Dr. Md. Mominul Islam Fellow (Vitreo-Retina)

Ispahani Islamia Eye Institute And Hospital Dhaka Bangladesh

Received 15 March 2010 and accepted 8 August 2010.

Participants

Screened patients 207 Eligible patients 151 Assigned Randomly 1:1:1 Ranibizumab injection:

• 0.3 mg :- n-51 • 0.5 mg :- n-51

Sham injection:

RESOLVE trial design

Randomized 1:1:1

Sham (n = 49)

Baseline fundus photograph, FA, and OCT (reading center)

Investigator identifies potential patients with DME with center involvement

Photocoagulation after 3 injections if needed

Assessment if “increase” is needed

Increase to 0.6 mg if needed

Ranibizumab 0.3 mg (n = 51)

Ranibizumab0.5 mg (n = 51)

Increase to 1.0 mg if needed

After1 month

Months 3–12treatment on demand based

on success, futility, and safety criteria

Monthly injections

DME, diabetic macular edema; FA, fluorescein angiography OCT, optical coherence tomography

Phase II, double-blind, multicenter study

Study objectives and endpointsObjective: -- Safety and efficacy of Ranibizumab in DME

involving the foveal center.Primary endpoints– Group A: Demonstrate superiority of Ranibizumab to sham in

reducing macular edema from baseline to Month 6 in DME

– Group B: Confirm the efficacy of Ranibizumab on VA as mean

average change from baseline through to Month 12

Study objectives and endpoints

Secondary endpoints

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

– Explore the superiority of Ranibizumab in reducing macular edema compared with sham

Key inclusion criteria• Male / female patients >18 years of age

• Diabetes mellitus type 1 or type 2

• HbA1C ≤ 12.0%

• 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 OCT and confirmed by the central reading center

– best-corrected visual acuity letter score between 73 and 39

Baseline demographics andocular disease characteristics

Age, yearsMean (range)

Gender, n (%)FemaleMale

Race, n (%)CaucasianBlackAsianOther

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

Time since first DME diagnosis, yearsMean (range)

Ranibizumab 6 mg/mL(n = 51)

Ranibizumab 10 mg/mL(n = 51)

Sham(n = 49)

63.2 (37-85)

22 (43.1)29 (56.9)

47 (92.2)0

4 (7.8)0

21 (41.2)27 (52.9)

1 (2.0)2 (3.9)

0

1.2 (0-7.2)

62.8 (32-84)

24 (47.1)27 (52.9)

44 (86.3)0

4 (7.8)3 (5.9)

25 (49.0)25 (49.0)

00

1 (2.0)

1.14 (0-7.2)

65.0 (41-82)

24 (49.0)25 (51.0)

41 (83.7)1 (2.0)

5 (10.2)2 (4.0)

25 (51.0)24 (49.0)

000

1.40 (0-19.8)

All patients, groups A+B randomized set; RC, reading center

Exclusion criteria

• Unstable medical status• Pan retinal photocoagulation performed within 6

months before study.• Grid/central laser photocoagulation Except for patients with only mild laser burns at least

1,000 µm from the center of the fovea performed > 6 months preceding day 1

Treatment adjustments:

Dose-doubling was performed under the following conditions:

• 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

1Kvanta et al. Invest Ophthalmol Vis Sci 1996; 37: 1929-19342Jonas & Neumaier. Ophthalmic Res 2007; 39: 139-142

Treatment adjustments (cont)

• Once the injection volume was increased to 0.6 ml, subsequent administrations remained at 0.6 ml (0.6 or 1.0 mg ranibizumab)

• If treatment had been withheld for 45 days, subsequent injections restarted with the initial injection volume of 0.3 ml or 0.5 ml.

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

• VA decreases by ≥5 letters and is <74 letters

At the investigator’s discretion:

Discontinue treatment if no borderline improvement after 3 consecutive injections

Borderline improvement defined as:-• Retinal thickness in study eye decrease ≥50 µm

and represents at least a 20% reductionor

• Increase in BCVA of ≥ 5 letters

Treatment adjustments: futility criteria

Treatment adjustments laser rescue

Criteria for laser rescue treatment after 3 consecutive monthly Ranibizumab / sham treatments

>10 letter decrease in BCVA at 2 consecutive visits ≥1 month apartand

The investigator does not consider the macula flat as assessed by OCT (defined as ≤225 µm).

Mean BCVA change

Mean BCVA change* from baseline (pooled dose data)

month

Mean CRT change

Mean CRT change* from baseline

Serious Adverse effects

Adverse effect

Conclusions - Efficacy

• The mean average change in BCVA from baseline to month 1 through 12 was statistically superior with ranibizumab (7.8 letters) compared with sham (-1.4 letters)

• The mean change in CRT from baseline to month 12 was significantly higher in the ranibizumab arm than in the sham arm (194.2 vs. 48.4 um).

Conclusions - safety

• The ocular SAEs in the study eye was comparable between the treatment arms ranibizumab: 3.9%

• Most of the SAEs were nonocular in origin in ranibizumab 13.7%.

• AEs was comparable between the ranibizumab 62.7%.

Author’s interpretation

• Ranibizumab led to significant and continuous improvements in both BCVA and CRT over 12 months compared with sham treatment in patients with VI due to DME.

• Future clinical trials are required to confirm its long-term efficacy and safety

My interpretation

• Well designed study• Sample size, randomization and base line

distribution were perfect• Financial biasness

Diabetic macular edema

Definition / Classification

ETDRS:– Thickening of the retina and/or hard exudates

within 1 disc diameter of the center of the macula

Retinal Edema = Increased thickening of the retinaIntracelullarExtracelullar

Epidemiology

1. Wild S et al. Diabetes Care 2004;27:1047–1053. 2. King H et al. Diabetes Care 1998;21:1414–1431. 3. Chen E et al. CMRO 2010;26:1587–1597. 4. RNIB and EpiVision. 2009; Future sight loss UK (2): An epidemiological and

Leading cause of visual impairment Prevalence of diabetes expected to approximately double

globally between 2000 and 2030 Number of diabetes cases estimated to reach 300 million

world wide by 2025 ˃50% of patients lose ˃2 lines of visual acuity within 2

years In the UK, prevalence of DME

– Estimated to be 187,842 in 2010– Expected to increase to 235,602 in 2020

Pathogenesis of macular oedema

• Vascular Endothelial Growth Factor ( VEGF) is released from ischemic retina

• Aqueous VEGF level remains elevated• VEGF 165 binds with VEGFR-1 & VEGFR-2 causes-

Loss of tight junction between endothelial cellsFormation of fenestration within endothelial cellsCalcium mediated permeability channel resulting in

loss of inner and outer blood-retinal barriers

• Thick Henles layer allows for more fluid to collect

• Avascularity of central area limits fluid absorption

• Thin basal lamina provides easy access to inflammatory products and toxins

OCT classification of DME

The first OCT-classification of DME (Otani et al.1999)is based on retinal morphological changes:

• Sponge-like swelling

• Cystoid oedema

• Serous retinal detachment

• Diffuse macular oedema

Classifications are presented by several authors

• Kang et al., 2004;

• Panozzo et al., 2004;

• Kim et al., 2006;

Sponge like retinal thickening

• Most common type

• Seen in 88% of eyes

• Responds to laser

Cystoid macular edema

• Seen in 47% of patients• Intra-retinal cystic

changes• Poor response to laser

• Diffuse macular edema

- Diffuse thickening without cysts

- Seen in 20.9 %

Serous retinal detachment

• Seen in 15% • May be associated with

retinal thickening or CME• Poor response to laser

Vitreo-macular traction syndrome

• Epiretinal traction• Thickened, taut hyaloid• ILM or epiretinal membrane • Management : PPV

Ischaemic Diabetic macular oedema

• Dot and blot heamorrhage

• Cottonwool spot• FA showis capillary drop

out or non perfusion at the macular area and elsewhere.

Clinically Significant Macular Edema (ETDRS)

Retinal thickening within 500 μm of the center of the

macula

.

Retinal thickening one disc area (1500 μm) or

larger, any part which is within

one disc diameter of the center of

the macula.

• Desislava Koleva-Georgieva (University Eye Clinic, University Hospital”St. George”, Bulgaria) proposed in 2012

• Summarizes from several quantitative and qualitative OCT data

• Classified based on:Retinal thicknessRetinal morphologyMacular traction and Foveal photoreceptor status

A. Retinal thickness:1. No macular edema2. Early subclinical macular edema –3. Established macular edema

C. Presence and severity of macular traction (incomplete PVD and/or ERM):1. No macular traction2. Questionable macular traction3. Definite macular traction B. Retinal morphology:

1. Simple non-cystoid macular edema 2. Cystoid macular edema

2.a. Mild cystoid macular edema 2.b. Intermediate cystoid macular edema 2.c. Severe cystoid macular edema

3. Serous macular detachment

D. Retinal outer layers integrity (IS/OS and ELM):1. IS/OS and ELM intact2. IS/OS and ELM with disrupted integrity

I. Retinal thickness:

1. No macular edema – normal macular morphology and thickness.

2. Early subclinical macular edema – no clinically detected retinal thickening on ophthalmoscopy, OCT measured retinal thickness.

3. Established macular edema – retinal thickening and evident morphological characteristics of oedema.

Simple non-cystoid macular edema Increased retinal thickness Reduced intraretinal reflectivity Irregularity of the layered structure Flattening of the foveal depression, without

presence of cystoid spaces

Cystoid macular edema Criteria of non-cystoid macular edema

+ intraretinal cystoid spaces

a. Mild cystoid macular edema –

cystoid spaces with horizontal diameter < 300μm

b. Intermediate cystoid macular edema –

cystoid spaces with horizontal diameter ≥ 300μm < 600μm

c. severe cystoid macular edema –

cystoid spaces with horizontal diameter ≥ 600μm,or large confluent cavities with retinoschisis appearance

3. Serous macular detachment –

• Any of the above, associated with

• Serous macular detachment hyper-reflective line of the pigment epithelium

IV. Presence and severity of macular traction (incomplete PVD and/or ERM):

1. No macular traction – Presence of complete PVD or no PVD and no ERM

2. Questionable macular traction –

Incomplete PVD with perifoveal or peripapillary adhesion and/or globally adherent ERM without detectable distortion of retinal surface contour at the points of adhesion

3. Definite macular traction –

Incomplete PVD with perifoveal adhesion and/or focal ERM with detectable distortion of retinal contour at the points of adhesion

V. Retinal outer layers integrity (IS/OS and ELM): IS/OS and ELM intact (fig. A); IS/OS and ELM with disrupted integrity (fig. B).

Treatment of DME

Systemic control• Metabolic control• Blood pressure control• DM control• Lipid lowering

Local control• Focal /Grid laser• IVTA /Ozudex• Ing Anti VEGF• Combination with

Vitrectomy.

Standard therapy

• Focal and/or grid laser• Recent trials: gain 0.9 letters to 3 letters

Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus lasermonotherapy for diabetic macular edema. Ophthalmology 2011; 118: 615–625

Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, Edwards AR et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema Ophthalmology 2010; 117: 1064–1077

Anti-VEGF

• Pegaptanib Sodium (Macugen)• Ranibizumab (Lucentis)• Bevacizumab (Avastin)

READ-2

126 patients, 1:1:10.5 mg Ranibizumab

at 0,1,3,5 months

Focal or grid laser at 0 and month 3

Combination of Ranibizumab and

laser at 0 and month 3

RESTORE studyTotal patient 345 > 18 years

Ranibizumab+

Sham lasern - 116

Ranibizumab+

lasern-118

Sham injection+

lasern -111

Meanaverage change in BCVA letter score from baseline to month 1 through 12

6.1 5.9 0.8

The mean central retinal thickness wassignificantly reduced from baseline

- 118.7 - 128.3 - 61.3

Conclusion: Ranibizumab alone or combined with laser were superior to laser monotherapy

RISE

RIDE

Inj. Bevacizumab in DME

BOLT

• Inj. Bevacizumab vs macular laser• Mean VA 20/50 vs 20/80 at 2 years• Gain of 9 letters vs 2.5 letters• Conclusions: provides evidence supporting

longer term use of Inj. Bevacizumab

IVTA

• IVB, Laser and 2 mg IVTA• 50 patients in each group

• Conclusions: Intravitreal bevacizumab injection in

patients with DME yielded a better visual

outcome at 24 weeks compared with macular

photocoagulation.

• No adjunctive effect of IVT was demonstrated

Conclusions

• The safety profile of Ranibizumab in patients with DME was similar to that reported in patients with AMD

• Ranibizumab is effective in improving BCVA , reducing CRT and well tolerated in DME.

Take Home Massage