatment Migration of

Ozurdex to anterior chamber

2828

InjectedRelated

Increased IOP Endophthalmitis Retinal

Detachment Intraocular

Hemorrhage Wound

problems

Systemic Drug-Related

Cardiovascular Cerebrovascular

The Diabetic Retinopathy Clinical Research NetworkThe Diabetic Retinopathy

Clinical Research Network

Thank you

29292929