The Diabetic Retinopathy Clinical Research Network

The Diabetic Retinopathy Clinical Research Network

The Diabetic Retinopathy Clinical Research Network

Protocol I: Clinical Applications Manuscript in Press: Ophthalmology

Susan Bressler, M.D.Supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes

and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services EY14231, EY14229, EY018817 

1

BackgroundBackground

Protocol I demonstrated that ranibizumab (with prompt or deferred focal/grid laser) resulted in superior visual acuity outcomes compared with laser alone through 2 years

The treatment regimen for ranibizumab (with prompt or deferred laser ) was very detailed and facilitated by a web-based system

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Purpose of this PresentationPurpose of this Presentation

This clinical application discussion aims to provide clinicians with:

a simplified approach to retreatment in the opinion of the DRCR.net

investigators, and based on the Protocol I retreatment

algorithm

3

Visit/Treatment Schedule: Year 1 – the “4:2:7” GuideVisit/Treatment Schedule: Year 1 – the “4:2:7” Guide

44

Sham+Prompt Laser

Ranibizumab+Prompt Laser

Ranibizumab+Deferred Laser

**Triamcinolone+Prompt Laser

0 4 8 12

‘4’ required injections

16 20

‘2’ required injections if not

a success*

24 28 32 36 40 44 48 52

‘7’ additional follow-up visits every 4 weeks; required injection if improvement†

but not success* since last injection; otherwise optional

Primary Endpoint

Visits were every 4 weeks regardless of whether the eye status was successful, improved, or failed.

*Success: Visual acuity letter score ≥84 (~20/20) or OCT CSF <250 µm; retreatment at investigator discretion.

† Improvement: OCT central subfield thickness decreased by >10% or visual acuity letter score improved by >5.

Sham+prompt laser

Ranibizumab+prompt laser

Ranibizumab+deferred laser

Triamcinolone+prompt laser

**Triamcinolone q 16 wks w/ sham q 4 wks in between.

Follow-up Visits at and After 52 Week Visit if Ranibizumab Injection Given

Follow-up Visits at and After 52 Week Visit if Ranibizumab Injection Given

5

Ranibizumab+Deferred

or Prompt LaserDrug

52 56

Four wks after any ranibizumab injection, the study eye is evaluated for possible additional ranibizumab injection using retreatment criteria as in year 1: If not a success*, but improvement† since last injection, retreatment required; otherwise, retreatment is up to investigator.

60 64 68…………104

*Success: Visual acuity letter score ≥84 (~20/20) or OCT CSF <250 µm; retreatment at investigator discretion.

† Improvement: OCT central subfield thickness decreased by >10% or visual acuity letter score improved by >5.

Drug Drug Drug Drug Drug

Visit Visit* Visit* Visit* Visit* Visit*

Follow-up Visits at and After 52 Week Visit if Ranibizumab Not Given (4 to 8 to 16 Weeks)Follow-up Visits at and After 52 Week Visit if Ranibizumab Not Given (4 to 8 to 16 Weeks)

6

Ranibizumab+deferred

or Prompt Laser

No Drug

52 56

If a ranibizumab injection is not given at the current and previous 2 visits (e.g. week 60 above), the next follow-up visit is in 8 weeks.

If at the next 8 week interval visit the injection is deferred again, the next follow-up visit is in 16 weeks; visits continue every 16 weeks unless a ranibizumab injection is given, at which point the visit schedule goes back to 4 week intervals.

No Drug

60 64 68……………….……84

No Drug No Drug No Drug

Visit Visit Visit Skip Visit VisitSkip 16

wksVisit

SIMPLIFIED Retreatment and Follow-up of Center-Involved DME with Anti-VEGF

DME Improving?

DME Worsens or

Recurs?

No Injection and return in 1 month

YES

NO

NO

YES

Assessment 1 month

after initial serial series of injection(s)

Double Follow-Up Interval Up to 4 Months

Re-inject and Return in 1 Month

Anti-VEGF Treatment ConceptsAnti-VEGF Treatment Concepts

Clinical Practice Considerations

DRCR.net Study

Patients could be enrolled if they had edema involving the center of the macula defined as central subfield thickness ≥250µm and vision impairment defined as Snellan equivalent of 20/32 to 20/320.

For which eyes with DME should anti-VEGF therapy be considered?

8

Anti-VEGF Treatment ConceptsAnti-VEGF Treatment Concepts

Clinical Practice Considerations

DRCR.net Study

Patients could be enrolled if they had edema involving the center of the macula defined as central subfield thickness ≥250µm and vision impairment defined as Snellan equivalent of 20/32 to 20/320.

For which eyes with DME should anti-VEGF therapy be considered?

9

Patients with edema involving the center of the macula

Anti-VEGF Treatment ConceptsAnti-VEGF Treatment Concepts

Clinical Practice Considerations

DRCR.net Study

4 required injections at 4-weekly intervals, followed by 2 injections at next 4-weekly intervals unless edema resolved or vision improved to 20/20 or better

What follow-up interval could be considered after initiating therapy?

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† “Improvement” in the DRCR.net study was defined as “increase of at least 5 letters (approximately 1 line) in visual acuity or at least a 10% reduction in the central subfield thickness on OCT since the last injection.

Anti-VEGF Treatment ConceptsAnti-VEGF Treatment Concepts

Clinical Practice Considerations

DRCR.net Study

4 required injections at 4-weekly intervals, followed by 2 injections at next 4-weekly intervals unless edema resolved or vision improved to 20/20 or better

What follow-up interval could be considered after initiating therapy?

11

† “Improvement” in the DRCR.net study was defined as “increase of at least 5 letters (approximately 1 line) in visual acuity or at least a 10% reduction in the central subfield thickness on OCT since the last injection.

Several serial monthly injec-tions until vision and edema are no longer improving† or can no longer improve

(e.g. vision 20/20 or better, or edema resolved)

Anti-VEGF Treatment ConceptsAnti-VEGF Treatment Concepts

Clinical Practice Considerations

DRCR.net Study

If no improvement from prior injection, decision to re-inject was at investiga-tor discretion. Injections were recommended if there still was edema to treat.

What treatment is employed when the DME no longer is improving?

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Anti-VEGF Treatment ConceptsAnti-VEGF Treatment Concepts

Clinical Practice Considerations

DRCR.net Study

If no improvement from prior injection, decision to re-inject was at investiga-tor discretion. Injections were recommended if there still was edema to treat.

What treatment is employed when the DME no longer is improving?

13

Focal/grid laser can be added if it not previously used and injections would continue. Injections may be withheld, but resumed if the edema worsens.

Anti-VEGF Treatment ConceptsAnti-VEGF Treatment Concepts

Clinical Practice Considerations

DRCR.net Study

Re-injection was at the investigator’s discretion if edema recurred or worsened, but was recommended if there was edema to treat; follow-up then returned to 4-week intervals once injections resumed

When should treatment be resumed after it has not been given?

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Anti-VEGF Treatment ConceptsAnti-VEGF Treatment Concepts

Clinical Practice Considerations

DRCR.net Study

Re-injection was at the investigator’s discretion if edema recurred or worsened, but was recommended if there was edema to treat; follow-up then returned to 4-week intervals once injections resumed

When should treatment be resumed after it has not been given?

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Injections may be re-sumed if edema recurs or worsens; follow-up then returns to monthly intervals until injection is not given

Anti-VEGF Treatment ConceptsAnti-VEGF Treatment Concepts

Clinical Practice Considerations

DRCR.net Study

Starting with the second year of treatment, if an injection was withheld at 3 consecutive 4-weekly visits, follow-up interval was extended to 8 weeks, and then again to 16 weeks if treatment still not warranted

What follow-up is employed when the DME does not recur or worsen after an injection is not given?

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Anti-VEGF Treatment ConceptsAnti-VEGF Treatment Concepts

Clinical Practice Considerations

DRCR.net Study

Starting with the second year of treatment, if an injection was withheld at 3 consecutive 4-weekly visits, follow-up interval was extended to 8 weeks, and then again to 16 weeks if treatment still not warranted

What follow-up is employed when the DME does not recur or worsen after an injection is not given?

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If injection was not given and edema does not recur, follow-up may be doubled (up to 4 months or longer).

Anti-VEGF Treatment ConceptsAnti-VEGF Treatment Concepts

Clinical Practice Considerations

DRCR.net Study

Randomized treatment groups included either prompt (within 3-10 days) or deferred (at least 24 weeks) focal/grid laser. If deferred, laser only could be added if edema was still present after 24 weeks and there was no improvement from two prior consecutive injections

When should focal/grid laser treatment be added?

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Anti-VEGF Treatment ConceptsAnti-VEGF Treatment Concepts

Clinical Practice Considerations

DRCR.net Study

Randomized treatment groups included either prompt (within 3-10 days) or deferred (at least 24 weeks) focal/grid laser. If deferred, laser only could be added if edema was still present after 24 weeks and there was no improvement from two prior consecutive injections

When should focal/grid laser treatment be added?

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Focal/grid laser may be given initially or deferred. If deferred, laser may be added at any time if edema is no longer improv-ing after an injection.

Anti-VEGF Treatment ConceptsAnti-VEGF Treatment Concepts

Clinical Practice Considerations

DRCR.net Study

Once initiated, focal/grid was re-applied if 1) edema was present, 2) eye did not have “complete” laser, and 3) it had been at least 13 weeks since last laser

When should focal/grid laser be repeated after initiation?

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Anti-VEGF Treatment ConceptsAnti-VEGF Treatment Concepts

Clinical Practice Considerations

DRCR.net Study

Once initiated, focal/grid was re-applied if 1) edema was present, 2) eye did not have “complete” laser, and 3) it had been at least 13 weeks since last laser

When should focal/grid laser be repeated after initiation?

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Focal/grid laser generally should be repeated at any time that edema persists or is not improving while giving anti-VEGF therapy

(as long as it is believed that additional laser may be of benefit)

36 40

311 389

20/20 20/25

44 48

253 316

20/20 20/25

Case Example #1Case Example #1

2222

WK 0 4 8 12

OCT 631 419 348 329

VA 20/40 20/32 20/25 20/20

IVR

Laser

Injection or sham trt required

Trt required if not a

success*

It not a success, trt required if improvement† since last injection.

Otherwise, retreatment is at investigator discretion

* Success = visual acuity letter score >84 (~20/20) or OCT CSF <250µ; retreatment at investigator discretion

† Improvement = OCT central subfield thickness decreased by >10% or visual acuity letter score improved by >5.

Ranibizumab Injection Performed

Focal/grid Laser Performed

16 20

332 408

20/20 20/20

24 28

354 327

20/20 20/20

32

319

20/25

Case Example #1 - Year 2Case Example #1 - Year 2

2323

WK

OCT

VA

IVR

Laser

Ranibizumab Injection Performed

Focal/grid Laser Performed

52 56

250 252

20/20 20/20

60

289

20/20

64 68

211 207

20/20 20/20

72

208

20/16

76 80 84 88 92

211

20/20

96

194

20/20

100 104

215

20/20

Extended Follow-up to 16 wks

Extended Follow-up to 8 wks

Baseline Color PhotoBaseline Color Photo

2424

OCT Baseline and 20/40OCT Baseline and 20/40

2525

Treatment Given: Injection Focal/Grid Laser

CSF = 631Volume = 9.15mm3

Case ExampleCase Example

2626

WK 0 4 8 12 16 20 24 28 32 36 40 44 48

OCT 631

VA 20/40

IVR

Laser

Injection or sham trt required

Trt required if not a

success*

It not a success, trt required if improvement† since last injection.

Otherwise, retreatment is at investigator discretion

* Success = visual acuity letter score >84 (~20/20) or OCT CSF <250µ; retreatment at investigator discretion

† Improvement = OCT central subfield thickness decreased by >10% or visual acuity letter score improved by >5.

Ranibizumab Injection Performed

Focal/grid Laser Performed

OCT 4 Weeks and 20/32OCT 4 Weeks and 20/32

2727

Treatment Given: Injection

CSF = 419Volume = 8.3mm3

Case ExampleCase Example

2828

WK 0 4 8 12 16 20 24 28 32 36 40 44 48

OCT 631 419

VA 20/40 20/32

IVR

Laser

Injection or sham trt required

Trt required if not a

success*

It not a success, trt required if improvement† since last injection.

Otherwise, retreatment is at investigator discretion

* Success = visual acuity letter score >84 (~20/20) or OCT CSF <250µ; retreatment at investigator discretion

† Improvement = OCT central subfield thickness decreased by >10% or visual acuity letter score improved by >5.

Ranibizumab Injection Performed

Focal/grid Laser Performed

OCT 16 Weeks and 20/20OCT 16 Weeks and 20/20

2929

Treatment Given: Focal/Grid Laser

CSF = 332Volume = 8.02mm3

Case ExampleCase Example

3030

WK 0 4 8 12 16 20 24 28 32 36 40 44 48

OCT 631 419 348 329 332

VA 20/40 20/32 20/25 20/20 20/20

IVR

Laser

Injection or sham trt required

Trt required if not a

success*

It not a success, trt required if improvement† since last injection.

Otherwise, retreatment is at investigator discretion

* Success = visual acuity letter score >84 (~20/20) or OCT CSF <250µ; retreatment at investigator discretion

† Improvement = OCT central subfield thickness decreased by >10% or visual acuity letter score improved by >5.

Ranibizumab Injection Performed

Focal/grid Laser Performed

OCT 24 Weeks and 20/20OCT 24 Weeks and 20/20

3131

Treatment Given: None (only 8 wks

since last laser)

CSF = 354Volume = 7.83mm3

Case ExampleCase Example

3232

WK 0 4 8 12 16 20 24 28 32 36 40 44 48

OCT 631 419 348 329 332 408 354

VA 20/40 20/32 20/25 20/20 20/20 20/20 20/20

IVR

Laser

Injection or sham trt required

Trt required if not a

success*

It not a success, trt required if improvement† since last injection.

Otherwise, retreatment is at investigator discretion

* Success = visual acuity letter score >84 (~20/20) or OCT CSF <250µ; retreatment at investigator discretion

† Improvement = OCT central subfield thickness decreased by >10% or visual acuity letter score improved by >5.

Ranibizumab Injection Performed

Focal/grid Laser Performed

OCT 32 Weeks and 20/25OCT 32 Weeks and 20/25

3333

Treatment Given: Injection Focal/Grid Laser

CSF = 319Volume = 7.69mm3

Case ExampleCase Example

3434

WK 0 4 8 12 16 20 24 28 32 36 40 44 48

OCT 631 419 348 329 332 408 354 327 319

VA 20/40 20/32 20/25 20/20 20/20 20/20 20/20 20/20 20/25

IVR

Laser

Injection or sham trt required

Trt required if not a

success*

It not a success, trt required if improvement† since last injection.

Otherwise, retreatment is at investigator discretion

* Success = visual acuity letter score >84 (~20/20) or OCT CSF <250µ; retreatment at investigator discretion

† Improvement = OCT central subfield thickness decreased by >10% or visual acuity letter score improved by >5.

Ranibizumab Injection Performed

Focal/grid Laser Performed

OCT 40 Weeks and 20/25OCT 40 Weeks and 20/25

3535

Treatment Given: Injection

CSF = 389Volume = 7.83mm3

Case ExampleCase Example

3636

WK 0 4 8 12 16 20 24 28 32 36 40 44 48

OCT 631 419 348 329 332 408 354 327 319 311 389

VA 20/40 20/32 20/25 20/20 20/20 20/20 20/20 20/20 20/25 20/20 20/25

IVR

Laser

Injection or sham trt required

Trt required if not a

success*

It not a success, trt required if improvement† since last injection.

Otherwise, retreatment is at investigator discretion

* Success = visual acuity letter score >84 (~20/20) or OCT CSF <250µ; retreatment at investigator discretion

† Improvement = OCT central subfield thickness decreased by >10% or visual acuity letter score improved by >5.

Ranibizumab Injection Performed

Focal/grid Laser Performed

OCT 48 Weeks and 20/20OCT 48 Weeks and 20/20

3737

Treatment Given: Injection (CSF increased) Focal/Grid Laser

CSF = 316Volume = 7.47mm3

Case ExampleCase Example

3838

WK 0 4 8 12 16 20 24 28 32 36 40 44 48

OCT 631 419 348 329 332 408 354 327 319 311 389 253 316

VA 20/40 20/32 20/25 20/20 20/20 20/20 20/20 20/20 20/25 20/20 20/25 20/20 20/20

IVR

Laser

Injection or sham trt required

Trt required if not a

success*

It not a success, trt required if improvement† since last injection.

Otherwise, retreatment is at investigator discretion

* Success = visual acuity letter score >84 (~20/20) or OCT CSF <250µ; retreatment at investigator discretion

† Improvement = OCT central subfield thickness decreased by >10% or visual acuity letter score improved by >5.

Ranibizumab Injection Performed

Focal/grid Laser Performed

OCT 52 Weeks and 20/20OCT 52 Weeks and 20/20

3939

Treatment Given: Injection (CSF

improved)

CSF = 250Volume = 7.15mm3

Color PhotosColor Photos

4040

Baseline 52 Week Visit

Case Example- Year 2Case Example- Year 2

4141

WK 52 56 60 64 68 72 76 80 84 88 92 96 100 104

OCT 250 252 289 211 207 208 211 194 215

VA 20/20 20/20 20/20 20/20 20/20 20/16 20/20 20/20 20/20

IVR

Laser

Extended Follow-up to 16 wks

Ranibizumab Injection Performed

Focal/grid Laser Performed

Extended Follow-up to 8 wks

SummarySummary This presentation provides guidelines based on DRCR.net

investigators’ opinion for a simplified retreatment approach when using intravitreal ranibizumab to treat center-involved DME with vision impairment

Duplication of the treatment approach used within the DRCR.net trial with its elaborate infrastructure may not be practical in clinical practice

Although, It is unknown if modifications to the DRCR.net protocol would result in different outcomes

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