1. Clinical Trials in Ophthalmology
Mohamed Soliman
PGY-2 Ophthalmology
LSUHSC Shreveport

2. Diabetic Retinopathy

3. ET DRS Early treatment Diabetic Retinopathy Study
Study Questions
Effectiveness of Photocoagulation DR and DME
Effectiveness of Asprin in preventing progresion of DR
Outcome Variables
SVL (Severe Visual Loss) : VA < 5/200 for at least 4 months
MVL (Moderate Visual Loss) : Doubling of Visual angle
Progression of DR

4. ET DRS Early treatment Diabetic Retinopathy Study
Results for Early Scatter Photocoagulation
Did not reduce the risk of SVL
Not indicated in Mild / Moderate NPDR
More effective for Type 2 DM
Mild NPDR
Moderate NPDR
Early PDR

5. ET DRS Early treatment Diabetic Retinopathy Study
Defined CSME as :
Retinal edema within 500 µm of center of macula
HE within 500 µm of center of macula if associated with thickening of adjacent retina
A zone of thickening larger than 1 DD if located within 1 DD of the center of the macula

6. ET DRS Early treatment Diabetic Retinopathy Study
Results for focal photocoagulation for DME
Decreased risk of MVL
Increased chance of visual gain
(halving of Visual angle)
Decreased retinal thickening

7. ET DRS Early treatment Diabetic Retinopathy Study
Results for Asprin
Did not alter progression of DR
Did not affect VA
Did not increase Vitreous Hemorrhage
Did decrease the risk of Cardiovascular Morbidity and mortality

8. DRS Diabetic Retinopathy Study
Study Question
Is Photocoagulation (argon or xenon arc) effective in treating DR
Eligibilty
PDR or Severe NPDR
Outcome variables
SVL ( VA < 5/200 )

9. DRS Diabetic Retinopathy Study
Results
Photocoagulation decreased the risk of SVL
Greatest benefit to High Risk PDR
Recommended prompt treatment
of “High Risk PDR”
Mild NVD + Vitreous Hemorrhage
Moderate NVE + Vitreous Hemorrhage
Mod/Severe NVD (1/4 – 1/3 NVD)
with or without Vitreous Hemorrhage
High Risk PDR
3 months after laser

10. DCCT Diabetes Control and Complications Trial
Study question
Will intensive control of Blood sugar (BS) in Type 1 DM slow the development of DR or slow its progression
Results
Intensive control of BS
Decreased risk of developing DR (76%)
Slowed progression of DR (54%)
Decreased risk of Neuropathy (60%) Albuminuria (54%)
But …
Early worsening of DR in 1st year
Increased risk of Hypoglycemic events

11. UKPDS United Kingdom Prospective Diabetes Study
Study Questions
Will intensive control of Blood Sugar (BS) in Type 2 DM decrease the microvascular complications of Diabetes
Will intensive control of Blood Pressure (BP) in Type 2 DM decrease the microvascular complications of Diabetes (including DR progression)
Results
Intensive control of BS slowed the progression of DR and decreased the risk of micro vascular complications
Intensive control of BP slowed the micro and macrovacular complications of DM

12. DVS Diabetic Vitrectomy Study
Objective
Natural course and effect of surgical intervention on severe PDR
Results
Type 1 DM with Dense Vitreous Hemorrhage (VH) and SVL in 1 eye :
Early Surgery (1-6 m after visual loss)
Type 2 DM with dense VH:
No difference between early and late vitrectomy
Note: Endolaser was not yet available during this study 1988 and microsurgical techniques have greatly improved so outcomes in PPV may be better than those reported in the DVS

13. AMD and CNV

14. AREDS Age-Related Eye Disease Study
Objective
To evaluate whether antioxidants
or zinc supplements can reduce
development or progression of AMD
Results
Patients with intermediate, dry AMD, or unilateral advanced AMD benefited from antioxidants and zinc supplementation with respect to vision loss and progression of AMD

15. MPS Macular Photocoagulation Study
Objective
Does laser treatment to leaking CNVs prevent significant visual loss compared to observation
Study design
Photocoagulation of Extrafoveal, juxtfoveal and subfoveal leaking CNVs
Outcome variables
Severe Visual loss (SVL) = loss of 6 or more lines, or quadrupling of the visual angle

16. MPS Macular Photocoagulation Study
Results
Laser decreased the risk of SVL in eyes with Extrafoveal and Juxtafoveal CNV (AMD,POHS and idopathic)compared to no treatment
In Subfoveal CNVs there was an initial drop in VA but after 1 year resulted in a decrease in SVL compared to observed eyes. Persistent or recurrent CNV was noted in 51% of lasered eyes in 24 months

17. The Photodynamic Thearpy (PDT) Era

18. TAP Treatment of AMD with PDT study
Objective
To determine if PDT with verteporfin
can reduce visual loss in patients with
subfoveal CNV
Results
Patients treated with PDT+Verteporfin sustained less MVL. This was mainly in seen in predominantly classic CNV (>50% of area is classic).

19. VIP Verteporfin in PDT Trial (AMD and Myopia)
Objective
To determine if PDT + Verteporfin can reduce visual loss in Patients with subfoveal CNV
Results
Decreased MVL and SVL
Note : PDT use has dropped significantly with the advent of pharmacotherapy, it may be used in combination with antiangiogenisis treatments.

20. The Anti-VEGF Era

21. VISION VEGF inhibition Study in Ocular Neovascularization
Objective
To determine if pegaptanib (Macugen) can reduce the risk of visual loss in subfoveal CNVs
Results
70% of patients lost < 3 lines
6% showed visual gain
Endophthalmitis after injection
(1.3 risk/patient/year)
Note: Use of this drug has dropped as newer antiangiogenesis agents have been developed

22. ANCHOR Anti-VEGF for the tretment of Predominantly Classic CNV in AMD
Objective
To determine if monthly intravitreal Ranibizumab (Lucentis) can reduce visual loss in patients with predominantly classic CNV 2ry to wet AMD
Study design
Patients were given Lucentis every month for 24 months and compared to PDT with verteporfin
Results
95% of patients given Lucentis maintained or improved their vision after 12 months
64% treated with PDT+ Verteporfin over 12 months

23. MARINA Minimally classic/Occult Trial of Ranibizumab in Neovascular AMD
Objective
To determine if monthly Ranibizumab (Lucentis) can reduce visual loss in Patients with occult Subfoveal CNV 2ry to wet AMD .
Study design
Patients were given Lucentis every 4 weeks for 24 months and compared to placebo
Results
95% of patients experienced visual improvement or stabilization after 12 months

24. Post-operative Endophthalmitis

25. EVS Endophthalmitis Vitrectomy Study
Objective
Evaluate the role of PPV and Intravenous antibiotics in post-operative bacterial endophthalmitis
Participants
Patients with bacterial endophthalmitis within 6 weeks of onset of infection
Study design
Patients randomized to systemic antibiotics or not, and to immediate PPV or to immediate tap/inject

26. EVS Endophthalmitis Vitrectomy Study
Results
Systemic Antibiotics not effective : No difference in VA whether or not systemic antibiotics (Amikacin/Ceftazidime) were employed
Tap/inject for better than LP vision : No difference in outcomes between PPV and tap/inject group for VA better than LP
Immediate PPV for LP vision: showed much better results
Note : Revolutionized treatment of post-cataract surgery endophthalmitis making it an office procedure of tap and inject for most eyes

27. Vein Occlusions

28. CVOS Central Vein Occlusion Study
Objective
To determine if grid laser improve VA with CRVO and perfused ME.
To determine if early PRP prevents NVI/NVA
Results
Grid laser treatment in the macula reduced FA evidence of macular edema, yet yielded no benefit in VA
(might be beneficial in younger patients with macular edema)

29. Most important risk factor for NVI is poor VA and larger areas of retinal capillary nonperfusion
PRP should be done after 2 clock hours of NVI
Prophylactic PRP does not decrease the incidence of NVI
(not done in clinical practice)

30. BVOS Branch Vein Occlusion Study
Objective
Can focal macular laser improve VA in BRVOs with ME and VA ≤ 20/40.
Can scatter laser prevent NV and VH in BRVOs.
Results
Improved VA after laser for ME with intact foveal vasculature and VA ≤ 20/40

31. BVOS Branch Vein Occlusion Study
Results
PRP to the area of nonperfusion caused regression of new vessels with retinal or disc neovascularization
Ischemia alone is not an indication for scatter laser
Patients should be observed for the development of neovascularization
Scatter laser reduced the risk of VH in eyes with recent BRVO that developed neovascularization

32. Retinopathy of Prematurity ROP

33. STOP-ROP Supplemental Therapeutic Oxygen for Prethreshold ROP
Objective
To test whether supplemental oxygen would decrease the progression from prethreshold to threshold disease.
Results
Supplemental oxygen did not cause further progression of prethershold ROP but also did not reduce the number of infants requiring ablative therapy
Oxygen increased the risk of adverse pulmonary events

34. CROP Trial of Cryotherapy for ROP
Objective
To determine if Cryotherapy to the
peripheral avascular retina in severe
ROP prevented cicatricial changes and RD.
Results
Cryotherapy to the avascular anterior retina in ROP eyes with thershold disease showed a reduction by half in unfavourable outcomes at 1 year
Threshold disease
Zone 1 or Zone 2
Stage 3 (5 contiguous or 8 total clock hours)
With plus disease
At 10 years eyes that received Cryotherapy were still much less than control eyes to be blind

35. ET-ROP Early Treatment for Retinopathy of Prematurity Study
Determined that earlier laser therapy can improve visual and anatomic outcomes in ROP
Recommended laser therapy for
Type 1 Prethreshold disease
Zone 1 with plus disease
Zone 1 with stage 3
Zone 2 , stage 2/3 with plus Disease
Implied treating an additional
50% more patients than with CROP guidlines

36. Herpetic Eye Disease

37. HEDS Herpetic Eye Disease Study
Objective:
To evaluate the efficacy of topical steroids and oral acyclovir in treating HSV stromal keratitis and iridocyclitis in conjunction with topical trifluridine (Viroptic).
Results
Do topical steroids treat stromal keratitis ?
Yes. They treat stromal inflammation
and shorten the duration of keratitis

38. HEDS Herpetic Eye Disease Study
Question and Answer
Is oral acyclovir helpful in:
A) treating stromal keratitis
(in addition to trifluridine and steriods)…………….. No
B)treating HSV iritis ……………………………….…..Not sure. Probably
C)prevent development of Stromal keratitis
and iritis in patients with epithelial keratitis…….… No
D)prophylaxis against HSV recurrences……………...Yes

39. Choroidal Melanoma

40. COMS Collaborative Ocular Melanoma Study
COMS large Choroidal Melanoma trial
Large Apex > 10 Base >16
Compared Enucleation alone to
Enucleation preceeded by External beam RT
Results
Established appropriateness of primary enucleation alone (RT did not improve overall survival)

41. COMS Collaborative Ocular Melanoma Study
COMS Medium Choroidal Melanoma trial
Medium Apex <10 Base <16
Compared Standardized enucleation
and brachytherapy (iodine 125)
Results
Enucleation
Brachytherapy
All cause mortality
18%
19%
Metastasis at 5 y
11% 9%
Other complications
Misdiagnosis in 0.3% of cases
Decline in VA to 20/200 in 3 years

42. COMS Collaborative Ocular Melanoma Study
COMS Small Choroidal Melanoma trial
Small Apex Base 4-8
Observational study for small tumors
Melanoma specific mortality 1 % at 5 y
Clinical Risk factors:
-Greater initial thinckness
-presence of orange pigment
-absence of Drusen &/or RPE changes

43. Audio-Visual tour