A Randomized Trial Comparing Intravitreal A Randomized Trial Comparing Intravitreal Triamcinolone Triamcinolone to Focal/Grid Photocoagulation to Focal/Grid Photocoagulation

for Diabetic Macular Edemafor Diabetic Macular Edema

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Sponsored by the National Eye Institute, National Institutes of Health, U.S. Department of Health and Human Services.

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Intravitreal Triamcinolone for DME 2001-2002: potential benefit first reported1,2

Short term improvement in visual acuity Rapid decrease in retinal thickening on OCT 2005: 91% of retina specialists surveyed (N=371)

would use IVT for persistent DME3

Community equipoise present: Randomized, controlled comparison with standard care (focal/grid photocoagulation) needed1- Jonas JB, et al. Am J Ophthalmol 2001;132:425-72- Martidis A, et al. Ophthalmology 2002;109:920-73- American Society of Retina Specialists Preferences and Trends Survey 2005

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DRCR.net Study Design Multicenter, randomized clinical trial Three treatment groups

• Focal/grid laser• 1 mg IVT• 4 mg IVT

Duration of follow-up: 3 years Follow-up visits and re-treatment as often as

every 4 months

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Primary Study Objective

To compare the efficacy and safety of preservative-free IVT (1 mg or 4 mg) with focal/grid laser

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Efficacy Outcomes

Primary outcome assessment at 2 years Primary outcome measure: visual acuity

• Scientific objective: mean change in VA• Regulatory objective for FDA: proportion with

decrease in VA letter score >15Secondary measure: Retinal thickening on OCT

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At least 18 years old Type 1 or type 2 diabetes Center-involved DME confirmed on OCT

• (central subfield thickness >250 microns) Best-corrected VA letter score 73 to 24

• (Snellen equivalent 20/40 to 20/320)

Major Eligibility Criteria

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ResultsResults

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840 eyes (693 subjects) enrolled at 88 clinical sites (2004-2006)

Treatment Groups• Laser: N = 330• 1 mg: N = 256• 4 mg: N = 254

2-year visit completion rate • 88% excluding deaths

Study Enrollment and Completion

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Primary Outcome:Mean Change in Visual Acuity at 2 Years

Mean Change in VA (letter score)

LaserN=330

1 mgN=256

4 mgN=254

+1 -2 -3 Pairwise

Comparisons Mean Difference* P value*

Laser vs. 1 mg +3.5 letters 0.02Laser vs. 4 mg +4.6 letters 0.0021 mg vs. 4 mg +1.1 letters 0.49

* Adjusted for baseline VA and prior focal/grid laser

0 4 8 12 16 20 24

Laser1 mg4 mg

10Months

VisualAcuityScore

20/80 -

20/50 -

20/32 -

Median Visual Acuity inLaser and IVT Treated Eyes

P < 0.005* Laser vs. 1mg# Laser vs. 4mg+ 1mg vs. 4mg

20/40 -

20/63 -

*

# + * # * #

0%

10%

20%

30%

40%

4 8 12 16 20 24

Laser1 mg4 mg

11Months

% Increased >10 Letters inLaser and IVT Treated Eyes

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Visual Acuity at 2 YearsAccording to Lens Status

Mean Change in VA (letter score) Laser 1 mg 4 mg

Pseudophakic at 2 Yrs or Minimal or No

Cataract at 2 Yrs

N=178 N=136 N=159

+3 0 0

Includes only subjects with a 2 year visit

Pseudophakic at Baseline

N=54 N=48 N=43

+2 +2 -1

Laser (All eyes)

1 mg (All eyes)

4 mg (All eyes)

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Mean Visual Acuity Over 3 Years in All Eyes

Months

VisualAcuityScore

20/80

20/50

20/32

20/40

20/63

0 12 16 20 244 8 28 32 36

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OCT Central Subfield (CSF) Thickening at 2 Years

Change in OCT CSF LaserN=220

1 mgN=178

4 mgN=162

Mean* -139 -86 -77

Thickening Decreased >50% 67% 46% 48%

Thickness <250 microns 53% 34% 38%

*Pairwise Comparisons P valueLaser v 1 mg <0.001Laser v 4 mg <0.0011 mg v 4 mg 0.91

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Median OCT Central Subfield Thickness in Laser and IVT Treated Eyes

200

250

300

350

400

450

0 4 8 12 16 20 24

Laser1 mg4 mg

Months

Central Subfield

Thickness(microns)

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Change in CSFfrom 2 Years to 3 Years*

2 year CSF >=250LaserN=50

1mgN=59

4mgN=54

Mean change (microns) -79 -44 -84<250 microns at 3 years 36% 31% 39%Decreased >=20% and >=50 microns 54% 34% 46%

Increased >=20% and >=50 microns 10% 12% 13%

* Among completers of both the 2 year and 3 year visit

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Major Ocular Adverse EventsDuring 2 Years of Follow-up

LaserN=330

1 mgN=256

4 mgN=254

Endophthalmitis* 0 0 0Pseudoendophthalmitis 0 0 0Retinal detachment† 2 2 3Retinal vein occlusion† 3 1 2Retinal artery occlusion† 1 0 0

Glaucoma procedure 0 0 4

Vitrectomy‡ 31 26 19

* 1 case of endophthalmitis occurred after vitrectomy, not related to study drug injection† Judged not necessarily related to treatment‡ Includes vitrectomy for diabetic macular edema, vitreous hemorrhage or other cause

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Intraocular Pressure During 3 Years of Follow-up*

LaserN=115

1 mgN=93

4 mgN=98

Increase >10 mmHg any time 3% 17% 31%Mean IOP at 3 yr visit (mmHg) 16 17 16IOP >21 mmHg at 3 yr visit 5% 15% 10%On IOP-lowering meds at 3 yr visit 8% 12% 30%

* Among completers of the 3 year visit

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Cataract Surgery Prior to 2 Years

Laser 1 mg 4 mg

Phakic at Baseline N=262 N=203 N=197

Cataract Surgery 13% 23% 51%

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Cumulative Probability of Cataract Surgery* Over 3 Years

* Among phakic eyes at baseline

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Laser (N=262)

1 mg (N=203)

4 mg (N=197)

4 8 12 16 20 24 28 32 36Months

83%

46%

31%

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Conclusion VA benefit in 4 mg IVT group at 4 months

consistent with published case series However, no difference in VA between IVT

groups and laser group by 1 year By 2 years, there was a greater VA benefit and

fewer side effects (IOP and cataract) in laser group compared with the IVT groups 3 year results similar to the 2 year results

OCT results mirrored VA results

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Conclusion

Results re-affirm importance of laser in management of DME

Focal/grid currently most effective treatment for patients with DME (with characteristics similar to those enrolled in this trial)

Focal/grid currently benchmark against which other new treatments for DME should be compared in clinical trials for DME