Yong Meng Hsien Lecturer & Ophthalmologist, UKM & HCTM, Malaysia yongmenghsien@ppukm.ukm.edu.my Last edited: Feb 202

1. Studies/Trials in Ophthalmology
Dr Yong Meng Hsien
Lecturer & Ophthalmologist, UKM & HCTM
yongmenghsien@ppukm.ukm.edu.my
Last edited: Feb 2022

2. List @ Master Manual
• The Herpetic Eye Disease Study (HEDS)
• The Fluorouracil Filtering Surgery Study (FFSS)
• The Normal Tension Glaucoma Study (NTGS)
• The Ocular Hypertension Study (OHTS)
• The Glaucoma Laser Trial (GLT)
• The Optic Neuritis Treatment Trial (ONTT)
• The Ischemic Optic Neuropathy Decompression Trial (IONDT)
• Studies of the Ocular Complications of AIDS (SOCA)
• Branch Vein Occlusion Studies (BVOS)
• Central Vein Occlusion Studies (CVOS)
• Macular Photocoagulation Study (MPS)
• Age-Related Eye Disease Study (AREDS)
• Verteporfin in Photodynamic Therapy (VIP) Study
• Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP)
• Silicone (oil) Study
• The Submacular Surgery Trials (SST)
• The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP)
• Diabetes Control and Complications Trial (DCCT)
• Diabetic Retinopathy Study (DRS)
• Early Treatment Diabetic Retinopathy Study (ETDRS)
• Randomized Trial of Acetazolamide for Uveitis-Associated Cystoid Macular Edema
• Collaborative Ocular Melanoma Study (COMS)

3. CORNEA

4. Clinical Trials @ Cornea
• Herpetic Eye Disease Study (HEDS) I & II
• Collaborative Longitudinal Evaluation of
Keratoconus (CLEK) study
• Collaborative Corneal Transplantation Studies
(CCTS)
• Prospective Evaluation of Radial Keratotomy
(PERK) study
• Steroids for Corneal Ulcers Trial (SCUT)

5. HEDS I & II
• HSV stromal K → use topical steroid (pred 1% q3h and
taper) + topical anti-viral (aciclovir/trifluridine)
– No role of systemic aciclovir
– 400mg BD 1yr to reduce recurrence x 50%
• HSV iridocyclitis → use oral aciclovir (400mg 5x/day x
10/52)
• HSV epiT K → use topical antiviral only
– No role of oral aciclovir
– No to use topical steroid
• Trigerring factor → unsure (stress/CL/environment)

7. Zoster Eye Disease Study (ZEDS)
• prolonged suppressive oral antiviral
treatment with valacyclovir reduces
complications (eye disease and neuralgia
PHN)
• 1 year valacyclovir

8. Steroids for Corneal Ulcers Trial
(SCUT)
• 2012
• Corticosteroids used in conjunction with
antibiotics do not offer any difference in BCVA
at 3-month follow-up.
• No safety-related concerns

10. ACSIKS 2018
• 6626 eyes (>male in general + w trauma, >female w CL)
• Bacterial38% vs fungal 33% vs viral 13%
• Major risk (trauma 35% > CL 11% > prior ocular surgery
7% > ocular surface dz 4%))
• Fusarium 18% > Pseudomonas aeruginosa 11% >
Aspergillus flavus 8% > Strep pneumoniae 6%
• Cornea transplantation 46% failed
• Moderate visual impairment (<20/60) 54%
• ACSIKS Clinical Protocol
• ACSIKS Microbiological Protocol
• Study did not standardize the treatment

13. Glaucoma

14. Clinical Trials in Glaucoma
• Early Manifest Glaucoma Trial (EMGT)
• Collaborative Initial Glaucoma Treatment Study
(CIGTS)
• Ocular Hypertension Treatment Study (OHTS)
• Collaborative Normal Tension Glaucoma Study
(CNTGS)
• Advanced Glaucoma Intervention Study (AGIS)
• Glaucoma Laser Trial Follow up Study (GLTFS)
• Fluorouracil Filtering Surgery Study (FFSS)
• Tube versus trabeculectomy study (TVT)

15. EMGT
• Target: POAG/NTG
• Arm: Rx (betaxolol + ALT) VS No Rx
• Outcome- HVF (30-2) & OD progression (at least 4yr f/up)
• Results:
– reduce IOP 25% → less & later progression (45 vs 62%)
– 1mmHg lower IOP = 10% risk reduction
– low CCT is risk factor for progression
• RCT/255pt/1992-1997

16. CIGTS
• Target: POAG
• Arm: initial medical vs initial trabec
• Outcome: VA/IOP/VF, QoL
• Results:
– trabec & medication: same outcome
– trabec: better IOP (3point), more cupping reversal,
more delay progression
– trabec: more discomfort & more loss in VF & VA (only
1st 3yr), more need for cataract op
• RCT/607pt/1993-1997

17. OHTS
• Target: OHT (moderate risk)
• Arms: Rx vs no RX
• Outcome: IOP/OD/HVF (5yr)
• Results:
– risks: age/IOP/CDR/CCT/PSD
– reduce IOP 23% → reduce risk to POAG 60% (9.5
→ 4.4%)
– cataract op- reduce IOP 16%
• RCT/1637pt/1994-2009

18. CNTGS
• Target: NTG
• Arms: Rx (30% IOP reduction) vs No Rx
• Outcome: HVF/OD
• Results:
– No progression in 5yr: 80 vs 40%
– so, treat if evidence of progression
• RCT/145pt/1988

19. AGIS
• Target: advanced glaucoma (failed medications)
• Arms: TAT vs ATT
• Outcome: HVF/VA (7yr & 10yr)
• Results:
– black- ATT better (28 vs 37% in VA reduction in 7yr)
– white- TAT better in 7yr (although ATT better in 4yr)
– trabec- more cataract
– <18mmHg can prevent progression
• RCT/789eyes/1988-1992

20. GLTS/GLTFS
• Target: POAG (new)
• Arms: medication vs ALT
• Outcome: IOP/VA/VF/OD (7yr)
• Results:
– ALT as least as effective as medication
– ALT- better IOP reduction (1.2), better VF/OD
• RCT/271pt (1eye each arm)/1984-1987

21. FFSS
• Target: filtration surgery pt (high risk: aphakia or prev failed
trabec)
• Arms: No 5FU vs 5FU (post op)
– subconjunctival 5 mg BD POD 1-7 → OD POD 8-14
• Outcome: IOP & cornea, reoperation (5yr)
• Results:
– 5FU- more success (80 vs 60% in 1yr, 48 vs 21% in 5yr)
– 5FU- more late leak (9 vs 2%)
– Both: same VA/VF loss (5FU more in 1st mth post op only)
– extra: risk of suprachoroidal h’rge related to pre op IOP/post op
hypotony
• RCT/213pt/1985-1988

22. TVT
• multicenter prospective RCT
• Targets: patients with previous cataract extraction
and/or failed trabeculectomy.
• Arms: tube-shunt (350-mm2 Baerveldt) and
trabeculectomy with MMC
• Outcome: safety and efficacy
• Results:
– Tube-shunt surgery had a higher success rate than
trabeculectomy during 5 years of follow-up
– both have similar IOP reduction, use of supplemental
medical therapy, serious complications, and vision loss at 5
years

23. Ahmed Baerveldt Comparison (ABC) &
Ahmed Versus Baerveldt (AVB) Study
• both multicenter RCT designed to compare the
safety and efficacy
• Greater reductions in IOP and use of glaucoma
medical therapy were seen following Baerveldt
implantation at 3 months and thereafter
• Serious complications in the ABC Study and
hypotony-related vision-threatening
complications in the AVB Study occurred less
frequently with the Ahmed implant.

24. Others (glaucoma)
• Baltimore Eye Survey 1991
– African Americans 4-5x higher than whites for
OAG
• EAGLE

29. Retina

30. Clinical Trials in DR/DME
DR
• DCCT (T1DM), UKPDS (T2DM + BP)
• Diabetic Retinopathy Study (DRS 1971)
• Diabetic retinopathy vitrectomy study (DRVS 1976)
DR & DME
• Early Treatment Diabetic Retinopathy Study (ETDRS 1979)
• Diabetic Retinopathy Clinical Research Network (DRCR.net)
DME
• A Study of Ranibizumab Injection in Subjects with Clinically Significant
Macular Edema with Center Involvement Secondary to Diabetes
Mellitus (RISE and RIDE)
• Safety and Efficacy of Ranibizumab in Diabetic Macular Edema with
Center Involvement (RESOLVE)
• Ranibizumab monotherapy or combined with laser versus laser
monotherapy for diabetic macular edema (RESTORE)
• VEGF Trap-Eye in Vision Impairment Due to DME (VIVID/VISTA DME)

31. DM vs Cx
• Diabetes Control and Complication Trial (DCCT)
– T1DM
– tight control (HbA1c 7.2% vs. 9%) was associated with 76% reduction
in retinopathy, 60% reduction in neuropathy, and 54% reduction in
nephropathy.
• United Kingdom Prospective Diabetic Study (UKPDS)
– T2DM
– tight control (HbA1c 7% vs. 7.9%) was associated with 25% reduction
in microvascular disease.
– Additionally tight BP control (144/82 vs. 155/87) was associated with a
37% reduction in microvascular disease and 32% reduction in
diabetes-related deaths
– ACCORD & ADVANCE
– Too tight control/low HbA1c <6.0%- increase mortality
– Good control HbA1c <6.5%- reduce Cx nephopathy (ADVANCE),
retinopathy (ACCORD)

32. DRS
• PDR & PRP (vs sham)
• PRP reduced the risk of SVL by 50% in high risk
PDR
• Defined high risk PDR:
– NVD >/= 1/3 DD
– NVD <1/3 DD with VH/PRH
– NVE >/= ½ DD with VH/PRH

33. ETDRS (DR)
• DR & laser photocoagulation (vs sham)
• Scattered PRP → severe NDPR, low risk PDR
• Prompt PRP → high risk PDR
• Aspirin no role/effect

34. ETDRS (DME)
• 754 eyes with DME with focal/grid laser (VS sham)
• Results: focal/grid laser reduce moderate visual acuity loss by
approximately 50%
• Defined CSME:
– Retinal thickening/500μm
– Hard exudates/500μm/adjacent retinal thickening
– Retinal thickening/1DD distance/1DD size
• Treatable lesions (with FFA)
– Located between 500μm and 2DD
– discrete points of retinal hyperfluorescence or leakage
(microaneurysms)
– areas of diffuse leakage within the retina (microaneurysms, intraretinal
microvascular abnormalities or diffusely leaking retinal capillary beds)
– Large areas of hypofluorescence (significant retinal avascular zones)

35. DRCR.net
• Protocol A: Pilot Study of Laser Photocoagulation for Diabetic Macular Edema (DME)
73
• Protocol B: Randomized Trial Comparing Intravitreal Triamcinolone Acetonide (IVTA)
and Laser Photocoagulation for DME 74
• Protocol C: Temporal Variation in OCT Measurements of DME 75
• Protocol D: Evaluation of Vitrectomy for DME 76
• Protocol E: A randomized trial of peribulbar triamcinolone Acetonide (TA)
• with and without focal photocoagulation for mild DME—a pilot study 77
• Protocol F: Observational Study of the Development of DME Following
• Scatter Laser Photocoagulation 78
• Protocol G: Subclinical Diabetic Macular Edema Study 78
• Protocol H: Phase 2 randomized clinical trial of intravitreal
• Bevacizumab (IVB) for DME 79
• Protocol I: Laser-Ranibizumab-Triamcinolone Study for DME 80
• Protocol J: Laser-Ranibizumab-Triamcinolone Study for DME + PRP 81
• Protocol K: The Course of Response to Focal Photocoagulation for DME 82
• Other important conclusions of various DRCR.net studies 83

36. DME Studies
DME with RBZ
• Rise & Ride 2007
• Resolve 2005
• Restore 2008
– RBZ mono/laser mono/combine
• Retain/Respond/DRCR.net Protocol I/Novel?
DME with Eylea
• Vivid/Vista DME 2011
• DRCR.net Protocol T (Eylea vs RBZ- better@ baseline VA =/<6/18 at
1yr, but same at 2yr)
Others
• > injection > better maintain VA (AURA)
• Loading > non-load (AURA)
• Earlier 2wk = 1line gain (Denmark study)

38. Clinical Trials in RVO
• Branch Vein Occlusion Study (BVOS)
• Central Vein Occlusion Study (CVOS)
• Standard care vs. Corticosteroid for Retinal Vein occlusion study
(SCORE)
• Ranibizumab for the Treatment of Macular Edema Following
Branchretinal Vein Occlusion: Evaluation of Efficacy and Safety
(BRAVO)
• Central Retinal Vein Occlusion Study: Evaluation of Efficacy and
Safety (CRUISE)
• Global Evaluation of implantable dExamethasone in retinal Vein
occlusion with macular edema (GENEVA)
• Controlled Phase 3 Evaluation of Repeated intravitreal
administration of VEGF
• Trap-Eye In Central retinal vein occlusion: Utility and Safety
(COPERNICUS)
• General Assessment Limiting Infiltration of Exudates in Central
Retinal Vein Occlusion with VEGF Trap-Eye (GALILEO)

39. BVOS
• Target:
– I. BRVO + CFO >5DD
– II. BRVO + NVD/NVE
– III. BRVO + CMO VA 6/12 or worse
– *BRVO all 3-18mth
• Arms:
– scatter argon laser vs observe @ Grp I & II
– Grid laser @ Grp III
• Outcome:
– scatter laser reduced CFO → NVD/NVE
– scatter laser reduced NVD/NVE → VH
– scatter laser b4 NeoV or after NeoV → same outcome
– grid laser reduced VA loss in CMO
– natural history (>5DD CFO) → 40% neoV, → 60% VH
• multicenter (UK) RCT/500pt

40. CVOS
• Target:
– N: CRVO + CFO >9DD
– P: CRVO + CFO <10DD
– I: CRVO + ?CFO (extensive hrge)
– M: CRVO + CMO VA 6/15 or worse
• Arms:
– N: PRP/not
– P & I: natural history
– M: macular laser/not
• Outcome:
– N report: NVI risk factor x 4 (high CFO 10-30-75DD/large hrge/short
duration/Male), NVI response to PRP (better if laser naïve)
– P report (natural history): 16% converted ischemia at 4/12
– I report: majority become ischemic cases
– M report: macular laser not effective in VA (reduce angiographic CMO only)
• multicenter (UK) RCT/728eyes

41. BRAVO
• Target:
– CMO due to BRVO (VA 6/12 or worse, CMT >250)
• Arms
– RBZ 0.3/0.5mg/sham (6mth)
• Outcome
– RBZ 0.3/0.5mg improve VA/gain (60 vs 30%)
– also improve CMT (340 vs 160 um)
• multicenter RCT (US)/397pt

42. CRUISE
• Target:
– CMO due to CRVO (VA 6/12 or worsen, CMT >250)
• Arms
– RBZ 0.3/0.5/sham (x 6mth)
• Outcome
– RBZ 0.3/0.5 improve VA/gain (47% vs 16%)
– also improve CMT 440 vs 170 um
• multicenter RCT (US)/392pt

43. GENEVA
• Target:
– CRVO/BRVO with CMO
• Arms:
– Ozurdex 0.7mg
– Ozurdex 0.35mg
– sham
– +- Ozurdex 0.7mg aft 6/12 if VA/CMT not good
• Outcome:
– Ozurdex 0.7mg- faster, better VA improvement/CMT reduction,
repeatable with same efficacy aft 6mth
– cataract 30% at 1yr
– IOP increase 10mmHg 15% (majority at day-60)
• multicenter RCT/1256 pt

44. Eylea for CMO due to CRVO
• COPERNICUS (189pt) & GALILEO (177pt)
– Eylea 2mg mthly x 6 then PRN VS sham
– Eylea +improve VA/CMT

45. SCORE
• Triamcinolone for CMO due to RVO
• triamcinolone for CMO/BRVO = grid laser
• triamcinolone for CMO/CRVO > grid laser

46. RVO studies-summary
• CVOS: full PRP @NVI/NVA, No grid for CMO
• BVOS: scatter PRP @NVE, grid laser @CMO
• BRAVO & CRUISE: RBZ (6+PRN) improve VA/CMT
• CRUISE/HORIZON/RETAIN: RBZ (6+PRN till 12/24/48mth)
• SCORE: IVTA @CMO
• GENEVA: Ozurdex (IOP peak 2mth, 20%>6mth, cataract 70%
@6mth)
• COPERNICUS/GALILEO: Aflibercept (6+PRN, cross/no cross
over, early Rx better)
• New studies
– SCORE II: CRVO with CMO
• monthly RBZ vs Eylea x 6mth → Ozurdex as 2nd line
– LEAVO: CRVO with CMO
• RBZ vs Eylea

48. Clinical Trial in dry ARMD

49. ARMD- Studies: AREDS
• AREDS1
– high dose antioxidant/vitamin (B-carotene/vit C/Vit E/zinc 80mg-
copper 2mg) for risk reduction to advanced ARMD in 10yr
– reduce risk (25-30%) in pt >55yo with:-
• extensive intermediate drusen
• 1 large drusen
• GA/late ARMD
• AREDS2
– revised formula (zeaxantein 2mg/lutein 10mg/Vit C 500mg/Vit E
400IU/Zink 25mg +- copper)
– another 18% risk reduction for advance ARMD + reduce risk of B-
carotene (lung Ca in smoker- new/ex), high dose Zn (GI/GU
disease) + 33% reduce risk of cataract op
– but not useful for ppl with diet rich in Vit A

50. AREDS
• Age-Related Eye Disease Study (AREDS)
• the risk of progression to advanced AMD over
a 5-year
– early AMD (many small drusen or few
intermediate drusen) was 1 .3%.
– many intermediate or larger drusen was 1 8%
(more likely to show RPE abnormalities and
geographic atrophy or CNV)

52. AREDS
• randomized, clinical trial that enrolled 4757 patients at 1 1 centers
• to evaluate the effect of high-dose micronutrient supplements (treated a median of
6.5 years)
– Antioxidants
– vitamins (500 mg vitamin C, 400 IU vitamin E, and 1 5 mg beta carotene)
– Zinc (80 mg zinc oxide and 2 mg cupric oxide to prevent zinc- induced anemia)
• intermediate AMD (extensive intermediate or at least 1 large druse, or nonsubfoveal
geographic atrophy) or advanced unilateral AMD (vision loss due to AMD in 1 eye)
– 25% reduction of risk for progression to advanced AMD
– 1 9% risk reduction in rates of moderate vision loss (>/=3 lines of visual acuity) by 5 years.
• Subjects with no AMD or only early AMD (a few small drusen)- no benefit.
• Patients, but the treatment effect
• At 10 years, 44% of placebo recipients compared with 34% of the supplement
recipients had advanced AMD (a 27% risk reduction).
• There was no increased mortality among patients taking the AREDS formula.

53. AREDS Risk Classification

54. Beta carotene vs smoking
• Supplementation without beta carotene is preferable for patients
who smoke,
• Large clinical trials sponsored by the National Cancer Institute
demonstrated that beta carotene increases the risk of lung cancer
in current smokers. In these trials, most of the smokers were
heavy smokers.
• However the Physicians' Health Study, no evidence of increased
cancer risk was found in those randomly assigned to receive beta
carotene, but few participants were active smokers. Also, no
evidence was found of an increased risk of lung cancer in former
smokers.
• Based on these clinical trials, it is reasonable to expect that beta
carotene may slightly increase the risk of cancer, at least for
several years after cessation of smoking.

55. • Large population-based studies suggest that the xanthophylls
lutein and zeaxanthin,
• as well as omega-3 long-chain polyunsaturated fatty acids
(LCPUFAs: docosahexaenoic
• acid [DHA] and eicosapentaenoic acid [EPA] ) , may also help
reduce AMD progression
• Omega-3 p olyunsaturated fatty acids are found
• mainly in fish and nuts and have been shown to have anti-
inflammatory and possibly antiangiogenic
• properties. In AREDS, a 50% reduction in advanced AMD was
found in the
• group that had the highest consumption of omega-3 LCPUFAs
compared with the group
• that had the lowest

56. • The National Eye Institute is now administering AREDS2, a clinical trial that is fully
• enrolled with more than 4000 participants. The goals of this 5 -year study are to
examine
• the effects of high supplemental doses of dietary xanthophylls ( 1 0 mg lutein and 2
mg
• zeaxanthin) and omega-3 LCPUFAs on the development of advanced AMD; to study
the
• effects of these supplements on the development of cataract and moderate vision
loss; to
• examine the effects of eliminating beta carotene from the original AREDS
formulation on
• the development and progression of AMD; and to study the effects on the
development
• and progression of AMD of reducing the zinc component to 25 mg from the original
• AREDS formulation of 80 mg.

57. • Three population based studies; the Beaver
Dam Eye Study, Blue Mountain Eye Study and
the Rotterdam study reported the prevalence
rates to be 1.7% in US, 1.9% in Australia and
1.7% in Netherlands respectively

58. Clinical Trials in wetARMD
• Macular Photocoagulation Study (MPS)
• Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP)
• Verteporfin In Photodynamic Therapy (VIP)
• Visudyne in Minimally Classic Choroidal Neovascularization (VIM)
• Submacular surgery trials (SST)
• VEGF Inhibition Study in Ocular Neovascularization (VISION)
• Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal
Neovascularization in AMD4-6 (Anchor)
• MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in
the Treatment of Neovascular ARMD) Phase IIIb, Multi-center, Randomized, Double-
Masked, Sham Injection-Controlled
• Study of Efficacy and Safety of Ranibizumab in Subjects with Subfoveal CNV with or
without Classic CNV secondary to AMD (PIER)
• Efficacy and Safety of Ranibizumab inpatients with Subfoveal CNV secondary to
• AMD (EXCITE)
• Prospective Optical Coherence Tomography Imaging of Patients with Neovascular
AMD Treated with intra-Ocular Ranibizumab (PrONTO)
• Study of Ranibizumab in Patients with Subfoveal CNV Secondary to AMD (SUSTAIN)

59. • Phase III, double-masked, multicenter, randomized, Active treatment-controlled study
• of the efficacy and safety of 0.5 mg and 2.0 mg Ranibizumab administered monthly
• or on an as-needed Basis (PRN) in patients with subfoveal neOvasculaR
• age-related macular degeneration (HARBOR) 166
• Safety Assessment of Intravitreal Lucentis for AMD17,18 (SAILOR) 167
• Extension Trial of Ranibizumab for Neovascular Age-related Macular Degeneration19
• (HORIZON) 169
• Systemic bevacizumab (Avastin) Therapy for Neovascular Age–related macular
• degeneration (SANA) 171
• Avastin (R) (Bevacizumab) for Choroidal neovascularisation trial (ABC) 172
• Comparison of Age-related Macular Degeneration Treatments Trials (CATT) 174
• Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN) 177
• CALEAR-IT-2 Trial 179
• VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW 1 and 2) 181
• 10. Clinical Trials in Age-related Macular Degeneration-III 189
• RhuFab V2 Ocular Treatment Combining the Use of Visudyne to Evaluate Safety
• (FOCUS) 190
• PROTECT study 191

60. • TORPEDO trial 192
• SUMMIT trials 193
• Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular
degeneration: DENALI study 194
• Verteporfin plus ranibizumab for choroidal neovascularization in Age-related macular
degeneration: MONT BLANC study 195
• Reduced FluenceVisudyne-Anti-VEGF-Dexamethasone In Combination for AMD
Lesions (RADICAL) 198
• The Choroidal neovascularisation Secondary to AMD Treated with Beta Radiation
Epiretinal Therapy (CABERNET) 200
• Age-related Eye Disease Study (AREDS) 206
• Age-related Eye Disease Study 2 (AREDS 2) 209
• Complications of Age-related Macular Degeneration Prevention Trial (CAPT) 211

61. ANCHOR and MARINA trials
• IVT RBZ in wet ARMD for 2yr
• Loading dose of monthly injections for 3 months then
monthly
• Outcomes
– Gain of 15+ ETDRS letters: 40% 0.5 mg RBZ vs 10% sham
– Loss of < 15 ETDRS letters: 95% 0.5 mg RBZ vs 60% sham
– SEVEN-UP: 7yr follow up
– 50% still on anti VEGF
– 1/3 LOV =/>15letters/3lines
– Majority +exudates

62. PIER
• Failure study
• RBZ 0.3mg vs 0.5mg vs sham
• 3 + q3mth- outcome poorer than monthly
EXCITE
• RBZ: monthly VS quarterly
• Monthly better

63. Pronto
• PRN
• Limitation: small, no mask, single center, open
label
Harbour
• monthly vs PRN antiVEGF for CNV (50% with PED)
– vision gain same
– Use SD OCT

64. CATT & IVAN
- RBZ vs BCZ
- BCZ Not inferior to RBZ

65. VIEW 1 & VIEW 2
• Target
– sub/juxta-foveal CNV
• Arms
– Eylea 0.5mg q4
– Eylea 2mg q4
– Eylea 2mg (3 + Q8) **
– RBZ 0.5mg q4
• Outcome
– VA maintained at 1yr (<15letter loss) → all same 95-96%
– Year 2 need 4X PRN injection- all same
– anatomical improvement- equal
– adverse effect- equal
• Multicenter RCT/2419 pt/View 1 (canada/US), view 2
(europe/Asia)

66. VISION
• 70% of pegaptanib vs. 55% of sham injections
lose <15 letters of visual acuity at 1 year.
• On average, the patient during the first 2
years of treatment continues to lose vision,
although at a significantly slower rate.

67. Regime- summary
• Fixed monthly (RBZ)- Anchor/Marina/Excite
• Fix & q2mth (Eylea)- View1/2
• Fix & PRN (RBZ)- Pronto/Sustain/Harbour
• Fix & PRN (BCZ)- CATT/IVAN
• Treat & extend- LUCAS
• In CATT/Harbour
– 1-2 letters gain only with double the injection
– 8-9 letters vs 6-7 letters
– Monthly (23-24 inj) vs 3+PRN (12-13 inj) in 2yr

68. • classic (predominant/minimal/50% area)
(location:extra/juxta/subfoveal)
vs
• occult CNV (FV PED/LLUS)
• PDT for subfoveal predominantly classic CNV with
visual acuity of 6/60 or better
• Argon laser vs no Rx in CNV (extra/juxta/subfoveal)
– Severe vision loss (>5 lines) less in laser (but still 20-50%, vs
>50%), recurrence less (9 vs 37%)
ARMD- Studies: MPS

69. ARMD- Studies: TAP
• Treatment of AMD with photodynamic therapy (TAP)
study
• Target:
– Subfoveal, classic/predominantly classic CNV, ≤ 5400 μm
– VA between 6/12 and 6/60
• Arms
– PDT vs placebo
• Outcome (12 & 24mth)
– Stable (< 15 logMAR letters lost)/improved vision: PDT grp
>50%, placebo <50%
– > classic >better

70. ARMD Studies
• Verteporfin also shown to be effective in:
– CNV associated with pathological myopia & pure
occult CNV: Verteporfin in Photodynamic Therapy
(VIP) study
– Minimally classic CNV: Verteporfin in Minimally
Classic CNV (VIM) study

71. • Evidence for PDT in subfoveal CNV due to AMD
• Predominantly classic CNV (include classic with no occult)
• Treatment benefi t demonstrated in the TAP (Treatment of AMD with
• Photodynamic therapy) study is as follows:
• • TAP1: fewer than 15 letters lost in 67% vs. 39% at 1 year (p < 0.001)
• • TAP2: fewer than 15 letters lost in 59% vs. 31% at 2 years (p < 0.001)
• Minimally classic CNV
• There is emerging evidence for treatment benefi t in those cases where
• there is documented progression of lesion (ilesion size on FA or dVA).
• 100% occult CNV
• Treatment benefi t demonstrated (mainly for small lesions or worse VA)
• in the VIP (Verteporfi n in Photodynamic therapy) study was overall. The
• TAP study showed a trend toward benefi t.
• • VIP2: fewer than 15 letters lost in 45% vs. 32% at 1 year (p = 0.03);
• subgroup analysis suggests that the main benefi t is for smaller lesions
• (<4 disc areas) or worse VA (<20/50).
• • TAP2: fewer than 15 letters lost in 56% vs. 30% at 2 years (p = 0.06)

72. • Evidence for PDT in subfoveal CNV due to
myopia
• Treatment benefi t was overall; most lesions
were predominantly classic. It
• is unclear whether there is benefi t for
minimally classic or occult lesions.
• • VIP1: fewer than 8 letters lost in 72% vs.
44% at 1 year (p < 0.01)

73. SEVEN-UP VS Fight Retinal
Blindness (FRB) for GA
• SEVEN-UP: 65 patients (ANCHOR/MARINA/HORIZON) 
macular atrophy was affecting the centre of the fovea in
nearly 90% of cases, suggesting that this would eventually
happen to practically all patients on chronic VEGF
inhibition.
• FRB: 120 eyes for 7 years  GA cause of a 10- or greater
letter loss in only around 40% of eyes
• The mean VA decline from baseline was -8.6 letters for
SEVEN-UP compared to -2.6 letters for the FRB study, with
40% of FRB eyes achieving 20/40 or better, compared to
23% in SEVEN-UP.
• FRB with two or three times as many injections as
patients received in the final three years of SEVEN-UP

74. RIVAL
• The Comparison of Ranibizumab and Aflibercept for the Development of
Geographic Atrophy in (Wet) AMD Patients
• 12-month/140 patients/Aus
• Three markers of disease activity
– loss of visual acuity of more than five letters compared to the best visual
acuity recorded since treatment began;
– new retinal haemorrhage;
– presence of any intraretinal fluid or subretinal fluid on OCT.
• If one marker  injection interval was reduced by two weeks, and if
two or more  interval was back to four weekly injections
• Conclusion:
– Similar visual acuity improvements + same mean number of injections
• 1yr: 9.7 inj both
• 2 years: RBZ gain mean 6.6 letters, AFB 4.6 letters

75. Clinical Trials in IPCV
• Efficacy and safety of verteporfin
photodynamic therapy in combination with
ranibizumab or alone versus ranibizumab
monotherapy in patients with symptomatic
macular polypoidal choroidal vasculopathy:
EVEREST study
• SUMMIT
• PLANET

76. EVEREST 1 (part of SUMMIT)
• Target:
– symptomatic PCV
• Arms
– 1. PDT + RBZ
– 2. PDT alone
– 3. RBZ alone
• Outcome
– regression of polyp (ICGA) at 6mth → 78%/71%/30%
– VA change at 6mth → 11/7.5/9 letters
– Safety (none for all)
• Multicenter RCT/61 pt (Asian)
• Everest II (2yr outcome/end 2017)

77. SUMMIT
• DENALI + MONT BLANC + EVEREST
• DENALI (US canada) & MONT BLANC
(europe)- subfoveal CNV/wAMD
–RBZ alone vs RBZ/PDT → same benefit in BCVA
–DENALI RBZ/PDT half fluence → no benefit
• EVEREST- for IPCV in Asia

78. Everest II
• Combine (RBZ + PDT) vs mono (RBZ mono)
• Outcome
–Combine > mono
– VA 8 vs 5
– more polyp regression
– less inj needed 5 vs 7

79. PLANET
• Eylea +- rescue/deferred PDT

80. Indication Trial Summary
wAMD VIEW 1
and 2
Objective: Two similarly designed, phase-3 studies of neovascular age-related macular degeneration (AMD)
compared monthly and every-2-month dosing of intravitreal aflibercept injection
with monthly ranibizumab.
Main Outcome Measures: The primary end point was noninferiority (margin of 10%) of the aflibercept regimens to
ranibizumab in the proportion of patients maintaining vision at week 52 (losing [1]15 letters on Early Treatment
Diabetic Retinopathy Study [ETDRS] chart). Other key end points included change in best-corrected visual acuity
(BCVA) and anatomic measures.
Conclusions: Intravitreal aflibercept dosed monthly or every 2 months after 3 initial monthly doses produced
similar efficacy and safety outcomes as monthly ranibizumab. These studies demonstrate that aflibercept is an
effective treatment for AMD, with the every-2-month regimen offering the potential to reduce the risk from monthly
intravitreal injections and the burden of monthly monitoring.
DME VIVID/VIS
TA
Objective: A head-to-head comparison was performed between vascular endothelial growth factor blockade and
laser for treatment of diabetic macular edema (DME).
Main Outcome Measures: The primary efficacy endpoint was the change from baseline in best-corrected visual
acuity (BCVA) in Early Treatment Diabetic Retinopathy Study (ETDRS) letters at week 52. Secondary efficacy
endpoints at week 52 included the proportion of eyes that gained 15 letters from baseline and the mean change
from baseline in central retinal thickness as determined by optical coherence tomography.
Conclusions: At week 52, IAI demonstrated significant superiority in functional and anatomic endpoints over laser,
with similar efficacy in the 2q4 and 2q8 groups despite the extended dosing interval in the 2q8 group. In general,
IAI was well-tolerated.
DME Protocol T Objective: To provide 2-year results comparing antievascular endothelial growth factor (VEGF) agents for center-
involved diabetic macular edema (DME) using a standardized follow-up and retreatment regimen.
Main Outcome Measures: Change in VA, adverse events, and retreatment frequency.
Conclusions: All 3 anti-VEGF groups showed VA improvement from baseline to 2 years with a decreased number
of injections in year 2. Visual acuity outcomes were similar for eyes with better baseline VA. Among eyes with
worse baseline VA, aflibercept had superior 2-year VA outcomes compared with bevacizumab, but superiority
of aflibercept over ranibizumab, noted at 1 year, was no longer identified. Higher APTC event rates with
ranibizumab over 2 years warrants continued evaluation in future trials.
EYLEA Studies

81. CRVO GALILEO Objective: To evaluate the efficacy and safety of intravitreal aflibercept injections for treatment of macular edema
secondary to central retinal vein occlusion (CRVO).
Main Outcome Measures: The primary efficacy end point was the proportion of patients who gained 15 letters or
more in best-corrected visual acuity (BCVA) at week 24. This study reports week 52 results including the
proportion of patients who gained 15 letters or more in BCVA and the mean change from baseline BCVA and
central retinal thickness. Efficacy end points at week 52 were all exploratory.
Conclusions: Treatment with intravitreal aflibercept provided significant functional and anatomic benefits after 52
weeks as compared with sham. The improvements achieved after 6 monthly doses at week 24 largely were
maintained until week 52 with as-needed dosing. Intravitreal aflibercept generally was well tolerated.
BRVO VIBRANT Objective: To determine week 52 efficacy and safety outcomes in eyes with macular edema after branch retinal
vein occlusion (BRVO) treated with 2 mg intravitreal aflibercept injection (IAI) compared with grid laser.
Main Outcome Measures: The primary outcome measure was percentage of eyes with improvement from
baseline best-corrected visual acuity (BCVA) letter score 15 at week 24. All outcome measures at week 52 were
exploratory, and P values are considered nominal.
Conclusions: After 6 monthly IAI, injections every 8 weeks maintained control of macular edema and visual
benefits through week 52. In the laser group, rescue IAI given from week 24 onward resulted in substantial visual
improvements at week 52.
mCNV MYRROR Objective: To evaluate intravitreal aflibercept 2 mg in patients with myopic choroidal neovascularization (CNV).
Main Outcome Measures: Mean change in BCVA from baseline to week 24.
Conclusions: Intravitreal aflibercept 2 mg was effective for treatment of myopic CNV with clinically important
visual and anatomic benefits achieved with a limited number of injections given in the first 8 weeks of treatment.
No new safety concerns occurred with treatment. Intravitreal aflibercept should be considered as a treatment
option for
myopic CNV.

82. Clinical Trials in
Uveitis
• MUST

83. The Multicenter
Uveitis Steroid Treatment trial
• oral corticosteroids and immunosuppression produced
superior visual outcomes than a long-lasting regional
corticosteroid therapy approach (ie, the fluocinolone
acetonide implant)
– largely because of chorioretinal damage that occurred during
periods of uveitis relapse before a reimplant of the regional
therapy.
• Strategy of adequate immunosuppression to taper
prednisone to 7.5 mg/day or less, the systemic adverse
effects with the systemic approach were no greater than
with the regional approach, except for a greater use of
antibiotics for infections

84. Clinical Trials in
VR & Endophthalmitis
• EVS
• CEVE
• ESCRS
• Silicone (oil) study
• The Submacular Surgery trials (SST)

85. EVS
• Target:
– post cataract op (within 6wk) bacterial endophthalmitis
• Arms:
– 1. TPPV + IVT AB (Vanco 1mg/Amikacin 0.4mg)
– 2. AC & vitreous tap + IVT AB
– subgroup to IV AB (ceftazidime/amikacin) or no
– change group if no response aft 36H
• Outcome( VA & media clarity)
– if VA PL or worse → TPPV better (3x better chance (33%) to get VA better than 6/12
– If VA HM or better → both same
– IV AB or not → both same
• Outcome (microbiology)
– positive yield: vitreous tap = TPPV fluid > AC tap
– overall yield 70% → gram + (94%) & gram – (6%)
– CONS (Staphy epidermitis) > Staphy aureus > gram –ve > strep sp > enterococcus sp (worse
outcome in reverse order)
• Outcome (other factors)
– RD, RAPD/poor VA/loss red reflex
– wound abn/corneal infiltrate
– early onset 2/7 post op, DM (may consider TPPV)
• Multicenter RCT/1990-1995/420pt
• limitation: majority ECCE, only post cataract case, no IV quinolone/intracameral AB,
exclude NPL/media opaque pt

86. CEVE
• complete and early vitrec for endophthalmitis
• benefits:
– obtain sample
– increase oxygenation
– increase Ab absorption/penetration
– remove necrotic/microorganism

87. ESCRS document ‘Guidelines for prevention and treatment of
endophthalmitis following cataract surgery’ (2013)
• Povidone iodine 5% @ocular surface/5-10%
@periocular skin/min 3 minutes
• intracameral antibiotics at the end of cataract surgery
– cefuroxime (std vs resistance vs MRSA/MRSE)
– vancomycin (promote resistance)
• Pre-/post-op topical AB
– no clear benefit/induce resistance
• wound construction
• foldable IOLs, choice of IOL material and coatings
• surgical complications
• shift of microorganism: > enterococcus

88. Silicone Study
• Aim
– SO VS GAS (SF6/C3F8) in TPPV (1st/rpt- grp1/2) @RD with PVR
– effectiveness (attach) & Cx (VA/IOP/Keratopathy/macula pucker)
• Outcome
– general in 3yr → attachment/VA/corneal abn/macula pucker/glaucoma →
SO=C3F8 >SF6
• SO: if severe PVR esp PVR
• C3F8: if no intact capsule
– Rpt TPPV → slightly worsen outcome/>Cx, may need relaxing retinotomy +
SO/C3F8
– Risk
• high IOP in SO 5%, low IOP in gas 24%
• macula pucker 15% (without prior PVR)
• poor prognostic factor: rpt TPPV, ant PVR

89. Paediatric Ophthalmology

90. Congenital ET
• The Congenital Esotropia Observational Study showed that
when patients with a constant esotropia of at least 40∆
present after 10 weeks of age, the deviations are unlikely to
resolve spontaneously. Using this as a basis, some surgeons
suggest even earlier surgery, with the aim of achieving a
superior sensory outcome. Smaller angles can be
monitored, as they may improve spontaneously.
• European multicenter prospective study (ELISS) comparing
early versus delayed strabismus surgery showed only a
slight improvement in gross binocularity in the early-
surgery group (lower amount of suppression), but a higher
number of procedures were performed in the early-surgery
group to achieve outcomes similar to those of the delayed-
surgery group.

91. Infant Aphakia Treatment Study (IATS)
• Target: UL aphakia <1yo → CL vs IOL
• Outcome
– VA @1yo: same
– Cx (glaucoma) @ 1yo: same 10% risk, more in
PHPV/early op
– IOL +extra procedure,