phase 2 evaluation of intravitreal bevacizumab for dme sponsored by the national eye institute,...

Phase 2 Evaluation of Intravitreal Bevacizumab for DME

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

Human Services.

Study Objectives Assess the dose and dose interval related effects

of intravitreal bevacizumab on central retinal thickness and VA in subjects with DME

Assess the effects of intravitreal bevacizumab combined with focal photocoagulation in DME

Assess the safety of intravitreal bevacizumab in subjects with DME

5 Treatment Groups Laser (0) Focal photocoagulation at baseline

Bev 1.25 (0,6) 1.25 mg intravitreal bevacizumab at baseline and at 6 wks

Bev 2.5 (0,6) 2.5 mg intravitreal bevacizumab at baseline and at 6 wks

Bev 1.25 (0) 1.25 mg intravitreal bevacizumab at baseline with sham injection at 6 wks

Bev 1.25 (0,6) + Laser (3)1.25 mg intravitreal bevacizumab at baseline, focal photocoagulation at 3 wks, and 1.25 mg intravitreal bevacizumab at 6 wks

Efficacy Outcomes Central subfield thickness on OCT

Electronic-ETDRS Visual Acuity (EVA)Efficacy Outcomes

Study Phases Weeks 0-12: no other treatment was

to be given for DME in the study eye (study visits every 3 weeks)

Weeks 13-24: treatment depended on response to treatment given during the first 12 wks (study visits every 6 weeks)

After 24 weeks: follow-up for safety (study visits at 41 and at 70 weeks)

Study Results Enrollment completed in 2 months

• 121 eyes of 121 subjects randomized• 109 eyes included in efficacy analyses

o Exclusions: 5 baseline CSF <275 um 1 nongradable baseline OCT 1 hx of laser 3 mos prior to randomization 2 CNV with diabetic retinopathy 2 no follow-up 1 endophthalmitis

• 19-24 subjects in each group

Baseline CharacteristicsMedian age: 65 yrsWomen: 39%Caucasian: 76%Diabetes type: 1 – 7%, 2 – 93%Median duration of diabetes: 17 yrsNo prior DME treatment: 31%

Baseline CharacteristicsVisual Acuity

Median (quartiles) letter score: 64 (71,56)

approx. Snellen equivalent 20/50 (20/40,20/80)

Central Subfield ThicknessMedian (quartiles) microns : 411 (334, 505)

1. Does 1.25 mg bevacizumab have a positive effect on DME?

Compare Laser (0) vs. Bevacizumab 1.25 mg (0,6) at 3, 6, 9, and 12 weeks

OCT Central Subfield ThicknessMedian Change (microns) from Baseline

Laser (0) N=19

Bev 1.25 (0,6)N=22

P value

3w +21 -35 .009

6w -40 -35 .22

9w -53 -74 .14

12w -40 -56 .32

OCT Central Subfield Thickness <250 microns or >50% Decrease in Thickening

Laser (0)N=19

Bev 1.25 (0,6)N=22

3w 11% 37%

6w 17% 30%

9w 19% 38%

12w 21% 33%

Visual Acuity Letter Score Median Change from Baseline

Laser (0)N=19

Bev 1.25 (0,6)N=22

P value

3w -2 +5 .06

6w +1 +5 .09

9w +3 +7 .07

12w -1 +5 .01

Visual Acuity Letter ScoreIncrease > 10 from Baseline

Laser (0)N=19

Bev 1.25 (0,6)N=22

3w 6% 19%

6w 11% 32%

9w 18% 29%

12w 16% 33%

2. Does 2.5 mg bevacizumab have a positive effect on DME?

Compare Laser (0) vs. Bevacizumab 2.5 mg (0,6) at 3, 6, 9, and 12 weeks

OCT Central Subfield ThicknessMedian Change (microns) from Baseline

Laser (0)N=19

Bev 2.5 (0,6)N=24

P value

3w +21 -86 <.001

6w -40 -42 .08

9w -53 -56 .43

12w -40 -47 .26

OCT Central Subfield Thickness <250 microns or >50% Decrease in Thickening

Laser (0)N=19

Bev 2.5 (0,6)N=24

3w 11% 38%

6w 17% 22%

9w 19% 22%

12w 21% 33%

Visual Acuity Letter Score Median Change from Baseline

Laser (0)N=19

Bev 2.5 (0,6)N=24

P value

3w -2 +6 .003

6w +1 +6 .03

9w +3 +8 .02

12w -1 +7 .003

Visual Acuity Letter ScoreIncrease > 10 from Baseline

Laser (0)N=19

Bev 2.5 (0,6)N=24

3w 6% 17%

6w 11% 29%

9w 18% 39%

12w 16% 25%

3. Does 2.5 mg bevacizumab produce a greater short-term

reduction in DME than 1.25 mg?Compare Bevacizumab 1.25

mg (0,6) vs. Bevacizumab 2.5 mg (0,6) at 3, 6, 9, and 12 weeks

OCT Central Subfield ThicknessMedian Change (microns) from Baseline

Bev 1.25 (0,6)N=22

Bev 2.5 (0,6)N=24

P value

3w -35 -86 .66

6w -35 -42 .49

9w -74 -56 .45

12w -56 -47 .90

OCT Central Subfield Thickness <250 microns or >50% Decrease in Thickening

Bev 1.25 (0,6)N=22

Bev 2.5 (0,6)N=24

3w 37% 38%

6w 30% 22%

9w 38% 22%

12w 33% 33%

Bev 1.25 (0,6)N=22

Bev 2.5 (0,6)N=24

P value

3w +5 +6 .42

6w +5 +6 .67

9w +7 +8 .48

12w +5 +7 .82

Visual Acuity Letter Score Median Change from Baseline

Bev 1.25 (0,6)N=22

Bev 2.5 (0,6)N=24

3w 19% 17%

6w 32% 29%

9w 29% 39%

12w 33% 25%

Visual Acuity Letter Score Increase> 10 from Baseline

4. What is the duration of effect of the initial injection?

Among eyes with a decrease in CSF thickness of >11% (the reliability limit for real change) from baseline to 3 weeks, evaluate change from 3 weeks to 6 weeks

Duration of Initial Injection Pooling 1.25 mg Groups [Bev 1.25 (0,6) and Bev 1.25 (0)]

OCT CSF % Change 0w to 3w

>11% decrease

(N=14)

Within +11% (N=22)

>11% increase

(N=2)

% Change 3w to 6w>11% decrease 1 2 1

Within +11% 11 16 1

>11% increase 2 4 0

Duration of Initial Injection Bevacizumab 2.5 mg (0,6) Group

OCT CSF % Change 0w to 3w

>11% decrease

(N=13)

Within +11% (N=10)

>11% increase

(N=0)

% Change 3w to 6w>11% decrease 0 0 0

Within +11% 9 9 0

>11% increase 4 1 0

5. What is the duration of effect of the second injection?

Among eyes with a decrease in CSF thickness of at least 11% from 6w to 9w, evaluate change from 9 weeks to 12 weeks

Duration of Second Injection Bevacizumab 1.25 mg (0,6) Group

OCT CSF % Change 6w to 9w

>11% decrease

(N=7)

Within +11% (N=9)

>11% increase

(N=2)

% Change 9w to 12w>11% decrease 0 1 0

Within +11% 4 6 2

>11% increase 3 2 0

Duration of Second Injection Bevacizumab 2.5 mg (0,6) Group

OCT CSF % Change 6w to 9w

>11% decrease

(N=3)

Within +11% (N=17)

>11% increase

(N=2)

% Change 9w to 12w>11% decrease 0 2 1

Within +11% 2 14 1

>11% increase 1 1 0

6. Is there a greater effect with bevacizumab followed by focal laser compared with bevacizumab alone?

Compare (at 12 weeks) bevacizumab 1.25 mg alone vs. bevacizumab 1.25 mg plus laser

Effect of Combining Focal Photocoagulation with Bevacizumab at 12 Weeks

Bev 1.25 (0,6)

Bev 1.25 (0,6)+ Laser (3)

Baseline to 12w

OCT CSF <250 or decrease >50% 33% 25%

VA Letter Score increase > 10 33% 20%

Subgroup Analyses at 3 Weekspooling all bevacizumab groups

Baseline CSF<400 (N=43)

Baseline CSF>=400 (N=41)

P value

MeanCSF microns change

-3 -102 <0.0001

MeanCSF % change in thickening

-2% -26% 0.12

Subgroup Analyses at 3 Weeks

pooling all bevacizumab groups

Baseline VA<65

(N=44)

Baseline VA>=65 (N=43)

P value

MeanVA letters change

+3 +1 0.006

MeanVA % reduction in deficit

+11% +7% 0.40

Subgroup Analyses at 3 Weeks pooling all bevacizumab groups

Chg in CSF thickness (microns)

Chg in VA (letters)

N Median P N Median P

Prior treatmentNoYes

2658

0.16-40 -29

2661

0.04+5 +2

Subretinal fluidDefinite/Questionable No evidence

2163

0.52-35 -29

2166

0.06+6 +1

Subgroup Analyses at 3 Weeks pooling all bevacizumab groups

Change in CSF thickness and change in VA from baseline to 3 weeks did not significantly vary according to:• Age, gender, baseline retinopathy

severity, baseline clinical characterization of DME as focal or diffuse

Outcome during weeks 13-24Among eyes meeting deferral criteria at 12

weeks, deferral criteria were also met at 18 weeks in:• 2 of 4 eyes in Laser (0) Group• 5 of 7 eyes in Bev 1.25 (0,6) Group• 1 of 8 eyes in Bev 2.5 (0,6) Group • 2 of 3 eyes in Bev 1.25 (0) Group • 3 of 5 eyes in Bev 1.25 (0,6) + Laser (3) Group

Ocular Adverse Events

1 eye in the Bev 1.25 (0,6) + Laser (3) Group with endophthalmitis

Cardiovascular Adverse Events

Fatal MI at 16 wks (1.25 inj at 0, 6 wks)

Non-fatal MI at 1 wk (2.5 inj at 0 wks)

CHF at 12 wks (1.25 inj at 0, 7 wks)

Other Systemic Adverse Events Of the 107 subjects treated with bevacizumab

• Death due to cancer (N=1)• Peripheral vascular disease (N=1)• Syncope (N=1)• Elevated BP (N=3)• Worsening renal function (N=3)• Anemia (N=4)

Of the 12 subjects receiving only focal photocoagulation• Peripheral vascular disease (N=2)• Elevated BP (N=1)• Worsening renal function (N=1)• Anemia (N=1)

Comparison of APTC events in Protocols H and B (IVT Study)

B: 11 of 693 (1.6%) subjects reported an APTC event over the first 24 weeks of follow-up

H: 2 of 107 (1.9%) subjects treated with bevacizumab reported an APTC event during the first 24 weeks of follow-up

Conclusions1. There is an apparent effect of 1.25

mg and 2.5 mg of bevacizumab when compared with focal photocoagulation, although the effect appears to be modest

2. It does not appear that 2.5 mg of bevacizumab has an appreciably larger effect on DME than 1.25 mg

Conclusions3. Injection intervals of 4 weeks are

probably more appropriate than intervals of 6 weeks

4. A study arm with combination treatment (bevacizumab plus focal photocoagulation) is feasible from a logistical standpoint

ConclusionsThe study was designed to evaluate short term effect. No conclusions should be made regarding clinical benefit. A large phase 3 randomized clinical trial is needed for this purpose.