1 diabetic macula edema. microaneurysms cws hard exudates beading of vessels irma nvd/nve ...

1

Diabetic macula edema

?

Microaneurysms

CWS

Hard exudates

Beading of vessels

IRMA

NVD/NVE

DME- Types

2

Definition of DME

Swelling of the retina due to leaking of fluid from blood vessels within the macula in patients with diabetes

Thickening of the basement membrane and a reduction in the number of pericytes are believed to lead to increased permeability and leakage of plasma constituents in the surrounding retina, resulting in retinal edema

3

http://www.medterms.com/script/main/art.asp?articlekey=16569. Accessed February 2009

http://www.medterms.com/script/main/art.asp?articlekey=16569

4

DME: retinal pathology

Retinal edema

Hard exudates

Retinal edema and hard exudates illustrated in a color fundus photography image

5

Factors affecting DME

Incidence of DME increases with

elevated levels of HbA1C

severity of DR

duration of DM

elevated diastolic blood pressure

gender (more frequent in females)

serum lipid levels

Klein et al. Ophthalmology 1998; 105: 1801-1815

6

Classification of DR

Microaneurysms only

Microaneurysms, hemorrhages, hard exudates, and cotton-wool spots

Venous abnormalities (beading, loops), intraretinal microvascular abnormalities (IRMA), increased hemorrhage, and exudation

NPDR(non-proliferative

diabetic retinopathy)

PDR(proliferative

diabetic retinopathy)

DME(diabetic

macular edema) Hard exudates, retinal thickening

Neovascularization, vitreous hemorrhage, and traction retinal detachment

Mild

Severe

Yam & Kwok. Hong Kong Med J 2007; 13: 46-60Adapted from: Royal College of Ophthalmology. Diabetic Retinopathy Guidelines 2005.

http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf .Accessed February 2009

http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf

7

Most common complications are microvascular changes1

Diabetic macula edema (DME) is a common cause of blindness in people of working age2,3 and can develop in both Type 1 and 2 DM4

About 8% of diabetic patients develop DME with visual impairment5

1King et al. Diabetes Care 1998; 21: 1414-1431; 2Royal College of Ophthalmology. Diabetic Retinopathy Guidelines 2005. http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf . Accessed February

2009; 3Watkins. BMJ 2003; 326: 924-926; 4Klein et al. Ophthalmology 1998; 105: 1801-1815; 5Calculated from: Ling et al. Eye 2002; 16: 140-145; Broadbent et al. Eye 1999; 13: 160-165; Knudsen et al. Br J Ophthalmol 2006; 90: 1404-1409; Hove et al.

Acta Ophthalmol Scand 2004; 82: 443-448; Romero-Aroca et al. Arch Soc Esp Oftalmol 2007; 82: 209-218; Zietz et al. Dtsch Med Wochenschr 2000; 125: 783-788; Kristinsson. Acta Ophthalmol Scand Suppl 1997; 223: 1-76

Diabetes and vision loss


8

Role of VEGF in DR

Vascular endothelial growth factor (VEGF) plays a major role in patients with DR

mediates active intraocular neovascularization and breakdown of the blood-retinal barrier1

associated with VEGF gene polymorphism2

1Aiello et al. N Engl J Med 1994; 331: 1480-14872Nakamura. Graefes Arch Clin Exp Ophthalmol 2009; 247: 21-26

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VEGF165 in DR

Retinal VEGF165 levels are elevated in experimental diabetes

Increased VEGF165 levels are found in the vitreous of eyes with proliferative DR

Patients with DR have higher VEGF165 levels in the aqueous

Qaum et al. IOVS 2001; 42: 2408-2413; Aiello et al. N Engl J Med 1994; 331: 1480-1487

Diagnosis of DR / DME

Diagnosis of DR / DME often occurs during routine eye examinations of patients with DM

Type 1 diabetes (no DR / DME) first examination 3–5 years after

diagnosis of diabetes, recommended yearly follow-up

Type 2 diabetes (no DR / DME) first examination at time of diagnosis

of diabetes, recommended yearly follow-up

Follow-up frequency increases with diagnosis of DR / DME

10

AAO Guidelines. Diabetic Retinopathy. http://www.aao.org/ppp. Accessed February 2009Royal College of Ophthalmology. Diabetic Retinopathy Guidelines 2005.

http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf. Accessed February 2009. Images: National Eye Institute, National Institutes of Health

Normal vision

DR

http://www.aao.org/ppp


11

DME: current treatment

Systemic treatment

glucose control

blood-pressure control

blood-lipid control

multifactorial metabolic interventions

Ocular treatment

laser photocoagulation (standard treatment for DR / DME)

vitrectomy

pharmacologic therapyAAO Guidelines. Diabetic Retinopathy. http://www.aao.org/ppp. Accessed February 2009

Royal College of Ophthalmology. Diabetic Retinopathy Guidelines 2005. http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf . Accessed February 2009



12

Reduction in vessel hyperpermeabilityand leakage in macular edema

DME: aims of therapy

Treatment of neovascularizationin PDR

13

Laser photocoagulation for DME

Standard treatment – helps to slow fluid leakage and reduce the amount of fluid in the retina (macula edema)

Aim of treatment is to stabilize / prevent further vision loss

Limitations of treatment include

does not eliminate possibility of further vision loss

improvement in visual acuity is uncommon

complications including permanent damage to the retinal pigment epithelium and secondary choroidal neovascularization

National Eye Institute, National Institutes of Health. Diabetic Retinopathy. http://www.nei.nih.gov/health/diabetic/retinopathy.asp#4a Accessed February 2009

AAO Guidelines. Diabetic Retinopathy. http://www.aao.org/ppp. Accessed February 2009Royal College of Ophthalmology. Diabetic Retinopathy Guidelines 2005.

http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf . Accessed February 2009

http://www.nei.nih.gov/health/diabetic/retinopathy.asp#4a



14

DR and DME: the unmet treatment needs

Despite the use of standard interventions for DR, vision loss as a result of the disease still occurs in many patients1

Good metabolic and blood-pressure control are often difficult to achieve in clinical practice, and sight-threatening DR still develops2

Laser treatment is destructive and cannot restore vision loss that has already occurred; it therefore cannot be regarded as an ideal treatment, and there is a need for better-tolerated and less-destructive therapies3

1Comer & Ciulla. Curr Opin Ophthalmol 2004; 15: 508-5182The DIRECT Programme Study Group. J Renin Angiotensin Aldosterone Syst 2002; 3: 255-261

3Fong. Surv Ophthalmol 2002; 47: S238-S245

RESTORE study in DME patients: 12-month results

Core slide resource

Primary objective

To demonstrate superiority of ranibizumab (0.5 mg) as monotherapy and/or adjunctive to laser treatment vs. laser therapy based on the mean average change from baseline in BCVA over a 12-month treatment period

Key secondary objectives

To evaluate whether ranibizumab (0.5 mg) as monotherapy or adjunctive to laser is superior to laser treatment in the proportion of patients with improvement in BCVA

To evaluate ranibizumab (0.5 mg) monotherapy and adjunctive to laser relative to laser treatment with respect to:

the time course of BCVA change

the effects on central retinal thickness (CRT) and other anatomical changes

the effect on patient-reported outcomes

safety

Primary endpoint

The mean average change in BCVA from baseline to Month 1 through Month 12

Mean average change is the mean difference between baseline BCVA and the average BCVA over time (Month 1 to Month 12)

RESTORE study design

Visual impairmentdue to DME(n=345)

Randomised 1:1:1

Ranibizumab 0.5 mg

+ active laser

Ranibizumab 0.5 mg

+ sham laser

Sham Injection+ active laser

Active/sham laser treatment was administered before sham/intravitreal injection on the same day (minimum interval between the two treatments was 30 minutes)

RESTORE treatment schedule

Primary endpoint

sham injection

Laser

(n=111)

0 1 2 3 4 5 6 7 8 9 10 11 12Month 0 1 2 3 4 5 6 7 8 9Month

ranibizumab

Laser

(n=118)

ranibizumab

sham laser

(n=116)

Treatment Initiation phase Continuous/resumed treatment phase

ranibizumab 0.5 mg

ranibizumab 0.5 mg PRN*

laser

laser PRN ≠

* According to pre-defined treatment criteria

≠ According to the judgment of the investigator and in accordance with ETDRS guidelines

2 years extension phase with

open-label ranibizumab 0.5 m

gA

rm 1

Arm

2A

rm 3

Randomized, double-masked, multicenter, laser-controlled Phase III (N=345)

RESTORE

Re-treatment criteria

Ranibizumab:

• monthly ranibizumab/sham injections suspended when:

• No further BCVA improvement due to treatment at 2 last consecutive visits OR

• BCVA >84 letters at 2 last consecutive visits

• monthly ranibizumab/sham injections reinitiated when:

• decrease in BCVA due to DME progression in the opinion of the

investigator

Laser photocoagulation (active or sham):

• in accordance with the ETDRS guidelines at intervals of ≥3 months from the last treatment AND

• if deemed necessary by the evaluating investigator

RESTORE

Key inclusion criteria

Male/female patients >18 years of age

Type 1 or type 2 diabetes mellitus

HbA1C ≤10.0%

Eligibility criteria for study eye:

BCVA score: 78-39 letters

Decrease in vision is due to DME and not due to other causes (based on investigator opinion)

Medication for the management of diabetes stable within 3 months prior to randomization and expected to remain stable during the course of the study

RESTORE

Key exclusion criteria

Ocular disorders of the study eye that may confound interpretation of study results

Systemic conditions such as:

history of stroke

renal failure requiring dialysis or renal transplant or renal insufficiency with creatinine levels > 2.0 mg/dl

untreated diabetes mellitus

blood pressure systolic >160 mmHg or diastolic >100 mmHg, untreated hypertension or change in antihypertensive treatment within 3 months preceding baseline

Treatment with anti-angiogenic drugs (study eye) within 3 months prior to randomization, ocular conditions requiring corticosteroid treatment or laser photocoagulation (study eye) within 6 months prior or during study

RESTORE

Demographic Variable (Randomized set)

Ranibizumab N = 116

Ranibizumab + LaserN=118

LaserN=111

Age (years)

Mean (SD) 62.9 (9.29) 64.0 (8.15) 63.5 (8.81)

Age group (years), n(%)

<55 24 (20.7) 14 (11.9) 13 (11.7)

55 - <65 41 (35.3) 42 (35.6) 53 (47.7)

65 - <75 40 (34.5) 53 (44.9) 31 (27.9)

≥75 11 (9.5) 9 (7.6) 14 (12.6)

Gender, n (%)

Male 73 (62.9) 70 (59.3) 58 (52.3)

Female 43 (37.1) 48 (40.7) 53 (47.7)

Predominant race, n(%)

Caucasian 109 (94.0) 111 (94.1) 106 (95.5)

Others* 7 (6.1) 7 (5.9) 5 (4.5)

Patient demographics

*Others include: Black, Asian, Pacific islander and missing

Characteristics (Randomized set)

Ranibizumab N=116

Ranibizumab + LaserN=118

LaserN=111

Diabetes type, n (%)

Type I 13 (11.2) 15 (12.7) 13 (11.7)

Type II 103 (88.8) 102 (86.4) 97 (87.4)

Not stated 0 1 (0.8) 1 (0.9)

HbA1c (%)

Mean (SD) 7.23 (1.085) 7.50 (1.099) 7.28 (1.105)

HbA1c group, n (%)

<8 84 (72.4) 85 (72.0) 80 (72.1)

8 - 10 30 (25.9) 31 (26.3) 28 (25.2)

>10 0 1 (0.8) 0

Missing 2 (1.7) 1 (0.8) 3 (2.7)

Time since first diagnosis of diabetes (years)

Mean (SD) 15.23 (9.909) 14.62 (9.835) 12.93 (9.024)

Diabetes characteristics at baseline

Mean average change in BCVA from Month 1 through Month 12 compared to baseline (primary endpoint)

Treatment

ranibizumab ranibizumab + laser laser

Me

an

ave

rag

e c

ha

ng

e (

SE

) o

f BC

VA

fr

om

ba

selin

e to

M1

-12

0

2

4

6

8

ranibizumab (n=115)ranibizumab + laser (n=118)laser (n=110)

6.15.9

0.8

p<0.0001*

p<0.0001*

* Differences in LS means and the two-sided 95% CIs are estimated from pair wise ANOVA (stratified) model

Full analysis set/LOCF

Mean change in BCVA from baseline over time

10

Month

0 2 4 6 8 10 12

Me

an

ch

an

ge

(±S

E)

in B

CV

A (

lett

ers

)

-2

0

2

4

6

8

ranibizumab (n=115)

ranibizumab + laser (n=118)

laser (n=110)

1 3 5 7 9 11

Ranibizumab injection

0.9

6.4

6.8

RESTORE

Full analysis set/LOCF

Mean change in CRST from baseline over time

*CRST: central retinal subfield thickness

Month

1 3 5 7 9 11

Ranibizumab injection

0 2 4 6 8 10 12

Mea

n ch

ange

(±S

E)

in C

RS

T (

µm

)

-160

-140

-120

-100

-80

-60

-40

-20

0

20

ranibizumab (n=115) ranibizumab + laser (n=118) laser (n=110)

-61.3

-128.3

-118.7

RESTOREFull analysis set/LOCF

Mean average change in BCVA from baseline over time according to type of DME

Numbers in boxes are mean average change of BCVA from baseline to Months 1-12 (primary endpoint)


FOCAL* DIFFUSE**

0.4

6.8

7.0

5.6

0.6

7.0

Month

0 1 2 3 4 5 6 7 8 9 10 11 12

Me

an

(±S

E)

VA

ch

ang

e

from

bas

elin

e,

lett

ers

-2

0

2

4

6

8

10

ranibizumab (n=63)ranibizumab+laser (n=68)laser (n=52)

Month

0 1 2 3 4 5 6 7 8 9 10 11 12

Me

an

(±S

E)

VA

ch

ang

e

from

ba

selin

e,

lett

ers

-4

-2

0

2

4

6

8

10


RESTORE

* focal (central reading center definition): >67% of leakage originated from leaking microaneurysms in the whole edema area. If around 30-67% leakage comes from microaneurysms, the edema is focal if in the central subfield >67% of the leakage originates from microaneurysms

**diffuse (central reading center definition): <33% of leakage comes from leaking microaneurysms and the rest comes from diffuse leaking capillaries in the whole edema area. If around 30-67% leakage comes from microaneurysms, the edema is diffuse if in the central subfield <33% of the leakage originates from microaneurysms

Mean average change in BCVA from baseline over time according to type of diabetes

TYPE I DIABETES

TYPE II DIABETES

Month

0 2 4 6 8 10 12

Me

an (

±SE

) V

A c

hang

e

from

bas

elin

e, le

tter

s

-1

0

1

2

3

4

5

6

7

8

9

10

11

12


Month

0 1 2 3 4 5 6 7 8 9 10 11 12M

ean

(±S

E)

VA

ch

ange

fr

om

bas

elin

e,

lett

ers

-4

-2

0

2

4

6

8

10

12


2.8

7.7

6.7

0.7

6.2

6.8



RESTORE

Mean average change in BCVA from baseline over time according to prior laser treatment status

WITH PRIOR LASER TREATMENT WITHOUT PRIOR LASER TREATMENT

Month

0 1 2 3 4 5 6 7 8 9 10 11 12

Mea

n (±

SE

) V

A c

hang

e

from

ba

selin

e, le

tter

s

-4

-2

0

2

4

6

8

10


Month

0 1 2 3 4 5 6 7 8 9 10 11 12M

ean

(±S

E)

VA

ch

ange

fr

om b

asel

ine,

lett

ers

-4

-2

0

2

4

6

8

10


1.2

4.5

7.6

0.6

8.0

5.9



RESTORE

Visual functioning questionnaire (VFQ-25): Mean change from baseline at Month 12

Full analysis set/LOCFQoL, quality of life; VFQ-25, Vision Function Questionnaire 25

QoL, quality of life; VFQ-25, Vision Function Questionnaire 25*p <0.05; **p <0.001 versus Laser

*p <0.05; **p <0.001 versus Laser

*

**

*

* *

* *

0

5

10

15

Composite General vision Near activities Distanceactivities

Ranibizumab 0.5 mgRanibizumab 0.5 mg + laserLaser

Mea

n ch

ange

in V

FQ

-25

sco

re f

rom

ba

selin

e to

mon

th 1

2 (±

SE

)

*

Treatment exposure

Safety setRanibizumab

N=115Ranibizumab + Laser

N=120LaserN=110

Number of injections (ranibizumab/sham)

Total 800 816 802

Mean (SD) 7.0 (2.81) 6.8 (2.95) 7.3 (3.22)

Frequency of injections, n (%)

1 - 3 16 (13.9) 23 (19.2) 19 (17.3)

4 - 6 37 (32.2) 34 (28.3) 32 (29.1)

7 - 9 40 (34.8) 35 (29.2) 22 (20.0)

10 - 12 22 (19.1) 28 (23.3) 37 (33.6)

Number of laser treatments (active/sham)

Total 217 198 233

Mean (SD) 1.9 (1.07) 1.7 (0.89) 2.1 (1.04)

Frequency of laser treatments, n (%)

1 57 (49.6) 67 (55.8) 40 (36.4)

2 29 (25.2) 36 (30.0) 30 (27.3)

3 15 (13.0) 10 (8.3) 27 (24.5)

≥ 4 14 (12.2) 7 (5.8) 13 (11.8)

Proportion of patients receiving injections over time

Month

Day 1 1 2 3 4 5 6 7 8 9 10 11

Pe

rce

nta

ge

of p

atie

nts

re

ce

ivin

g tre

atm

en

t (%

)

0

20

40

60

80

100


Safety set

Summary of ocular adverse events (AEs)

Main AEs

eye pain (8.3-11.3%)

conjunctival hyperemia (5.0-7.8%)

conjunctival hemorrhage (0-8.3%)

Low level of intra-ocular pressure (IOP) increased (<1%)

Suspected to be related to study drug and/or ocular injection:

eye pain (8.3-10.4%)

conjunctival hyperemia (3.3-7.0%)

conjunctival hemorrhage (0-7.5%)

RESTORE

Summary of ocular serious adverse events (SAEs)

No ocular SAEs were reported in the ranibizumab monotherapy arm

Ocular SAEs reported in two patients each in the ranibizumab + laser and laser arms (one patient in the laser arm reported both cataract and maculopathy)

No cases of endophthalmitis were reported in any of the treatment arms

None of the ocular SAEs were suspected to be related to study drug and/or ocular injection

RESTORE

Proportion of patients with ocular SAEs of the study eye

Preferred term (Safety set)

RanibizumabN=115n (%)

Ranibizumab + Laser N=120 n (%)

Laser N=110

n (%)

Total 0 2 (1.7) 2 (1.8)

Cataract 0 2 (1.7) 2 (1.8)

Maculopathy 0 0 1 (0.9)

No ocular SAEs reported in the ranibizumab monotherapy arm

Summary of non-ocular SAEs (per system organ class)

Non-ocular SAEs with incidence rates >1% were low

cardiac disorders (3.3-7.0%)

infections and infestations (2.5-5.2%)

metabolism and nutrition disorders (1.7-3.5%)

Suspected to be related to study drug and/or ocular injection:

3 patients in ranibizumab arm (intestinal obstruction, hypoglycemia, pulmonary embolism, dyspnea, arterial thrombosis limb) and

1 patient in ranibizumab+laser arm (coronary artery occlusion)

Two deaths reported in each treatment arm, none suspected to be related to the study drug and/or injection procedure

RESTORE

Proportion of patients with AEs potentially related to systemic VEGF inhibition

Preferred term (Safety set)

RanibizumabN=115n (%)

Ranibizumab + LaserN=120n (%)

LaserN=110n (%)

Arterial thromboembolic events* 4 (3.5) 4 (3.3) 3 (2.7) Arterial thrombosis limb 1 0 0 Carotid artery stenosis 1 1 1 Cerebral artery embolism 1 0 0 Cerebrovascular accident 1 0 0 Cerebrovascular disorder 0 1 0 Coronary artery occlusion 0 1 1 Myocardial infarction 1 1 0 Peripheral arterial occlusive disease 1 0 1 Vertebrobasilar insufficiency 0 1 0

Venous thromboembolic events* 2 (1.7) 0 2 (1.8) Axillary vein thrombosis 0 0 1 Deep vein thrombosis 0 0 1 Pulmonary embolism 2 0 1

Hypertension 9 (7.8) 6 (5.0) 9 (8.2)

Non-ocular haemorrhage 1 (0.9) 0 1 (0.9)

Epistaxis 1 (0.9) 0 1 (0.9)

Proteinuria 1 (0.9) 1 (0.8) 0* ATEs by defined RMP version 6 “identified risks”

RESTORE

Summary

The primary objective of the study was met with statistically significant superiority of ranibizumab 0.5 mg monotherapy and ranibizumab 0.5 mg adjunctive to laser compared to laser alone with BCVA improvement from baseline to Month 1 through Month 12 of 5.4 and 4.9 letters, respectively

In contrast to laser monotherapy, ranibizumab alone or in combination with laser leads to a rapid and continuous VA improvement within the initial 3 months followed by VA stabilization under PRN treatment

Patients received on average 6.8-7.3 ranibizumab/sham injections and 1.7-2.1 laser (active or sham) treatments in all treatment arms

No new ocular or non-ocular safety risks were identified

Conclusions - Efficacy

Ranibizumab monotherapy or as adjunctive therapy to laser photocoagulation provided superior benefits in BCVA improvement as compared to laser monotherapy at Month 12 (primary endpoint met)

The study shows that 37-43% of ranibizumab-treated patients improved vision by 10 letters or more as compared to 16% with standard laser therapy

Ranibizumab given alone or as adjunctive to laser showed rapid mean average BCVA gain which was sustained over 12 months of treatment at around 6 letters above baseline compared to 0.8 letter with laser therapy alone

Ranibizumab was well tolerated as monotherapy or as adjunctive to laser therapy in patients with visual impairment due to DME

no cases of endophthalmitis

ranibizumab showed low incidence (<1%) of IOP increased

systemic safety: low incidence of hypertension (5.0-8.2%) and ATEs (2.7-3.5%) in all treatment groups

Conclusions - Safety

TURKEYProf. Dr. Bora EldemAssoc.Prof.Dr Ziya KapranProf. Dr. Cezmi AkkinProf. Dr. Mehmet ErginDr Berati Hasanreisoglu

BELGIUMDr Joachim Van CalsterDr. Marlene Devriendt

FRANCEDr Pascale MASSIN

Dr. Jean- Paul RomanetPr. Michel Weber

Pr Catherine Creuzot-Garche

GERMANYProf. Dr. Antonia JoussenProf. Dr. med. Karl-Heinz EmmerichProf. Dr. med.Katrin EngelmannProf. Dr. med. Lutz HansenProf. Dr. med. Helmut HoehProf. Dr. med. Frank HolzProf. Dr. med. Anselm KampikProf. Dr. med. Ulrich KellnerProf. Dr. med. Bernd KirchhofProf. Dr. med. Gabriele LangProf. Dr. med. Andreas MohrDr. med. Georg SpitalProf. Dr. med. Peter WiedemannProf. Dr. med. Salvatore GrisantiProf. Dr. med. Norbert Schrage

GREECEProf. Miltiadis TsilibarisAssoc. Prof. Periklis BrazitikosAss. Prof. Vergados IoaanisProf Stavros DimitrakosDr Stamatina Kabanarou

ITALYProf. F. BandelloProf. Ugo MenchiniProf. Carlo SborgiaProf. Alfredo ReibaldiProf. Emilio BalestrazziDr.ssa Anna TarantiniProf. Nicola Delle Noci

NETHERLANDSProf. Dr. R.O. SchlingemannDr. J.P. Martinez CirianoDr. B.J. Kleverling

SPAINDr. Josep Garcia ArumiDr. Francisco Gomez UllaDr. Ramon Torres ImazDr. Enrique CerveraDr. Alfredo Adan CiveraDr. Jose Ruiz Moreno

SWITZERLANDDr. med. Malaika Kurz-LevinProf. Dr. med Ulrike SchneiderProf. Dr. med. Justus GarwegDr. med. Christoph TappeinerProf. Dr. med Heinrich GerdingDr. med. Patrik Kloos

UKDr Nicholas BeareDr. Geeta MenonDr Clare Bailey

HUNGARYDr. Andras PappDr. Andras SeresDr Andras BertaDr. Árpád BereckiDr Ágnes Kerény

List of PIs in RESTORE study Slide 1/2

AUSTRALIAProf. Paul MitchellA/Prof Mark GilliesA/Prof Tien WongDr Brendan VoteDr. Dianne Sharp

CANADADr John GonderDr Peter KertesDr David MaberleyDr Shelley BoydDr Sébastien OlivierDr Vladimir KozousekDr. John Chen

List of PIs in RESTORE study

RESTORE

Slide 2/2

Primary and secondary BCVA endpoints: subset of RESTORE (Baseline VA ≤73 letters, CRT ≥300 μm) vs RESOLVE

Primary endpoint: Mean average change in BCVA from baseline to Month 1 through Month 12

Ranibizumab

(n=80)

Ranibizumab+laser

(n=81)

Laser

(n=75)

RESOLVE

(n=102)

7.4 7.2 1.4 7.6

Secondary endpoint: Mean change in BCVA from baseline at Month 12

Ranibizumab Ranibizumab+laser Laser RESOLVE

8.4 8.0 1.7 10.3

RESTORE

Treatment regimen concepts / hypotheses

Treatment is individualized

No relevant increase in efficacy upon further treatment in patients who had become stable for at least three consecutive months under ranibizumab treatment

Treatment

Starts and continues until stability of disease

Interruption when disease stabilises

Monitor for disease activity on monthly basis

Restart when disease activity is observed

Continue until disease stability is observed

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

47

48

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

49

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 Completion

50

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

51

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

52

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

53

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).

54

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

Visual Acuity

55

Mean Change in Visual Acuity* at Follow-up Visits

56* 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*

57

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*

58

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

Visual AcuitySubgroup Analyses

59

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

60

N=146

Change in Visual Acuity at 1 Year Stratified by Baseline CSF

61

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

62

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

63

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

64

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

65

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

Pseudophakic at Baseline*

66

Visit Week

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

Retinal Thickening

67

Mean Change in Central Subfield Thickening at Follow-up Visits

68

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.

Change in Retinal Thickening at 1 Year*

69

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*

70

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

Retinopathy

71

Retinopathy Progression During 1 Year of Follow-up

72

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

Safety

73

74

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

74

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.

75

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

75

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

76

Cataract Surgery During 2-Years of Follow-up

76

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%

Number of Deaths

77

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.

78

Cardiovascular or Cerebrovascular Events According to Antiplatelet Trialists’ Collaboration

through 2-Years

78

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

Discussion

79

80

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

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

80

81

Intravitreal Ranibizumab Summary

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.

81

82

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.

82

83

Intravitreal Triamcinolone Conclusion

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

83

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

84

52 clinical study sites

RESOLVE: Study Purpose and Population

Phase II study to evaluate the safety and explore the effect of ranibizumab in patients with diabetic macular edema (DME) with center involvement

Study parts and population

Group A: Pilot 42 patients analyzed in the 6-month interim analysis

Group B: Confirmatory* 109 patients not analyzed at interim

Group A+B (all patients): primarily safety and overall efficacy

*Clinical Trial Protocol Amendment 3 released May 29, 2008

RESOLVE: Study Objectives and Endpoints

Primary endpoints

Group A: demonstrate superiority of ranibizumab to non-treatment in reducing macular edema from baseline to Month 6 in DME

Group B: confirm the efficacy of ranibizumab on visual acuity (VA) as mean average change from baseline to Month 1 through Month 12 in best-corrected VA (BCVA)

Secondary endpoints

explore the treatment effect on VA, retinal structure, and need for laser photocoagulation

explore the superiority of ranibizumab effect on macular edema compared with sham

RESOLVE: Trial DesignRESOLVE: Trial Design

FA, fluorescein angiography OCT, optical coherence tomography

Randomized 1:1:1

Sham

Baseline fundus photograph, FA and OCT(reading center)

Investigator identifies potential DME patients

Photocoagulation after 3 injections if needed

Assessment if “increase” is needed

Increase to 0.6 mg if needed

Ranibizumab 0.3 mg

Ranibizumab0.5 mg

Increase to 1.0 mg if needed

N = 151

Key Inclusion Criteria

Male / female patients >18 years of age

Patients with type 1 or type 2 diabetes mellitus

HbA1C ≤ 12.0%

Patients with DME with center involvement in at least one eye (focal or diffuse)

Eligibility criteria for the study eye at Visit 1:

► Central macular thickness must be ≥300 µm in the center subfield, as assessed by optical coherence tomography (OCT) and confirmed by the central reading center

► BCVA letter score between 73 and 39

RESOLVE Treatment Dosing Schedule

Month*

Ranibizumab10 mg/ml

Sham

0

Ranibizumab6 mg/ml

12

Primary endpoint

21

Dose may be doubled from 0.5 mg to 1.0 mg after 1 mo if indicated

Dose may be doubled from 0.3 mg to 0.6 mg after 1 mo if indicated

3 4 5 6 7 8 9 10 11

*Months 3-12 treatment on demand based on success, futility, and safety criteria

Treatment Adjustments: Dose Doubling* Criteria

Retinal thickness in the study eye remains >300 µm at the Month 1 visit following baseline injection

or

Retinal thickness in the study eye is >225 µm and a reduction in retinal edema from the previous assessment is <50 µm, at any monthly visit after Month 1 following the baseline injection

*By doubling the injection volume from 50 to 100 μl ywo formulations of 6 mg/ml and 10 mg/ml have been used

1. Kvanta et al., Invest Ophthalmol Vis Sci 1996; 37: 1929-1934.2. Jonas JB, Neumaier M. Ophthalmic Res 2007, 39: 139-142.

Treatment Adjustments:

Success and Re-initiation Criteria

Discontinuation because of success if:

Retinal thickness in the study eye is ≤225 µm

and

BCVA is ≥79 letters (≥20/25)

at any visit following the third injection

Re-initiation of treatment if:

Retinal thickness increases by ≥50 μm

or

Visual acuity decreases by ≥5 letters and is <74 letters

Treatment Adjustments: Futility Criteria - No Borderline Improvement

Borderline improvement defined as:

Decrease in retinal thickness of ≥50 µm and representsat least a 20% reduction

or

Increase in BCVA of ≥5 letters

At the investigator’s discretion: discontinue treatmentafter 3 consecutive injections if no borderline improvement

000

62.8

2427

44

43

2525

1

(32-84)

(47.1)(52.9)

(86.3)

(7.8)(5.9)

(49.0)(49.0)

(2.0)

0

00

Baseline Demographics andOcular Disease Characteristics

All patients, Group A+B randomized set

Age, yearsMean (range)

Gender, n (%)FemaleMale

Race, n (%)CaucasianBlackAsianOther

DME type (RC), n (%)FocalDiffuseQuestionableCannot gradeMissing

Time since first DME diagnosis, yearsMean (range)

63.2

2229

47

4

2127

12

(37-85)

(43.1)(56.9)

(92.2)

(7.8)

(41.2)(52.9)(2.0)(3.9)

0

0

0

1.2 (0-7.2)

65.0

2425

41152

2524

(41-82)

(49.0)(51.0)

(83.7)(2.0)(10.2)(4.0)

(51.0)(49.0)

Ranibizumab 6 mg/mL(n=51)

Ranibizumab 10 mg/mL(n=51)

Sham(n=49)

1.14 (0-7.2) 1.40 (0-19.8)

RESOLVE Results: Mean BCVA Change* From Baseline

Time (months)

Mean VA change from BL ± SE (letters)

Pooled ranibizumab (N = 102)Sham (N = 49)

0

*All patients, Group A+BFull analysis set; first VA value post-baseline was assessed at Day 8BCVA, best-corrected visual acuity; BL, baseline; *LOCF, last observation carried forward SE, standard error of the mean

RESOLVE: mean CRT change*from baseline

Pooled ranibizumab (N = 102)Sham (N = 49)

Mean CRT change from BL ± SE (µm)

Time (months)

0

*All patients, Group A+BFull analysis set; first VA value post-baseline was assessed at Day 8BL, baseline; *LOCF, last observation carried forward SE, standard error of the mean

Ocular Adverse Events

All patients, Group A+B randomized set

Patients experiencingat least one ocular AE

Most common ocular AEs

Conjunctival hemorrhage

Eye pain

Ranibizumab6 mg/mL

(n=51)

Ranibizumab10 mg/mL

(n=51)

Sham

(n=49)

38 (74.5)

10 (19.6)

9 (17.6)

42 (82.4)

13 (25.5)

9 (17.6)

28 (57.1)

7 (14.3)

10 (20.4)

Adverse event (AE), n (%)

Serious Ocular Adverse Events

Ranibizumab6 mg/ml(n=51)

Ranibizumab10 mg/ml

(n=51)Sham(n=49)

Vitreous hemorrhage 1 0 0

Peripheral retinal ischemia 0 1 0

Retinal artery occlusion* 0 1 0

Endophthalmitis 1 1 0

Retinal detachment 0 0 1

Total patients 1 3 1

* transient post-injection of other non-serious ocular adverse events that occurred, no new or unexpected events were observed for this patient population and treatment

Adverse Events Potentially Related to Systemic VEGF Inhibition

Ranibizumab6 mg/ml(n=51)

Ranibizumab10 mg/ml

(n=51)Sham(n=49)

Arterial thromboembolic events 0 (0.0%) 2 *(4.0%) 2 (4.1%)

Hypertension 4 (7.8%) 5 (9.8%) 5 (10.2%)

Total 4 (7.8%) 7 (13.8%) 6 (12.2%)

* 1 Myocardial infarction, 1 Transient ischemic attack

All patients, Group A+B. Safety set.

RESOLVE: Conclusions

The Phase II RESOLVE study results indicate DME response to treatment with intravitreal ranibizumab

Efficacy in the ranibizumab-treated arms showed clinical and statistical superiority compared with sham treatment in terms of mean average change in BCVA and CRT

The safety profile of ranibizumab in patients with DME was similar to that in patients with AMD

These results provide a sound basis for continuing development of ranibizumab in Phase III trials

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