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

Diabetic Retinopathy

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

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

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

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

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

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 )

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

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

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

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

AMD and CNV

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

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

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

The Photodynamic Thearpy (PDT) Era

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).

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.

The Anti-VEGF Era

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

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

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

Post-operative Endophthalmitis

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

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

Vein Occlusions

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)

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)

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

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

Retinopathy of Prematurity ROP

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

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

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

Herpetic Eye Disease

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

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

Choroidal Melanoma

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)

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

COMS Collaborative Ocular Melanoma Study COMS Small Choroidal Melanoma trial Small Apex 1-2.4 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

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