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PRP has been the mainstay for treatment of PDR since the Diabetic Retinopathy Study Research Group reported its results in the 1970s

Those of us who have been in practice for more than two decades have had many patients with PDR who received PRP, resulting in stabilization of vision and retinopathy for years without further treatment.

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Loss of peripheral vision

Development of diabetic macular

edema

Difficulty with night vision, especially if

the patient receives the recommended

2,000–3,000 burns.

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As we have moved to treatment to

inhibit VEGF and away from focal/grid

laser for DME based on DRCR.net

Protocol I, we have noticed a reduction

in the progression of nonproliferative

diabetic retinopathy to PDR.

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Prompt PRP vs.

Ranibizumab + Deferred PRP for PDR Study

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

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Participants meeting all of the following criteria:

• Age ≥18 years with Type 1 or type 2 diabetes

Study eye(s) meeting all of the following criteria (a participant can

have 2 study eyes):

• PDR

• No history of PRP

• Best corrected visual acuity letter score ≥24

(~Snellen equivalent 20/320 or better)

• Eyes with or without central-involved DME were eligible

Randomized, multi-center clinical trial (55 Sites)

Primary Objective: Compare the efficacy and safety of

PRP with that of intravitreous ranibizumab (0.5-mg in

0.05 mL) for proliferative diabetic retinopathy (PDR)

Is visual acuity using ranibizumab for PDR not

worse than treatment with PRP at 2 years?

Non-inferiority margin of 5 letters

Secondary Question Are there potential benefits of ranibizumab on:

Vision throughout follow-up (area under the curve)

Peripheral vision

Macular edema

Incidence of vitrectomy

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Baseline to

1 Year

1 Year to

2 Years

PRP group: Visits every 16 weeks*

Ranibizumab group: Visits every 4

weeks to assess for PDR treatment

Both groups simultaneously

evaluated for DME treatment

PRP group: Visits every 16 weeks*

Ranibizumab group: Visits every 4wk

to 16wk to assess for PDR treatment

Interval is extended if injections for

PDR and DME deferred (“Defer and

Extend”)

*Eyes with DME could be seen more frequently for DME treatment as needed.

6 initial injections q4 weeks

One exception: if no neovascularization (NV) at

4-month or 5-month visit, then injection withheld

Starting at 6-month visit:

Inject if NV improved compared with any previous 3

consecutive visits where injection given

Withhold injections if NV stable over previous 3

consecutive injections

After injection withheld, resume injections if NV

worsens

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Prompt PRP- Initial

1 to 3 sittings within 8 weeks of randomization

Standard laser initial full session = 1200 to 1600 burns

Automated pattern initial full session = 1800 to 2400

burns

Ranibizumab required for eyes with central

involved DME and vision loss at baseline.

If the size or amount of NV increased following

initial PRP, then additional PRP could be given.

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PRP Group

Additional PRP Overall

(N = 203)

Eyes given additional PRP

(after completing initial full PRP) 45%

Distribution of timing to additional PRP

From completion of initial full PRP:

median time to additional PRP ~7 months

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Ranibizumab Group

# of Ranibizumab Injections

Eyes With Baseline

DME

(N = 36)

Eyes Without

Baseline DME

(N = 133)

Prior to 1-year Visit (Max possible = 13)

Median 9 7

Mean 8.9 6.9

Prior to 2-year visit (Max possible= 26)

Median 14 10

Mean 13.3 10.1

Note: 97% of protocol-required injections for PDR were given

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Ranibizumab Group

Received PRP for PDR

Overall

N = 191

Received PRP* before 2 years 12 (6%)

*1 met failure criteria, 1 with Protocol Chair approval, 1

without Chair approval, 8 during vitrectomy (e.g., via

endolaser), and 1 by non-study physician

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18 Outlying values were truncated to 3 SD from the mean

-5

0

5

10

15

0 16 32 52 68 84 104

Me

an

Vis

ua

l A

cu

ity

Ch

an

ge

(Le

tte

r Sc

ore

)

Visit Week

19 Outlying values were truncated to 3 SD from the mean

-5

0

5

10

15

0 16 32 52 68 84 104

Me

an

Vis

ua

l A

cu

ity

Ch

an

ge

(Le

tte

r Sc

ore

)

Visit Week PRP Group N = 203

+ 0.2

N = 168

20 Outlying values were truncated to 3 SD from the mean

-5

0

5

10

15

0 16 32 52 68 84 104

Me

an

Vis

ua

l A

cu

ity

Ch

an

ge

(Le

tte

r Sc

ore

)

Visit Week

Ranibizumab Group PRP Group

N = 191

N = 203

+ 2.8

+ 0.2

N = 168

N = 160

2-Year Adjusted Mean Difference: +2.2 letters

95% Confidence Interval: (-0.5, +5.0)

(Meets pre-specified non-inferiority criterion: lower

bounds of the 95% CI of -0.5 letters was greater than

the non-inferiority limit of -5.0 letters)

21 Area under the curve (AUC) analysis: Pre-planned secondary outcome

-5

0

5

10

15

0 16 32 52 68 84 104

Me

an

Vis

ua

l A

cu

ity

Ch

an

ge

(Le

tte

r Sc

ore

)

Visit Week

Ranibizumab Group PRP Group

N = 191

N = 203

+ 4.5

-0.3

Adjusted Mean Difference over 2 years (AUC): +4.2

P-value<0.001

95% Confidence Interval: (+3.0, +5.4)

N = 168

N = 160

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0 16 32 52 68 84 104

Visit Week

Without “Baseline DME”

-4

-2

0

2

4

6

8

10

12

14

0 16 32 52 68 84 104 Me

an

Vis

ua

l A

cu

ity

Ch

an

ge

(Le

tte

r Sc

ore

)

Visit Week

With “Baseline DME”

Ranibizumab Group PRP Group

+2

+7.9

- 0.5

+1.8

N = 42 N = 33 N = 147

N = 46 N = 37 N = 155 N = 130

N = 126

*Outlying values were truncated to 3 SD from the mean

Mean Change in Visual Acuity

Stratified by Baseline DME

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Humphrey Visual Field

30-2 + 60-4

Ranibizumab

Group

(N = 58)

PRP

Group

(N = 57)

Cumulative Point Score Change from Baseline

Mean -23 -422

Difference (P-Value) 372 dB (P<0.001)

Mean Deviation Change from Baseline

Mean -0.08 -2.50

Difference (P-Value) 2.2 (P< 0.001)

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Ranibizumab

Group

PRP

Group

Mean Change (µm) -47 -3

Adjusted Difference (P-value) -45 µm (P < 0.001)

Eyes with “Baseline DME”

Mean Change (µm) -153 -48

Adjusted Difference (P-value) -54 µm (P = 0.006)

Eyes without “Baseline DME”

Mean Change (µm) -18 +10

Adjusted Difference (P-value) -31 µm (P < 0.001)

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2-Year Adjusted Difference: 19%

95% Confidence Interval: (10% to 28%)

P-value < 0.001

N = 155

N = 147

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Ranibizuma

b Group

(N = 191)

PRP Group

(N = 203) P-value

Any retinal

detachment 6% 10% 0.08

Neovascular

glaucoma 2% 3% 0.50

Iris neovascularization 1% 1% 0.96

Vitreous hemorrhage 27% 34% 0.09

Vitrectomy 4% 15% < 0.001

PDR = proliferative diabetic retinopathy

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Ranibizumab

Group

(N = 142)

Prompt PRP

Group

(N = 148)

P-

value

Fundus Photos Graded by Reading Center* 0.41

No PDR 35% 30% -

Regressed NV 23% 24% -

Active NV 42% 46% -

* Only includes eyes with active NV at baseline

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Diabetic Retinopathy Improvement:

Ranibizumab Group (Note: Cannot determine for PRP Group)

Ranibizumab

Group

2-Year Visit N = 142

Eyes improving 2 or more steps in DR

severity on fundus photos 47%

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Summary of Ranibizumab group results vs. PRP:

Mean change in VA from baseline to 2-years with

ranibizumab no worse than with PRP

Superior mean visual acuity over course of 2-years

(area under the curve analysis)

Superior mean visual field outcomes

Decreased occurrence of vitrectomies

Decreased development of central involved DME

PRP rarely given for failure or futility of ranibizumab

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Rates of endophthalmitis or other injection-

related serious adverse events were very

low

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Typically able to be completed in one or two visits

Often long-lasting effect requiring no additional treatment However, study suggests approximately 45% given

additional PRP after initial full PRP was completed

From completion of initial full PRP, median time to additional PRP ~7 months

May cost less than ranibizumab injections

No risk of endophthalmitis

No risk of systemic exposure to anti-VEGF

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Presence of DME may influence the relative benefit of ranibizumab over PRP

When DME is present and treatment with an anti-VEGF agent is planned, PRP may be unnecessary in most cases provided that the patient is expected to be compliant with follow-up

When DME is not present, ranibizumab is more effective than PRP in preserving central and peripheral visual function, on average, but cost, follow-up compliance, and patient preference need to be considered

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Anti-VEGF initially for three injections

followed by PRP for more long-term

stability?

This approach would require a lighter

amount of PRP, thus reducing the

adverse effects on peripheral vision and

development of DME.

Full PRP and still NVE?

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PRP effective for PDR over last 4 decades;

remains effective in 21st century

Ranibizumab for PDR is at least as good as

(non-inferior to) PRP for visual acuity at 2 years

Ranibizumab is an effective treatment alternative to

PRP for PDR

No substantial safety concerns for at least 2 years

Looking forward to the five-year results of this

important ongoing clinical trial.

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