the diabetic retinopathy clinical research network protocol i: clinical applications supported...

The Diabetic Retinopathy Clinical Research Network

The Diabetic Retinopathy Clinical Research Network

Protocol I: Clinical ApplicationsSupported 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

Diabetic Macular Edema TreatmentDiabetic Macular Edema Treatment

Focal/Grid Photocoagulation• ~25 years following ETDRS

Intravitreal Steroids• ~10 years

Anti-VEGF Agents• Late stage studies ~15 months

Mean Change in Visual Acuity* Mean Change in Visual Acuity*

3

* Values that were ±30 letters were assigned a value of 30P-values for difference in mean change in visual acuity from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001; and triamcinolone+prompt laser=0.31.

Ranibizumab + prompt laser

Ranibizumab + deferred laser

Primary Outcome Time Point (1 Year)

Lett

er I

mpr

ovem

ent

Weeks

Sham+ prompt laser

P<0.001

DRCR Protocol I Overall Study: 854 eyes, 691 participants

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 real-time web-based system

4

Purpose of this PresentationPurpose of this Presentation

To discuss clinical applications that might provide clinicians with:

• a simplified approach to retreatment

• in accord with the general opinion of the DRCR.net investigators, and is

• based on the Protocol I retreatment algorithm

5

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

66

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

7

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)

8

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?

10



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?

11

Patients with edema involving the center of the macula



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?

12

† “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.



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?

13

† “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)



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?

14



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?

15

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.



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?

16



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?

17

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



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?

18



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?

19

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



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?

20



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?

21

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.



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?

22



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?

23

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)

SummarySummary Given that duplication of the treatment approach used within

the DRCR.net trial with its elaborate infrastructure may not be practical in all clinical settings

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

However, it is unknown whether these or other modifications to the DRCR.net protocol would result in better, same or worse outcomes

24

the diabetic retinopathy clinical research network protocol i: clinical applications supported...

Documents

week visit

followup visit

visit schedule

clinical applicationssupported

visual acuity letter

weeks visits

deferred focalgrid laser

retreatment algorithm