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Neovascular age-related macular degeneration (AMD) is the leading cause of blindness in industrialized countries.1 4 Over the past decade, major advancements have occurred in the understanding, diagnosis, and treatment of this disease, with a much improved visual prognosis.5 Several drugs have been approved for the treatment of neovascular AMD, including pegaptanib,6,7 ranibizumab,8 11 and aflibercept.12,13 In addition, bevacizumab commonly is used off label.14 Although these treatments provide patients with impressive benets in terms of visual acuity (VA), all require regular intravitreal injections, and they generally suppress rather than eliminate disease activity. Ionizing radiation can damage the ability of vascular endothelial cells to divide and reproduce, can induce genetic
2013 by the American Academy of Ophthalmology Published by Elsevier Inc.
mutations, can impair cellular function, and ultimately can lead to cell death.15 As replicating tissue is more susceptible to the effects of radiation than nonreplicating tissue, choroidal neovascular lesions, which consist of proliferating endothelial cells, are more sensitive to radiation treatment than normal nonproliferating capillary endothelial cells and larger vessels.16 Replicating human endothelial cells in culture are affected by radiation doses as low as 6 Gy, with complete inhibition of growth at 8.7 Gy.17 Radiation also can target proliferating inammatory and broblastic cells, both of which contribute to AMD disease activity and progression.18 External beam therapy, or teletherapy, was introduced as a treatment for neovascular AMD in 1993.19 Since
ISSN 0161-6420/13/$see front matter http://dx.doi.org/10.1016/j.ophtha.2012.07.068
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Participants
Participants were men and women 50 years of age or older diagnosed with subfoveal CNV associated with neovascular AMD, conrmed by uorescein angiography (FA). The ETDRS bestcorrected VA (BCVA) had to be from 69 to 24 letters (20/40 20/ 320 Snellen equivalent). One eye per participant was deemed the study eye. If the participant had bilateral disease and both eyes were eligible, then the eye with the worse VA was treated. Participants with predominantly classic, minimally classic, or occult subtype CNV lesions with a total lesion size (including blood, scarring, and neovascularization) of less than 12 total disc areas (21.24 mm2) and a greatest linear diameter of 5.4 mm or less were eligible. Minimally classic and occult lesions had to have evidence of presumed recent disease progression, dened as the presence of subretinal hemorrhage, subretinal uid, lipid, or a combination thereof; or loss of at least 1 line of VA (ETDRS or equivalent) during the previous 6 months; or FA-documented lesion growth by 10% or more during the previous 6 months. The study did not exclude participants with retinal angiomatous proliferation or pigment epithelial detachment. See Appendix 2 (available at http:// aaojournal.org) for a complete list of the eligibility criteria.
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Figure 1. The computer-generated image showing the endoscopic probe used to deliver epimacular brachytherapy. When the radiation source is engaged, it moves down inside the lumen of the probe and comes to rest at a point marked by a crosshair etched on the external surface of the probe. The crosshair is positioned over the area of greatest disease activity, dened using uorescein angiography. The tip of the probe rests lightly on the internal limiting membrane of the retina. The retina directly underneath the crosshair receives 24 Gy. The dose reduces by the inverse square of distance from the radiation source, which is approximately 10% for each 1 mm from the crosshair. The image shows the isodose lines for this attenuation in dose. Points on each isodose line receive the same dose of radiation.
the eye; Sr90/Y90 delivers a very high dose to a small volume of tissue over a short period. The dose delivered falls off dramatically as a function of distance from the source, thus minimizing offtarget doses to ocular structures such as the optic nerve or the lens (Fig 1). A multispecialty team consisting of a retinal surgeon, radiation oncologist, and medical physicist participated in each treatment.
Dose Determination
A standardized point dose of 24 Gy was delivered to the lesion. Because the activity of sources varied, the manufacturer calibrated each device to determine the treatment time required, with a range from 3 to 5 minutes. A dose of 24 Gy was conrmed before each procedure based on activity calculation and taking into account predicted decay. Source position within the device was determined by the use of a multichannel tester before and after each procedure to conrm that the source was deploying correctly within the probe and that the prescribed dose was delivered.
Ranibizumab Therapy
Participants in the EMBT arm received a mandated, intravitreal 0.5-mg ranibizumab injection at the conclusion of surgery and again 30 days later. At each subsequent monthly follow-up visit, participants received an additional PRN injection if 1 or more of the retreatment criteria were met. In the control group, participants received 3 monthly mandated ranibizumab injections at the commencement of therapy, and thereafter both quarterly mandated injections and monthly PRN injections, using the same retreatment criteria. The full details of the retreatment criteria are provided in Appendix 3 (available at http://aaojournal.org). To summarize, retreatment was mandated if any of the following applied: loss of 10 letters of VA, veried by repeat testing within 7 days; 50-m increase in OCT central retinal thickness; new subretinal hemorrhage; or new neovascularization visible using FA.
Assessments
Study visits were scheduled every 4 weeks (7 days) to include safety evaluation, BCVA, intraocular pressure, slit-lamp examination, indirect ophthalmoscopy, and OCT. Additionally, FA and fundus photography were undertaken at baseline and months 1, 6, 12, and 24. Those in the surgical arm also were reviewed 1 day and 1 week after EMBT. All OCT, FA, and fundus images were graded at a central reading center. Visual acuity was assessed according to the ETDRS testing protocol, including full refraction, with testing by certied examiners, commencing at 4 m, and moving to 1 m if required.35 It is well known that radiation retinopathy can occur
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Outcomes
The coprimary efcacy measures were the proportion of participants losing fewer than 15 ETDRS letters of BCVA from baseline and the proportion of participants gaining 15 ETDRS letters or more of BCVA, both at 24 months. Secondary outcomes at 24 months were mean change in BCVA, mean change in FA lesion size, mean change in OCT central foveal thickness, and the mean number of ranibizumab retreatments.
Safety Analyses
At each study site, a retina specialist monitored all study participants. Safety was assessed through collection and summary of ocular and nonocular adverse events, serious adverse events (SAEs), unexpected adverse device effects, ocular assessments, and deaths. At each study visit, nondirective questioning was used to assess adverse event reports from participants. Investigators reported all adverse events, SAEs, and unexpected adverse device effects, whether volunteered by the patient, discovered by study site personnel during questioning, detected by clinical examination, or detected by the reading center. Safety analysis included all participants treated with the investigational device or receiving at least 1 ranibizumab injection. Data analysis occurred after all participants completed the month 24 visit or discontinued early. Events were coded according to the Medical Dictionary for Regulatory Activities system. A data monitoring committee, comprising 2 ophthalmologists and 1 epidemiologist, was established to monitor safety and study conduct by periodically reviewing unmasked data. Possible radiation retinopathy was diagnosed when at least 1 of the following signs was present on examination, fundus photography, or FA: telangiectasia, retinal hemorrhage (other than that related to the CNV), microaneurysms (other than that related to the CNV), capillary nonperfusion, nerve ber layer infarcts, vascular sheathing, and retinal edema. An independent committee reviewed all clinical data related to possible radiation toxicity. If radiation retinopathy was diagnosed by the reading center, all images then were forwarded to the independent committee for nal analysis.
Results
Patient Demographics and Follow-up
In total, 494 participants were enrolled and randomized to study treatment (331 in the EMBT arm and 163 in the ranibizumab monotherapy group; Fig 2). All efcacy results are reported for the modied intent-to-treat population. Randomized groups generally were well balanced for baseline demographic variables (Table 1) and study eye characteristics (Table 2). The angiographic total lesion size and CNV lesion size were somewhat larger in the control group, but this difference was not statistically signicant (P 0.1026). The investigator at each site determined lesion eligibility and lesion subtype for the stratied randomization. The central reading center performed its own determination of lesion subtype when grading the baseline angiograms and fundus photographs. The study sample size was designed prospectively to allow for 10% of participants to be lost to follow-up. At 24 months, 91% of participants in the EMBT arm and 95% of those in the ranibizumab monotherapy arm were available for analysis. Mean follow-up time in the EMBT and ranibizumab monotherapy arms were 23.0 and 23.2 months, respectively.
Efcacy Analysis
Testing for noninferiority (loss of 15 ETDRS letters) and superiority (gain of 15 ETDRS letters) was performed using stratied Mantel-Haenszel tests with a 1-sided type I error rate of 0.0125. Efcacy analyses were stratied by baseline study center, baseline ETDRS VA, and lesion subtype as determined by the principal investigator. The sample size of 494 participants provided 457 participants in the modied intent-to-treat population (302 participants in the EMBT treatment group and 155 in the ranibizumab monotherapy group) and provided 89% power for the noninferiority end point (expecting 82% of participants in the ranibizumab monotherapy group to lose fewer than 15 letters, based on results of the Phase IIIb, Multicenter, Randomized, Double-Masked, Sham Injection-Controlled Study of the Efcacy and Safety of Ranibizumab in Subjects with Subfoveal CNV with or without Classic CNV Secondary to Age-Related Macular Degeneration [PIER] study, and a 10% margin of noninferiority).11 There was 88% power to detect a statistically signicant difference for the superiority end point (expecting 8.5% of the participants in the ranibizumab monotherapy group to gain 15 letters or more based on results of the PIER study11 and 20% in the EMBT group). The
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Excluded (n=154) Not meeting inclusion criteria (n=140) Declined to participate (n=7) Other (n=7).
Randomized (n=494).
Allocated to intervention (n=331) Received allocated intervention (n=310) Did not receive allocated intervention (n=21): withdrew consent (14); other (7).
Allocated to intervention (n=163) Received allocated intervention (n=157) Did not receive allocated intervention (n=6): withdrew consent (5); other (1).
p
Lost to follow-up (n=3) Discontinued intervention (n=30): withdrew consent (11); death (8); illness (6); adverse event (4); other (1). Lost to follow-up (n=1) Discontinued intervention (n=11): withdrew consent (6); death (2); illness (2); other (1).
Analy
Analyzed (n=302). Analyzed (n=155).
Figure 2. Diagram showing the CONSORT 2010 ow diagram detailing the enrollment, intervention allocation, follow-up, and data analysis for this study. In the epimacular brachytherapy (EMBT) arm, 302 participants were analyzed, comprising the 310 patients who underwent the allocated intervention, less 8 participants who died.
ranibizumab monotherapy for classic and minimally classic lesions. A secondary outcome was mean change in VA from baseline. At months 12 and 24, the EMBT arm was not superior to the control arm for this end point. The mean change in VA was 0.5 letters in the EMBT arm and 6.0 letters in the control arm at month 12 and 2.5 letters and 4.4 letters, respectively, at month 24.
Ranibizumab Treatment
Compliance with protocol-mandated ranibizumab treatment was high, as shown in Table 3 (available at http://aaojournal.org). Participants in the EMBT arm had a mean of 1.7 PRN retreatment injections (a total of 3.7 including all protocol-mandated injections that were delivered) at month 12, and 4.2 (a total of 6.2 including protocol-mandated injections) at month 24. After 12 months, 42% of participants in the EMBT arm did not require any PRN retreatment injections; the proportion was 27% at month 24. Participants in the ranibizumab monotherapy arm had a mean of 0.4 PRN retreatment injections (a total of 6.2 including protocol-mandated injections) at month 12 and a mean of 1.0 PRN retreatment injections at month 24 (a total of 10.4 including protocol-mandated
injections) at month 24 (Fig 5). After 12 months, 71% of participants in the ranibizumab monotherapy arm did not require any PRN retreatments; the proportion was 58% at month 24. Figure 5 presents the total number of ranibizumab injections received over 24 months. Figure 6 presents the probability at each time point of receiving the rst PRN retreatment injection. Of the 42% of participants in the EMBT group who required no PRN retreatment in year 1, 93% lost fewer than 15 letters and 20% gained more than 15 letters, with a mean VA change of 4.7 letters at month 12. At month 24, this population had a mean VA change of 3.3 letters. Of the 45% (132 of 294) of participants requiring no PRN retreatment in year 1, 60% of those who made it to year 2 (75 of 125) remained injection free in year 2, and in the 50 who did require PRN retreatment in year 2, 78% lost fewer than 15 letters and 22% gained more than 15 letters, with a mean VA change of 0.22 letters at month 24. Of the 71% of participants in the control group who required no PRN retreatment in year 1, 94% lost fewer than 15 letters and 31% gained more than 15 letters, with a mean VA change of 8.2 letters at month 12. At month 24, this population had a mean VA change of 6.8 letters. Of the 71% of participants requiring no PRN retreatment in year 1, 81% (84 of 104) had no
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injections). By denition, no unexpected adverse device effects occurred in the ranibizumab monotherapy group. Arterial Thromboembolic Events. Analysis of arterial thromboembolic events, a subgroup of events potentially related to systemic vascular endothelial growth factor (VEGF) inhibition, can be challenging because of variations in the denition, assessment, and reporting of events. In the CABERNET study, all participants received anti-VEGF therapy (ranibizumab), and therefore arterial thromboembolic events are reported for all participants. Antiplatelet Trialists Collaboration criteria36 were used to summarize SAEs potentially related to VEGF inhibition, as shown in Table 6 (available at http://aaojournal.org). The results were similar in both treatment arms.
Discussion
The objective of this study was to evaluate the safety and efcacy of EMBT for treatment-nave subfoveal CNV associated with wet AMD. More specically, this study compared EMBT delivered with PRN anti-VEGF therapy with anti-VEGF monotherapy delivered both quarterly and PRN. The results do not support the routine use of EMBT in treatment-nave patients, because EMBT resulted in a greater proportion of eyes losing more than 15 ETDRS letters and a lesser proportion of eyes gaining 15 letters or more.
Table 2. Baseline Ocular Characteristics
Epimacular Brachytherapy ETDRS BCVA No. Mean (SD) Range (minimum, maximum) Quartiles (25th, median, 75th) Lesion subtype (INV), n/N (%) Predominantly classic Minimally classic Occult Lesion subtype (RC), n/N (%) Predominantly classic Minimally classic Occult Disciform scar None Missing Total lesion size (mm2) (RC) No. Mean (SD) Range (minimum, maximum) Quartiles (25th, median, 75th) CNV size (mm2) (RC) No. Mean (SD) Range (minimum, maximum) Quartiles (25th, median, 75th) 302 53.3 (12.8) 16, 84 44, 56, 64 119/302 (39) 74 (25) 109 (36) 62/302 (21) 97 (32) 111 (37) 3 (1) 11 (4) 18 (6) 284 7.1 (5.9) 0, 41 3, 6, 10 284 6.0 (5.3) 0, 37 2, 5, 8 Ranibizumab Monotherapy 155 53.6 (13.7) 15, 82 46, 55, 65 61/155 (39) 41 (26) 53 (34) 26/155 (17) 49 (32) 60 (39) 4 (2) 8 (5) 8 (5) 147 8.1 (7.3) 0, 37 3, 7, 11 147 6.7 (5.7) 0, 26 2, 5, 10
SD standard deviation. Denominators and column header counts are the number of randomized participants in the modied intent-to-treat population.
further PRN injections in year 2, and in those who did receive further PRN injections in year 2, 95% lost fewer than 15 letters and 37% gained more than 15 letters, with a mean VA change of 9.3 letters, at month 24.
Adverse Events
Ocular Serious Adverse Events. Ocular SAEs affecting study eyes are summarized in Table 4 (available at http://aaojournal.org). The most common SAE was cataract formation. Cataracts that warranted surgical removal were declared serious. Rates of endophthalmitis were low, with one event in the EMBT arm and no case in the ranibizumab monotherapy arm. Rates of retinal hemorrhage, vitreous hemorrhage, intraocular inammation, and glaucoma were similar. There were more retinal tears in the EMBT arm. The most common cause of severe vision loss was disease progression. Unexpected Adverse Device Effects. Unexpected adverse device effects, which are summarized in Table 5 (available at http:// aaojournal.org), were dened as any serious adverse effect on health or safety; any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not identied previously in nature, severity, or degree of incidence in the application; or any other unanticipated serious problem associated with a device that related to the rights, safety, or welfare of participants. The United States Food and Drug Administration requested including any possible cases of radiation retinopathy in this category for regulatory reporting purposes. Ten cases of possible radiation retinopathy were identied, 2 of which were reported in the rst year after treatment and 8 of which were reported in year 2. The mean time from EMBT to the diagnosis of radiation retinopathy was 17 months (range, 10 22 months). No cases of proliferative radiation retinopathy were determined to be present after review of all images by the independent committee. Of 10 eyes that were diagnosed with radiation retinopathy, all lost fewer than 15 letters, with a mean gain of 4.4 letters at 24 months. In this group, the mean VA at baseline was 49.5 letters. At the time of diagnosis with radiation retinopathy the mean VA had increased to 54.4 letters (53.9 letters at month 24). Of the 10 eyes with suspected radiation retinopathy, 8 were phakic at baseline, and 4 of these underwent cataract surgery. This group required a mean of 2.0 PRN ranibizumab retreatments (a total of 4.0 including protocol-mandated
BCVA best-corrected visual acuity; CNV choroidal neovascularization; ETDRS Early Treatment Diabetic Retinopathy Study; INV determination by investigator, RC determination by reading center; SD standard deviation. Denominators are the number of randomized participants in the modied intent-to-treat population with data for that category.
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-0.3
-0.2
-0.1
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The primary VA results were driven in part by poor results in participants with occult neovascularization. The occult-only lesions represented larger lesions as compared with those with a classic component (3.4 vs. 2.0 mm2, respectively). The EMBT device delivers 24 Gy as a point dose to the center of the lesion, but the dose reduces exponentially with increasing distance from the probe.28 This is advantageous in terms of ocular safety, because off-target structures receive an attenuated dose, but it is possible that the edge of large lesions is undertreated relative to smaller lesions. This is borne out by the analysis of response in relation to FA lesion size. As shown in Figures 3 and 4, lesions of 3.5 disc areas or smaller had better results than larger lesions. A second reason for inferior VA results may relate to probe positioning. The attenuation in dose with the EMBT device is heavily reliant on probe positioning, and it is important that surgeons position the probe over the area of greatest activity, up to a maximum of 2 mm from the foveal center. An angiogram is used before surgery to select an
appropriate probe position over the area of greatest activity. Slight deviations in the positioning of the source can increase or decrease signicantly the dose delivered to the active component of the AMD lesions. In the context of occult lesions, particularly if there is brosis, it can be hard to locate accurately the area of greatest activity, or the variable topography of the lesion makes it difcult to dene a geometric center. By comparison, classic lesions often are well demarcated and easy to locate based on uorescein leakage, and this may make it easier to center the probe tip correctly. Although the mean VA was lower in the EMBT arm, there were important differences in the ranibizumab treatment regimen relative to the control group. In the control group, participants received 3 monthly mandated ranibizumab injections at the commencement of therapy, and thereafter received both quarterly mandated injections and PRN injections during the intervening monthly visits. In addition, a mandated injection was given to the control arm at month 23, the visit immediately before the primary VA
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[Favors Ranibizumab]
[Favors EMBT]
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milestone. The more intensive retreatment regimen in the control arm stemmed from the regulatory requirement to compare results with those from published outcomes, which in this case required a study that included classic, minimally classic, and occult lesions. At the time the CABERNET study was designed, the PIER study11 was the only appropriate comparator that included all lesion subtypes. Asneeded dosing was added to the quarterly injections used in PIER, because treating less frequently may have affected outcome adversely, and it was deemed ethically inappropriate to withhold treatment if needed. Ultimately, very few PRN retreatment injections (mean, 1.0) were delivered to the control group over the 2 years of follow-up, and this may reect that fact that there were 10 mandated injections. Epimacular brachytherapy seemed to reduce the need for anti-VEGF therapy, because 42% of participants in the EMBT group did not require any retreatment in the rst 12 months, and this subgroup required only 1 retreatment, on average, during the second year. It is not possible to compare this treatment demand directly with the control group, because the latter had regular mandated injections, but this treatment demand is substantially less than that in any
published study using anti-VEGF therapy to treat wet AMD. Interestingly, this group had a particularly favorable visual outcome, with 93% losing fewer than 15 letters at 1 year and a mean increase in VA of 4.7 letters. Predicting which participants respond well to EMBT is difcult, but may relate to the lesion size, lesion type, and perhaps also probe placement and positioning, as noted previously. Other unidentied variables, such as genetic or other factors, also may play a role and may justify further investigation, because at present none of the subgroups identied had results that were better than those of controls. The EMBT group had a favorable safety prole at 2 years. Both arms had similar, low rates of arteriothrombotic events, consistent with other trials of intravitreal anti-VEGF therapy.8,10,14 The most common serious adverse event was cataract surgery, occurring in 40% of the EMBT arm as compared with 11% of the ranibizumab arm. It is well documented in the literature that vitrectomy is associated with cataract formation.37,38 The dose of radiation received by the lens during EMBT is approximately 0.00056 Gy, well below the reported threshold for cataractogenesis (2 Gy).28,39 As such, it seems likely that cataract resulted
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0.0 Mos. from elig. 0 2 4 6 8 10 12 14 16 No. at risk EMBT 302 277 221 186 159 147 124 115 105 RBZ 155 149 140 130 123 111 98 97 95 Censored subject
18
93 89
20
85 88
22
81 69
Figure 6. Kaplan-Meier plot showing the time to the rst as required (pro re nata [PRN]) ranibizumab (RBZ) retreatment, comparing those in the epimacular brachytherapy (EMBT) arm with those in the RBZ monotherapy control arm. The EMBT time 0 is study month 1, and the RBZ time 0 is study month 2, because these were the earliest times that participants were eligible to receive a PRN injection. This difference was because those in the EMBT arm commenced RBZ treatment with 2 mandated, monthly injections, whereas those in the control arm commenced treatment with 3 mandated monthly RBZ injections. Subsequent months are those from this point of eligibility (Mos. from elig.)
in whom frequent and protracted injections are not possible or are contraindicated, EMBT may be a treatment option. Further analysis is planned to try to identify which participants respond best to EMBT, because the clinical response showed substantial variation. In addition, the Macular EpiRetinal Brachytherapy versus Lucentis Only Treatment (MERLOT) trial is an investigator-initiated, randomized, controlled trial of EMBT (clinicaltrials.gov identier, NCT01006538) designed to determine if EMBT has a role as a second-line treatment.
References
1. Finger RP, Fimmers R, Holz FG, Scholl HP. Incidence of blindness and severe visual impairment in Germany: projections for 2030. Invest Ophthalmol Vis Sci 2011;52: 43819. 2. Congdon N, OColmain B, Klaver CC, et al, Eye Diseases Prevalence Research Group. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol 2004;122:477 85. 3. Gunnlaugsdottir E, Arnarsson A, Jonasson F. Five-year incidence of visual impairment and blindness in older Icelanders: the Reykjavik Eye Study. Acta Ophthalmol 2010;88:358 66. 4. Bunce C, Xing W, Wormald R. Causes of blind and partial sight certications in England and Wales: April 2007March 2008. Eye (Lond) 2010;24:16929. 5. Bressler NM, Doan QV, Varma R, et al. Estimated cases of legal blindness and visual impairment avoided using ranibizumab for choroidal neovascularization: non-Hispanic white population in the United States with age-related macular degeneration. Arch Ophthalmol 2011;129:709 17.
Figure 5. Graph showing the number of ranibizumab injections administered over 24 months, comparing those in the epimacular brachytherapy arm with those in the ranibizumab monotherapy control arm. The number of injections shown includes the 2 mandated injections in the epimacular brachytherapy arm and the 10 mandated injections in the ranibizumab monotherapy arm, combined with any as-required (pro re nata) retreatment injections that were administered.
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Elias Reichel: Financial supportNeoVista. Michael Singer: Financial supportNeoVista. Manuscript no. 2012-342. Adiel Barak: Financial supportNeoVista. Susanne Binder: Financial supportNeoVista. Timothy L. Jackson: Financial supportNeoVista. Jeffrey Nau: EmployeeNeoVista. Judith D. Bebchuk: Financial support to employerNeoVista. The sponsor (NeoVista, Inc) participated in the design, conduct, data collection, data management, data analysis, interpretation of the data, preparation, review, and approval of the manuscript. Correspondence: Timothy L. Jackson, PhD, FRCOphth, Kings College London, Department of Ophthalmology, Kings College Hospital, London SE5 9RS, United Kingdom. E-mail: t.jackson1@nhs.net. *Principal investigators in the CNV Secondary to AMD Treated with Beta Radiation Epiretinal Therapy (CABERNET) Study Group are listed in Appendix 1 (available at http://aaojournal.org).
Retinal Consultants of Arizona, Phoenix, Arizona. Statistics Collaborative, Inc, Washington, DC. NeoVista, Inc, Newark, California. Tufts Medical Center, Boston, Massachusetts. Medical Center Ophthalmology Associates, San Antonio, Texas. Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
The Ludwig Boltzmann Institute for Retinopathy and Biomicroscopic Laser Surgery, Rudolf Foundation Clinic, Vienna, Austria. Kings College London, United Kingdom. Presented at: Pravin U. Dugel, Angiogenesis, Exudation and Degeneration, Coral Gables, Florida, 2012. Financial Disclosure(s): The author(s) have made the following disclosure(s): Pravin U. Dugel: Financial support, equity ownerNeoVista.
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