Transcript Diabetes and Vision Loss - Kashyap Memorial Eye Hospital

1
Diabetic macula edema
2
?
Microaneurysms
CWS
Hard exudates
Beading of vessels
IRMA
NVD/NVE
DME- Types
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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
http://www.medterms.com/script/main/art.asp?articlekey=16569. Accessed February 2009
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
 serum
(more frequent in females)
lipid levels
Klein et al. Ophthalmology 1998; 105: 1801-1815
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Classification of DR
Mild
 Microaneurysms only
NPDR
(non-proliferative
diabetic retinopathy)
 Microaneurysms, hemorrhages,
hard exudates, and cotton-wool
spots
 Venous abnormalities (beading,
loops), intraretinal microvascular
abnormalities (IRMA), increased
hemorrhage, and exudation
DME
(diabetic
macular edema)
PDR
(proliferative
diabetic retinopathy)
 Hard exudates, retinal thickening
 Neovascularization, vitreous
hemorrhage, and traction retinal
Severe
detachment
Yam & Kwok. Hong Kong Med J 2007; 13: 46-60
Adapted from: Royal College of Ophthalmology. Diabetic Retinopathy Guidelines 2005.
http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf.
Accessed February 2009
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Diabetes and vision loss
 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
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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
2Nakamura.
et al. N Engl J Med 1994; 331: 1480-1487
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
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Diagnosis of DR / DME
 Diagnosis of DR / DME often occurs
during routine eye examinations of
patients with DM
Normal vision
 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)

DR
first examination at time of diagnosis
of diabetes, recommended yearly
follow-up
 Follow-up frequency increases with
diagnosis of DR / DME
AAO 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. Images: National Eye Institute, National Institutes of Health
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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 therapy
AAO 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
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DME: aims of therapy
 Reduction in vessel hyperpermeability
and leakage in macular edema
 Treatment of neovascularization
in PDR
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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 2009
Royal College of Ophthalmology. Diabetic Retinopathy Guidelines 2005.
http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf. Accessed February 2009
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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: 508-518
2The 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: 12month 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 impairment
due to DME(n=345)
Randomised 1:1:1
Ranibizumab
0.5 mg
+ sham laser
Ranibizumab
0.5 mg
+ active 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
Randomized, double-masked, multicenter, lasercontrolled Phase III (N=345)
Month
0
1
2
Continuous/resumed treatment phase
3
4
5
6
7
8
9
10
11
ranibizumab
sham laser
(n=116)
ranibizumab
Laser
(n=118)
sham injection
Laser
(n=111)
ranibizumab 0.5 mg
laser
ranibizumab 0.5 mg PRN*
laser PRN ≠
Primary endpoint
* According to pre-defined treatment criteria
≠ According
guidelines
RESTORE
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to the judgment of the investigator and in accordance with ETDRS
2 years extension phase with
open-label ranibizumab 0.5 mg
Arm 3Arm 2 Arm 1
Treatment Initiation phase
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
investig
ator
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
Patient demographics
Demographic Variable
(Randomized set)
Ranibizumab
N = 116
Ranibizumab + Laser
N=118
Laser
N=111
Age (years)
Mean (SD)
62.9 (9.29)
64.0 (8.15)
63.5 (8.81)
<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)
11 (9.5)
9 (7.6)
14 (12.6)
Male
73 (62.9)
70 (59.3)
58 (52.3)
Female
43 (37.1)
48 (40.7)
53 (47.7)
109 (94.0)
111 (94.1)
106 (95.5)
7 (6.1)
7 (5.9)
5 (4.5)
Age group (years), n(%)
≥75
Gender, n (%)
Predominant race, n(%)
Caucasian
Others*
*Others include: Black, Asian, Pacific islander and missing
Diabetes characteristics at baseline
Characteristics
(Randomized set)
Ranibizumab
N=116
Ranibizumab + Laser
N=118
Laser
N=111
Type I
13 (11.2)
15 (12.7)
13 (11.7)
Type II
103 (88.8)
102 (86.4)
97 (87.4)
0
1 (0.8)
1 (0.9)
7.23 (1.085)
7.50 (1.099)
7.28 (1.105)
84 (72.4)
85 (72.0)
80 (72.1)
30 (25.9)
31 (26.3)
28 (25.2)
0
1 (0.8)
0
2 (1.7)
1 (0.8)
3 (2.7)
14.62 (9.835)
12.93 (9.024)
Diabetes type, n (%)
Not stated
HbA1c (%)
Mean (SD)
HbA1c group, n (%)
<8
8 - 10
>10
Missing
Time since first diagnosis of diabetes (years)
Mean (SD)
15.23 (9.909)
Mean average change in BCVA from Month 1 through
Month 12 compared to baseline (primary endpoint)
p<0.0001*
p<0.0001*
Mean average change (SE) of BCVA
from baseline to M1-12
8
6
6.1
5.9
4
2
0.8
0
ranibizumab ranibizumab + laser
laser
Treatment
* Differences in LS means and the two-sided 95% CIs are estimated
from pair wise ANOVA (stratified) model
Full analysis set/LOCF
ranibizumab (n=115)
ranibizumab + laser (n=118)
laser (n=110)
Mean change in BCVA from baseline over time
10
ranibizumab (n=115)
ranibizumab + laser (n=118)
Mean change (±SE) in BCVA (letters)
8
laser (n=110)
6.8
6.4
6
4
2
0.9
0
-2
0
1
2
3
4
5
6
7
8
Month
Ranibizumab injection
RESTORE
Full analysis set/LOCF
9
10
11
12
Mean change in CRST from baseline over time
Mean change (±SE) in CRST (µm)
20
ranibizumab (n=115)
ranibizumab + laser (n=118)
laser (n=110)
0
-20
-40
-60
-61.3
-80
-100
-118.7
-120
-128.3
-140
-160
0
1
2
3
4
5
6
7
8
9
10
11
Month
Ranibizumab injection
*CRST: central retinal subfield thickness
RESTORE
Full analysis set/LOCF
12
Mean average change in BCVA from baseline
over time according to type of DME
FOCAL*
ranibizumab (n=63)
ranibizumab+laser (n=68)
laser (n=52)
10
ranibizumab (n=45)
ranibizumab+laser (n=46)
laser (n=52)
10
8
7.0
6
6.8
4
2
0.4
0
Mean (±SE) VA change
from baseline, letters
8
Mean (±SE) VA change
from baseline, letters
DIFFUSE*
*
7.0
6
5.6
4
2
0.6
0
-2
-2
-4
0
1
2
3
4
5
6
Month
7
8
9 10 11 12
0
1
2
3
4
5
6
7
8
9 10 11 12
Month
Numbers in boxes are mean average change of BCVA from baseline to Months 1-12 (primary endpoint)
* 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
RESTORE <33% of the leakage originates from microaneurysms
Mean average change in BCVA from baseline
over time according to type of diabetes
12
TYPE I
DIABETES
ranibizumab (n=13)
ranibizumab+laser (n=15)
laser (n=12)
TYPE II
DIABETES
ranibizumab (n=102)
ranibizumab+laser (n=102)
laser (n=96)
12
11
10
9
8
7.7
7
6.7
6
5
4
3
2.8
2
1
Mean (±SE) VA change
from baseline, letters
Mean (±SE) VA change
from baseline, letters
10
8
6.8
6
6.2
4
2
0.7
0
-2
0
-1
-4
0
2
4
6
Month
8
10
12
0
1
2
3
4
5
6
7
8
9 10 11 12
Month
Numbers in boxes are mean average change of BCVA from baseline to Months 1-12 (primary endpoint)
RESTORE
Mean average change in BCVA from baseline over
time according to prior laser treatment status
WITHOUT PRIOR LASER TREATMENT
WITH PRIOR LASER TREATMENT
ranibizumab (n=60)
ranibizumab+laser (n=55)
laser (n=47)
10
10
8
7.6
6
4.5
4
2
1.2
0
-2
Mean (±SE) VA change
from baseline, letters
Mean (±SE) VA change
from baseline, letters
ranibizumab (n=55)
ranibizumab+laser (n=63)
laser (n=63)
8
8.0
6
5.9
4
2
0.6
0
-2
-4
-4
0
1
2
3
4
5
6
Month
7
8
9 10 11 12
0
1
2
3
4
5
6
7
8
9 10 11 12
Month
Numbers in boxes are mean average change of BCVA from baseline to Months 1-12 (primary endpoint)
RESTORE
Visual functioning questionnaire (VFQ-25): Mean
change from baseline at Month 12
Mean change in VFQ-25 score from
baseline to month 12 (±SE)
15
Ranibizumab 0.5 mg
Ranibizumab 0.5 mg + laser
Laser
*
**
*
*
10
*
*
*
*
5
0
Composite
General vision
Near activities
Distance
activities
*p <0.05; **p <0.001 versus Laser
QoL, quality of life; VFQ-25, Vision Function Questionnaire 25
Full analysis set/LOCF
Treatment exposure
Ranibizumab + Laser
N=120
Laser
N=110
800
816
802
7.0 (2.81)
6.8 (2.95)
7.3 (3.22)
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)
217
198
233
1.9 (1.07)
1.7 (0.89)
2.1 (1.04)
Safety set
Ranibizumab
N=115
Number of injections (ranibizumab/sham)
Total
Mean (SD)
Frequency of injections, n (%)
Number of laser treatments (active/sham)
Total
Mean (SD)
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)
Percentage of patients receiving treatment (%)
Proportion of patients receiving injections over time
100
ranibizumab (n=115)
ranibizumab+laser (n=120)
laser (n=110)
80
60
40
20
0
Day 1
1
2
3
4
5
6
7
8
9
10
Month
Safety set
11
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
Ranibizumab
N=115
n (%)
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)
Preferred term
(Safety set)
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
Ranibizumab
N=115
n (%)
Ranibizumab + Laser
N=120
n (%)
Laser
N=110
n (%)
Arterial thromboembolic events*
Arterial thrombosis limb
Carotid artery stenosis
Cerebral artery embolism
Cerebrovascular accident
Cerebrovascular disorder
Coronary artery occlusion
Myocardial infarction
Peripheral arterial occlusive disease
Vertebrobasilar insufficiency
Venous thromboembolic events*
Axillary vein thrombosis
Deep vein thrombosis
Pulmonary embolism
Hypertension
4 (3.5)
1
1
1
1
0
0
1
1
0
2 (1.7)
0
0
2
9 (7.8)
4 (3.3)
0
1
0
0
1
1
1
0
1
0
0
0
0
6 (5.0)
3 (2.7)
0
1
0
0
0
1
0
1
0
2 (1.8)
1
1
1
9 (8.2)
Non-ocular haemorrhage
Epistaxis
Proteinuria
1 (0.9)
1 (0.9)
1 (0.9)
0
0
1 (0.8)
1 (0.9)
1 (0.9)
0
Preferred term
(Safety set)
RESTORE
* ATEs by defined RMP version 6 “identified risks”
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
Conclusions - Safety
 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
List of PIs in RESTORE study
UK
Dr Nicholas Beare
Dr. Geeta Menon
Dr Clare Bailey
NETHERLANDS
Prof. Dr. R.O. Schlingemann
Dr. J.P. Martinez Ciriano
Dr. B.J. Kleverling
BELGIUM
Dr Joachim Van Calster
Dr. Marlene Devriendt
FRANCE
Dr Pascale MASSIN
Dr. Jean- Paul Romanet
Pr. Michel Weber
Pr Catherine Creuzot-Garche
Slide 1
GERMANY
Prof. Dr. Antonia Joussen
Prof. Dr. med. Karl-Heinz Emmerich
Prof. Dr. med.Katrin Engelmann
Prof. Dr. med. Lutz Hansen
Prof. Dr. med. Helmut Hoeh
Prof. Dr. med. Frank Holz
Prof. Dr. med. Anselm Kampik
Prof. Dr. med. Ulrich Kellner
Prof. Dr. med. Bernd Kirchhof
Prof. Dr. med. Gabriele Lang
Prof. Dr. med. Andreas Mohr
Dr. med. Georg Spital
Prof. Dr. med. Peter Wiedemann
Prof. Dr. med. Salvatore Grisanti
Prof. Dr. med. Norbert Schrage
HUNGARY
Dr. Andras Papp
Dr. Andras Seres
Dr Andras Berta
Dr. Árpád Berecki
Dr Ágnes Kerény
SPAIN
Dr. Josep Garcia Arumi
Dr. Francisco Gomez Ulla
Dr. Ramon Torres Imaz
Dr. Enrique Cervera
Dr. Alfredo Adan Civera
Dr. Jose Ruiz Moreno
TURKEY
Prof. Dr. Bora Eldem
Assoc.Prof.Dr Ziya Kapran
Prof. Dr. Cezmi Akkin
Prof. Dr. Mehmet Ergin
Dr Berati Hasanreisoglu
SWITZERLAND
Dr. med. Malaika Kurz-Levin
Prof. Dr. med Ulrike Schneider
Prof. Dr. med. Justus Garweg
Dr. med. Christoph Tappeiner
Prof. Dr. med Heinrich Gerding
Dr. med. Patrik Kloos
ITALY
Prof. F. Bandello
Prof. Ugo Menchini
Prof. Carlo Sborgia
Prof. Alfredo Reibaldi
Prof. Emilio Balestrazzi
Dr.ssa Anna Tarantini
Prof. Nicola Delle Noci
GREECE
Prof. Miltiadis Tsilibaris
Assoc. Prof. Periklis Brazitikos
Ass. Prof. Vergados Ioaanis
Prof Stavros Dimitrakos
Dr Stamatina Kabanarou
List of PIs in RESTORE study
Slide 2
CANADA
Dr John Gonder
Dr Peter Kertes
Dr David Maberley
Dr Shelley Boyd
Dr Sébastien Olivier
Dr Vladimir Kozousek
Dr. John Chen
AUSTRALIA
Prof. Paul Mitchell
A/Prof Mark Gillies
A/Prof Tien Wong
Dr Brendan Vote
Dr. Dianne Sharp
RESTORE
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
Ranibizumab+laser
Laser
RESOLVE
(n=80)
(n=81)
(n=75)
(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
47
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
Study Design
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
Primary outcome: Change in visual acuity from
baseline to 1 year (intent to treat analysis)
48
Follow-up Schedule
Baseline to
1 Year
1 Year to
3 Years
49
• 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
Eyes Randomized:
N = 854 (691 Participants)
Sham
+Prompt Laser
N = 293
Ranibizumab
+Prompt Laser
N = 187
Ranibizumab
+Deferred Laser
N = 188
Triamcinolone
+Prompt Laser
N = 186
1 Year Visit Completion:
94%*
2 Year Visit Completion:
87%**
*50
Includes deaths
** Includes deaths and excludes pending and dropped who are not yet in window
Baseline Characteristics
Sham
+Prompt
Laser
Ranibizumab
+Prompt
Laser
Ranibizumab
+Deferred
Laser
Triamcinolone
+Prompt
Laser
63
62
64
62
Type I
9%
6%
8%
8%
Type II
89%
92%
90%
89%
3%
2%
2%
3%
65 (20/50)
66 (20/50)
66 (20/50)
66 (20/50)
407
371
382
374
Median age
Diabetes type
Uncertain
Median E-ETDRS©
visual acuity letter
score (Snellen
equivalent)
Median OCT CSF
thickness (µm)
51
Injections/Sham Prior to 1 Year
Sham
+Prompt
Laser
N = 274
Ranibizumab
+Prompt
Laser
N = 171
Ranibizumab
+Deferred
Laser
N = 178
Triamcinolone
+Prompt
Laser
N =176
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%
Maximal possible # of
sham/injections
52
*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
Laser Treatments Prior to 1 Year
Sham
+Prompt
Laser
Ranibizumab
+Prompt
Laser
Ranibizumab
+Deferred
Laser*
(permitted
starting at 24week visit)
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
Triamcinolone
+Prompt
Laser
13%,
27%,
31%,
32%,
70%,
20%,
26%,
30%,
40%,
20%
27%,
11%
10%,
1%
28%,
15%
* 353
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).
Alternative* Treatments Prior to 1 Year
Eyes with alternative
treatments
(number of treatments)
Per protocol (failure‡
criteria met)
Deviations from
protocol - clinical
care
*Alternative
Sham
+Prompt
Laser
N = 293
Ranibizumab
+Prompt
Laser
N = 187
Ranibizumab
+Deferred
Laser
N = 188
Triamcinolone
+Prompt
Laser
N = 186
14 (25)
1 (1)
0
1 (1)
5
1
0
1
9
0
0
0
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
54that is cause of visual loss, “complete laser” given AND ≥13 weeks since last laser
exam
treatment with no improvement since the last laser treatment
Visual Acuity
55
Mean Change in Visual Acuity*
at Follow-up Visits
11
10
Sham+prompt
laser
9
8
Ranibizumab+
prompt laser
7
Primary outcome time point
6
5
4
Ranibizumab+
deferred laser
Triamcinolone
+prompt laser
3
2
1
0
0
* Values
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
56 that were ±30 letters were assigned a value of 30
P-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
(letters)
Mean
Difference in
mean change from
Sham +Prompt
Laser
[P Value]**
Sham
+Prompt
Laser
N = 293
+3
Ranibizumab Ranibizumab
+Prompt
+Deferred
Laser
Laser
N = 187
N = 188
Triamcinolone
+Prompt
Laser
N = 186
+9
+9
+4
+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.
57
**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 (letters)
Mean
Difference in mean
change from Sham
+Prompt Laser
[P Value]**
Sham
+Prompt
Laser
N = 163
Ranibizumab
+Prompt
Laser
N = 106
Ranibizumab
+Deferred
Laser
N = 112
Triamcinolone
+Prompt
Laser
N = 103
+2
+7
+10
0
+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
58
Visual Acuity
Subgroup Analyses
59
Change in Visual Acuity at 1 Year
Stratified by Baseline Visual Acuity
N=146
60
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
N=130
63
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*
Visit Week
66* Values that were ±30 letters were assigned a value of 30
Retinal Thickening
67
Mean Change in Central Subfield
Thickening at Follow-up Visits
Visit Week
P values
68 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*
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
-55
[P<0.001]
-49
[P<0.001]
-52
[P<0.001]
53%
42%
47%
Difference in mean
change from Sham
Prompt+Laser
[P Value]**
Thickness <250 µm
with at least a 25
µm decrease from
baseline
27%
*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
69
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 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
-31
[P = 0.01]
-36
[P = 0.004]
-3
[P = 0.81]
54%
55%
44%
Difference in mean
change from Sham
+ Laser [P Value]**
Thickness <250 µm
with at least a 25 µm
decrease from
baseline
38%
*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 eyes
ª Excluding pending- Missing data for 2 eyes in the sham+prompt laser group, 2 eyes in the ranibizumab+prompt laser group, 2
in the
70ranibizumab +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
Reported vitreous
hemorrhage OR
received PRP
P Value for
comparison with
sham
72
Sham
N = 293
Ranibizumab
N = 375
Triamcinolone
N = 186
8%
3%
3%
--
0.002
0.02
Safety
73
74
Major Ocular Adverse Events
During 2-Years of Follow-up
Sham
+Prompt
Laser
N = 293
Number of injections
Ranibizumab
+Prompt
Laser
N = 187
Ranibizumab
+Deferred
Laser
N = 188
Triamcinolone
+Prompt
Laser
N = 186
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%)
0
0
1 (1%)
0
Vitrectomy
15 (5%)
4 (2%)
7 (4%)
2 (1%)
Vitreous Hemorrhage
27 (9%)
6 (3%)
8 (4%)
7 (4%)
Retinal detachment§
*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.
74
‡ 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
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 IOPlowering meds at any
visit*
5%
5%
3%
28%
Number of eyes
meeting ≥1 of the
above
11%
11%
7%
50%
<1%
1%
0
1%
Elevated Intraocular
Pressure/Glaucoma
Glaucoma surgery**
*Excludes eyes with IOP lowering medications at baseline
**Includes 2 filter and 2 cilliary body destruction
75
76
Cataract Surgery During 2-Years of
Follow-up
Sham
+Prompt
Laser
Phakic at
baseline
Eyes that had
cataract surgery
Ranibizumab Ranibizumab Triamcinolone
+Prompt
+Deferred
+Prompt
Laser
Laser
Laser
N = 192
N = 131
N = 134
N = 124
12%
12%
13%
55%
76
Number of Deaths
Sham Ranibizumab Triamcinolone
N = 130
N = 375
N = 186
Deaths*
7 (5%)
15 (4%)
6 (3%)
*Study participants with 2 study eyes are counted
77
in their injection group.
Cardiovascular or Cerebrovascular Events
According to Antiplatelet Trialists’ Collaboration
through 2-Years
Sham‡
N* = 130
Ranibizumab Triamcinolone
N* = 375
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%
12%
5%
6%
Any APTC event
* 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
78
78
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
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
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)
 52 clinical study sites
84
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 Design
Investigator identifies potential DME patients
N = 151
Baseline fundus photograph, FA and OCT
(reading center)
Randomized 1:1:1
Sham
Ranibizumab
0.3 mg
Ranibizumab
0.5 mg
Assessment if
“increase” is needed
Increase to
0.6 mg if needed
Increase to
1.0 mg if needed
Photocoagulation after
3 injections if needed
FA, fluorescein angiography
OCT, optical coherence tomography
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*
0
1
2
3
4
5
6
7
8
9
10 11 12
Dose may
be doubled
from 0.5 mg
to 1.0 mg
after 1 mo if
indicated
Ranibizumab
10 mg/ml
Dose may
be doubled
from 0.3 mg
to 0.6 mg
after 1 mo if
indicated
Ranibizumab
6 mg/ml
Sham
Primary endpoint
*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 represents
at least a 20% reduction
or
 Increase in BCVA of ≥5 letters
At the investigator’s discretion: discontinue treatment
after 3 consecutive injections if no borderline improvement
Baseline Demographics and
Ocular Disease Characteristics
Ranibizumab 6 mg/mL
(n=51)
Ranibizumab 10 mg/mL
(n=51)
Sham
(n=49)
Age, years
Mean (range)
63.2 (37-85)
Gender, n (%)
Female
22 (43.1)
Male
29 (56.9)
Race, n (%)
Caucasian
47 (92.2)
Black
0
Asian
4 (7.8)
Other
0
DME type (RC), n (%)
Focal
21 (41.2)
Diffuse
27 (52.9)
Questionable
1 (2.0)
Cannot grade
2 (3.9)
Missing
0
Time since first DME diagnosis, years
Mean (range)
1.2 (0-7.2)
All patients, Group A+B randomized set
62.8 (32-84)
65.0 (41-82)
24 (47.1)
27 (52.9)
24 (49.0)
25 (51.0)
44 (86.3)
0
4 (7.8)
3 (5.9)
41
1
5
2
25 (49.0)
25 (49.0)
0
0
1 (2.0)
25 (51.0)
24 (49.0)
0
0
0
1.14 (0-7.2)
(83.7)
(2.0)
(10.2)
(4.0)
1.40 (0-19.8)
RESOLVE Results:
Mean BCVA Change* From Baseline
Mean VA
change from
BL ± SE
(letters)
Pooled ranibizumab (N = 102)
Sham (N = 49)
0
Time (months)
*All patients, Group A+B
Full analysis set; first VA value post-baseline was assessed at Day 8
BCVA, best-corrected visual acuity; BL, baseline; *LOCF, last observation carried forward
SE, standard error of the mean
RESOLVE: mean CRT change*
from baseline
Mean CRT
change from
BL ± SE
(µm)
Pooled ranibizumab (N = 102)
Sham (N = 49)
0
Time (months)
*All patients, Group A+B
Full analysis set; first VA value post-baseline was assessed at Day 8
BL, baseline; *LOCF, last observation carried forward
SE, standard error of the mean
Ocular Adverse Events
Adverse event (AE),
n (%)
Patients experiencing
at least one ocular AE
Ranibizumab
6 mg/mL
(n=51)
Ranibizumab
10 mg/mL
(n=51)
Sham
(n=49)
38 (74.5)
42 (82.4)
28 (57.1)
10 (19.6)
13 (25.5)
7 (14.3)
9 (17.6)
9 (17.6)
10 (20.4)
Most common ocular AEs
Conjunctival hemorrhage
Eye pain
All patients, Group A+B randomized set
Serious Ocular Adverse Events
Ranibizumab
6 mg/ml
(n=51)
Ranibizumab
10 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
Ranibizumab
6 mg/ml
(n=51)
Ranibizumab
10 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