the diabetic retinopathy clinical research network randomized trial evaluating ranibizumab plus...

The Diabetic Retinopathy Clinical Research Network

The Diabetic Retinopathy Clinical Research Network

Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone

Plus Prompt Laser for Diabetic Macular Edema

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

2

Focal/grid photocoagulation has been the standard care for DME for the past 25 years

In a randomized, multicenter clinical trial, DRCR.net showed (Protocol B – IVT vs Laser): Focal/grid photocoagulation in eyes with center-

involved DME produces gradual visual acuity improvement of ≥2 lines in about 30% of eyes after 2 years, although approximately 20% of laser treated eyes worsen by ≥2 lines

Other treatment modalities, including anti-vascular endothelial growth factor (VEGF) therapy and steroids, alone or in combination with laser, are under investigation

Background: Laser Therapy for DME

Background: Laser Therapy for DME

Background: Anti-VEGF Therapy for DME

Background: Anti-VEGF Therapy for DME

3

VEGF levels are increased in the retina and vitreous of eyes with diabetic retinopathy

Therapy that inhibits VEGF may represent a useful therapeutic modality which targets the underlying pathogenesis of DME

Prior studies, that were small with short-term follow-up, have reported promising results

Background: Intravitreal Triamcinolone for DME

Background: Intravitreal Triamcinolone for DME

4

Intravitreal triamcinolone was evaluated previously as a treatment for DME in a randomized trial conducted by DRCR.net (Protocol B – IVT vs Laser): Results suggested that triamcinolone treatment without

laser was not superior to focal/grid photocoagulation Results suggested that triamcinolone treatment without

laser likely was superior to no treatment

5

Study RationaleStudy Rationale To determine if anti-VEGF therapy alone or in

combination with laser, or if triamcinolone in combination with laser, might result in improved outcomes compared with laser alone for treatment of DME, the DRCR.net designed a clinical trial to evaluate 3 treatment modalities for DME in comparison with focal/ grid laser:

Intravitreal ranibizumab+prompt (within 1 week) focal/grid laser

Intravitreal ranibizumab + focal/grid laser deferred for at least 24 weeks

Intravitreal triamcinolone+prompt (within 1 week) focal/grid laser

6

Laser-Ranibizumab-Triamcinolone Randomized Clinical Trial for DME:Laser-Ranibizumab-Triamcinolone Randomized Clinical Trial for DME:

Study Objective

Evaluate efficacy and safety of 0.5-mg intravitreal ranibizumab plus prompt (within 1 week) or deferred laser (≥24 weeks), or 4-mg intravitreal triamcinolone

plus prompt (within 1 week) laser, in comparison with sham plus prompt laser for treatment of

diabetic macular edema.

7

Study DesignStudy Design

Primary outcome: Change in visual acuity from baseline to 1 year (intent to treat analysis)

Randomized, multi-center clinical trial

At least one eye meeting all of the following criteria:• Electronic-ETDRS© best corrected visual acuity

letter score of 78 to 24 (~20/32 to 20/320)• Definite retinal thickening due to diabetic macular

edema involving the center of the macula on clinical examination

• Central subfield (Stratus OCT™) ≥250 µm

Follow-up Schedule Follow-up Schedule

8

Baseline to 1 Year

1 Year to 3 Years

• Every subject has a follow-up visit at 1 year• Follow-up every 4 weeks• All groups except ranibizumab plus deferred

laser group: Additional follow-up visit occurs 3 to 10 days after injection if focal/grid laser also is to be given

• Every subject has a follow-up visit at 2 years• Follow-up every 4 to 16 weeks depending on

treatment group, disease progression, and treatment administered

• Triamcinolone plus prompt laser group only: Additional safety visit every 4 weeks after triamcinolone injection

Study Enrollment and CompletionStudy Enrollment and Completion

9

Ranibizumab+Prompt Laser

N = 187

Ranibizumab+Deferred Laser

N = 188

Sham+Prompt Laser

N = 293

Triamcinolone+Prompt Laser

N = 186

Eyes Randomized: N = 854 (691 Participants)

1 Year Visit Completion: 94%*

2 Year Visit Completion: 87%**

* Includes deaths** Includes deaths and excludes pending and dropped who are not yet in window

10

Baseline CharacteristicsBaseline CharacteristicsSham

+Prompt

Laser

Ranibizumab

+Prompt

Laser

Ranibizumab

+Deferred

Laser

Triamcinolone

+Prompt

Laser

Median age 63 62 64 62

Diabetes type

Type I 9% 6% 8% 8%

Type II 89% 92% 90% 89%

Uncertain 3% 2% 2% 3%

Median E-ETDRS©

visual acuity letter score (Snellen equivalent)

65 (20/50) 66 (20/50) 66 (20/50) 66 (20/50)

Median OCT CSF thickness (µm) 407 371 382 374

11

Injections/Sham Prior to 1 YearInjections/Sham Prior to 1 YearSham

+Prompt

Laser

N = 274

Ranibizumab

+Prompt

Laser

N = 171

Ranibizumab

+Deferred

Laser

N = 178

Triamcinolone

+Prompt

Laser

N =176

Maximal possible # of sham/injections 13 sham* 13 drug 13 drug 9 sham/4 drug

Median number of sham/study drug injections to 1 year

11* 8 9 5 sham/3 drug

AE Precluding Study Drug Injection† NA 2% 2% 15%

Compliance with sham/drug injection when required by protocol

96% 95% 97% 97%

Masked participant with 1 study eye identified correct assignment at 1 year

10% 88% 90% 44%

*Excludes 56 eyes among 163 participants with 2 study eyes unmasked at baseline when assigned ranibizumab + deferred laser. † % of visits reported; 12% of eyes in the triamcinolone group compared with 3% and 4% in the ranibizumab groups

12

Laser Treatments Prior to 1 YearLaser Treatments Prior to 1 Year

Sham

+Prompt

Laser

Ranibizumab

+Prompt

Laser

Ranibizumab

+Deferred

Laser*

(permitted starting at 24-

week visit)

Triamcinolone

+Prompt

Laser

Median number of laser treatments including baseline

3 2 0 2

Proportion of eyes receiving laser at 48-week visit

26% 16% 8% 21%

No, only 1, only 2 or 3 more lasers after baseline

13%, 27%, 31%, 32%, 70%, 20%, 26%, 30%,

40%, 20% 27%, 11% 10%, 1% 28%, 15%

* 3 eyes deviated from the protocol and received laser prior to 24 weeks (2 were given laser at the 1 week safety visit and 1 at the 20 week visit).

13

Sham

+Prompt

Laser

N = 293

Ranibizumab

+Prompt

Laser

N = 187

Ranibizumab

+Deferred Laser

N = 188

Triamcinolone

+Prompt

Laser

N = 186

Eyes with alternative treatments(number of treatments)

14 (25) 1 (1) 0 1 (1)

Per protocol (failure‡ criteria met) 5 1 0 1

Deviations from protocol - clinical care

9 0 0 0

Alternative* Treatments Prior to 1 YearAlternative* Treatments Prior to 1 Year

*Alternative treatments include: intravitreal bevacizumab, intreavitreal triamcinolone acetonide, vitrectomy, and intravitreal bevacizumab + intravitreal triamcinolone.‡Failure is defined as: ≥10 letter loss from baseline, OCT CSF ≥250 µm, DME present on clinical exam that is cause of visual loss, “complete laser” given AND ≥13 weeks since last laser treatment with no improvement since the last laser treatment

14

Sham

+Prompt

Laser

N = 274

Ranibizumab

+Prompt

Laser

N = 171

Ranibizumab

+Deferred

Laser

N = 178

Triamcinolone

+Prompt

Laser

N = 176

Eyes with alternative treatments*(number of treatments)

29 (55) 1 (1) 0 3 (4)

Per protocol (failure‡ criteria met) 20 1 0 2

Deviations from protocol - clinical care

9 0 0 1

Alternative* Treatments From 1 Yearand Prior to 2 Years

Alternative* Treatments From 1 Yearand Prior to 2 Years

* Alternative treatments include: intravitreal bevacizumab, intravitreal ranibizumab intreavitreal triamcinolone acetonide, vitrectomy, intravitreal bevacizumab + intravitreal ranibizumab, and intravitreal bevacizumab + intravitreal ranibizumab + intravitreal triamcinolone.‡ Failure is defined as: ≥10 letter loss from baseline, OCT CSF ≥250 µm, DME present on clinical exam that is cause of visual loss, “complete laser” given AND ≥13 weeks since last laser treatment with no improvement since the last laser treatment

Visual AcuityVisual Acuity

15

Mean Change in Visual Acuity* at Follow-up Visits

Mean Change in Visual Acuity* at Follow-up Visits

16* 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.

Change in Visual Acuity (LOCF) at 1 Year*

Change in Visual Acuity (LOCF) at 1 Year*

17

Change in Visual Acuity (letters)

Sham

+Prompt

Laser

N = 293

Ranibizumab

+Prompt

Laser

N = 187

Ranibizumab

+Deferred

Laser

N = 188

Triamcinolone

+Prompt

Laser

N = 186

Mean +3 +9 +9 +4

Difference in mean change from Sham +Prompt Laser

[P Value]**

+5.8[P<0.001]

+6.0 [P<0.001]

+1.1[P = 0.31]

*Visits occurring between 308 and 420 days from randomization were included as 1-year visits. When more than 1 visit occurred in this window, data from the visit closest to the 1-year target date were used. For other eyes with out any 1-year data (19 eyes in the sham+prompt laser group, 16 eyes in the ranibizumab+prompt laser group, 10 eyes in the ranibizumab+deferred laser group, and 10 eyes in the triamcinolone+prompt laser group) the last observation carried forward (LOCF) method was used to impute data for the primary analysis.**Analysis of covariance adjusted for correlation between 2 study eyes and baseline visual acuity

Change in Visual Acuity at 2 Years*Change in Visual Acuity at 2 Years*

18

Change in Visual Acuity (letters)

Sham

+Prompt

Laser

N = 163

Ranibizumab

+Prompt

Laser

N = 106

Ranibizumab

+Deferred

Laser

N = 112

Triamcinolone

+Prompt

Laser

N = 103

Mean +2 +7 +10 0

Difference in mean change from Sham +Prompt Laser

[P Value]**+5.0

[P = 0.01]+7.2

[P<0.001]-1.6

[P = 0.43]

*Visits occurring between 616 and 840 days from randomization were included as 2-year visits**Analysis of covariance adjusted for correlation between 2 study eyes and baseline visual acuity

≥10 Letter Improvement in Visual Acuity at Follow-up Visits


19P values for the difference in proportion of 10 letter improvement in visual acuity from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001; triamcinolone+prompt laser = 0.16

Visit Week



20

Visit Week

P values for the difference in proportion of 15 letter improvement in visual acuity from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001; triamcinolone+prompt laser = 0.07

≥10 Letter Worsening in Visual Acuity at Follow-up Visits


21

Visit Week

P values for the difference in proportion of 10 letter worsening in visual acuity from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser <0.001; ranibizumab+deferred laser =0.001; triamcinolone+prompt laser = 0.75



22

Visit Week

P values for the difference in proportion of 15 letter worsening in visual acuity from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser = 0.009; ranibizumab+deferred laser = 0.01; triamcinolone+prompt laser = 0.95

≥10 Letter Improvement or Worsening in Visual Acuity at Follow-up Visits

≥10 Letter Improvement or Worsening in Visual Acuity at Follow-up Visits

23

Visit Week

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100104

Visu

al A

cuity

>

10 L

ette

r Im

prov

emen

t

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

55%

Sham+Prompt LaserRanibizumab+Prompt LaserRanibizumab+Deferred LaserTriamcinolone+Prompt Laser

Visit Week

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100104

Visu

al A

cuity

>

10 L

ette

r W

orse

ning

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

55%


N = 799 (52 weeks)N = 484(104 weeks)

> 10 Letter Improvement > 10 Letter Worsening

P values for the difference in proportion of 10 letter improvement in visual acuity from sham+prompt laser at the 52-week visit: : ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001; triamcinolone+prompt laser = 0.16

P values for the difference in proportion of 10 letter worsening in visual acuity from sham+prompt laser at the 52-week visit: : ranibizumab+prompt laser <0.001; ranibizumab+deferred laser =0.001; triamcinolone+prompt laser = 0.75

≥15 Letter Improvement or Worsening In Visual Acuity at Follow-up Visits

≥15 Letter Improvement or Worsening In Visual Acuity at Follow-up Visits

24

Visit Week

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100104

Vis

ual A

cuity

>

15 L

ette

r Im

prov

emen

t

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

55%


Visit Week

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100104

Vis

ual A

cuity

>

15 L

ette

r W

orse

ning

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

55%


N = 799 (52 weeks)N = 484 (104 weeks)

≥15 Letter Improvement ≥15 Letter Worsening

P values for the difference in proportion of 15 letter improvement in visual acuity from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001; triamcinolone+prompt laser = 0.07

P values for the difference in proportion of 15 letter worsening in visual acuity from sham+prompt laser at the 52-week visit: : ranibizumab+prompt laser = 0.009; ranibizumab+deferred laser = 0.01; triamcinolone+prompt laser = 0.95

Visual AcuitySubgroup Analyses

Visual AcuitySubgroup Analyses

25

26

Subgroup AnalysesSubgroup Analyses No obvious clinically important difference in

results at 1-year primary outcome visit for any of the following subgroups:

• Prior treatment for DME• Baseline visual acuity• Baseline OCT-measured central subfield thickening• Baseline level of diabetic retinopathy on photos• Description of edema by ophthalmologist as

predominantly focal or predominantly diffuse

In the subset of pseudophakic eyes at baseline (n = 273), visual acuity improvement in the triamcinolone+prompt laser group appeared comparable to the ranibizumab groups

Change in Visual Acuity at 1 Year Stratified by Baseline Visual AcuityChange in Visual Acuity at 1 Year

Stratified by Baseline Visual Acuity

27

N=146

Change in Visual Acuity at 1 Year Stratified by Baseline CSF

Change in Visual Acuity at 1 Year Stratified by Baseline CSF

28

Change in Visual Acuity at 1 Year Stratified by Prior DME TreatmentChange in Visual Acuity at 1 Year Stratified by Prior DME Treatment

29

Change in Visual Acuity at 1 Year Stratified by Number of Study EyesChange in Visual Acuity at 1 Year

Stratified by Number of Study Eyes

30

N=130

Change in Visual Acuity (LOCF) at 1 Year Stratified by Eyes with Diffuse vs. Focal Edema at Baseline as

Graded by Study Ophthalmologist

Change in Visual Acuity (LOCF) at 1 Year Stratified by Eyes with Diffuse vs. Focal Edema at Baseline as

Graded by Study Ophthalmologist

31

Change in Visual Acuity at 1 Year Stratified by Pseudophakic at Baseline

Change in Visual Acuity at 1 Year Stratified by Pseudophakic at Baseline

32

Mean Change in Visual Acuity at Follow-up Visits among Eyes that were

Pseudophakic at Baseline*

Mean Change in Visual Acuity at Follow-up Visits among Eyes that were

Pseudophakic at Baseline*

33

Visit Week

* Values that were ±30 letters were assigned a value of 30

Retinal ThickeningRetinal Thickening

34

Mean Change in Central Subfield Thickening at Follow-up Visits

Mean Change in Central Subfield Thickening at Follow-up Visits

35

Visit Week

P values are for the difference in mean change in OCT CSF retinal thickness from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser <0.001, ranibizumab+deferred laser <0.001, and triamcinolone+prompt laser <0.001.

Central Subfield Thickness <250 µm with at Least a 25 µm Decrease in Thickness from Baseline at

Follow-up Visits

Central Subfield Thickness <250 µm with at Least a 25 µm Decrease in Thickness from Baseline at

Follow-up Visits

36

Visit Week

P values for difference in proportion in OCT central subfield thickness <250 microns with at least a 25 µm decrease in thickness from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser <0.001, ranibizumab+deferred laser = 0.001, and triamcinolone+prompt laser <0.001.

Two or More Step Improvement in the Logarithmic Transformation of Optical Coherence Tomography*

Data from Baseline

Two or More Step Improvement in the Logarithmic Transformation of Optical Coherence Tomography*

Data from Baseline

37

Visit Week

*Logarithmic optical coherence tomography is calculated by taking the log base 10 of the ratio of the central subfield thickness divided by 200 and rounded to the nearest hundredth

Change in Retinal Thickening at 1 Year*Change in Retinal Thickening at 1 Year*

38

Change in OCT Central Subfield Thickeninga

Sham

+Prompt Laser

N = 271

Ranibizumab

+Prompt Laser

N = 171

Ranibizumab

+Deferred Laser

N = 175

Triamcinolone

+Prompt Laser

N = 173

Mean change from baseline (µm) -102 -131 -137 -127

Difference in mean change from Sham Prompt+Laser

[P Value]**

-55[P<0.001]

-49[P<0.001]

-52[P<0.001]

Thickness <250 µm with at least a 25 µm decrease from baseline

27% 53% 42% 47%

*Visits occurring between 308 and 420 days from randomization were included as 1 year visits. When more than 1 visit occurred in this window, data from the visit closest to the 1 year target date were used. **Analysis of covariance adjusted for baseline OCT retinal thickness and visual acuity and correlation between 2 study eyes

a Missing data for 22 eyes in the sham+prompt laser group, 16 eyes in the ranibizumab+prompt laser group, 13 in the ranibizumab+deferred Laser, and 13 eyes in the triamcinolone+prompt laser group (includes missing and ungradeable data [3 in sham+prompt laser, 2 in ranibizumab+deferred laser and 2 in triamcinolone+prompt laser]

Change in Retinal Thickening at 2 Years*Change in Retinal Thickening at 2 Years*

39

Change in OCT Central Subfield Thickeninga

Sham

+Prompt Laser

N = 152

Ranibizumab

+Prompt Laser

N = 99

Ranibizumab

+Deferred Laser

N = 100

Triamcinolone

+Prompt

Laser

N = 93

Mean change from baseline (µm) -133 -144 -170 -95

Difference in mean change from Sham + Laser [P Value]**

-31[P = 0.01]

-36[P = 0.004]

-3[P = 0.81]

Thickness <250 µm with at least a 25 µm decrease from baseline

38% 54% 55% 44%

*Visits occurring between 616 and 840 days from randomization were included as 2-year visits. When more than 1 visit occurred in this window, data from the visit closest to the 2-year target date were used. ** Analysis of covariance adjusted for baseline OCT retinal thickness and visual acuity and correlation between 2 study eyesª Excluding pending- Missing data for 2 eyes in the sham+prompt laser group, 2 eyes in the ranibizumab+prompt laser group, 2 in the ranibizumab +deferred laser, and 6 eyes in the triamcinolone+prompt laser group; Ungradeable data for 1 in the ranibizumab+prompt laser, 1 in ranibizumab+deferred laser and 2 in triamcinolone+prompt laser

Comparison of Visual Acuity and OCT Central Subfield

Thickness

Comparison of Visual Acuity and OCT Central Subfield

Thickness

40

Visit Week

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100104

Mean

Ch

an

ge i

n V

isu

al

Acu

ity

fro

m B

aseli

ne (

lett

er

sco

re)

0

1

2

3

4

5

6

7

8

9

10

11

12


Visit Week

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100104

>2

Ste

p Im

pro

vem

ent

in L

og

OC

T f

rom

Bas

elin

e

0%

10%

20%

30%

40%

50%

60%


Mean Change in Visual Acuity ≥2 Step Improvement in Log OCT

RetinopathyRetinopathy

41

42

Step Changes of Improvement/Worsening in Diabetic Retinopathy by Baseline Severity

Step Changes of Improvement/Worsening in Diabetic Retinopathy by Baseline Severity

Change from baseline to 1-year visit*

Sham

+Prompt

Laser

Ranibizumab

+Prompt

Laser or Deferred Laser

Triamcinolone

+Prompt

Laser

Baseline Severity: Moderately Severe NPDR or Better

N = 150 N = 182 N = 80

Improved by ≥2 levels 4% 25% 25%

Worsened by ≥2 levels 7% 3% 3%

P value for comparison with Sham

P = 0.08 P =0.17

Baseline Severity: Severe NPDR or worse

N = 83 N = 121 N = 70

Improved by ≥2 levels 19% 28% 13%

Worsened by ≥2 levels 8% 1% 3%

P value for comparison with Sham

P = 0.03 P = 0.17

*Photos were missing or ungradeable for 61 eyes in the sham+prompt laser group, 72 eyes in the ranibizumab groups, and 33 eyes in the triamcinolone+prompt laser group

Retinopathy Progression During 1 Year of Follow-up

Retinopathy Progression During 1 Year of Follow-up

43

Sham

N = 293

Ranibizumab

N = 375

Triamcinolone

N = 186

Reported vitreous hemorrhage OR received PRP

8% 3% 3%

P Value for comparison with sham -- 0.002 0.02

SafetySafety

44

45

Major Ocular Adverse Events During 2-Years of Follow-up

Major Ocular Adverse Events During 2-Years of Follow-up

45

Sham

+Prompt Laser

N = 293

Ranibizumab

+Prompt Laser

N = 187

Ranibizumab

+Deferred Laser

N = 188

Triamcinolone

+Prompt Laser

N = 186

Number of injections 1833 2140 685

Endophthalmitis* 1 (<1%) 2 (1%) 2 (1%) 0

Pseudoendophthalmitis† 1(<1%) 0 0 1 (1%)

Ocular vascular event‡ 1 (<1%) 1 (1%) 1 (1%) 3 (2%)

Retinal detachment§ 0 0 1 (1%) 0

Vitrectomy 15 (5%) 4 (2%) 7 (4%) 2 (1%)

Vitreous Hemorrhage 27 (9%) 6 (3%) 8 (4%) 7 (4%)*One case unrelated to study drug injection (following cataract extraction) in the sham+prompt laser group; 1 case related to study drug injection and 1 case unrelated to injection (following cataract surgery) in the ranibizumab+prompt laser group; 2 cases related to study drug injection in the ranibizumab+deferred laser group. The 3 cases related to study drug injection in the ranibizumab groups are 0.08% of ranibizumab study drug injections given. † One case unrelated to the study drug injection (vitreous opacity with hypopyon) and one case related to study drug injection in the triamcinolone group. ‡ Includes 2 central retinal vein occlusions and 4 branch retinal vein occlusions. §Includes 1 traction retinal detachment with proliferative diabetic retinopathy and prior panretinal photocoagulation at baseline.

46

Elevated Intraocular Pressure/Glaucoma During 2-Years of Follow-up

Elevated Intraocular Pressure/Glaucoma During 2-Years of Follow-up

46

Elevated Intraocular Pressure/Glaucoma

Sham

+Prompt

Laser

N = 293

Ranibizumab +Prompt Laser

N = 187

Ranibizumab

+Deferred Laser

N = 188

Triamcinolone +Prompt Laser

N = 186

Increase ≥10 mmHg from baseline 8% 9% 6% 42%

IOP ≥30 mmHg 3% 2% 3% 27%

Initiation of IOP-lowering meds at any visit*

5% 5% 3% 28%

Number of eyes meeting ≥1 of the above

11% 11% 7% 50%

Glaucoma surgery** <1% 1% 0 1%

*Excludes eyes with IOP lowering medications at baseline**Includes 2 filter and 2 cilliary body destruction

47

Cataract Surgery During 2-Years of Follow-up

Cataract Surgery During 2-Years of Follow-up

47

Sham

+Prompt

Laser

Ranibizumab

+Prompt

Laser

Ranibizumab

+Deferred Laser

Triamcinolone

+Prompt Laser

Phakic at baseline

N = 192 N = 131 N = 134 N = 124

Eyes that had cataract surgery

12% 12% 13% 55%

Cumulative Probability of Cataract Surgery Over 2-Years

Cumulative Probability of Cataract Surgery Over 2-Years

48Month

0 120 240 360 480 600 720 8400%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Sham+LaserRanibizumab Triamcinolone

84 12 16 20 24

59%

14%

14%

Number of DeathsNumber of Deaths

49

Sham

N = 130

Ranibizumab

N = 375

Triamcinolone

N = 186

Deaths* 7 (5%) 15 (4%) 6 (3%)

*Study participants with 2 study eyes are counted in their injection group.

50

Cardiovascular or Cerebrovascular Events According to Antiplatelet Trialists’

Collaboration through 2-Years

Cardiovascular or Cerebrovascular Events According to Antiplatelet Trialists’

Collaboration through 2-Years

50

Sham‡

N* = 130

Ranibizumab

N* = 375

Triamcinolone

N* = 186

Non-fatal myocardial infarction 3% 1% 3%

Non-fatal cerebrovascular accident-ischemic or hemorrhagic (or unknown)

6% 2% 2%

Vascular death (from any potential vascular or unknown cause†)

5% 2% 2%

Any APTC event 12% 5% 6%

* N=Number of Study Participants. Study participants with 2 study eyes are assigned to the non-sham group. Multiple events within a study participant are only counted once per event.‡One participant had a non-fatal myocardial infarction and a non-fatal stroke (only counted once in the any cardiovascular event row)†Four of the vascular deaths in the sham group, 1 of the vascular deaths in the ranibizumab group, and 1 of the vascular deaths in the triamcinolone group were from an unknown cause

DiscussionDiscussion

51

52

Intravitreal Ranibizumab Summary


Intravitreal ranibizumab with prompt or deferred (≥24 weeks) focal/grid laser had superior VA and OCT outcomes compared with focal/grid laser treatment alone.

• ~50% of eyes had substantial improvement (≥10 letters) while ~30% gained ≥15 letters

• Substantial visual acuity loss (≥10 letters) was uncommon

• Results were similar whether focal/grid laser was given starting with the first injection or it was deferred >24 weeks

52

53



If ranibizumab is to be given as it was in this study, the data indicate a need to follow eyes continuously undergoing this treatment

• Additional ranibizumab and/or laser were needed in most eyes through ≥2 years, even if ‘success’ criteria were met early in the course of treatment.

53

54

Intravitreal Ranibizumab Treatment Protocol


Results are based on rigorous adherence to a detailed retreatment protocol on a web-based real-time data entry system that provided feedback to the treating physician regarding the treatment to be prescribed at each follow-up visit.

The underlying rationale of the treatment algorithm is to continue treatment, as needed, until stabilization or lack of further improvement is noted.

55



Once a retreatment is withheld, the algorithm is designed to identify when there is a need to re-initiate treatment.• The goal was to avoid substantial vision loss while

also avoiding a regimen which requires monthly treatments regardless of the clinical course.

The impact of different retreatment approaches or use of other anti-VEGF drugs (such as bevacizumab) in clinical practice cannot be determined from this study.

55

56

Intravitreal Ranibizumab Conclusion

Intravitreal Ranibizumab Conclusion

Ranibizumab as applied in this study, Ranibizumab as applied in this study, although uncommonly associated with although uncommonly associated with endophthalmitis, should be considered endophthalmitis, should be considered for patients with DME and for patients with DME and characteristics similar to those in this characteristics similar to those in this clinical trial. clinical trial.

56

57

Intravitreal Triamcinolone Summary

Intravitreal Triamcinolone Summary

Intravitreal triamcinolone combined with focal/grid laser did not result in superior VA outcomes compared with laser alone.

Intravitreal triamcinolone did result in a greater reduction in retinal thickening at 1 year but not 2 years compared with laser alone.

In an analysis limited to pseudophakic eyes, the triamcinolone group’s outcome for VA appeared to be of similar magnitude to that of the 2 ranibizumab groups. 57

58

Intravitreal Triamcinolone Conclusion

Intravitreal Triamcinolone Conclusion

In pseudophakic eyes, intravitreal intravitreal triamcinolone with prompt focal/grid laser may triamcinolone with prompt focal/grid laser may be equally effective as ranibizumab at be equally effective as ranibizumab at improving visual acuity and reducing retinal improving visual acuity and reducing retinal thickening, but is associated with an increased thickening, but is associated with an increased risk of intraocular pressure elevation.risk of intraocular pressure elevation.

58

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

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

59

52 clinical study sites Study participants who volunteered to participate in this

trial DRCR.net Data and Safety Monitoring Committee Genentech (provided the ranibizumab) and Allergan, Inc.

(provided the triamcinolone) for the study and collaborated in a manner consistent with the DRCR.net Industry Collaboration Guidelines, the DRCR.net had complete control over the design of the protocol, ownership of the data, and all editorial content of presentations and publications related to the protocol.

DRCR.net investigators and staff

60

Additional SlidesAdditional Slides

60

61


854 study eyes (691 study participants) from 52 clinical sites Treatment Groups

•Sham+prompt laser: N= 293

•Ranibizumab+prompt laser group: N= 187

•Ranibizumab+deferred laser: N= 188

•Triamcinolone+prompt laser: N= 186

1 year visit completion rate* = 95%• Including deaths = 94%

2 year visit completion rate† = 91%• Including deaths = 87%

*1-year analysis window +/- 8 weeks; N=799 completed of 841 (Excludes deaths)† 2-year analysis window +/- 16 weeks; N=484 completed of 534 (Excludes deaths, pending, and dropped participants who are not yet in window)


62

Ranibizumab+Prompt Laser

N = 187

Completed=274 (94%)

Completed=171 (91%)

Completed=178 (95%)

Completed=176 (95%)

Ranibizumab+Deferred Laser

N = 188

Sham+Prompt Laser

N = 293

Triamcinolone+Prompt Laser

N = 186

Eyes Randomized: N = 854 (691 Participants)

1 Year Visit

Completed=163 Completed=106 Completed=112 Completed=103

Pending=91 Pending=56 Pending=55 Pending=63

2 Year Visit

63

Protocol B: VA and OCT CSF Results at 1 and 2 Years

Protocol B: VA and OCT CSF Results at 1 and 2 Years

Laser 1 mg 4 mg

Change in VA at 1 Year N = 286 N = 230 N = 221

Mean change from baseline (letters)

+1 0 0

Change in VA at 2 Years (primary outcome)

N = 272 N = 220 N = 204

Mean change from baseline (letters)

+2 -2 -4

Change in OCT CSF at 1 Year

N = 278 N = 225 N = 213

Mean change from baseline (microns)

-98 -55 -93

Change in OCT CSF at 2 Years

N = 220 N = 178 N = 162

Mean change from baseline (microns)

-139 -86 -77 63

64

Protocol I: VA and OCT CSF Results at 1 and 2 Years

Protocol I: VA and OCT CSF Results at 1 and 2 Years

64

Sham

+Prompt

Laser

Ranibizumab

+Prompt

Laser

Ranibizumab

+Deferred

Laser

Triamcinolone

+Prompt

Laser

Change in VA at 1 Year (LOCF)

N = 293 N = 187 N = 188 N = 186

Mean change from baseline (letters) +3 +9 +9 +4

Change in VA at 2 Years N = 163 N = 106 N = 112 N = 103

Mean change from baseline (letters) +2 +7 +10 0

Change in OCT CSF at 1 Year N = 271 N = 171 N = 175 N = 173

Mean change from baseline (microns) -102 -131 -137 -127

Change in OCT CSF at 2 Years N = 152 N = 99 N = 100 N = 93

Mean change from baseline (microns) -133 -144 -170 -95

65

Additional Information on Injections/Sham Prior to 1 YearAdditional Information on Injections/Sham Prior to 1 YearSham

+Prompt

Laser

N = 274

Ranibizumab

+Prompt

Laser

N = 171

Ranibizumab

+Deferred

Laser

N = 178

Triamcinolone

+Prompt

Laser

N = 176

Success criteria* at 16-week study visit and no injection

31 (11%) 47 (25%) 41 (22%) 38 (20%)

No more injections through 1 year of 16-week successes*†

13 (42%) 17 (36%) 15 (37%) 10 (27%)

% of eyes meeting success criteria* at 1-year study visit

32% 64% 52% 56%

% of eyes with letter score >84 (~>20/20) at 1-year study visit

8% 13% 13% 11%

*VA letter score ≥84 (~20/20 or better) or OCT CSF <250 microns†Excludes 56 eyes among 163 participants with two study eyes unmasked at baseline when assigned ranibizumab+deferred laser

66

Additional Information On Injections/Sham to 2 YearsAdditional Information On Injections/Sham to 2 YearsSham

+Prompt

Laser

N = 274

Ranibizumab

+Prompt

Laser

N = 171

Ranibizumab

+Deferred

Laser

N = 178

Triamcinolone

+Prompt

Laser

N = 176

% of eyes meeting failure criteria* at 1-year study visit

4% 2% 1% 2%

Maximal # of drug injections prior to 2 years

n/a 25 25 8

Median drug injections prior to 1 year

n/a 8 9 3

Median drug injections prior to 2 years

n/a 11 13 4

* Failure is defined as: VA 10 or more worse than baseline, OCT CSF ≥250 microns, DME present on clinical exam that is the cause of the visual loss, complete laser given AND ≥13w since last laser treatment with no improvement since the last laser treatment

67

TreatmentInjection Protocol up to 48-Week Visit

TreatmentInjection Protocol up to 48-Week Visit

All subjects are given an injection/sham* on the day of randomization

Every group receives an injection/sham* at each 4-week interval visit through the 12-week visit

At 16 and 20-week visits, injection/sham* is at investigator discretion if visual acuity ≥84 or OCT CSF <250

Between 24 and 48 weeks, the study eye is evaluated using retreatment criteria† at each 4-week interval visit for injection/sham*

*Both ranibizumab groups receive true injection. Sham group receives sham injection. Triamcinolone group receives: true injection if one has not been given in the prior 15 weeks, sham otherwise.

†The retreatment criteria for evaluation: 1) reinjection with randomized treatment at investigator discretion if VA>84 or OCT CSF <250; 2) injection if VA<84 and evidence of improvement (OCT CSF thickness decreased by 10% or more OR VA improved 5 or more letters); 3) treated at investigator discretion if failure criteria‡ met; 4) reinjection with randomized treatment at investigator discretion if failure criteria not met but no evidence of improvement.

68

TreatmentInjection Protocol at and After 1-Year Visit

TreatmentInjection Protocol at and After 1-Year Visit

Sham injections are discontinued for

Groups A and DFor Groups B and C, the study eye is

evaluated for ranibizumab injection using retreatment criteria at each 4-week interval visit

For Group D, the study eye is evaluated for triamcinolone injection using retreatment criteria at each 16-week interval visit

69

TreatmentLaser ProtocolTreatment

Laser Protocol The 3 non-deferral groups (ranibizumab,

triamcinolone, and sham) receive initial laser 3-10 days after the baseline injection Retreatment is given 3 to 10 days after each injection (or

at the time of visit if an injection is not given) unless laser already given within 13 wks, maximum laser already given, or CSF <250

The ranibizumab + deferred laser group does not receive laser prior to 24 weeks At 24-week or later visits, laser is given if CSF decreased

<10% (or increased) and VA improved <5 (or worsened) from the last 2 consecutive injections and between the last 2 consecutive injections and macular edema needing laser still present

DRCR.net Retreatment Algorithm FlowchartsDRCR.net Retreatment Algorithm Flowcharts

70

71

Intravitreal Injection Treatment at 16 to 48 Weeks (Following 4 Intravitreal or Sham Injections Every 4 Weeks

Through Week 12)

72

Treatment at and after the 52-Week Follow-Up VisitSHAM+PROMPT LASER GROUP (A)

73

Treatment at and after the 52-Week Follow-Up VisitRANIBIZUMAB+PROMPT LASER GROUP (B)

74

Treatment at and after 52 Week Follow-Up VisitRANIBIZUMAB+DEFERRED LASER GROUP (C)

75

Treatment at and after the 52-Week Follow-Up VisitTRIAMCINOLONE+PROMPT LASER GROUP (D)

76

Laser Treatment at and after the 16-Week Follow-Up Visit(Following Focal/Grid Laser Treatment at 1 Week in Groups

A, B, and D)

Visual Acuity Change at 1 YearVisual Acuity Change at 1 Year

77

N=293 N=187 N=188 N=186

Visual Acuity ≥10 or ≥15 Letter Improvement or Worsening at 1 Year

Visual Acuity ≥10 or ≥15 Letter Improvement or Worsening at 1 Year

78

Visual Acuity Improvement at 1 YearVisual Acuity Improvement at 1 Year

79N = 293 N = 187 N = 188 N = 186

Visual Acuity Loss at 1 YearVisual Acuity Loss at 1 Year

80N = 293 N = 187 N = 188 N = 186

Visual Acuity Improvement at 2 YearsVisual Acuity Improvement at 2 Years

81

N = 163 N = 106 N = 112 N = 103

Visual Acuity Loss at 2 YearsVisual Acuity Loss at 2 Years

82N = 163 N = 106 N = 112 N = 103

≥10 Letter Visual Acuity Improvement/Worsening among Eyes Not Pseudophakic and Eyes that were

Pseudophakic at Baseline

≥10 Letter Visual Acuity Improvement/Worsening among Eyes Not Pseudophakic and Eyes that were

Pseudophakic at Baseline

83

Eyes not Pseudophakic at Baseline Eyes Pseudophakic at Baseline

the diabetic retinopathy clinical research network randomized trial evaluating ranibizumab plus...

Documents