This document summarizes several landmark clinical trials related to diabetic retinopathy. It discusses trials evaluating metabolic control like the DCCT and UKPDS, laser photocoagulation trials like DRS and ETDRS, vitrectomy trials like DRVS, and recent anti-VEGF trials. It also summarizes protocols from the Diabetic Retinopathy Clinical Research Network evaluating treatments for diabetic macular edema and proliferative diabetic retinopathy.

1. DIABETIC RETINOPATHY
TRIALS
MODERATOR: DR.LAVANYA

2. DR TRIALS
METABOLIC CONTROL
DCCT
UKPDS
PHOTOCOAGULATION
DRS
ETDRS
VITRECTOMY
DRVS
INTRAVITREAL
INJECTIONS DRCR.NET
PROTOCOL A
I S T

3. DR TRIALS
METABOLIC CONTROL
DCCT
UKPDS
PHOTOCOAGULATION
DRS
ETDRS
VITRECTOMY
DRVS
INTRAVITREAL
INJECTIONS DRCR.NET
PROTOCOL A

4. METABOLIC CONTROL
DIABETES CONTROL AND COMPLICATIONS TRIAL (DCCT)
• Examined whether intensive treatment with the goal of maintaining
blood glucose concentrations close to normal range could decrease
the frequency and severity of complications of DM
• To assess the effect of tight glycaemic control on complications of
diabetes (nephropathy, neuropathy and diabetic retinopathy) for
persons with Type 1 DM

5. Study pattern: Type 1 DM
With no retinopathy
Urine albuminuria <40
Intensive treatment
Conventional
treatment
With mild to moderate NPDR
Urine albuminuria <200
Intensive treatment
(Insulin pump or >3 insulin dose per day
Frequent RBS monitoring)
Conventional treatment
(1 or 2 insulin dose per day)
2 GROUPS
RANDOMIZED

6. Type 1 DM
With no retinopathy
Urine albuminuria <40
Intensive treatment
REDUCE 76%
PROGRESSION OF
DR
With mild to moderate NPDR
Urine albuminuria <200
Intensive treatment
(Insulin pump or >3 insulin dose per day
Frequent RBS monitoring)
REDUCE
- PROGRESSION OF DR 54%
- PDR / SEVERE NPDR 47 %
2 GROUPS
RANDOMIZED

7. Conclusion
• Intensive therapy effectively delays onset and slows progression of
microvascular complications of diabetes – DR, nephropathy and
neuropathy in patients with Type 1 DM

8. 1. To determine whether the risk of microvascular complications in
type 2 diabetes can be reduced by intensive blood glucose control.
2. In patients with high blood pressure, to determine whether the risk
of complications can be reduced by tight control of blood pressure.
UNITED KINGDOM PROSPECTIVE DIABETES STUDY (UKPDS)

9. Result
• For every percentage point decrease in HbA1C (e.g.9% to 8%), there
was a 35% reduction in the risk of microvascular complications of
disease
• More intensive blood pressure control resulted in a 37% reduction in
microvascular complications of DM

10. DR TRIALS
METABOLIC CONTROL
DCCT
UKPDS
PHOTOCOAGULATION
DRS
ETDRS
VITRECTOMY
DRVS
INTRAVITREAL
INJECTIONS
RESOLVE
RESTORE
RISE and RIDE
DRCR.NET
PROTOCOL A TO E

11. LASER PHOTOCOAGULATION
DIABETIC RETINOPATHY STUDY (DRS)
laser photocoagulation – introduced in 1959
Inadequate evidence of actual value of laser photocoagulation
DRS started in 1971
PURPOSE
1.To determine whether laser photocoagulation helps to prevent severe
visual loss from PDR
2.To determine whether a difference exists in the efficacy and safety of argon
versus xenon photocoagulation for PDR

12. Study Pattern
randomized
Photocoagulation (both argon &
xenon) reduced risk of visual loss by
50 % or more compared with no
treatment
Severe vision loss (5 year rate)
reduced from 50% without
treatment to 20% with treatment.
The study identified a stage of
retinopathy, termed high-risk
PDR, where the benefits of
photocoagulation definitely
outweighed the risks
Argon = xenon ,in efficacy
But Argon is safer than Xenon

13. CONCLUSION
laser photocoagulation inhibited the progression of retinopathy.
Thus eyes with high-risk PDR should receive prompt treatment with
PRP.

14. EARLY TREATMENT DIABETIC RETINOPATHY STUDY (ETDRS)
• DRS – Speaks only about PDR ,,,,,,,, IT DID NOT
• Clarify role of Laser photocoagulation in NPDR and early PDR
• ETDRS – Purpose
1. To evaluate the effectiveness of argon laser photocoagulation in delaying or
preventing progression of early diabetic retinopathy to more severe stages of
visual loss and blindness.
2. To determine if photocoagulation is effective in the management of diabetic
macular edema.
3.To evaluate the effectiveness of aspirin treatment in altering the course of
diabetic retinopathy.

15. Study design
GROUP 1
GROUP 2
GROUP 3

16. Group 1
Subsequent analyses of
ETDRS data suggest that,
patients with severe NPDR to
early PDR , the benefit of
treatment is greater in those
who have type 2 diabetes and
older than 40 years of age

18. ‘Clinically significant
macular edema’ ,
ETDRS Classification of
DR are coined to
designate this level of
severity
Group 2

19. Group 3

20. Laser Photocoagulation
should be deferred for
eyes with mild to
moderate NPDR.
As the retinopathy
progresses to the severe
nonproliferative or early
proliferative stage, scatter
treatment should be
considered, especially for
patients with TYPE-2
DM and old age.
Conclusion :
GROUP -1

21. Focal/grid photocoagulation should be
considered for eyes with CSME
GROUP 2
Fluorescein leakage – not a
sufficient indication for laser
treatment in absence of CSME.
Observe at 4 monthly intervals

22. DR TRIALS
METABOLIC CONTROL
DCCT
UKPDS
PHOTOCOAGULATION
DRS
ETDRS
VITRECTOMY
DRVS
INTRAVITREAL
INJECTIONS
RESOLVE
RESTORE
RISE and RIDE
DRCR.NET
PROTOCOL A TO E

23. DIABETIC RETINOPATHY VITRECTOMY STUDY (DRVS)
Purpose:
1. To compare early vitrectomy versus conventional management for recent severe
vitreous hemorrhage secondary to diabetic retinopathy
2. To compare early vitrectomy and conventional management in eyes that have
good vision but a poor prognosis because they are threatened with hemorrhage
or retinal detachment from very severe PDR

24. SEVERE VISION LOSS
DUE TO VH
Randomized
Early
Vitrectomy
Conventional
management
Medical management
(vitrectomy was carried out 1 year
later if hemorrhage persisted (or) if
retinal detachment involving the
center of the macula )
SEVERE PDR IN EYES
WITH USEFUL VISION
Randomized
Early
Vitrectomy
Conventional
management
laser photocoagulation if needed ,
vitrectomy was carried out 6 months
later if hemorrhage persisted (or) if
retinal detachment involving the
center of the macula
PDR
GROUP 1
GROUP 2

25. SEVERE VISION LOSS DUE TO
VH
Randomized
Early Vitrectomy
Recovery of
Good vision –
50% / 25%
Conventional
management
Recovery of Good
vision –
17 % /15%
SEVERE PDR IN EYES WITH USEFUL
VISION
Randomized
Early Vitrectomy
Recovery of
Good vision –
44%
Conventional
management
Recovery of
Good vision –
28%
PDR
GROUP 1
GROUP 2
The advantage was more apparent in type 1
diabetics who were younger
1 / 2 Year
follow up

27. CONCLUSION
• For eyes with recent severe vitreous hemorrhage early vitrectomy provided a greater chance
of prompt recovery of visual acuity
• The benefits are more pronounced for patients with type 1 diabetes
• The study recommended early surgery in eyes with useful vision and advanced active PDR

28. DR TRIALS
METABOLIC CONTROL
DCCT
UKPDS
PHOTOCOAGULATION
DRS
ETDRS
VITRECTOMY
DRVS
INTRAVITREAL
INJECTIONS DRCR.NET
PROTOCOL A TO E

29. INTRAVITREAL
INJECTIONS
RESOLVE
RESTORE
RISE and RIDE
BOLT
DA VINCI
VISTA
VIVID
RANIBIZUMAB BEVACIZUMAB AFLIBERCEPT

30. INTRAVITREAL
INJECTIONS
RESOLVE
RESTORE
RISE and RIDE
BOLT
DA VINCI
VISTA
VIVID
RANIBIZUMAB BEVACIZUMAB AFLIBERCEPT

31. RANBIZUMAB
RESOLVE
Safety and Efficacy of Ranibizumab in Diabetic Macular Edema with
Center Involvement (RESOLVE)(2005)
Purpose
To investigate the safety and efficacy of RBZ in DME involving the foveal centre
3 monthly injection

32. At 12 month
end, in ETDRS
Chart
Gain of ≥ 10 letters BCVA from
baseline
RBZ- 60.8%
Sham-18.4%
Conclusion
RBZ is effective in improving BCVA and is well
tolerated in DME
Future clinical trials are required to confirm its
long term efficacy and safety

33. A Study of Ranibizumab Injection in Subjects with Clinically Significant Macular Edema
with Center Involvement Secondary to Diabetes Mellitus (RISE and RIDE)(2007-2010)
Purpose
To evaluate the safety and efficacy of intravitreal RBZ in DME patients

34. RISE RIDE
RANDOMIZED
MONTHLY INJECTION
AT THE END OF 24 MONTHS, 15 LETTERS GAIN IN ETDRS CHART FROM BASELINE BCVA

35. RISE RIDE
RANDOMIZED
> 15 LETTERS GAINED IN ETDRS CHART

36. Ranibizumab Monotherapy or Combined with Laser Versus Laser Monotherapy for
Diabetic Macular Edema(RESTORE)(2008)
Purpose
• To demonstrate superiority of RBZ 0.5 mg monotherapy or combined with laser over laser
alone based on change in BCVA over 12 months in DME

37. AT 12 MONTH,
BCVA letter score ≥ 15
BCVA letter score level
>73(20/40)
Conclusion
RBZ monotherapy and combined with
laser provided superior visual acuity
gain over standard laser

38. INTRAVITREAL
INJECTIONS
RESOLVE
RESTORE
RISE and RIDE
BOLT
DA VINCI
VISTA
VIVID
RANIBIZUMAB BEVACIZUMAB AFLIBERCEPT

39. A Prospective Randomised Trial of Intravitreal Bevacizumab or Laser
Therapy in the Management of Diabetic Macular Edema (BOLT)
• Purpose
To compare repeated intravitreal bevacizumab(IVB) and modified
ETDRS macular treatment therapy(MLT) in patients with persistent
CSME

40. DME
IVB 1.25mg
8 letters
improvement
CMT
CMT-
507µm(baseline)
to 378µm
Mod. ETDRS LT
0.5 letter improvement
481µm to 413µm
ETDRS CHART
AT THE END OF 1
YEAR

41. INTRAVITREAL
INJECTIONS
RESOLVE
RESTORE
RISE and RIDE
BOLT
DA VINCI
VISTA
VIVID
RANIBIZUMAB BEVACIZUMAB AFLIBERCEPT

42. 1. DA VINCI (DME and VEGF Trap eye : investigation of clinial impact)
2. VISTA (VEGF Trap – Eye in vision impairment due to DME)
3. VIVID
• Purpose
To compare different doses and dosing regimens of VEGF Trap-Eye
with laser photocoagulation in eyes with DME
RESULT
Intravitreal VEGF Trap-Eye a statistically significant and clinically
relevant improvement in visual acuity when compared with macular
laser photocoagulation in patients with DME

43. DR TRIALS
METABOLIC CONTROL
DCCT
UKPDS
PHOTOCOAGULATION
DRS
ETDRS
VITRECTOMY
DRVS
INTRAVITREAL
INJECTIONS DRCR.NET
PROTOCOL A
I, S, T

44. Diabetic Retinopathy Clinical Research Network(DRCR.net)
DRCR.net is a collaborative network dedicated to facilitating multicenter clinical research of diabetic
retinopathy, diabetic macular edema and associated conditions
Formed in September 2002
Funded by the National Eye Institute (NEI), a part of National Institutes of Health

45. Protocol A: Pilot Study of Laser Photocoagulation for Diabetic Macular Edema
• Purpose
To compare 2 laser photocoagulation techniques for treatment of DME
• Modified ETDRS technique
• Mild macular grid(MMG) technique

47. • Conclusion
MMG technique was less effective at reducing retinal thickening than mETDRS technique
VA outcome with both approaches was not considerably different
• Application in clinical practice
Modified ETDRS photocoagulation should continue as a standard approach for treating DME

48. Protocol I:Laser-Ranibizumab-Triamcinolone Study for DME
• Purpose
To evaluate intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined
with focal/grid laser compared with focal/grid laser alone for treatment of DME
• Conclusion
Intravitreal RBZ with prompt or deferred laser is more effective at 2 year
compared with prompt laser alone for the treatment of DME involving the central
macula
In pseudophakic eyes, intravitreal triamcinolone + prompt laser seem more
effective than laser alone but frequently increase the risk of IOP elevation

49. Protocol S: Panretinal Photocoagulation vs Intravitreal
Ranibuzumab for Proliferative Dibaetic Retinopathy
• Outcome: VA at the end of 2 year
• Conclusion : Ranibuzumab was not inferior to PRP in PDR at 2 years

50. Protocol T: Aflibercept, Bevcizumab, or Ranibizumab for
Diabetic Macular Edema
• Purpose
To assess the relative efficacy and safety of intravitreous Aflibercept, Bevcizumab
and Ranibizumab in the treatment of Diabetic Macular Edema
• Conclusion
At the end of 2 years,
When the initial visual acuity loss was mild there was no apparent differences
among the study groups
At worse levels of initial visual acuity ( 20/50 or worse) aflibercept was more
effective at improving vision

51. • THANK YOU