Diabetic Retinopathy Clinical Research Network Comparative Effectiveness Study of Aflibercept,...

Diabetic Retinopathy Clinical Research Network

Diabetic Retinopathy Clinical Research Network

Comparative Effectiveness Study of Aflibercept, Bevacizumab, or

Ranibizumab for DMESupported through a cooperative agreement from the

National Eye Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health, Department of Health and Human Services EY14231, EY14229, EY018817

1

Disclosure Disclosure Funding/Support: Cooperative Agreement with NEI and

NIDDK of NIH, U.S. Department of Health and Human Services.

Additional Contributions: Regeneron Pharmaceuticals, Inc. provided the aflibercept; Genentech Inc. provided the ranibizumab. Genentech Inc. also provided funding for blood pressure cuffs and collection of plasma and urine that are not part of the main study reported herein.

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

2

http://www.drcr.net/

Background Background

3

Diabetic macular edema (DME) affects ~750,000 people in the U.S.

Intravitreous anti-vascular endothelial growth factor (anti-VEGF) injections of either aflibercept (Eylea), bevacizumab (Avastin), or ranibizumab (Lucentis) are effective in treating DME.

The relative efficacy and safety of these agents within a head-to-head study were unknown prior to the results of this trial

Background Background

4

Aflibercept and ranibizumab are FDA approved for DME treatment.

Bevacizumab is not FDA approved for intraocular use, used “off-label” for DME treatment and repackaged into aliquots ~1/500 of

systemic dose in cancer treatments. Medicare allowable charges:

Aflibercept (2.0 mg): $1961 Bevacizumab (repackaged 1.25mg): $67 Ranibizumab (0.3 mg): $1189

Primary ObjectivePrimary Objective

For eyes with center involved DME with decreased visual acuity, compare one year efficacy and safety of,

1. intravitreous aflibercept (Eylea®),2. intravitreous bevacizumab (Avastin®)

and3. intravitreous ranibizumab (Lucentis®)

Study DesignStudy Design

6

Participants meeting all of the following criteria:• At least 18 years old• Type 1 or type 2 diabetes

Study eye meeting all of the following criteria:• ~Snellen equivalent visual acuity 20/32 or worse and 20/320 or

better• Central-involved DME on clinical exam• Central subfield (CSF) thickness ≥ protocol-defined gender and

optical coherence tomography (OCT) machine-specific thresholds

• No history of an anti-VEGF treatment for DME in the past 12 months or any other DME treatment in the past 4 months

Randomized, multi-center clinical trial (N = 89 Sites)

Primary Outcome: Change in visual acuity at one year adjusted for baseline visual acuity using the intent-to-treat principle

Baseline to 1 year

Follow-up ScheduleFollow-up Schedule

• Visits every 4 weeks• Primary outcome at 1 year

Visit Procedures Refraction with Electronic-ETDRS visual

acuity measurement OCT spectral domain (97%) or time domain Dilated ocular exam Color fundus photos (baseline/1 year only)

ETDRS = Early Treatment Diabetic Retinopathy Study

Treatment Schedule Through 1 Year (q4 weeks)

Treatment Schedule Through 1 Year (q4 weeks)

Repeat injections at every 4-week visit if eye “improved”* or “worsened”*

Otherwise, defer injections if either: Visual acuity 20/20 or better and OCT CST

“normal” or, At or after 24 weeks, visual acuity and

OCT stable after 2 consecutive injections Resume injections if VA or OCT worsened*

*Improved/worsened defined as:≥ 5 letter change (~1 Snellen line) from last injection, or,≥ 10% CST change on OCT from last injection

Treatment Schedule Through 1 Year

Treatment Schedule Through 1 Year

Focal/grid laser: initiated at or after 24 weeks only if persistent DME not improving after at least 2 injections

Randomization Randomization

10

Bevacizumab (1.25 mg)N = 218

Aflibercept (2.0 mg)N = 224

Ranibizumab(0.3 mg)N = 218

Randomly Assigned Eyes(one per participant):

N = 660

N = 206 (94%)N = 208 (93%) N = 206 (94%)One Year

97%94% 96%One Year Excluding

Deaths

Baseline

Baseline CharacteristicsBaseline Characteristics

11

Aflibercept(N = 224)

Bevacizumab(N = 218)

Ranibizumab(N = 218)

Age (years) – Median 61 63 59

Gender: Women 49% 47% 43%

Race

White 65% 64% 67%Black/African American

14% 17% 17%

Hispanic 17% 17% 14%

Other 4% 3% 3%

Type 2 diabetes 88% 94% 90%

Median HbA1c 7.6 7.7 7.8

12

Ocular Baseline CharacteristicsOcular Baseline CharacteristicsAflibercept(N = 224)



Mean visual acuity letter score (~Snellen Equivalent)

69(20/40)

69(20/40)

68(20/50)

Mean OCT CST (µm) 387 376 390

Any Prior Focal/Grid Laser

36% 39% 37%

Any Prior Treatment with anti-VEGF

11% 14% 13%

Phakic 74% 73% 79%

Treatment for Diabetic Macular Edema

Treatment for Diabetic Macular Edema

13

14

DME Treatment Through 1 Year: anti-VEGF and Laser

DME Treatment Through 1 Year: anti-VEGF and Laser

AfliberceptN = 208

BevacizumabN = 206

RanibizumabN = 206

P-Value

# of Injections (Max = 13)

Mean 9.2 9.7 9.4

Median (25th, 75th percentile)

9 (8, 11) 10 (8, 12) 10 (8, 11) 0.045†

At least one focal/grid laser

37% 56% 46% <0.001‡

†Global (overall 3 group comparison) P-value. Pairwise comparisons (adjusted for multiple comparisons): aflibercept-bevacizumab: P = 0.045, aflibercept-ranibizumab: P = 0.19, bevacizumab-ranibizumab: P = 0.22.

‡Global (overall 3 group comparison) P-value. Pairwise comparisons (adjusted for multiple comparisons): aflibercept-bevacizumab: P<0.001, aflibercept-ranibizumab: P = 0.058, bevacizumab-ranibizumab: P = 0.061.

15

EfficacyEfficacy

16

0 4 8 12 16 20 24 28 32 36 40 44 48 5202468

101214161820

Aflibercept Bevacizumab Ranibizumab

Weeks

Me

an

Ch

an

ge

in V

isu

al A

cu

ity

Le

tte

r S

co

re 52 Week Treatment Group Comparison*:• Aflibercept vs. Bevacizumab P<0.001• Aflibercept vs. Ranibizumab P = 0.034 • Ranibizumab vs. Bevacizumab P = 0.12

* P-values adjusted for baseline visual acuity and multiple comparisons

+13

+11

+10

Mean Change in Visual Acuity Letter Score, Full Cohort

Mean Change in Visual Acuity Letter Score, Full Cohort

Mean Change in Visual Acuity Letter ScoreBaseline Visual Acuity 20/32 to 20/40

Mean Change in Visual Acuity Letter ScoreBaseline Visual Acuity 20/32 to 20/40

17

0 4 8 12 16 20 24 28 32 36 40 44 48 5202468

101214161820

Aflibercept Bevacizumab RanibizumabWeeks

Mea

n Ch

ange

in V

isua

l Acu

ity

Lett

er S

core

~+8

~50% of Cohort

Mean Change in Visual Acuity Letter ScoreBaseline Visual Acuity 20/50 or Worse

Mean Change in Visual Acuity Letter ScoreBaseline Visual Acuity 20/50 or Worse

18

0 4 8 12 16 20 24 28 32 36 40 44 48 5202468

101214161820

Aflibercept Bevacizumab RanibizumabWeeks

Me

an

Ch

an

ge

in V

isu

al A

cu

ity

Le

tte

r S

co

re

1-Year Treatment Group Comparison*:• Aflibercept vs. Bevacizumab P<0.001• Aflibercept vs. Ranibizumab P = 0.0031• Ranibizumab vs. Bevacizumab P = 0.21

* P-values adjusted for baseline visual acuity and multiple comparisons

+19

+14

+12

~ 50% of Cohort

Subgroup Analysis Baseline Best-corrected Visual Acuity

Subgroup Analysis Baseline Best-corrected Visual Acuity

19

0 8 16 24 32 40 48Visit Week

20/50 or worse

+19+14

+12

0 8 16 24 32 40 480

5

10

15

20

Visit Week

Mea

n Ch

ange

is V

isua

l Acu

ity

Lett

er S

core

20/32-20/40

~+8


78-74(20/32)

73-69(20/40)

68-64 (20/50)

63-54 (20/63-20/80)

53-24 (20/100-20/320)

Baseline Visual Acuity Letter Score

N =

Aflibercept 54 52 36 29 37

Bevacizumab 41 63 35 38 29

Ranibizumab 46 59 32 37 32

Visual Acuity Mean Change: Baseline to 1 Year

Visual Acuity Mean Change: Baseline to 1 Year

0

5

10

15

20

25

30

Aflibercept

Bevacizumab

RanibizumabMe

an

Ch

an

ge

in

Vis

ua

l A

cu

ity

Le

tte

r S

co

re

Visual Acuity OutcomesBaseline = 20/32 to 20/40


21Afli

berce

pt

Bevac

izum

ab

Ranib

izum

ab

8 7.58.3

Observed Data

Me

an

Vis

ua

l Ac

uit

y L

ett

er

Sc

ore

Treatment Group Comparisons

Difference CIP-

Value

Aflibercept vs

Bevacizumab+0.7

-1.3 to +2.7 0.69

Aflibercept vs

Ranibizumab-0.4 -2.3 to

+1.5 0.69

Ranibizumab vs

Bevacizumab+1.1 -0.9 to

+3.1 0.69



22Afli

berce

pt

Bevac

izum

ab

Ranib

izum

ab

50% 45% 50%

Observed Data

Per

cen

t


Difference CIP-

Value

Aflibercept vs

Bevacizumab+6%

-9% to +21% 0.82

Aflibercept vs

Ranibizumab0% -13% to

+14% 0.95

Ranibizumab vs

Bevacizumab+6% -10% to

+21% 0.82

>10 Letter Improvement



23Afli

berce

pt

Bevac

izum

ab

Ranib

izum

ab

18% 16% 15%

Observed Data

Per

cen

t


Difference CIP-

Value

Aflibercept vs

Bevacizumab+2%

-7% to +11% 0.73

Aflibercept vs

Ranibizumab+4% -5% to

+12% 0.73

Ranibizumab vs

Bevacizumab-2% -10% to

+7% 0.73




24Afli

berce

pt

Bevac

izum

ab

Ranib

izum

ab

4% 2% 1%

Observed Data

Per

cen

t


Difference CIP-

Value

Aflibercept vs

Bevacizumab+2%

-3% to +6% 0.54

Aflibercept vs


+7% 0.54

Ranibizumab vs


+2% 0.54

>10 Letter Worsening

Visual Acuity OutcomesBaseline = 20/50 or Worse


25

Afliber

cept

Bevac

izum

ab

Ranib

izum

ab

18.9

11.814.2

Observed Data

Me

an

Vis

ua

l Ac

uit

y L

ett

er

Sc

ore


Difference CIP-

Value

Aflibercept vs

Bevacizumab+6.5

+2.9 to +10.1 <0.001

Aflibercept vs

Ranibizumab+4.7 +1.4 to

+8.0 0.0031

Ranibizumabvs

Bevacizumab+1.8 -1.1 to

+4.8 0.21



26Afliber

cept

Bevac

izum

ab

Ranib

izum

ab

77%

60%69%

Observed Data

Per

cen

t


Difference CIP-

Value

Aflibercept vs

Bevacizumab+17%

+2% to +31% 0.018

Aflibercept vs


+23% 0.20

Ranibizumab vs


+20% 0.28




27Afliber

cept

Bevac

izum

ab

Ranib

izum

ab

67%

41%50%

Observed Data

Per

cen

t


Difference CIP-

Value

Aflibercept vs

Bevacizumab+24%

+9% to +39% <0.001

Aflibercept vs

Ranibizumab+18% +4% to

+32% 0.0078

Ranibizumab vs


+19% 0.34




28Afliber

cept

Bevac

izum

ab

Ranib

izum

ab

1% 4% 2%

Observed Data

Per

cen

t


Difference CIP-

Value

Aflibercept vs

Bevacizumab-3%

-7% to +2% 0.56

Aflibercept vs

Ranibizumab-1% -5% to

+3% 0.56

Ranibizumab vs


+3% 0.56

>10 Letter Worsening

Overall Mean (µm) Change in OCT CST Over Time

Overall Mean (µm) Change in OCT CST Over Time

29

0 4 8 12 16 20 24 28 32 36 40 44 48 52-250

-200

-150

-100

-50

0


Visit Week

Me

an

Imp

rov

em

en

t in

OC

T C

SF

Th

ick

ne

ss

fro

m

Ba

se

line

(µ

m)

Thinner is decreased DME

-169

-147

-101

1-Year Treatment Group Comparison*:• Aflibercept vs. Bevacizumab P < 0.001• Aflibercept vs. Ranibizumab P = 0.036• Ranibizumab vs. Bevacizumab P = <0.001

* P-values adjusted for baseline visual acuity, OCT central subfield thickness, and multiple comparisons

Mean (µm) Change in OCT CSTBaseline visual acuity 20/32 to 20/40

Mean (µm) Change in OCT CSTBaseline visual acuity 20/32 to 20/40

30

0 4 8 12 16 20 24 28 32 36 40 44 48 52-250

-200

-150

-100

-50

0

Aflibercept Bevacizumab RanibizumabVisit Week

Mea

n I

mp

rove

men

t in

OC

T C

SF

T

hic

knes

s fr

om

Bas

elin

e (µ

m)


1-Year Treatment Group Comparison*:• Aflibercept vs. Bevacizumab P <0.001• Aflibercept vs. Ranibizumab P = 0.057• Ranibizumab vs. Bevacizumab P = <0.001

-67

-129

-119


Mean (µm) Change in OCT CSTBaseline visual acuity 20/50 or Worse

Mean (µm) Change in OCT CSTBaseline visual acuity 20/50 or Worse

31

0 4 8 12 16 20 24 28 32 36 40 44 48 52-250

-200

-150

-100

-50

0


Visit Week

Me

an

Imp

rov

em

en

t in

OC

T C

SF

Th

ick

ne

ss

fr

om

Ba

se

line

(µ

m)


1-Year Treatment Group Comparison*:• Aflibercept vs. Bevacizumab P < 0.001• Aflibercept vs. Ranibizumab P = 0.22• Ranibizumab vs. Bevacizumab P = <0.001

-135

-176

-210


32

-129

-67

-119

Observed Data

Mea

n O

CT

CS

F C

han

ge


Difference CI P- Value

Aflibercept vs

Bevacizumab-55.8

-78.3 to -32.9 <0.001

Aflibercept vs


+0.6 0.057

Ranibizumab vs

Bevacizumab-37.7 -59.3 to

-16.1 <0.001

OCT CSF OutcomesBaseline = 20/32-20/40

OCT CSF OutcomesBaseline = 20/32-20/40

Visual Acuity OutcomesBaseline = 20/32-20/40

Visual Acuity OutcomesBaseline = 20/32-20/40

33Afli

berce

pt

Bevac

izum

ab

Ranib

izum

ab

62%

34%

60%

Observed Data

Per

cen

t


Difference CIP-

Value

Aflibercept vs

Bevacizumab+31%

+16% to +45% <0.001

Aflibercept vs

Ranibizumab-2% -16% to

+12% 0.79

Ranibizumabvs

Bevacizumab+33% +17% to

+48% 0.001

CSF <250 µm

34

-210

-135

-176

Observed Data

Mea

n O

CT

CS

F C

han

ge


Difference CIP-

Value

Aflibercept vs

Bevacizumab-85.8

-121.9 to -49.7 <0.001

Aflibercept vs


+11.2 0.22

Ranibizumab vs

Bevacizumab-67.3 -101.4 to

-33.1 <0.001

OCT CSF OutcomesBaseline = 20/50 or WorseOCT CSF Outcomes

Baseline = 20/50 or Worse



35Afli

berce

pt

Bevac

izum

ab

Ranib

izum

ab

70.00

39

56

Observed Data

Per

cen

t


Difference CIP-

Value

Aflibercept vs

Bevacizumab +32%+16%

to +48% <0.001

Aflibercept vs

Ranibizumab+16% +3% to

+30% 0.025

Ranibizumab vs

Bevacizumab+16% +2% to

+29% 0.025

CSF <250 µm

SafetySafety

36

Ocular Adverse Events through 1 Year (Study Eye)

Ocular Adverse Events through 1 Year (Study Eye)

37




P-Value

No. of injections prior to 1 year

1991 2055 2011

Endophthalmitis 0 0 0

Inflammation† <1% <1% <1% 1.0

Retinal detachment/tear

0 <1% <1% 0.55

Vitreous hemorrhage

2% 4% 3% 0.35

Injection related cataract

<1% <1% 0 0.55

IOP elevation‡ 14% 9% 11% 0.18

†Includes anterior chamber cell/flare, choroiditis, episcleritis, iritis, vitreous cells.‡Includes intraocular pressure increase ≥10mmHg from baseline at any visit, intraocular pressure ≥30 mmHg at any visit, or initiation of intraocular pressure-lowering medications not in use at baseline. There were no glaucoma surgeries.IOP= Intraocular Pressure

Ocular Adverse Events through 1 Year

(Non-Study Eye: Study Drug)

Ocular Adverse Events through 1 Year

(Non-Study Eye: Study Drug)

38




No. of injections prior to 1 year

753 841 766

Endophthalmitis <1% 0 <1%Inflammationǁ 2% <1% 0

Retinal detachment/tear 0 0 0Vitreous hemorrhage 4% 7% 2%Injection related cataract <1% 0 0Intraocular pressure elevation‡

12% 9% 9%

ǁIncludes anterior chamber cell/flare, choroiditis, episcleritis, iritis, vitreal cells.‡Includes intraocular pressure increase ≥10mmHg from baseline at any visit, intraocular pressure ≥30 mmHg at any visit, or initiation of intraocular pressure-lowering medications not in use at baseline. There were no glaucoma surgeries.

Systemic Adverse Events APTC* through 1-Year

Systemic Adverse Events APTC* through 1-Year

39




Non-fatal MI 2% <1% 1%

Non-fatal stroke 0 2% 2%

Vascular death <1% 2% 1%

Any APTC Event 3% 4% 5%Global P = 0.56

* Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. BMJ 1994;308:81-106.

Systemic Adverse Events Through 1 Year

Pre-specified (Per Participant)

Systemic Adverse Events Through 1 Year

Pre-specified (Per Participant)

40




P-Value*

Death (any cause) 1% 2% 2% 0.72

Hospitalization 21% 18% 22% 0.51

SAEs 26% 21% 25% 0.40

Gastrointestinal † 20% 18% 17% 0.84

Kidney Events‡ 13% 11% 11% 0.81

Hypertension Events

12% 7% 12% 0.20

*Global (overall 3 group comparison) P-value from Fisher’s Exact Test. †Includes events with a Medical Dictionary for Regulatory Activities system organ class of gastrointestinal disorders‡Includes a subset of Medical Dictionary for Regulatory Activities system organ class of renal and urinary disorders events indicative of intrinsic kidney disease, plus increased/abnormal blood creatinine or renal transplant from other system organ classesSAEs = Serious adverse events

Post Hoc Analysis: Cardiovascular Events Through 1 Year

Post Hoc Analysis: Cardiovascular Events Through 1 Year

41




Global P-Value unadjusted/

adjusted*

Any Cardiovascular Event,† excluding Hypertension

9% 9% 17% 0.0121

0.0242

Any Cardiovascular Event†

19% 16% 26% 0.0383

0.0814

* Adjusted for potential confounders: gender, age at baseline, Hemoglobin A1c at baseline, diabetes type, diabetes duration at baseline, insulin use, prior coronary artery disease, prior myocardial infarction, prior stroke, prior transient ischemic attack, prior hypertension, smoking status

† Events with a MedDRA system organ class of cardiac disorder or vascular disorder OR considered by the medical monitor as related to a cardiac or vascular event (cardiac murmur, cardiac pacemaker insertion/replacement, coronary arterial stent insertion, heart rate irregular, and stent placement)

Pairwise comparisons (adjusted for multiple comparisons): 1. A-B: P=1.0, A-R: P=0.015, B-R: P = 0.014 2. A-B: P=0.68, A-R: P=0.040, B-R: P = 0.0243. A-B: P=0.53, A-R: P=0.087, B-R: P = 0.0384. A-B: P=0.37, A-R: P=0.19, B-R: P = 0.081

Post Hoc Analysis: Cardiovascular Events

Post Hoc Analysis: Cardiovascular Events

42




Any Cardiovascular Event

Cardiac Events 6% 6% 11%Cerebrovascular

Events0 2% 5%

Peripheral Vascular Disease Events

<1% <1% <1%

Venous Disease Events <1% <1% <1%

Hypertension Events 12% 7% 12%Other Cardiovascular Events

3% <1% 2%

DiscussionDiscussion All three anti-VEGF agents, on average, produced

substantial visual acuity improvement by 1 month, sustained through 1 year.

On average, greater improvement occurred with aflibercept, but relative effect varied by initial visual acuity. Mild initial vision loss (20/32-20/40, 50% of study eyes):

little difference in mean visual acuity at 1 year Worse initial vision loss: aflibercept had an advantage

over the other agents• Statistically significant: Mean improvement of 18.9 for aflibercept vs.

11.8 for bevacizumab (P<0.001) and vs. 14.2 with ranibizumab (P = 0.003)• Clinically meaningful: For example, relative improvement ≥15 letters (>3

Snellen lines) in 63% more aflibercept-treated eyes than bevacizumab-treated eyes, and 34% more than ranibizumab-treated eyes

43

Discussion Discussion Bevacizumab had a lesser effect on reducing

macular edema than the other two agents, regardless of starting acuity.

Few eyes in any group had substantial visual acuity loss.

Median number of injections: 9 to 10 in all three groups.

Fewer eyes in the aflibercept group received focal/grid laser for DME after 24 weeks, presumably because a greater % of eyes in the aflibercept group had resolution of central DME (which drives decision to apply laser).

44

DiscussionDiscussion Serious adverse event, death, and

hospitalization rates appeared similar among treatment groups.

Significant differences in frequencies of major cardiovascular events were not identified • However, post-hoc analysis combining MedDRA

system organ classes of cardiac and vascular resulted in more participants in the ranibizumab group reporting these adverse events.

• This is inconsistent with prior studies and may be due to chance.

Endophthalmitis was rare: 0.02% of injections.No differences in intraocular inflammation.

45

Bevacizumab: Note: a central pharmacy repackaged into single use

vials• Testing was completed for sterility, purity, and

potency, a standard that may not be available in a clinical practice setting

Results may not apply to eyes with persistent or recurrent DME already receiving anti-VEGF

46

DiscussionDiscussion

Conclusion Conclusion

All three anti-VEGF agents are effective treatments for DME causing vision impairment.

When initial visual acuity loss is mild, on average there is little difference in visual acuity at 1-year.

At worse levels of initial visual acuity aflibercept is more effective at improving vision.

47

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

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

48

A complete list of all DRCR.net investigator financial disclosures and these slides can be found at www.drcr.net.

Full protocol available on clinicalTrials.gov (NCT01627249)

Reference: DOI: 10.1056/NEJMoa1414264

Diabetic Retinopathy Clinical Research Network. Aflibercept, ranibizumab, or bevacizumab for diabetic macular edema. NEJM 2015;372:xxx-xxx.

http://www.drcr.net/

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