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The Diabetic Retinopathy Clinical Research Network The Diabetic Retinopathy Clinical Research Network

The Diabetic Retinopathy Clinical Research Network - PowerPoint Presentation

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The Diabetic Retinopathy Clinical Research Network - PPT Presentation

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 ID: 759612

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Slide1

The Diabetic Retinopathy Clinical Research Network

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 

1

Slide2

Disclosure

2

Funding/Support:

Cooperative Agreement with NEI and NIDDK of NIH, U.S. Department of Health and Human Services.

Additional

Contributions

: Genentech Inc.

provided the

ranibizumab and clinical site funding.

A

complete list of all DRCR.net investigator financial disclosures can be found at

www.drcr.net

.

Slide3

Background

Proliferative diabetic retinopathy (PDR):Left untreated, is a leading cause of blindness~12,000 to 24,000 new cases of diabetic retinopathy-induced blindness each year*Without treatment, ~50% of eyes with high-risk PDR experience severe vision loss within 5 years

3

* CDC: National diabetes fact sheet, 2007

Slide4

Background

Panretinal photocoagulation (PRP) has been the treatment for PDR over last 4 decadesSubstantially reduces risk of severe vision loss, but . . .Inherently destructivePeripheral visual field lossNight vision lossExacerbation of pre-existing DMENot perfect: 5% severe vision loss (worse than 5/200 at 2 consecutive visits) despite PRPAnti-VEGF, when given for DME, decreases risk of diabetic retinopathy worsening and increases chance of improved retinopathy level

4

Slide5

Study Design

5

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):PDRNo history of PRPBest 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)

Slide6

Primary Question

Is visual acuity using ranibizumab for PDR not worse than treatment with PRP at 2 years?Non-inferiority margin of 5 lettersSecondary QuestionAre there potential benefits of ranibizumab on:Vision throughout follow-up (area under the curve)Peripheral vision Macular edemaIncidence of vitrectomy

6

Slide7

Follow-up Schedule

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

7

PRP group: Visits every 16 weeks*Ranibizumab group: Visits every 4wk to 16wk to assess for PDR treatmentInterval 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.

Slide8

PDR Treatment Schedule: Ranibizumab Group – Year 1

6 initial injections q4 weeksOne exception: if no neovascularization (NV) at 4-month or 5-month visit, then injection withheldStarting at 6-month visit:Inject if NV improved compared with any previous 3 consecutive visits where injection givenWithhold injections if NV stable over previous 3 consecutive injectionsAfter injection withheld, resume injections if NV worsens

8

Slide9

PDR Treatment Schedule: PRP Group

9

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.

Slide10

DME Treatment Schedule: Ranibizumab or PRP Groups

Eyes in both groups could receive 0.5-mg ranibizumab for DME treatmentAt randomization, treatment was required for central DME with visual acuity 20/32 or worse – defined as “Baseline DME” throughout remainder of presentationOtherwise initiation and retreatment with ranibizumab for DME at follow-up was at investigator discretionDRCR.net protocol comparing ranibizumab with prompt or deferred focal/grid laser with focal/grid laser (Protocol I) retreatment regimen provided as guidelineFocal/grid laser at investigator discretion

10

Slide11

Randomization

11

Participants:

N = 304

Eyes: N = 394

Ranibizumab Group N = 191

PRP Group N = 203

N = 168 (83%)

N = 86%

N = 160 (84%)

N = 88%

2-Years

2-Years

Excluding Death

Baseline

N = 16 (9, 22)

N = 22 (18, 24)

Median (Quartiles) No. Visits over 2 years

Slide12

Baseline Characteristics

12

Ranibizumab

Group

(N = 191)

PRP

Group

(N = 203)

Age (

yrs

) – Median

52

51

Women

43%

45%

Race

White

52%

50%

Type 2 diabetes

73%

76%

Duration of Diabetes (

yrs

)

18

17

Median HbA1c (%)

8.6

8.9

Slide13

Ocular Baseline Characteristics

13

Ranibizumab

Group

(N = 191)

PRP

Group

(N = 203)

Mean visual acuity

letter score

(~Snellen Equivalent)

75.0

(20/32)

75.2

(20/32)

20/25 or better

46%

46%

20/32 to 20/40

34%

33%

20/50 to 20/100

16%

17%

20/125 to 20/320

5%

4%

Slide14

Ocular Baseline Characteristics

RanibizumabGroup(N = 189)PRPGroup(N = 201)Mean OCT CST* (µm)262249< 250 µm66%67%250 to 349 µm19%26%≥ 350 µm15%7%Presence of central-involved DME with VA loss**22%23%

*OCT values are Stratus equivalents **Eyes with visual acuity letter score ≤ 78 (20/32 or worse) AND OCT CST ≥ machine and gender specific thresholds

Required ranibizumab at baseline

Slide15

Ocular Baseline Characteristics

15

RanibizumabGroup(N = 189)PRPGroup(N = 199)Diabetic Retinopathy Severity by Reading CenterNPDR†10%13%Mild to moderate PDR52%49%High risk PDR to advanced PDR38%37%

There were

46 eyes (12%) for

which NV was not identified by the reading center on the submitted color images or quality precluded identification. In

29 of

these

cases (63%),

subsequent review of additional images (e.g. FA) confirmed

NV, leaving 17 (4%) of 394 subjects with no photographic documentation of PDR.

Slide16

Treatment For Proliferative Diabetic Retinopathy

16

Slide17

17

PRP Group Baseline PRP

Overall

(N = 203)

Completed initial full PRP

98%

Performed in 1 Sitting

54%

Slide18

18

PRP GroupAdditional 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

Slide19

19

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)Median9 7Mean8.96.9Prior to 2-year visit (Max possible= 26)Median1410 Mean13.310.1

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

Slide20

20

Ranibizumab Group Received PRP for PDR

OverallN = 191Received PRP* before 2 years12 (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

Slide21

Treatment For Diabetic Macular Edema

21

Slide22

PRP GroupRanibizumab Treatment for DME

22

Timing of first ranibizumab injection for DME

Overall

(N

= 203)

Never

47%

Baseline

35%

Follow-up

18%

Slide23

23

PRP Group:# of Ranibizumab Injections for DME

Eyes with baseline DME

(N = 42)

Eyes without

baseline DME

(N = 135)

Prior to 1-year Visit (Max = 13)

Median

5

0

Mean

5.7

1.4

Prior to 2-year Visit (Max = 26)

Median

9

0

Mean

9.1

2.2

Slide24

24

Additional Treatment for DME

Ranibizuma

b Group

PRP

Group

Focal/grid laser

8%

10%

Received 1 or more alternative treatment

<1%

2%

Slide25

Efficacy

25

Slide26

Visual Acuity

26

Slide27

Mean Change in Visual Acuity

27

Outlying values were truncated to 3 SD from the mean

Slide28

Mean Change in Visual Acuity

28

Outlying values were truncated to 3 SD from the mean

Slide29

Mean Change in Visual Acuity

29

Outlying values were truncated to 3 SD from the mean

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)

Slide30

Mean Change in Visual AcuityArea under the Curve Analysis

30

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

Slide31

Mean Change in Visual AcuitySubset that Completed 2 Yrs

31

N = 160 of 191

N = 168 of 203

Slide32

Mean Change in Visual Acuity:Eyes “Baseline DME”

32

N = 33

+7.9

N = 37

N = 42

Slide33

Mean Change in Visual AcuityEyes Without “Baseline DME”

33

Slide34

34

- 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

Slide35

≥10 Letter Score Improvement*

35

*Baseline VA 20/32 or worse

N = 104

N = 110

N = 81

N = 86

Slide36

36

≥10 Letter Score Worsening

P= #

Slide37

≥15 Letter Score Worsening

37

N = 191

N = 203

N = 160

N = 168

2-Year Adjusted Difference: -2%

95% Confidence Interval: (-8%, +

3

%)

Slide38

Peripheral Visual Field Outcomes2-Year Visit

38

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)

Slide39

Optical Coherence TomographyCentral Subfield Thickness

39

Slide40

Central Subfield Thickness Change: 2-Year Visit

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)

Slide41

Proportion of Eyes Developing Center Involved DME with Vision

Impairment

(Eyes without Baseline DME and Vision Impairment)

41

2-Year Adjusted Difference: 19% 95% Confidence Interval: (10% to 28%)P-value < 0.001

N = 155

N = 147

Slide42

Diabetic Retinopathy

42

Slide43

Complications of PDR

43

Ranibizumab Group(N = 191)PRP Group(N = 203)P-valueAny retinal detachment6%10%0.08Neovascular glaucoma2%3%0.50Iris neovascularization1%1%0.96Vitreous hemorrhage27%34%0.09Vitrectomy4%15%< 0.001

PDR = proliferative diabetic retinopathy

Slide44

Diabetic Retinopathy: 2-Year Visit

44

Ranibizumab Group(N = 142)Prompt PRP Group(N = 148)P-valueFundus Photos Graded by Reading Center*0.41No PDR35%30%-Regressed NV23%24%-Active NV42%46%-

* Only includes eyes with active NV at baseline

Slide45

45

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%

Slide46

Safety

46

Slide47

Ocular Adverse Events*

47

Ranibizumab GroupN = 191PRP GroupN = 203P-valueEndophthalmitis0.5%0%--Inflammation1%4%0.02Retinal Tear0%0%--Cataract Surgery2%6%0.06Elevation in IOP9%13%0.16

*Event defined as occurring at least once through 2 years.

Slide48

Systemic Adverse EventsAPTC Events*

48

One Study Eye 2- Study EyesN = 89Ranibizumab GroupN = 102PRP GroupN = 114Non-fatal MI2%3%2%Non-fatal stroke1%2%4%Vascular/Unknown Death 4%4%<1%Any APTC eventP = 0.808%9%6%

*Anti-platelet Trialists` Collaboration defined events. Occurring at least once

through 2 years.

Slide49

Pre-Specified Systemic Adverse Events*

49

One Study Eye 2- Study EyesN = 89Ranibizumab GroupN = 102PRP GroupN = 114P-valueDeath (any cause)4%6%4%0.70Hospitalization42%47%35%0.20Serious adverse event43%48%37%0.26Hypertension 16%25%18%0.23

*Occurring at least once through 2 years

Slide50

MedDRA Systems (P value < 0.05)

50

N = 26 Systems

One Study Eye

% Per Participant

2- Study Eyes

N = 89

Ranibizumab Group

N = 102

PRP Group

N = 114

P

-value

Cardiac

13%

18%

5%

0.01

Endocrine

20%

25%

11%

0.02

Infections/

infestations

28%

27%

14%

0.02

Respiratory

35%

46%

30%

0.04

Skin

20%

24%

11%

0.03

Surgical

8%

24%

16%

0.01

Slide51

Discussion

DRCR.net Protocol S (PRP vs. Ranibizumab for PDR):Treatment with 0.5-mg ranibizumab met primary non-inferiority outcome for VA being no worse than PRPSummary of Ranibizumab group results vs. PRP:Mean change in VA from baseline to 2-years with ranibizumab no worse than with PRPSuperior mean visual acuity over course of 2-years (area under the curve analysis)Superior mean visual field outcomesDecreased occurrence of vitrectomies Decreased development of central involved DMEPRP rarely given for failure or futility of ranibizumab

51

Slide52

Discussion

No systemic safety concerns with ranibizumab identified among pre-specified major safety outcomesIncreased frequency of adverse events defined by cardiac, endocrine, respiratory, infections/infestations, skin and surgical conditions MedDRA systems in ranibizumab groups could be real, due to chance, or due to ascertainment bias (more visits in ranibizumab group)Interpretation of systemic safety difficult since large proportion of PRP group received ranibizumab per protocol for DME

52

Slide53

Discussion

Rates of endophthalmitis or other injection-related serious adverse events were very low

53

Slide54

Discussion

Key aspects of study design related to interpretation of resultsParticipant retention through two years (87% of those who had not died) lower than desiredHowever, no obvious baseline differences between groups for completers and non-completers that would suggest bias Participants and clinicians were not masked   However, high adherence to PDR treatment protocol Primary outcome assessors were masked Unknown if similar outcomes with 0.3-mg ranibizumab or other anti-VEGF agents (bevacizumab or aflibercept)

54

Slide55

Advantages of PRP

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 completedFrom completion of initial full PRP, median time to additional PRP ~7 monthsMay cost less than ranibizumab injectionsNo risk of endophthalmitisNo risk of systemic exposure to anti-VEGF

55

Slide56

Advantages of Ranibizumab

Mean change in VA from baseline to 2-years no worse than with PRPSuperior mean visual acuity over course of 2-years (area under the curve analysis)Superior mean visual field outcomesDecreased chance of vitrectomies Decreased chance of developing DMEPRP rarely given for futility or failure Unknown if similar outcomes with 0.3-mg ranibizumab or other anti-VEGF agents (bevacizumab or aflibercept)

56

Slide57

Potential Impact of DME when Initiating Treatment of PDR

Presence of DME may influence the relative benefit of ranibizumab over PRPWhen 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-upWhen 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

57

Slide58

Conclusions

PRP effective for PDR over last 4 decades; remains effective in 21st centuryRanibizumab for PDR is at least as good as (non-inferior to) PRP for visual acuity at 2 yearsRanibizumab is an effective treatment alternative to PRP for PDRNo substantial safety concerns for at least 2 yearsMay be the preferred initial treatment approach for some patients, for example, those who have both PDR and DME. Longer follow-up should determine whether effects sustained through 5 years

58

Slide59

Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net)

59

A complete list of all DRCR.net investigator financial disclosures and

many of these

slides can be found at

www.drcr.net

.

Full protocol available on clinicalTrials.gov (NCT01489189)