RESOLVE STUDY , Journal presentation And discussion about Diabetic macular edema

1. Dr. Md. Mominul Islam
Fellow (Vitreo-Retina)
Ispahani Islamia Eye Institute And Hospital
Dhaka
Bangladesh

2. Received 15 March 2010 and accepted 8 August 2010.

3. 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:

4. 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)
Ranibizumab
0.5 mg (n = 51)
Increase to
1.0 mg if needed
After
1 month
Months 3–12
treatment 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

5. Study objectives and endpoints
Objective:
-- 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

6. 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

7. 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

10. Baseline demographics and
ocular disease characteristics
Age, years
Mean (range)
Gender, n (%)
Female
Male
Race, n (%)
Caucasian
Black
Asian
Other
DME type (RC), n (%)
Focal
Diffuse
Questionable
Cannot grade
Missing
Time since first DME diagnosis, years
Mean (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)
0
0
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)
0
0
0
1.40 (0-19.8)
All patients, groups A+B randomized set; RC, reading center

11. 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

12. 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: 1929-1934
2Jonas & Neumaier. Ophthalmic Res 2007; 39: 139-142

13. 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.

14. 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

15. 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% reduction
or
•Increase in BCVA of ≥ 5 letters
Treatment adjustments:
futility criteria

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

17. Mean BCVA change

18. Mean BCVA change* from baseline
(pooled dose data)
month

19. Mean CRT change

20. Mean CRT change* from baseline

22. Serious Adverse effects

23. Adverse effect

24. 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).

25. 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%.

26. 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

27. My interpretation
• Well designed study
• Sample size, randomization and base line
distribution were perfect
• Financial biasness

29. 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 retina
Intracelullar
Extracelullar

30. 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

31. 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 cells
Formation of fenestration within endothelial cells
Calcium mediated permeability channel resulting in
loss of inner and outer blood-retinal barriers

32. • 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

33. 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;

35. Sponge like retinal
thickening
• Most common type
• Seen in 88% of eyes
• Responds to laser

36. Cystoid macular
edema
• Seen in 47% of patients
• Intra-retinal cystic
changes
• Poor response to laser

37. • Diffuse macular
edema
- Diffuse thickening
without cysts
- Seen in 20.9 %

38. Serous retinal
detachment
• Seen in 15%
• May be associated with
retinal thickening or CME
• Poor response to laser

39. Vitreo-macular traction syndrome
• Epiretinal traction
• Thickened, taut hyaloid
• ILM or epiretinal membrane
• Management : PPV

40. Ischaemic Diabetic
macular oedema
• Dot and blot
heamorrhage
• Cottonwool spot
• FA showis capillary drop
out or non perfusion at
the macular area and
elsewhere.

41. Clinically Significant Macular Edema
(ETDRS)
Retinal thickening
within 500 μm of
the center of the
macula
Hard exudates at or
within 500 μm of
the center of the
macula (if associate
with retinal
thickening of the
adjacent retina
.
Retinal thickening
one disc area (1500
μm) or larger, any
part which is within
one disc diameter of
the center of the
macula.

43. • 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 thickness
Retinal morphology
Macular traction and
Foveal photoreceptor status

44. A. Retinal thickness:
1. No macular edema
2. Early subclinical macular
edema –
3. Established macular edema
C. Presence and severity of
macular traction (incomplete
PVD and/or ERM):
1. No macular traction
2. Questionable macular
traction
3. Definite macular tractionB. 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 intact
2. IS/OS and ELM with
disrupted integrity

45. 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.

46. 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

47. Cystoid macular edema
Criteria of non-cystoid macular edema
+
intraretinal cystoid spaces
a. Mild cystoid macular edema –
cystoid spaces with horizontal diameter < 300μm

48. 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

49. 3. Serous macular detachment –
• Any of the above, associated with
• Serous macular detachment hyper-reflective line of
the pigment epithelium

50. 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

51. 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

52. 3. Definite macular traction –
 Incomplete PVD with perifoveal adhesion and/or
focal ERM with detectable distortion of retinal
contour at the points of adhesion

53. 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).

54. 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.

55. 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

56. Anti-VEGF
• Pegaptanib Sodium (Macugen)
• Ranibizumab (Lucentis)
• Bevacizumab (Avastin)

58. READ-2
Combination of
Ranibizumab and
laser at 0 and
month 3
Focal or grid laser
at 0 and month 3
0.5 mg
Ranibizumab at
0,1,3,5 months
126 patients, 1:1:1

63. RESTORE study
Total patient
345 > 18 years
Ranibizumab
+
Sham laser
n - 116
Ranibizumab
+
laser
n-118
Sham injection
+
laser
n -111
Mean
average change in
BCVA letter score
from baseline to
month 1 through 12
6.1 5.9 0.8
The mean central
retinal thickness
was
significantly
reduced from
baseline
- 118.7 - 128.3 - 61.3
Conclusion: Ranibizumab alone or combined with laser
were superior to laser monotherapy

65. RISE

66. RIDE

67. Inj. Bevacizumab in
DME

69. 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

70. IVTA

72. • 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

75. 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.

76. Take Home Massage