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QUESTION

I JUST CAN’T KEEP UP WITH ALL OF THE CLINICAL TRIAL ACRONYMS. CAN YOU TELL ME WHAT STUDY EACH REFERS TO?

A. Yasin Alibhai, MD
Nadia K. Waheed, MD, MPH

Many years of clinical research have provided ophthalmologists with valuable information on natural history and treatment strategies for common retinal diseases such as age-related macular degeneration (AMD), diabetic retinopathy, and retinal vein occlusion. The introduction of intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections approximately a decade ago brought about a paradigm shift in the management of some of these diseases; however, with the large number of clinical trials that have taken place in the last decade, it is often hard for the practicing ophthalmologist to keep up with the evidence base that guides our daily practice. In this chapter, we attempt to simplify and present outcomes from various landmark studies that have shaped the practice of retinal medicine as it stands today. Table 13-1 presents a summary of the clinical trials.

AGE-RELATED EYE DISEASE STUDY: The AREDS studies were multicenter, randomized clinical trials that looked at the effects of antioxidants and minerals on AMD progression. AREDS1 found that people with at least intermediate AMD or with advanced AMD (geographic atrophy or macular CNV) in one eye lowered their risk of progression to advanced AMD by about 25% when treated with a high-dose combination of Vitamin C, Vitamin E, beta-carotene, and zinc.1 AREDS2 found that omega-3 fatty acid supplementation to the original AREDS1 formulation provided no extra benefit, and that substitution of beta-carotene (associated with lung cancer in smokers) with lutein and zeaxanthin was safe and equally effective.²

ANCHOR AND MARINA

ANTI-VEGF ANTIBODY FOR THE TREATMENT OF PREDOMINANTLY CLASSIC CNV IN AMD AND MINIMALLY CLASSIC/OCCULT TRIAL OF THE ANTI-VEGF ANTIBODY RANIBIZUMAB IN THE TREATMENT OF NEOVASCULAR AMD: The ANCHOR and MARINA studies were 2 randomized, controlled, multicenter clinical trials that compared the efficacy of monthly intravitreal injections of the anti-VEGF drug Lucentis (ranibizumab) in the management of predominantly classic CNV and in minimally classic or occult CNV secondary to neovascular AMD, respectively.3,4 Patients were injected with monthly ranibizumab in the treatment arm and received photodynamic therapy (PDT) in the control arm. The ANCHOR study showed an improvement of greater than or equal to 15 letters of best-corrected visual acuity (BCVA) in up to 40% of the patients receiving ranibizumab compared to 5.6% who received PDT at 1 year. The MARINA study showed that almost 95% of patients in the ranibizumab treatment arm lost less than 15 letters at 1 year compared with 62.2% in the sham injection group. Patients receiving ranibizumab gained a mean of 7 letters compared with a loss of almost 10 letters in the control group. Consequently, ANCHOR and MARINA both proved to be landmark trials that provided strong evidence of the efficacy of ranibizumab for managing the entire spectrum of neovascular AMD.

PRONTO

PROSPECTIVE OCT IMAGING OF PATIENTS WITH NEOVASCULAR AMD: The PrONTO trial was one of the first as-needed trials in the anti-VEGF treatment of neovascular AMD. This was a prospective single center study that examined the efficacy of giving monthly intravitreal ranibizumab for the first 3 months followed by injections on an as-needed basis as determined on OCT.⁵ The trial followed 40 patients with CNV secondary to neovascular AMD for 2 years with monthly clinical evaluation and OCT imaging. Following the initial 3 injections, intravitreal ranibizumab was administered based on a drop in visual acuity and/or OCT findings suggestive of CNV activity. The study found that at 1 year, 82.5% of patients maintained baseline vision and 95% lost less than 15 letters (similar to MARINA and ANCHOR). The average number of injections given at months 12 and 24 were 5.6 and 9.9, respectively. Thus, the PrONTO trial demonstrated that using an OCT-guided variable-dosing regimen meant that patients could receive fewer intravitreal injections and still achieve visual outcomes comparable to patients receiving monthly injections as had been demonstrated in ANCHOR and MARINA.

CATT AND IVAN

COMPARISON OF AMD TREATMENTS TRIALS AND INHIBITION OF VEGF IN AGE-RELATED CNV TRIAL: The CATT (North America) and IVAN (UK) were 2 randomized, multicenter clinical trials that compared the safety and efficacy of Avastin (bevacizumab) to that of ranibizumab in treating neovascular AMD.^6,7 They also compared individualized dosing regimen (PRN) to monthly injections. At the 1- and 2-year analysis, bevacizumab was equivalent to ranibizumab for all visual acuity outcomes when comparing monthly or PRN regimens. Fixed monthly dosing with either drug resulted in a statistically significant but clinically small improvement of about 1.5 lines of visual acuity compared with PRN dosing. Incidence of geographic atrophy development was greatest in the monthly ranibizumab group. The results of both trials provided evidence that off-label bevacizumab was an effective alternative to ranibizumab in the treatment of wet AMD at the 1- and 2-year time-points.

VIEW 1 & VIEW 2

VEGF TRAP-EYE: INVESTIGATION OF EFFICACY AND SAFETY IN WET AMD: VIEW 1 (North America) and VIEW 2 (rest of the world) were 2 parallel, multicenter, randomized, controlled non-inferiority clinical trials that compared monthly Eylea (aflibercept) to monthly ranibizumab in the management of neovascular AMD.⁸ Both trials showed aflibercept was non-inferior to ranibizumab at maintaining visual acuity at 2 years. These results led to aflibercept gaining US Food and Drug Administration (FDA) approval.

SEVEN YEAR OBSERVATIONAL UPDATE OF MACULAR DEGENERATION PATIENTS POST-MARINA/ANCHOR AND HORIZON TRIALS: The SEVEN-UP study assessed long-term visual outcomes in patients who had participated in the ANCHOR, MARINA and HORIZON (An Open-Label Extension Trial of Ranibizumab for CNV Secondary to AMD) trials.9 The HORIZON study was an open-label extension trial, which included patients from ANCHOR and MARINA. The study’s authors reported that after a mean of 7.3 years from initially having enrolled into either ANCHOR or MARINA, only 37% of patients had a BCVA greater than or equal to 20/70. An equal number were found to have BCVA less than or equal to 20/200. These findings were attributed to undertreatment, development of fibrosis, and atrophy.

Clinical Trials in Diabetic Macular Edema and Diabetic Retinopathy

ETDRS

EARLY TREATMENT DIABETIC RETINOPATHY STUDY: The ETDRS was a multicenter, randomized clinical trial designed to investigate the effectiveness of laser treatment in diabetic retinopathy. More than 3700 patients were followed for a minimum period of 4 years. The ETDRS study is of great significance because it demonstrated conclusively the benefits of focal laser photocoagulation in treating what the authors defined as clinically significant macular edema.¹⁰ The study also showed that aspirin therapy had no effect on halting disease progression and that it was safe to use in patients with diabetic retinopathy who might require it for cardiovascular indications.¹¹

DRCRNET

DIABETIC RETINOPATHY CLINICAL RESEARCH NETWORK: The DRCRnet is a research consortium set up in 2002 that facilitates multicenter clinical research of diabetic retinopathy, DME, and associated conditions. With more than 8500 patients enrolled in multiple protocols, it has contributed valuable research in topics ranging from follow-up using OCT, use of anti-VEGF therapy, and management of complications.

Protocol B demonstrated that intravitreal triamcinolone, when used to treat DME, had a more rapid rate of onset compared to focal laser but had poorer visual outcomes at 2 years due to a higher incidence of cataract and elevated IOP.¹²

Protocol I determined that the addition of focal/grid laser treatment at the initiation of intravitreal ranibizumab therapy for DME involving the fovea was no better, and possibly worse, for visual outcomes at 5 years compared with deferred laser treatment for ≥ 24 weeks.¹³

Protocol T showed that anti-VEGF therapy for center-involving DME using either bevacizumab, ranibizumab, or aflibercept was an effective form of treatment. For patients with visual acuity at baseline of 20/40 or better, all 3 drugs showed similar efficacy at 1 and 2 years. In patients with baseline vision of 20/50 or worse, aflibercept demonstrated statistically superior efficacy to both ranibizumab and bevacizumab at 1 year, and aflibercept and ranibizumab both demonstrated statistically similar efficacy at the 2 years, both superior to bevacizumab. All 3 drugs showed visual gains at the 2 years and a decreased need for injections, follow-up visits, and laser treatment in the second year.¹⁴

Protocol S reported that intravitreal ranibizumab treatment for PDR was non-inferior to panretinal laser photocoagulation at 2 years. Patients receiving monthly ranibizumab gained more letters, required fewer vitrectomies, and had lower incidences of DME.¹⁵

A STUDY OF RANIBIZUMAB INJECTION IN SUBJECTS WITH CLINICALLY SIGNIFICANT MACULAR EDEMA WITH CENTER INVOLVEMENT SECONDARY TO DIABETES MELLITUS: These were 2 identical, multicenter clinical trials that evaluated the efficacy of monthly intravitreal ranibizumab for the treatment of center-involving DME.16 At 2 years, subjects in the 2 treatment arms of both trials reported significant gains in visual acuity (≥ 15 letters) compared to controls. Sub-analysis determined ranibizumab to be equally effective irrespective of baseline HbA1c levels. Those receiving ranibizumab were also noted to be less likely to progress to more advanced forms of diabetic retinopathy. A more recent report on the 2 trials suggested that ranibizumab slowed the progression of peripheral retinal nonperfusion in these patients with DME. The results of RISE and RIDE led to ranibizumab gaining FDA approval for the treatment of DME.

VIVID AND VISTA

INTRAVITREAL AFLIBERCEPT INJECTION IN VISION IMPAIRMENT DUE TO DME AND STUDY OF INTRAVITREAL AFLIBERCEPT INJECTION IN PATIENTS WITH DME: VIVID and VISTA were 2 identical, multicenter clinical trials that compared the efficacy of monthly and 2 monthly dosing regimens of aflibercept to macular laser therapy in treating eyes with center-involving DME.¹⁷ For the aflibercept arm, subjects initially received monthly injections for 5 months, followed by injections either every month or every 2 months. At 2 years, subjects receiving aflibercept (either regimen) had significantly better visual outcomes and decreased central foveal thickness on OCT when compared to those receiving macular laser. The FDA only approved the every 2 months dosing schedule of aflibercept for DME treatment as the monthly regimen did not show any additional benefit.

MEAD

A STUDY OF THE SAFETY AND EFFICACY OF A NEW TREATMENT FOR DME: The MEAD study was a randomized, multicenter trial that evaluated the safety and efficacy of 0.35 mg and 0.7 mg intravitreal Ozurdex implants (dexamethasone) compared to sham injections for the treatment of DME.¹⁸ At 3 years, patients in either of the treatment arms had significantly better visual acuity outcomes than those receiving sham injections, but the development of cataract and glaucoma was higher in the patients receiving the higher dose steroid implant. Patients in the treatment arms received an average of 4 to 5 injections over the entire 3-year period; however, those receiving steroid also had significantly higher rates of developing cataracts and elevated intraocular pressure (IOP) with around 10% in the 0.35 mg group, with less than 1% requiring glaucoma surgery. Following cataract surgery, patients had visual acuity improvements to better than baseline. As a result, the FDA-approved the Ozurdex implant for the treatment of DME, but limited its use to pseudophakic patients or in phakic patients scheduled to undergo cataract surgery.

FAME

FLUOCINOLONE ACETONIDE IN DME TRIAL: The FAME study evaluated the efficacy of long-acting intravitreal fluocinolone implants in patients with persistent DME who had previously undergone macular laser therapy.¹⁹ After 3 years, fluocinolone showed significant improvements in visual outcomes compared with those who received sham injections. Further analysis showed that fluocinolone implants slowed diabetic retinopathy progression and delayed the onset of PDR. The rates of progression were similar to those seen with anti-VEGF treatments, but with fewer injections being required (1.3 to 1.4 injections in 3 years vs 15 to 16 injections over 2 years). However, fluocinolone implants were associated with a high incidence of cataracts (90%), elevated IOP (61%), and need for glaucoma surgery (34%).

BRANCH VEIN OCCLUSION STUDY AND CENTRAL VEIN OCCLUSION STUDY: BVOS and CVOS were randomized, multicenter trials investigating the efficacy of grid-pattern laser photocoagulation for perfused macular edema secondary to BRVO and CRVO, respectively.20,21 The results of the BVOS showed that grid-pattern laser photocoagulation was effective in treating perfused macular edema due to BRVO; however, the CVOS results showed that visual outcomes for macular edema in eyes with CRVO treated with laser photocoagulation were not significantly different from untreated eyes.

BRAVO AND CRUISE

A STUDY OF THE EFFICACY AND SAFETY OF RANIBIZUMAB INJECTION IN PATIENTS WITH MACULAR EDEMA SECONDARY TO BRVO AND A STUDY OF THE EFFICACY AND SAFETY OF RANIBIZUMAB INJECTION IN PATIENTS WITH MACULAR EDEMA SECONDARY TO CRVO: The BRAVO and CRUISE studies were 2 Phase III clinical trials designed to investigate the efficacy and safety of ranibizumab injections in the treatment of macular edema secondary to BRVO and CRVO, respectively.^22,23 Subjects were randomized to receive either monthly ranibizumab or monthly sham injections for 12 months. Both trials showed that subjects who received ranibizumab showed a statistically significant improvement in visual acuity compared to subjects in the sham group.

SCORE

STANDARD CARE VERSUS CORTICOSTEROID FOR RETINAL VEIN OCCLUSION: The SCORE studies were 2 randomized, multicenter clinical trials designed to compare the safety and efficacy of intravitreal triamcinolone with standard of care in patients with macular edema secondary to CRVO and BRVO.^24,25 Subjects in both trials were divided into 1 of 3 groups: 2 groups received either 1 mg or 4 mg doses of triamcinolone and one group received standard clinical care (clinical observation in the CRVO trial and grid-laser in the BRVO trial). In the SCORE CRVO trial, 27% of subjects in the 1 mg group and 26% of subjects in the 4 mg group gained 15 letters or more compared with 7% in the observation only group after 12 months. In the SCORE BRVO trial, 29% of subjects in the grid-pattern laser treatment group, 26% in the 1 mg group, and 27% s in the 4 mg group gained 15 letters or more in vision at 1 year follow-up. The results of the SCORE CRVO trial were important because they showed that intravitreal triamcinolone was the first effective, long-term treatment option for CRVO patients with vision loss due to macular edema. The SCORE BRVO trial showed that while grid-laser and intravitreal triamcinolone had similar efficacy, grid-laser remains the treatment of choice in macular edema due to BRVO because of the high rates of cataract formation and elevated IOP associated with intravitreal corticosteroids.

GALILEO AND COPERNICUS

VEGF TRAP-EYE: INVESTIGATION OF EFFICACY AND SAFETY IN CRVO: These were 2 identical, randomized, multicenter trials that evaluated efficacy and safety of intravitreal aflibercept injections for treatment of macular edema secondary to CRVO.^26,27 Participants were randomized to receive either 6 monthly intravitreal injections of 2 mg aflibercept or sham injections. At the 6-month primary endpoint, 60.2% of patients in GALILEO and 56.1% in COPERNICUS receiving aflibercept gained 15 or more letters of vision compared with 22.1% and 12.3% of patients receiving sham injections, respectively. Results from both trials led to FDA approval of aflibercept treatment for macular edema secondary to CRVO.

STUDY TO ASSESS THE CLINICAL EFFICACY AND SAFETY OF INTRAVITREAL AFLIBERCEPT INJECTION IN PATIENTS WITH BRVO: The VIBRANT study was a randomized, multicenter clinical trial that compared the efficacy of aflibercept with grid-pattern laser treatment in treating macular edema following BRVO.28 In the trial, 53% of patients who received 2 mg aflibercept every 4 weeks gained at least 15 letters in vision from baseline at week 24, the primary endpoint of the study. This compared with 27% of patients in the laser treatment group who experienced similar gains in vision. Rates of serious adverse events were similar in both treatment groups (9.9% vs 9.8%). The results of VIBRANT showed aflibercept’s superiority over laser treatment in treating macular edema secondary to BRVO and thus led to aflibercept gaining FDA approval for this indication.

References

1.     Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Archives Ophthalmol. 2001;119(10):1417-1436.

2.     Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Archives Ophtahlmol. 2001;119(10):1439-1452.

3.     Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study. Ophthalmology. 2009;116(1):57-65.e55.

4.     Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431.

5.     Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol. 2009;148(1):43-58.e41.

6.     Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmol. 2012;119(7):1388-1398.

7.     Chakravarthy U, Harding SP, Rogers CA, et al. Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet. 2013;382(9900):1258-1267.

8.     Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537-2548.

9.     Rofagha S, Bhisitkul RB, Boyer DS, Sadda SR, Zhang K. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmol. 2013;120(11):2292-2299.

10.   Early Treatment Diabetic Retinopathy Study Research Group. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 2. Ophthalmology. 1987;94(7):761-774.

11.   Early Treatment Diabetic Retinopathy Study Research Group. Effects of aspirin treatment on diabetic retinopathy. ETDRS report number 8. Ophthalmology. 1991;98(5 Suppl):757-765.

12.   Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115(9):1447-1449, 1449 e1441-1410.

13.   Elman MJ, Ayala A, Bressler NM, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results. Ophthalmology. 2015;122(2):375-381.

14.   Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016;123(6):1351-1359.

15.   Gross JG, Glassman AR, et al; Writing Committee for the Diabetic Retinopathy Clinical Research Network. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial. JAMA. 2015;314(20):2137-2146.

16.   Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789-801.

17.   Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(11):2247-2254.

18.   Boyer DS, Yoon YH, Belfort R, Jr., et al. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121(10):1904-1914.

19.   Campochiaro PA, Brown DM, Pearson A, et al. Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology. 2011;118(4):626-635.e622.

20.   Branch Vein Occlusion Study Group. Argon laser photocoagulation for macular edema in branch vein occlusion. Am J Ophthalmol. 1984;98(3):271-282.

21.   Central Vein Occlusion Study Group. Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. The Central Vein Occlusion Study Group M report. Ophthalmology. 1995;102(10):1425-1433.

22.   Brown DM, Campochiaro PA, Bhisitkul RB, et al. Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study. Ophthalmology. 2011;118(8):1594-1602.

23.   Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6):1124-1133.e1121.

24.   Ip MS, Scott IU, VanVeldhuisen PC, et al; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Archives Ophthalmol. 2009;127(9):1101-1114.

25.   Scott IU, Ip MS, VanVeldhuisen PC, et al; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophtahlmol. 2009;127(9):1115-1128.

26.   Korobelnik JF, Holz FG, Roider J, et al. Intravitreal aflibercept injection for macular edema resulting from central retinal vein occlusion: one-year results of the phase 3 GALILEO Study. Ophthalmology. 2014;121(1):202-208.

27.   Heier JS, Clark WL, Boyer DS, et al. Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS study. Ophthalmology. 2014;121(7):1414-1420.e1411.

28.   Clark WL, Boyer DS, Heier JS, et al. Intravitreal Aflibercept for Macular Edema Following Branch Retinal Vein Occlusion: 52-Week Results of the VIBRANT Study. Ophthalmology. 2016;123(2):330-336.

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