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Verteporfin Therapy of Subfoveal Minimally Classic Choroidal Neovascularization in Age-Related Macular Degeneration
2-Year Results of a Randomized Clinical Trial
Visudyne in Minimally Classic Choroidal Neovascularization Study Group*
Arch Ophthalmol. 2005;123:448-457.
ABSTRACT
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Objective To compare the treatment effect and safety of photodynamic therapy with verteporfin using a standard (SF) or reduced (RF) light fluence rate with that of placebo therapy in patients with subfoveal minimally classic choroidal neovascularization (CNV) with age-related macular degeneration.
Design Phase 2, multicenter, double-masked, placebo-controlled, randomized clinical trial.
Setting Nineteen ophthalmology practices in North America and Europe.
Participants Patients with initial best-corrected visual acuity of at least 20/250 and a lesion size of no greater than 6 Macular Photocoagulation Study (MPS) disc areas.
Methods We randomly assigned 117 patients (1:1:1) to verteporfin infusion (6 mg/m2) and light application with an RF rate (300 mW/cm2) for 83 seconds (light dose of 25 J/cm2) or an SF rate (600 mW/cm2) for 83 seconds (light dose of 50 J/cm2) or to placebo infusion with RF or SF. Treatment was repeated every 3 months if the treating physician noted fluorescein leakage from CNV on angiography. Patients in whom a predominantly classic lesion developed could receive open-label standard verteporfin treatment. Best-corrected visual acuity was measured every 3 months, and angiographic changes were assessed by the Photograph Reading Center through the 3-month examination unless an ocular adverse event or conversion to a predominantly classic lesion was identified by an investigator. Safety was assessed throughout the study. All outcomes were on an intent-to-treat basis.
Results One hundred three (88%) of 117 patients completed the 24-month examination. Twelve (30%) of 40 patients assigned to placebo received open-label standard verteporfin treatment after confirmation of presence of predominantly classic CNV. At month 12, a loss of at least 3 lines of visual acuity occurred in 5 (14%) of 36 eyes assigned to RF and 10 (28%) of 36 eyes assigned to SF, compared with 18 (47%) of 38 eyes assigned to placebo (RF, P = .002; SF, P = .08; RF + SF, P = .004). At month 24, this loss occurred in 9 (26%) of 34 eyes assigned to RF and 17 (53%) of 32 assigned to SF, compared with 23 (62%) of 37 eyes assigned to placebo (RF, P = .003; SF, P = .45; RF + SF, P = .03). Progression to predominantly classic CNV by 24 months was more common in the placebo group (11 [28%] of 39 patients compared with 2 [5%] of 38 in the RF group [P = .007] and 1 [3%] of 37 in the SF group [P = .002]). No unexpected ocular or systemic adverse events were identified. Treatment-related, usually transient visual disturbances were 13% with SF, 10% with placebo, and 5% with RF.
Conclusions Verteporfin therapy safely reduced the risks of losing at least 15 letters ( 3 lines) of visual acuity and progression to predominantly classic CNV for at least 2 years in individuals with subfoveal minimally classic lesions due to age-related macular degeneration measuring 6 MPS disc areas or less. Based on the overall evidence available on verteporfin therapy for these lesions, the VIM Study Group would consider recommending verteporfin therapy for relatively small minimally classic lesions similar to those enrolled in the VIM Trial.
INTRODUCTION
Photodynamic therapy with verteporfin (Visudyne; Novartis Pharma AG, Basel, Switzerland) (hereafter referred to as verteporfin therapy) decreases the risk of vision loss in selected patients with subfoveal choroidal neovascularization (CNV) caused by age-related macular degeneration (AMD).1-5 The strongest evidence from the Treatment of Age-related Macular Degeneration With Photodynamic Therapy (TAP) Investigation and Verteporfin in Photodynamic Therapy (VIP) Trial suggests that this benefit applies to patients with a predominantly classic lesion composition (in which the area of classic CNV was 50% of the area of the entire lesion) and those with an occult with no classic lesion composition with presumed recent disease progression (blood associated with CNV, recent vision loss, or recent lesion growth)6-7 using standardized definitions for these features.8-9 In contrast, visual acuity benefits owing to verteporfin therapy were not found in the subgroup of patients with minimally classic lesions (in which the area of classic CNV was <50% but >0% of the area of the entire lesion) in the TAP Investigation, although treatment effect in contrast sensitivity and several secondary angiographic outcomes, including a reduced risk of lesion growth, was observed.1-3 One possible explanation for the lack of a visual acuity treatment benefit among the subgroup of patients in the TAP Investigation with minimally classic lesions could be that an undetected imbalance in baseline lesion characteristics between the placebo and treatment groups created a bias against showing a treatment benefit for these lesions in that study. Another possible explanation is that patients with small ( 4 Macular Photocoagulation Study [MPS] disc areas) minimally classic lesions may benefit from the treatment in the same way as those with occult with no classic lesions did in the VIP Trial.5
Retrospective exploratory analyses of data from the TAP Investigation and the VIP Trial demonstrated that smaller minimally classic lesions and smaller occult with no classic lesions were more likely to have a reduced risk of visual acuity loss with verteporfin therapy than were larger lesions.10 The apparent interaction between treatment group and baseline lesion size suggests that minimally classic lesions could benefit from verteporfin therapy if only smaller lesions are treated rather than lesions of up to 9 MPS disc areas, such as were evaluated in the TAP Investigation. The Visudyne in Minimally Classic CNV (VIM) Trial was designed, in part, to evaluate standard verteporfin therapy of smaller lesions of 6 MPS disc areas or less.
The VIM Trial also was designed to explore outcomes of a reduced fluence (RF) rate of 300 mW/cm2 for 83 seconds, resulting in a decrease in the total light dose to 25 J/cm2. This RF rate and light dose were used in a theoretical attempt to increase the selectivity of the photodynamic treatment effect and to minimize the inflammatory component of the photodynamic treatment reaction, as suggested by several recent publications.11-13 The potential benefits of the RF rate are based on a hypothesis that, with the standard light fluence (SF) rate, the tissue oxygen concentration determines the rate of the photochemical reaction within the area of light application. If oxygen is at similar concentrations in the CNV, choriocapillaries, and adjacent tissues, application of light when oxygen is rate determining would not result in selectivity of treatment, despite a preferential accumulation of verteporfin in the CNV. With RF, the delivery of light photons becomes the rate-determining step in the photochemical reaction, so selective accumulation of verteporfin in the CNV would result in selective treatment in the CNV and lessen effects in the choriocapillaries and pigment epithelial cells. No safety concerns were identified when an RF was used in a previous study.14 The present study compares the effects of verteporfin infusion or placebo infusion followed by exposure to SF or RF rates for all patients participating in the VIM Trial through 24 months of follow-up.
METHODS
This clinical study protocol BPD OCR 011 (originally dated November 30, 2000) and 5 protocol amendments through June 10, 2003, are on file with regulatory agencies in the United States, Canada, and Europe. The highlights of the protocol are described in this section.
PATIENT SELECTION AND ENTRY EVALUATIONS
Nineteen clinical centers enrolled patients from April 2, 2001, through January 31, 2002, when the target sample size was approached. Vision testing, color photographs, fluorescein angiograms, indocyanine green angiography, medical histories, and physical examinations were completed within 7 days of study enrollment before patients were randomly assigned to treatment in the trial.
ELIGIBILITY CRITERIA
Ophthalmologists certified to enroll and treat study participants determined whether potential study candidates fulfilled the eligibility criteria. Key features of the eligibility criteria included a best-corrected visual acuity letter score (following the TAP vision protocol1) of at least 30 (Snellen equivalent, approximately 20/250 or better) for lesions of 4 MPS disc areas or less and of 30 to 65 (approximate Snellen equivalent of 20/50) for lesions of greater than 4 but no greater than 6 MPS disc areas; fluorescein angiographic evidence of subfoveal CNV due to AMD in which at least 50% of the lesion was CNV; and a fluorescent pattern of some classic CNV (bright area of fluorescence in early-phase frames with leakage at the boundaries of this area through the middle- and late-phase frames) that was less than 50% of the entire area of the lesion using previously defined terms.8-9
VIM PHASE 2 STUDY DESIGN
The primary objective at the start of the study was to determine whether an RF rate of 300 mW/cm2 delivered for 83 seconds (light dose of 25 J/cm2) compared with verteporfin therapy using the SF rate of 600 mW/cm2 delivered for 83 seconds (light dose of 50 J/cm2) resulted in improved angiographic outcomes with an acceptable safety profile at 3 months. The study participants receiving the fluence rate determined to have the better angiographic outcome would then roll over with additional participants into a phase 3 trial comparing visual acuity outcomes of verteporfin therapy with those of placebo. However, before any unmasking of individual patient treatment assignments, the protocol was amended to remove the phase 3 part and to extend the phase 2 part for 12 months of follow-up with a primary outcome of at least 15 letters (3 lines) of visual acuity loss at 12 months. It was argued that longer follow-up would provide more clinically relevant visual acuity data. Subsequently, the study was further extended through 24 months of follow-up, again before any unmasking of individual patient treatment assignments.
VISION TESTING, PHOTOGRAPHS, AND STUDY ENTRY
After patients reviewed and signed a written informed consent form accompanied by an oral consent process with a certified investigator (ophthalmologist), best-corrected visual acuity testing, stereoscopic color fundus photography, film-based stereoscopic fluorescein angiography, and other procedures as described in previous verteporfin trials1, 5 were undertaken. In addition, indocyanine green angiography was obtained at baseline and follow-up at some sites but was not analyzed for this report and will be reported separately. Patients who were judged by a VIM-certified enrolling ophthalmologist to satisfy all eligibility criteria were assigned randomly to verteporfin with the RF rate, verteporfin with the SF rate, placebo with the RF rate, and placebo with the SF rate in a 2:2:1:1 ratio, respectively.
RANDOM ASSIGNMENTS AND MASKING
Patients were randomly assigned to 1 of 2 fluence groups; at the same time, patients were randomly assigned to receive verteporfin therapy or placebo. The ratio of patients receiving the SF rate compared with the RF rate was maintained at 1:1, and the ratio of patients receiving verteporfin therapy compared with placebo was maintained at 2:1. All study participants and outcome assessors, including vision examiners, photographers, ophthalmologists, Photograph Reading Center personnel, and clinic monitors, were masked to the treatment assignment. The ophthalmologist responsible for applying the laser light was not masked to the fluence rate (RF or SF) because the treating ophthalmologist was responsible for the light fluence rate being applied to the study participant’s retina. Only the study coordinators and any other person who might assist in the setup of verteporfin or placebo solutions were aware of the treatment assignment with respect to verteporfin or placebo; these individuals were trained to make every reasonable attempt to maintain masking of participating patients and all other study personnel. However, treatment assignment was unmasked for a total of 3 patients. Investigators were unmasked to the treatment assignment of 2 patients. One patient was identified by the Reading Center as having a predominantly classic lesion at the initial visit; the other was identified by the Reading Center as having a predominantly classic lesion at the 6-week examination. In both cases, the treating ophthalmologist believed that verteporfin therapy should not be delayed until the next scheduled visit. Therefore, the ophthalmologist for each patient wanted to know whether placebo or verteporfin had been given at the study visit just before identification of the predominantly classic CNV. If verteporfin had been given, then the ophthalmologist reasoned that no additional treatment would be considered until the next scheduled study visit. If placebo had been given, then the ophthalmologist reasoned that verteporfin therapy would be recommended promptly. A third patient inadvertently was unmasked to the sponsor by the study coordinator at the site where the patient was being treated because the coordinator asked the sponsor what the site should do with a reconstituted vial of verteporfin, thus indirectly and inadvertently revealing the treatment assignment for a particular randomization number. The success of masking otherwise was not evaluated formally.
VERTEPORFIN THERAPY, PATIENT FOLLOW-UP, AND FLUORESCEIN AND INDOCYANINE GREEN ANGIOGRAPHIC ASSESSMENT AT FOLLOW-UP
Verteporfin and placebo therapy were administered and patient follow-up was performed at all clinical centers according to a standard protocol. Fluorescein angiographic assessments at follow-up were graded by masked personnel at all treating centers 6 weeks and 3 months after the baseline treatment and at 3-month intervals thereafter. In addition, fluorescein angiography was performed 1 week after the baseline verteporfin therapy until 10 patients had been enrolled in each treatment group, but to maintain masking, the treating ophthalmologists did not assess these angiograms. The Photograph Reading Center evaluated all the angiograms performed during the first 3 months of the study and at any visit that a serious adverse event involving the retina in the study eye was identified by the treating ophthalmologist. If a treating ophthalmologist judged that a predominantly classic lesion had developed, and if this development was confirmed by the Photograph Reading Center, or if the Photograph Reading Center identified a predominantly classic lesion by the 3-month examination that was not first identified by the treating ophthalmologist, then the treating ophthalmologist could give verteporfin therapy in an unmasked fashion to the study participant for the duration of the study; such patients were still analyzed within the treatment arm to which they were randomized.
STATISTICAL METHODS
No formal power calculation was performed for this study. Forty patients per treatment group were judged to be adequate to generate descriptive statistics for fluorescein angiographic and visual acuity outcomes.
When the phase 2 trial was extended to 24 months of follow-up with continuation of both verteporfin treatment groups, a statistical analysis plan was finalized by the sponsors in January 2003 before unmasking of individual patient assignments. The primary efficacy analyses were based on a strict intent-to-treat analysis; patients were analyzed within the group to which they were randomized, even if the Reading Center judged that the lesion was predominantly classic at baseline and even if a study participant originally assigned to placebo subsequently received open-label verteporfin therapy because of progression to a predominantly classic lesion. The primary efficacy outcome after the study’s extension to 24 months of follow-up was defined prospectively as the proportion of eyes that lost at least 15 letters from baseline at the 12-month examination. This end point was analyzed using a Pearson  2 test.15(pp331-333) Distribution of visual acuity scores and distribution of changes in scores from baseline were compared between groups using a Wilcoxon rank sum test.15(pp277-280,286-290) Assessments of progression to a predominantly classic lesion were compared between groups using a Pearson 2 test.15(pp331-333)
The analysis chosen prospectively by the study group was an intent-to-treat analysis, including all patients who were randomized and who had measurements at specified follow-up examinations, without imputation for missing observations. The sponsor’s prospective statistical analysis plan was an intent-to-treat analysis with the last observation carried forward to impute missing visual acuity values. Outcomes by both methods were reported to regulatory authorities, although this report concentrates mainly on outcomes with the observed data that had no imputation for missing observations. The sponsor’s prospective analysis plan also described the pooling of data from the 2 verteporfin groups if a difference of no more than 5 letters (1 line) was noted between the mean visual acuity score changes of the 2 verteporfin groups from baseline to the 12-month examination using the last observation carried forward. The P value for the primary comparison of the proportion of eyes that lost at least 15 letters from baseline at the 12-month examination was adjusted to .048 to account for the statistical testing performed on visual acuity outcome during the initial phase 2 part of the study. For all other analyses, P>.05 was deemed to be statistically insignificant.
DATA MONITORING AND REPORTING
Data monitoring was evaluated by an independent Data and Safety Monitoring Committee approximately every 6 months after enrollment began. No safety concerns were voiced by the committee at its reviews. On December 13, 2002, 6-month data analyzed by the sponsors were reviewed by the Data and Safety Monitoring Committee. Based on this review of the data and to comply with Securities and Exchange Commission policies in Canada and the United States, the topline results of this 6-month analysis were shared with the public via a news release from the sponsors on December 17, 2002, and did not result in any known unmasking of the study patients or assessors of outcomes for this trial. Subsequent 12- and 24-month data were reviewed by the Verteporfin Study Advisory Group and the VIM Study Group and are presented herein.
RESULTS
One hundred seventeen eyes in 117 patients were assigned randomly to verteporfin therapy (77 eyes) or placebo infusion with light exposure (40 eyes). Of the 77 eyes assigned to verteporfin therapy, 39 were assigned to the SF rate and 38 to the RF rate; of those assigned to placebo therapy, 19 were assigned to the SF rate and 21 to the RF rate. The baseline characteristics for these participants appeared balanced (Table 1 and Table 2) except for lesion size; the placebo group (Table 2) was more likely to have smaller lesions (4 MPS disc areas). One patient in the placebo group and 2 patients in the SF treatment group had a lesion in the study eye with a predominantly classic composition at baseline, as judged by the Photograph Reading Center. The 12- and 24-month follow-up examinations were completed by 36 patients (95%) and 34 (89%), respectively, of the RF group; 36 (92%) and 32 (82%), respectively, of the SF group; and 38 (95%) and 37 (93%), respectively, of the placebo group (Figure 1). At each follow-up examination after month 3, the verteporfin-treated groups with RF or SF were less likely to receive an additional course of study treatment compared with the placebo group (Figure 2). Patients could receive a maximum possible 4 courses of treatment per year (8 courses in 2 years), including the initial course of study treatment at the baseline visit. Until the 12-month examination (including the application of verteporfin therapy at baseline and any subsequent therapy given at the 3-, 6-, and 9-month examinations), patients assigned to verteporfin therapy and the RF rate received an average of 3.1 treatments compared with 2.9 treatments for those assigned to the SF rate and 3.0 treatments for those assigned to placebo. In the time from the 12-month to the 24-month examinations, patients received an additional 1.5, 0.8, and 1.5 treatments on average, respectively, during the 12-, 15-, 18-, and 21-month examinations. Twelve patients (30%) assigned to the placebo group, 2 (5%) assigned to the RF group, and 2 (5%) assigned to the SF group received open-label verteporfin treatment in the study eye after the treating ophthalmologist confirmed the development of a predominantly classic lesion. Eight patients (20%) assigned to the placebo group, 1 (3%) assigned to the RF group, and 3 (8%) assigned to the SF group received verteporfin therapy to their fellow eye during follow-up within the trial. Overall, a total of 17 placebo-treated patients (42%) received verteporfin therapy in the study eye, the fellow eye, or both eyes during the study.
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Table 1. Principal Baseline Characteristics
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Table 2. Principal Baseline Photograph Reading Center Evaluations
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Figure 1. Profile of participants completing follow-up (at least a protocol visual assessment) through 24 months.
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Figure 2. Percentage of eyes receiving treatment at baseline or follow-up examinations. The reduced fluence (RF) group received light application at a rate of 300 mW/cm2; the standard fluence (SF) group, a rate of 600 mW/cm2.
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VISION OUTCOMES
For the primary outcome at the 12-month examination (without the last observation carried forward as chosen by the VIM Study Group), 18 (47%) of 38 study eyes assigned to placebo compared with 5 (14%) of 36 assigned to the RF rate (P = .002) and 10 (28%) of 36 assigned to the SF rate (P = .08) lost at least 15 letters or 3 lines on the Early Treatment of Diabetic Retinopathy Study visual acuity chart. The direction of these differences was maintained through the 24-month examination, when 23 (62%) of 37 eyes assigned to placebo compared with 9 (26%) of 34 assigned to the RF rate (P = .003) and 17 (53%) of 32 assigned to the SF rate (P = .45) lost at least 15 letters of visual acuity. When the RF and SF groups assigned to verteporfin were pooled, the combined verteporfin groups had a reduced risk of losing 15 or more letters at the 12- (P = .004) and 24-month examinations (P = .03), compared with the placebo group.
When the median change in visual acuity at each 3-month follow-up visit from baseline was examined (Figure 3), each group assigned to verteporfin treatment had a smaller median change in visual acuity through the 24-month examination than did the group assigned to placebo, with the RF group losing 2.0 letters (0.4 line; P = .05) and the SF group losing 16 letters (3.2 lines; P = .12) compared with the placebo group losing 21.0 letters (4.2 lines) at the 24-month examination. When the 2 verteporfin treatment groups were compared, the P value was .03 in favor of the RF group at month 12 and .14 at month 24 (Table 3). The mean change in visual acuity from baseline showed a similar treatment benefit in favor of the verteporfin groups (Figure 4), but the difference between the RF and SF regimens was much smaller (a difference of 5 letters [1.0 line] at 12 months [P = .08] and 4 letters [0.8 line] at 24 months [P = .45]). With respect to the distribution of visual acuity letter scores (in Snellen equivalents) (Table 4), the visual acuity of eyes assigned to placebo compared with those assigned to verteporfin therapy with the RF rate or the SF rate favored the verteporfin groups at the 12- and 24-month examinations, ranging from 20/160–1 to 20/200+1 for the placebo group compared with 20/80–2 to 20/160+2 for the verteporfin groups. Similar trends were observed in the distribution of visual acuity changes at the 12- and 24-month examinations (Table 3), whether the eyes assigned to placebo were compared with those assigned to the RF rate with verteporfin (P = .001 at month 12 and P = .004 at month 24) or the SF rate with verteporfin (P = .16 at month 12 and P = .08 at month 24).
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Figure 3. Median change from baseline in visual acuity scores for patients receiving verteporfin or placebo followed by exposure to a reduced (RF) or a standard (SF) fluence rate (1 line equals 5 letters). The RF group received light application at a rate of 300 mW/cm2; the SF group, a rate of 600 mW/cm2.
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Table 3. Frequency Distribution of Changes in Visual Acuity From Baseline by Treatment at the 12- and 24-Month Follow-up Examinations*
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Figure 4. Mean change from baseline in visual acuity scores for patients receiving verteporfin or placebo followed by exposure to a reduced (RF) or a standard (SF) fluence rate (1 line equals 5 letters). The RF group received light application at a rate of 300 mW/cm2; the SF group, a rate of 600 mW/cm2.
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Table 4. Visual Acuity Categories in Study Eyes by Treatment at the 12- and 24-Month Follow-up Examinations*
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When these results were analyzed with the last observation carried forward for missing values, the prospective statistical analysis method for the primary outcome chosen by the sponsors, the results were similar, with 18 (45%) of 40 study eyes assigned to placebo compared with 7 (18%) of 38 assigned to the RF rate (P = .01) and 10 (26%) of 39 assigned to the SF rate (P = .07), losing at least 15 letters of visual acuity at the 12-month examination. Again, the direction of these differences between treatment arms, with the last observation carried forward, was maintained through the 24-month examination. Also, the distribution of visual acuity changes at the 12-month examination showed similar trends in favor of the verteporfin treatment groups when the results were analyzed with the last observation carried forward for missing values.
Because patients assigned to the placebo group were more likely to have smaller lesions, visual acuity outcomes were also evaluated by lesion size, specifically for lesions of 4 MPS disc areas or less and greater than 4 MPS disc areas. Within both subgroups, those assigned to placebo were still more likely to lose 3 or more lines (assuming 5 letters per line) of visual acuity by the 24-month examination. In subjects with lesions of 4 MPS disc areas or less, these included 10 (53%) of 19 in the placebo, 4 (27%) of 15 in the RF, and 6 (50%) of 12 in the SF groups (2 placebo and 2 SF group patients had no 24-month examination); in subjects with lesions of greater than 4 MPS disc areas, 9 (64%) of 14 in the placebo, 2 (15%) of 13 in the RF, and 6 (43%) of 14 in the SF groups (1 placebo, 3 RF, and 4 SF group patients without a 24-month examination) lost 3 or more lines of visual acuity.
Similarly, within both subgroups, the median loss from baseline of lines of visual acuity was higher for patients assigned to placebo. Patients assigned to placebo with lesions of 4 MPS disc areas or less lost a median of 3.0 lines by the 24-month examination compared with 1.8 lines for the RF and 2.5 lines for the SF groups. Patients assigned to placebo with lesions of greater than 4 MPS disc areas lost a median of 5.5 lines by the 24-month examination compared with a gain of 2.0 lines for the RF and a loss of 1.8 lines for the SF groups.
FLUORESCEIN ANGIOGRAPHIC OUTCOMES
As can be seen in Figure 5, and excluding 1 patient from the placebo group and 2 patients from the SF group judged by the Photograph Reading Center to have a predominantly classic lesion at baseline, angiographic progression to predominantly classic CNV confirmed by the Reading Center was more common in the placebo group, with 11 (28%) of 39 placebo group patients converting to predominantly classic CNV lesions by 24 months compared with 2 (5%) of 38 RF group patients (P = .007) and 1 (3%) of 37 SF group patients (P = .002).
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Figure 5. Percentage of patients with minimally classic lesions at baseline (as judged by the enrolling ophthalmologist) who had predominantly classic lesions by the 24-month examination (as confirmed by the Photograph Reading Center), excluding 1 patient in the placebo group and 2 patients in the standard fluence (SF) group with lesions judged to be predominantly classic at baseline by the Photograph Reading Center. Limit lines represent 95% confidence intervals of the percentages. The reduced fluence (RF) group received light application at a rate of 300 mW/cm2; the SF group, a rate of 600 mW/cm2.
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SAFETY
Adverse events occurring by the 24-month examination that were judged to be clinically relevant and treatment related (Table 5) included visual disturbances in 4 (10%) of the patients assigned to placebo compared with 2 (5%) assigned to verteporfin with the RF rate and 5 (13%) assigned to verteporfin with the SF rate. The incidence of visual disturbances was similar between the pooled verteporfin-treated (9%) and the placebo-treated (10%) groups. Acute severe visual acuity decrease16 was seen in 1 patient (3%) in the placebo group (after receiving a placebo, not open-label verteporfin), in no patients in the verteporfin group with RF rate, and in 1 patient (3%) in the verteporfin group with SF rate. In both cases, the acute severe visual acuity decrease occurred after the first baseline treatment. There were 4 patients (10%) assigned to placebo compared with 1 patient (3%) assigned to verteporfin with the RF rate and 2 patients (5%) assigned to verteporfin with the SF rate who had injection-site adverse events by the 24-month examination. One patient (3%) reported infusion-related pain in the group assigned to placebo (and had received open-label verteporfin therapy) compared with 3 patients (8%) in the group assigned to verteporfin with the RF rate and 6 patients (15%) in the group assigned to verteporfin with the SF rate. These events usually were graded as mild to moderate in intensity and self-limiting, resolving spontaneously by the end of the 10-minute infusion in most cases. No treatment-related allergic reactions were noted in any of the treatment arms, and no deaths occurred through the 24-month examination. With the protocol requiring protection from direct sunlight for up to 48 hours, no photosensitivity reactions were noted in any of the treatment arms. No retinal vascular occlusive events were noted by the treating ophthalmologists through the 12-month examination, and none were noted by the Photograph Reading Center on review of fluorescein angiograms from the 3-month examination. Among study patients with a 3-month examination, the Photograph Reading Center graders noted an increase in subretinal or intraretinal hemorrhage at the 3-month examination compared with the baseline examination in 16 (41%) of 39 study participants assigned to placebo, 13 (35%) of 37 assigned to the RF rate, and 5 (14%) of 37 assigned to the SF rate.
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Table 5. Summary of Adverse Events Judged to Be Clinically Relevant
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COMMENT
To our knowledge, this is the first randomized, controlled, double-masked trial studying efficacy and safety outcomes of verteporfin therapy in minimally classic CNV in patients with AMD. This randomized clinical trial showed outcomes in favor of reducing the risk of loss of at least 15 letters of visual acuity when 2 different verteporfin therapy fluence rates each were compared with placebo treatment through at least 2 years in patients with AMD and subfoveal minimally classic lesions measuring 6 MPS disc areas or less. When pooling the 2 verteporfin arms, the difference between the placebo and pooled verteporfin arms reached a significance level of P = .004 at the 12-month examination and P = .03 at the 24-month examination. These outcomes in favor of the verteporfin arms were supported by a reduction in the development of predominantly classic CNV in verteporfin-treated patients compared with placebo-treated patients (P<.001). Also, these outcomes in favor of the verteporfin arms were achieved despite the fact that 12 (30%) of 40 placebo-treated patients received open-label verteporfin treatment in the study eye at least once during the 24 months of follow-up for treatment of a predominantly classic lesion. These results suggest that treatment of relatively small minimally classic lesions before they convert to a predominantly classic lesion, as in the VIM Trial, will lead to a better outcome than if treatment is applied only after conversion to a predominantly classic lesion.
When the change from baseline in median visual acuity for the RF group was compared with that for the SF group, the difference was almost 2 lines (P = .03) at 1 year and almost 3 lines (P = .14) at 2 years. However, this difference at the 15-, 18-, and 21-month examinations was smaller (approximately 1 line). In addition, the difference in the mean visual acuity score change between the fluence groups was approximately 1 line or less at the 12- and 24-month examinations.
With the recent decision of the US Centers for Medicare and Medicaid Services in January 2004 that "evidence is adequate to conclude that ocular photodynamic therapy (OPT) with verteporfin is reasonable and necessary" for treating relatively small subfoveal minimally classic lesions with recent disease progression, and with "small" defined as 4 MPS disc areas or less,17 the VIM Study Group believed it was reasonable to perform a retrospective analysis of VIM Trial results limited to lesions of 4 disc areas or less. The outcomes were in the same direction as that reported for the entire cohort, although there were only 21, 15, and 14 patients in the placebo, RF, and SF arms, respectively.
Although there were a limited number of participants in this study (approximately 40 in each group), the treatment benefit is unlikely to be due to chance because of the results in each of the 2 fluence groups and the confirmatory information on fluorescein angiography showing fewer instances of conversion to predominantly classic lesions (likely to have a more aggressive natural course than other lesion compositions) in the verteporfin-treated groups. This study confirms the results of retrospective analyses using the minimally classic lesion population from the TAP Investigation suggesting that lesions of 4 MPS disc areas or less with a Snellen equivalent visual acuity of 20/40 to 20/200 had better visual acuity outcomes with verteporfin therapy compared with placebo.10 Not all retrospective data completely support the VIM Trial results. Although fraught with many limitations, when minimally classic lesions as identified by the Photograph Reading Center in the TAP Investigation were limited to the lesion sizes and visual acuities eligible for the VIM Trial, there were only small differences between the verteporfin and placebo groups (3-line loss in 50% of 124 verteporfin-treated eyes compared with 59% of 63 placebo-treated eyes and 6-line loss in 15% of verteporfin-treated eyes compared with 27% of placebo-treated eyes). As mentioned already, a direct comparison of the VIM Trial with this retrospective analysis of a subgroup of the TAP Investigation has many limitations. For example, the patients were not enrolled concurrently, so there may be factors other than initial lesion size, lesion composition, and visual acuity that were not balanced in the absence of randomization to verteporfin or placebo. Also, a minimally classic case was determined by a central reading center in the TAP Investigation, in contrast to determination by the treating ophthalmologist in the VIM Trial. Although the VIM Trial had a relatively small number of patients, the results were consistent with the hypothesis generated by multiple logistic regression analysis showing a visual acuity outcome in favor of relatively small minimally classic lesions in the TAP Investigation10 and relatively small occult with no classic lesions in the VIP Trial. The data also was consistent with a decreased risk of visual acuity loss in the subgroup analysis of minimally classic lesions and occult with no classic lesions with a lesion size of 4 MPS disc areas or less.5, 10
CONCLUSIONS
Based on the totality of the evidence, the VIM Study Group would consider recommending verteporfin therapy for relatively small minimally classic lesions as were enrolled in the VIM Trial. Although no conclusive evidence of differences between the 2 verteporfin regimens was identified, the results warrant further evaluations of the RF rate in patients with AMD with different lesion compositions and sizes.
Submitted for Publication: May 25, 2004; final revision received November 13, 2004; accepted December 15, 2004.
AUTHOR INFORMATION
Correspondence: Neil M. Bressler, MD, Wilmer Eye Institute (Department of Ophthalmology), The Johns Hopkins University School of Medicine, Suite 115, 550 N Broadway, Baltimore, MD 21205-2002 (nmboffice{at}jhmi.edu).
Reprints: Novartis Ophthalmics Medical Affairs, One Health Plaza, Bldg 118, East Hanover, NJ 07936.
Funding/Support: This study was supported financially by Novartis Pharma AG, Basel, Switzerland, and QLT Inc, Vancouver, British Columbia.
Acknowledgment: We thank Christy V. Costello, ELS,* who provided editing and writing assistance.
| Visudyne In Minimally Classic (VIM) CNV Study Group
Clinical Centers
Includes participating clinics, investigators (principal investigators are listed first), clinic coordinators, vision examiners, and photographers in the VIM Study Group as of May 3, 2004.
Alberta Retina Consultants, Edmonton, Alberta: Mark D. J. Greve, MD, Bradley J. Hinz, MD, Michelle Schulha, Brad Wakeman, George Colgon, Bernd Schwanke, Ken Dalton; Bascom Palmer Eye Institute, Miami, Fla: Philip Rosenfeld, MD, Sander Dubovy, MD, Mary-Lou Lewis, MD, Belen Rodriguez, Nayla Muniz, Arelys Torres, Michelle Galvez, Kristin Lipka, Ditte Hess, Antonio Cubillas, Isabel Rams-McPhee; Doheny Eye Institute, University of Southern California, Los Angeles: Jennifer Lim, MD, Christina Flaxel, MD, Margaret Padilla, Elizabeth Perez, Frances Walonker, Jesus Garcia, Mark Thomas; Fakultni Nemocnice Kralovske Vinohrady, Prague, Czech Republic: Petr Soucek, MD, Pavel Kuchynka, MD, Ilona Cihelkova, MD, Lucie Firichova, Lucie Sotolova, Vojtech Polak; HYKS Eye-Ear Hospital, Helsinki, Finland: Ilkka Immonen, MD, Petri Tommila, MD, Paivi Ranta, Eeva-Maria Sankila, Seppo Lemberg; Illinois Retina Associates, Irwin Retina Center, Ingall’s Memorial Hospital, Harvey: David Orth, MD, Joseph Civantos, MD, Tana Drefcinski, Tammy Roark, Carrie Violetto, Celeste Figliulo, Douglas Bryant; Med-West Medical Centre, Toronto, Ontario: Patricia Harvey, MD, Mariel Escover, Josephine Flores, Doris Leuschner, Susan Bolychuk, Ian Brown, Mary Fischer, Kevin Whitfield; Retina Associates of Florida, Tampa: Sanderson Grizzard, MD, Mark Hammer, MD, Ilse Corydon, Jennifer Echevery, Melissa Hardy, Mona Shepard, Janet Traynorm, Maria Santos; Retina Northwest, Lovejoy Medical Building, Portland, Ore: Colin Ma, MD, Richard Dreyer, MD, Pat Bartholomew, Debra DeShazer, Wendy Raunig, Milt Johnson, Joe Logan, Harry Wohlsein; Retina Vitreous Associates Medical Group, Beverly Hills, Calif: David Boyer, MD, Thomas Chu, MD, Ron Gallemore, MD, Roger Novack, MD, Edward Thomas, MD, Joe Martinez, Sandra Gould, Adam Smucker, Dennis Thayer, Jackie Sanguinet; Scott and White Clinic, Temple, Tex: Robert Rosa, MD, Margaret Kriegel, James Whiteis, Susan Hinkle, Dora Rios, George Methvin, Joaquin deVarona; Texas Retina Associates, Dallas: Gary Fish, MD, Bradley Jost, MD, Sally Arceneaux, Dustin Pierce, Jean Arnwine, Brenda Sanchez, Penny Ellenich, Hank Aguado; The Wilmer Ophthalmological Institute, Baltimore, Md: Andrew Schachat, MD, Susan B. Bressler, MD, Neil M. Bressler, MD, Pat Nesbitt, Peggy Orr, Ann Eager, Stacy Seabrook, Siobhan Sheehan, Judith Belt, Rachel Falk, Jacquelyn McDonald, Dennis Cain, David Emmert, Mark Herring; University of Florence, Department of Oto-Neuro-Ophthalmological Surgical Sciences, Eye Clinic II, Florence, Italy: Ugo Menchini, MD, Gianni Virgili, MD, Maria Chiara Arena, Benedetta Pieri, Luciano Galeotti; VGH/UBC Eye Care Center, Vancouver, British Columbia: Michael Potter, MD, Dawne Gillies, RN, Zarina Pardhan, Bryan Joseph Harrison, Laura Hall; Vitreous-Retina-Macula Consultants of New York, LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear & Throat Hospital, New York: Jason Slakter, MD, Richard Spaide, MD, John Sorenson, MD, Namrata Saroj, Joan Daly, RN, Ellen Scott, RN, Maria Scolero, Elisabeth Schnipper, Eugene Agresta, Michael Riff; VitreoRetinal Surgery, PA, Minneapolis, Minn: Robert Mittra, MD, Edwin Ryan, MD, Julianne Enloe, Neal Oestreich, Martha Moos, Lisa Mayleben, Ryan Neist, Julene Gamblain, Holly Cheshier; Wake Forest University Eye Clinic, Winston-Salem, NC: Craig Greven, MD, Madison Slusher, MD, Joan Winnicki, RN, Karen McHugh; and Wolverhampton Eye Infirmary, Wolverhampton, England: Yit-Chiun Yang, FRCOphth, Mohammed Masadiq, FRCOphth, Alison Brown, Jennifer Nosek, Bhogal Singh Bhogal, Sharon Hughes.
Fundus Photograph Reading Center
The Wilmer Ophthalmological Institute: Susan B. Bressler, MD, Neil M. Bressler, MD, Kelly A. Davies, Rita L. Denbow, MLA, Kelly S. Manos, MAS, Srivinas Sadda, MD, Rochelle E. Smith, Sharon D. Solomon, MD, Stephanie K. Thibeault, MFA, Yan Tian, and Deborah A. Phillips.
Visual Acuity Monitors/Certifiers
The Wilmer Ophthalmological Institute: M. Michaele Hartnett, COT, Patricia L. Hawse, MS, COMT, Peggy R. Orr, MPH, COMT, and Tracey Porter, COMT.
Clinic Monitors
Heidi Biagi, Nadine Black, Sue-Anne Crocker, Katy Ford, Janet Hrbolich, Lee Jennings, Mehran Kavoosi, Melissa Kaye, Zdenek Klanc, Kim Mowbray-Martin, Lynn Murray, Birgitta Olsen, Valérie Plante, Katerina Poslusna, Brett Ryan, Tracey Stapleton-Hayes, Claudia Ulbricht, and Wendy Wilson.
Novartis Ophthalmics, Basel, Switzerland
Marcia de Souza Lima, MD.
Novartis Ophthalmics, East Hanover, NJ
Kathleen Meer and Al Reaves, PhD.
QLT Inc, Vancouver, British Columbia
Mohammad Azab, MD, Noel Buskard, MD, Robert Butchofsky, Denise Galipeau, Yong Hao, MD, PhD, Joel Naor, MD (VIM clinical study director for QLT Inc), Edward Ronyecz, H. Andrew Strong, PhD, Xiang Yao Su, Ronald Taylor, Stéphane Vannier, and Maurice Wolin, MD.
Writing Committee
The following individuals take authorship responsibility for the VIM Trial 2-year results: Mohammad Azab, MD,* David S. Boyer, MD, Neil M. Bressler, MD, Susan B. Bressler, MD, Ilona Cihelkova, MD, Yong Hao, MD, PhD,* Ilkka Immonen, MD, Jennifer I. Lim, MD, Ugo Menchini, MD, Joel Naor, MD,* Michael J. Potter, MD, FRCSC, Al Reaves, PhD,* Philip J. Rosenfeld, MD, PhD (writing committee chair); Jason S. Slakter, MD, Petr Soucek, MD, H. Andrew Strong, PhD,* Andrea Wenkstern, MD,* Xiang Yao Su, PhD,* and Yit C. Yang, MBChB, FRCOphth.
Data and Safety Monitoring Committee
Roy Beck, MD (through December 2003), Usha Chakravarthy, MD, PhD, Lee Jampol, MD (chair), Maureen Maguire, PhD, Travis Meredith, MD, and Mario Stirpe, MD.
Verteporfin Study Advisory Group
Neil M. Bressler, MD (chair), Michael Altaweel, MD, David S. Boyer, MD, Susan B. Bressler, MD, Peter Hnik, MD,* Peter Kaiser, MD, Jordi Monés, MD, Joel Naor, MD,* Al Reaves,* PhD, Philip J. Rosenfeld, MD, PhD, Jason Slakter, MD, and Michael Stur, MD.
*Indicates individuals who are employees of Novartis Ophthalmics or QLT Inc, which sponsored the trial.
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Financial Disclosure: The Johns Hopkins University, but not Neil M. Bressler, MD, is paid for consulting services provided by Dr Bressler to Novartis Ophthalmics and QLT Inc. The terms of this institutional consulting arrangement are managed by The Johns Hopkins University in accordance with its conflict-of-interest policies. Michael J. Potter, MD, FRCSC, and Philip J. Rosenfeld, MD, PhD, have been paid as consultants to QLT Inc or Novartis AG or both (which may also include travel expenses at meetings or participation in a speakers bureau). David S. Boyer, MD, Susan B. Bressler, MD, Ilona Cihelkova, MD, Jennifer I. Lim, MD, Jason S. Slakter, MD, and Petr Soucek, MD, have received support for travel expenses at meetings or participation in a speakers bureau. Detailed statements are on file with the chair of the Verteporfin Study Advisory Group’s office.
*Authors: The Writing Committee served as author for the Visudyne in Minimally Classic Choroidal Neovascularization (VIM) Study Group.
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