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Figure 1.
Profile of participants randomized, receiving treatment for choroidal neovascularization (CNV), and completing follow-up (at least a protocol visual acuity assessment) through the month 24 examination.

Profile of participants randomized, receiving treatment for choroidal neovascularization (CNV), and completing follow-up (at least a protocol visual acuity assessment) through the month 24 examination.

Figure 2.
Kaplan-Meier estimate of the cumulative probability of eyes treated with verteporfin or given placebo with moderate visual acuity loss (≥15 letters or approximately 3 lines) at each 3-month study visit over time. First row of numbers below each 3-month follow-up indicates number at risk assigned to verteporfin. Second row of numbers below each 3-month follow-up indicates number at risk assigned to placebo.

Kaplan-Meier estimate of the cumulative probability of eyes treated with verteporfin or given placebo with moderate visual acuity loss (≥15 letters or approximately 3 lines) at each 3-month study visit over time. First row of numbers below each 3-month follow-up indicates number at risk assigned to verteporfin. Second row of numbers below each 3-month follow-up indicates number at risk assigned to placebo.

Figure 3.
Kaplan-Meier estimate of the cumulative probability of eyes treated with verteporfin or given placebo with severe visual acuity loss (≥30 letters or approximately 6 lines) at each 3-month study visit over time. First row of numbers below each 3-month follow-up indicates number at risk assigned to verteporfin. Second row of numbers below each 3-month follow-up indicates number at risk assigned to placebo.

Kaplan-Meier estimate of the cumulative probability of eyes treated with verteporfin or given placebo with severe visual acuity loss (≥30 letters or approximately 6 lines) at each 3-month study visit over time. First row of numbers below each 3-month follow-up indicates number at risk assigned to verteporfin. Second row of numbers below each 3-month follow-up indicates number at risk assigned to placebo.

Figure 4.
Mean number of letters of contrast sensitivity lost at each 3-month study visit over time for eyes assigned to verteporfin treatment or placebo, with last observation carried forward for missing values.

Mean number of letters of contrast sensitivity lost at each 3-month study visit over time for eyes assigned to verteporfin treatment or placebo, with last observation carried forward for missing values.

Figure 5.
On left, percentage of eyes treated with verteporfin (n = 361) and eyes given placebo (n = 187) identified at baseline with classic choroidal neovascularization (CNV) with complete absence of leakage from classic CNV at the month 24 examination, with last observation carried forward for missing values. On right, percentage of eyes treated with verteporfin (n = 402) and eyes given placebo (n = 207) with progression of classic CNV beyond the lesion's area at baseline at the month 24 examination, with last observation carried forward for missing values.

On left, percentage of eyes treated with verteporfin (n = 361) and eyes given placebo (n = 187) identified at baseline with classic choroidal neovascularization (CNV) with complete absence of leakage from classic CNV at the month 24 examination, with last observation carried forward for missing values. On right, percentage of eyes treated with verteporfin (n = 402) and eyes given placebo (n = 207) with progression of classic CNV beyond the lesion's area at baseline at the month 24 examination, with last observation carried forward for missing values.

Figure 6.
Distribution of lesion sizes at the month 24 examination for 402 eyes assigned to verteporfin treatment and 207 eyes assigned to placebo, with last observation carried forward for missing values.

Distribution of lesion sizes at the month 24 examination for 402 eyes assigned to verteporfin treatment and 207 eyes assigned to placebo, with last observation carried forward for missing values.

Table 1. 
Treatments Administered Through the Month 21 Examination*
Treatments Administered Through the Month 21 Examination*
Table 2. 
Frequency Distribution of Changes in Visual Acuity From Baseline by Treatment at the Month 24 Follow-up Examination*
Frequency Distribution of Changes in Visual Acuity From Baseline by Treatment at the Month 24 Follow-up Examination*
Table 3. 
Visual Acuity Categories in Study Eyes by Treatment at the Month 24 Follow-Up Examination*
Visual Acuity Categories in Study Eyes by Treatment at the Month 24 Follow-Up Examination*
Table 4a. 
Eyes With a Loss of Less Than 15 Letters at Month 24 by Treatment Group and Baseline Characteristics* Table 4. Eyes With a Loss of Less Than 15 Letters at Month 24 by Treatment Group and Baseline Characteristics* (cont)
Eyes With a Loss of Less Than 15 Letters at Month 24 by Treatment Group and Baseline Characteristics* Table 4. Eyes With a Loss of Less Than 15 Letters at Month 24 by Treatment Group and Baseline Characteristics* (cont)
Table 4b. 
Eyes With a Loss of Less Than 15 Letters at Month 24 by Treatment Group and Baseline Characteristics* Table 4. Eyes With a Loss of Less Than 15 Letters at Month 24 by Treatment Group and Baseline Characteristics* (cont)
Eyes With a Loss of Less Than 15 Letters at Month 24 by Treatment Group and Baseline Characteristics* Table 4. Eyes With a Loss of Less Than 15 Letters at Month 24 by Treatment Group and Baseline Characteristics* (cont)
Table 5. 
Visual Acuity, Contrast Sensitivity, and Fluorescein Angiography Outcomes at Month 24 Examination for Predominantly Classic CNV Lesions at Baseline*
Visual Acuity, Contrast Sensitivity, and Fluorescein Angiography Outcomes at Month 24 Examination for Predominantly Classic CNV Lesions at Baseline*
Table 6. 
Clinically Relevant Adverse Events Irrespective of Relationship to Treatment
Clinically Relevant Adverse Events Irrespective of Relationship to Treatment
1.
Treatment of Age-Related Macular Degeneration With Photodynamic Therapy(TAP) Study Group, Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials—TAP report 1. Arch Ophthalmol. 1999;1171329- 1345Article
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Macular Photocoagulation Study Group, Subfoveal neovascular lesions in age-related macular degeneration: guidelines for evaluation and treatment in the Macular Photocoagulation Study. Arch Ophthalmol. 1991;1091242- 1257Article
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Bressler  NMGragoudas  ESBressler  SB Age-related macular degeneration, part 2: RPE detachment and subretinal neovascularization. Albert  DMJakobiec  FAeds.Principles and Practice of Ophthalmology. 2nd Philadelphia, Pa WB Saunders Co1999;1992- 2013
4.
Chow  SCLui  JP Analysis of categorical data. Design and Analysis of Clinical Trials: Concepts and Methodologies. New York, NY John Wiley & Sons Inc1998;331- 333
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Chow  SCLui  JP Analysis of continuous data. Design and Analysis of Clinical Trials: Concepts and Methodologies. New York, NY John Wiley & Sons Inc1998;277- 280, 286-290
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Lee  ET Nonparametric methods of estimating survival functions. Statistical Methods for Survival Data Analysis. 2nd New York, NY John Wiley & Sons Inc1992;66- 78
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Hosmer  DWLemeshow  S Interpretation of the coefficients of the logistic regression model. Applied Logistic Regression. New York, NY John Wiley & Sons Inc1989;63- 68
8.
McClure  MEHart  PMJackson  AJStevenson  MRChakravarthy  U Macular degeneration: do conventional measurements of impaired visual function equate with visual disability? Br J Ophthalmol. 2000;84244- 250Article
Clinical Sciences
February 2001

Photodynamic Therapy of Subfoveal Choroidal Neovascularization in Age-Related Macular Degeneration With VerteporfinTwo-Year Results of 2 Randomized Clinical Trials—TAP Report 2

Treatment of Age-Related Macular Degeneration With Photodynamic Therapy(TAP) Study Group
Author Affiliations

A complete list of the participants in the TAP Study Group is available in Arch Ophthalmol. 1999;117:1343-1344, with updates as of January 11, 2000, shown below.

Arch Ophthalmol. 2001;119(2):198-207. doi:10-1001/pubs.Ophthalmol.-ISSN-0003-9950-119-2-ecs00156
Abstract

Objective  To report 24-month vision and fluorescein angiographic outcomes from trials evaluating photodynamic therapy with verteporfin (Visudyne; CIBA Vision Corp, Duluth, Ga) in patients with subfoveal choroidal neovascularization(CNV) caused by age-related macular degeneration (AMD).

Design  Two multicenter, double-masked, placebo-controlled, randomized clinical trials.

Setting  Twenty-two ophthalmology practices in Europe and North America.

Participants  Patients with subfoveal CNV lesions caused by AMD with greatest linear dimension on the retina measuring 5400 µm or less, with evidence of classic CNV and best-corrected visual acuity (approximate Snellen equivalent) between 20/40 and 20/200.

Methods  The methods were similar to those described in our 1-year results,1 with follow-up examinations beyond 1 year continuing every 3 months (except for Photograph Reading Center evaluations, which occurred only at month 18 and month 24 examinations). During the second year, the same regimen (with verteporfin or placebo as applied at baseline) was used if angiography showed fluorescein leakage from CNV. The primary outcome was the proportion of eyes with fewer than 15 letters (approximately 3 lines) of visual acuity loss at the month 24 examination, adhering to an intent-to-treat analysis. The last observation was carried forward to impute for any missing data.

Results  Three hundred fifty-one (87%) of 402 patients in the verteporfin group compared with 178 (86%) of 207 patients in the placebo group completed the month 24 examination. Beneficial outcomes with respect to visual acuity and contrast sensitivity noted at the month 12 examination in verteporfin-treated patients were sustained through the month 24 examination. At the month 24 examination for the primary outcome, 213 (53%) of 402 verteporfin-treated patients compared with 78 (38%) of 207 placebo-treated patients lost fewer than 15 letters (P<.001). In subgroup analyses for predominantly classic lesions (in which the area of classic CNV makes up at least 50% of the area of the entire lesion) at baseline, 94 (59%) of 159 verteporfin-treated patients compared with 26 (31%) of 83 placebo-treated patients lost fewer than 15 letters at the month 24 examination (P<.001). For minimally classic lesions (in which the area of classic CNV makes up <50% but >0% of the area of the entire lesion) at baseline, no statistically significant differences in visual acuity were noted. Few additional photosensitivity adverse reactions and injection site adverse events were associated with verteporfin therapy in the second year of follow-up.

Conclusions  The visual acuity benefits of verteporfin therapy for AMD patients with predominantly classic CNV subfoveal lesions are safely sustained for 2 years, providing more compelling evidence to use verteporfin therapy for these cases. For AMD patients with subfoveal lesions that are minimally classic, there is insufficient evidence to warrant routine use of verteporfin therapy.

IN 1999, THE Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group reported 1-year results from 2 randomized clinical trials of photodynamic therapy with verteporfin (Visudyne; CIBA Vision Corp, Duluth, Ga) conducted among patients with subfoveal choroidal neovascularization(CNV) caused by age-related macular degeneration (AMD).1 At the time of enrollment, patients were randomly assigned to verteporfin or placebo infusion followed by application of laser light to activate verteporfin or to serve as a sham treatment for patients given placebo. A visual acuity benefit through 1 year of follow-up was demonstrated for the entire study group assigned to verteporfin therapy and was even stronger for subfoveal lesions that were predominantly classic (in which the area of classic CNV was at least 50% of the area of the entire lesion). Based on these 1-year outcomes, verteporfin therapy was recommended for treatment of patients with predominantly classic CNV lesions due to AMD. However, at the time of this recommendation, it was not possible to determine whether these benefits would persist beyond 1 year.

Minimally classic lesions (in which the area of classic CNV was <50% of the area of the entire lesion) fared better when assigned to verteporfin therapy (202 patients) compared with placebo (103 patients) with respect to contrast sensitivity measurements (mean of 2.0 vs 4.1 letters lost), progression of classic CNV beyond the area of the entire lesion noted at baseline (37.1% vs 62.1%), and lesion growth (>6 disc areas in 45.5% vs 71.8%). However, visual acuity outcomes of minimally classic lesions assigned to verteporfin were not significantly different from those assigned to placebo. The purpose of this report is to provide additional information on the potential of verteporfin therapy to reduce the risk of vision loss compared with placebo therapy for the entire study group and for predominantly classic lesions, as well as to determine if the visual acuity outcomes for minimally classic lesions were significantly different from those assigned to placebo, based on 2-year outcomes completed by participants as of October 14, 1999.

PATIENTS AND METHODS

The highlights of the study protocol are described in our earlier report1 with pertinent aspects summarized as follows. Before patient enrollment began, the design was reviewed by a study advisory group(members of the TAP Study Group who advise the study sponsors on the scientific aspects of the investigation), the institutional review board of the participating clinical center, and a data- and safety-monitoring committee independent of the study sponsors and the TAP Study Group. Monitoring of the clinical centers(including all visual acuity examiners) and the Photograph Reading Center continued through the second year of follow-up.

PATIENT SELECTION AND ENTRY EVALUATIONS

Regulatory agencies require 2 randomized clinical trials to independently confirm a statistically significant benefit for a primary outcome to be considered for regulatory approval. As described previously,1 the TAP Investigation consisted of 2 randomized clinical trials that were designed identically and run concurrently, except that 10 of the clinical centers from North America and Europe were assigned to study A, and the other 12 were assigned to study B. Patients were enrolled in these 2 trials from December 1996 through October 1997, when the target sample size was attained. Vision testing, color photographs, fluorescein angiography, medical histories, and physical examinations were completed within 8 days prior to enrollment in the trial.

Patient Selection

Patients had to fulfill eligibility criteria determined by an ophthalmologist certified to enroll and treat study participants. Key features of the eligibility criteria included a best-corrected visual acuity (following the TAP protocol1) letter score of between 73 and 34 (Snellen equivalent, approximately 20/40 to 20/200), fluorescein angiographic evidence (using definitions previously described2,3) of subfoveal CNV in which at least 50% of the lesion was CNV, at least some of the lesion had classic CNV, and the lesion's greatest linear dimension was no larger than 5400 µm.

TAP Investigation Design

As with the 1-year results,1 because the investigation used the same organizational structure concurrently and because baseline characteristics, completeness of follow-up, and outcomes were similar for the 2-year results of study A and study B, the Data and Safety Monitoring Committee recommended (with agreement by the TAP Study Group) that the scientific presentation of the results in peer-reviewed publications should use the combined data set in accordance with the design and primary goal of the investigation.

Vision Testing, Photographs, Other Medical Aspects, and Study Entry

Vision testing, stereoscopic color fundus photographs, fluorescein angiograms, and other medical aspects were described in detail previously.1 After reviewing and signing a statement of written informed consent accompanied by an oral consent process with a certified investigator (ophthalmologist), patients judged by a TAP-certified enrolling ophthalmologist to satisfy all eligibility criteria were assigned randomly to verteporfin or placebo infusion in a 2:1 ratio, respectively.

Random Assignments and Masking

Random assignments and masking were performed as described in our previous study.1 Masking with regard to treatment assignment was done with all patients, vision examiners, photographers, ophthalmologists, Photograph Reading Center personnel, and clinic monitors. Only the study coordinator and any other person assisting in the setup of verteporfin or placebo solutions were aware of the treatment assignment; these individuals were trained to make every reasonable attempt to maintain masking of participating patients and all other study personnel. In the first year of follow-up, 2 patients were likely unmasked, and 4 treating ophthalmologists (but not the patients) were unmasked on 1 patient each. There were no known additional instances of unmasking in the second year of follow-up. All investigators and study coordinators were informed of their patients' treatment assignments on February 18, 2000, after the database for this investigation was finalized on February 17, 2000. Patients were subsequently informed of their assignments; the success of masking was not formally evaluated.

Verteporfin Therapy, Placebo Therapy, Patient Follow-up, and Fluorescein Angiographic Assessment

Verteporfin therapy, placebo therapy, and patient follow-up were performed in all clinical centers according to a standard protocol described previously1 that remained unchanged through the second year of follow-up. Fluorescein angiographic assessment at follow-up was graded in a masked fashion at treating centers every 3 months and at the Photograph Reading Center at the month 18 and month 24 examination.

STATISTICAL METHODS
Sample Size Estimation and Outcome Measurements

A target sample size of 270 patients in each trial or 540 patients for both trials was needed for the evaluation of at least 225 patients in each trial at the last follow-up, assuming 17% died or were lost to follow-up.

The primary efficacy outcome at 2 years, as at 1 year,1 was the proportion of eyes that had lost fewer than 15 letters (<3 lines of visual acuity loss) compared with the baseline examination. Secondary efficacy outcomes included the proportion of eyes that had lost fewer than 30 letters(<6 lines of visual acuity loss) compared with baseline, mean changes in visual acuity, proportion of study eyes with visual acuity of 20/200 or less at the month 24 examination, mean changes in contrast threshold, and angiographic outcomes (progression of classic CNV and size of lesion) at the month 24 examination.

Statistical Analysis

The primary efficacy analyses were based on a strict intent-to-treat analysis; patients were analyzed within the group to which they were randomized. The proportion of eyes that lost fewer than 15 or 30 letters from baseline to the month 24 examination were analyzed using a Pearson χ2test.4 The frequency distributions of changes in visual acuity from baseline, visual acuity categories, and changes in contrast sensitivity from baseline were compared between groups using a Wilcoxon rank sum test.5 The mean change in visual acuity and contrast sensitivity from baseline was compared between groups using a 2-sample t test.5 The times to a loss of 15 or more letters and separately of 30 or more letters were analyzed using the Kaplan-Meier method.6 The loss counted as an event only if it was confirmed at the next visit or observed at the patient's final visit. The complements of the Kaplan-Meier estimates at each scheduled visit are displayed graphically using point estimates from each visit. Assessments of fluorescein leakage and lesion size were compared between groups using a Pearson χ2 test.4 The intent-to-treat analysis included all randomized patients; missing values were imputed by carrying the last observation forward. All primary and secondary outcomes for the entire study group and the predominantly classic subgroup were similar without this imputation. Wherever outcomes are given at specific time points (eg, at the month 24 examination), the results are for that time point with the last observation carried forward. The phrase "last observation carried forward" is repeated in tables and figures only where appropriate; it does not appear within the text of the "Results" section. To test for interactions between treatment and subgroup variables, a logistic regression model was used for binary response variables.7

DATA MONITORING AND REPORTING

Data monitoring was continued by the same Data and Safety Monitoring Committee approximately every 6 months as described previously,1 with no prospectively defined stopping rules. No safety concerns were voiced by the committee at its reviews on January 28, 1999, and August 9, 1999. On March 22, 2000, 12-month data analyzed by the sponsors were reviewed along with an independent analysis of the month 12 through month 24 efficacy analyses conducted by the Jaeb Center for Health Research (Tampa, Fla) to verify the accuracy of the sponsors' data analyses. Based on this review of the data and to comply with Securities and Exchange Commission policies in Canada and the United States, the top-line results of these analyses were shared with the public via a news release from the sponsors on March 27, 2000. The data on which this public announcement was based were reviewed by the TAP Study Advisory Group and the TAP Study Group on April 16, 2000, and are presented in this report.

RESULTS

Three hundred fifty-one (87%) of the 402 patients in the verteporfin-treated group compared with 178 (86%) of the 207 patients in the placebo-treated group completed the month 24 examination (Figure 1), a loss of only an additional 7% in each group during the second 12 months of follow-up. By the month 21 examination (the last visit within the investigation when retreatment could be applied), 181 patients (45%) of the verteporfin-treated group and 135 patients (65%) of the placebo-treated group received retreatment (Figure 1), down from 64% and 79%, respectively, at the month 12 examination. Patients in the verteporfin-treated group received an average of 2.2 treatments per participant from the month 12 through the month 21 examination (Table 1), for a total of 5.6 treatments from the onset of the study.

VISION OUTCOMES

The distribution of change in visual acuity at the month 24 examination is shown in Table 2. For the primary outcome, the beneficial effects noted at the month 12 examination were sustained through the month 24 examination; 213 (53%) of 402 study eyes in the verteporfin-treated group compared with 78 (38%) of 207 study eyes in the placebo-treated group(P<.001) lost fewer than 15 letters (<3 lines) of visual acuity. This outcome represented 8% fewer study eyes in both the verteporfin- and placebo-treated groups compared with the month 12 examination results. The avoidance of severe visual acuity loss (<30 letters or <6 lines) was also sustained, occurring more often (82% vs 70%) in the verteporfin-treated group (P<.001) and representing 3% and 6% fewer study eyes in the verteporfin- and placebo-treated groups, respectively, compared with the month 12 examination results. Based on estimates from Kaplan-Meier rates at every follow-up examination after study entry, the proportion of eyes with a loss of 15 or more letters (≥3 lines; Figure 2) or of 30 or more letters (≥6 lines; Figure 3) at each visit remained lower in the verteporfin-treated group through the month 24 examination.

The actual visual acuity scores at the month 24 examination (Table 3) show that the proportion of study eyes with a visual acuity of 20/200 or less remained smaller in the verteporfin-treated group compared with the placebo-treated group (41.0% vs 55.2%; P = .001), representing a 6% and 7% increase over the month 12 outcomes, respectively. The change in the mean contrast sensitivity score from baseline(Figure 4) remained stable through the month 24 examination only in the verteporfin-treated group. The verteporfin-treated group lost 1.3 letters at both the month 12 and month 24 examination compared with the baseline score. In contrast, the placebo-treated group lost 4.5 letters at the month 12 examination and 5.2 letters at the month 24 examination compared with baseline. The difference in change from baseline at the month 24 examination(1.3 letters vs 5.2 letters) was statistically significant (P<.001).

FLUORESCEIN ANGIOGRAPHIC OUTCOMES

The proportion of eyes with progression of classic CNV beyond the area of the lesion identified at baseline (Figure 5) was significantly smaller in the verteporfin-treated group compared with the group given placebo (23.1% vs 53.6%; P<.001), a decrease from 46% and 71.1%, respectively, at the month 12 examination. The proportion of eyes with absence of classic CNV either within or beyond the area of the lesion identified at baseline (Figure 5) continued to increase through the month 24 examination and remained higher in study eyes assigned to verteporfin compared with placebo(51.2% vs 28.5%; P<.001), an increase from 18.8% and 9.1%, respectively, at the month 12 examination. Lesion size at the month 24 examination is shown in Figure 6. Placebo-treated lesions were almost twice as likely as those treated with verteporfin to be more than 6 disc areas in size, and 2.5 times more likely to be greater than 9 disc areas in size.

SUBGROUP ANALYSES

Subgroup analyses for the primary outcome (Table 4) were undertaken at the month 24 examination to determine treatment effects in different subpopulations and to further explore outcomes based on lesion composition that were judged to be clinically relevant at the month 12 examination. As noted earlier,1 no subgroups were identified at the month 24 examination in which eyes given placebo had a better outcome than eyes treated with verteporfin. Consistent with the 1-year results, only lesion components at baseline as judged by the Photograph Reading Center affected the magnitude of the treatment benefit to a statistically significant degree (Table 4; Pi≤.05 for the test of interaction). A large treatment benefit was sustained when the lesion was predominantly classic CNV (ie, the area of classic CNV occupied at least 50% of the area of the entire lesion) at baseline, with 94 (59%) of the 159 eyes treated with verteporfin losing less than 15 letters at the month 24 examination, compared with 26 (31%) of the 83 eyes given placebo. As with the primary outcome for the entire group, this subgroup represented 8% fewer study eyes in both the verteporfin-treated and placebo-treated groups compared with the month 12 examination results.

No clinically meaningful difference with respect to the primary visual acuity outcome was observed in the group of patients with minimally classic lesions (ie, the area of classic CNV occupied <50% but >0% of the area of the entire lesion) at baseline, with 96 (47.5%) of 202 verteporfin-treated patients compared with 46 (44.2%) of 104 placebo-treated patients losing less than 15 letters at the month 24 examination (P =.58). For the subgroup of lesions with no classic CNV at baseline, the number of patients was small; these cases should not have been enrolled, because the eligibility criteria required evidence of classic CNV at baseline. At the month 24 examination, 23 (56%) of 41 verteporfin-treated patients compared with 6 (30%) of 20 placebo-treated patients lost less than 15 letters of visual acuity (P = .06). When the entire study population was analyzed by absence or presence of occult CNV, the treatment benefit for the subgroup without occult CNV (ie, lesions with classic CNV but no occult CNV) remained substantial at the month 24 examination, with 65 (70%) of 93 verteporfin-treated patients losing less than 15 letters, compared with 14(29%) of 49 placebo-treated patients (P<.001).

ADDITIONAL ANALYSES FOR PREDOMINANTLY CLASSIC LESIONS

Because the visual acuity benefit at the month 12 examination was stronger in eyes with predominantly classic CNV at baseline and because this benefit was sustained through the month 24 examination, further information on outcomes for this subgroup is given in Table 5. At the month 24 examination for this subgroup, the proportion of eyes losing at least 15 or 30 letters, the proportion of eyes with a letter score below 34 (Snellen equivalent, ≤20/200), the mean change in visual acuity score or contrast sensitivity score from baseline, the proportion of eyes losing at least 9 letters (≥3 segments) in contrast sensitivity score from baseline, and angiographic outcomes were significantly better (P<.001) in the verteporfin-treated patients compared with the placebo-treated patients. In a subsequent exploratory analysis, even when study eyes with classic but no occult CNV were removed from the subgroup with predominantly classic CNV, visual acuity benefits for predominantly classic with occult CNV were noted and were even stronger than at the month 12 examination. For example, 12 (17%) of the 69 patients treated with verteporfin that had this lesion composition at baseline, compared with 14 (36%) of the 39 patients treated with placebo, had lost at least 30 letters (P = .03) at the month 24 examination. Also, for lesions with predominantly classic CNV with occult CNV at baseline, the mean change from baseline in contrast sensitivity score was almost 0 in the verteporfin-treated group compared with −6 letters(approximately 2 segments of contrast) in the placebo-treated group.

SAFETY

An adverse event (irrespective of relationship to treatment) was reported in 378 patients (94%) in the verteporfin-treated group and 192 patients (92.8%) in the placebo-treated group. Adverse events considered by the treating ophthalmologist to be associated with therapy were reported in 192 patients (47.8%) treated with verteporfin and 70 (33.8%) patients given placebo. Adverse events judged to be clinically relevant, listed in Table 6, included visual disturbances in 89 verteporfin-treated patients(22.1%) compared with 32 placebo-treated patients (15.5%). This represents only 18 and 8 more patients with adverse events, respectively, compared with the month 12 examination. Only 10 (2.5%) and 5 (2.4%) additional patients had injection site adverse events, respectively, between the month 12 and month 24 examination. One additional patient in the verteporfin-treated group reported infusion-related back pain in the second 12 months of follow-up. Allergic reactions remained uncommon and were less frequent in the verteporfin-treated group (2.0%) compared with the placebo-treated group (3.9%). In the verteporfin-treated group, 2 additional photosensitivity reactions were noted in the second 12 months of follow-up for a total of 14 adverse effects (3.5%). Also in the second 12 months of follow-up, there were 5 and 4 additional deaths, respectively, for a total number of 13 deaths (3.2%) in the verteporfin-treated group and 8 (3.9%) in the placebo-treated group. No additional patients stopped treatment because of an adverse event judged by the treating ophthalmologist to be related to study treatment in the second 12 months of follow-up, keeping the total number of withdrawals due to adverse events, as described previously,1 at 7 patients (1.7%), all in the verteporfin-treated group. For both groups, the distribution of the size of the lesion plus any surrounding atrophy was not significantly different from the distribution of the size of the lesion without the inclusion of surrounding atrophy, suggesting that by the month 24 examination, verteporfin-treated eyes had developed no additional surrounding atrophy compared with placebo-treated eyes.

COMMENT

The overall beneficial outcomes with verteporfin therapy reported previously1 in cases of subfoveal CNV in AMD, with evidence of classic CNV at enrollment in the TAP Investigation, were sustained through 2 years of follow-up. The results from this additional year provide more compelling evidence for the effectiveness of verteporfin therapy in the management of lesions judged to be predominantly classic CNV at baseline. Most of the visual acuity loss in both the verteporfin-treated group and the placebo-treated group occurred in the first year, especially during the first 3 to 6 months of therapy. No striking loss of vision or atrophy of the retinal pigment epithelium was noted in the verteporfin-treated group in the second year of follow-up. The minimal additional visual acuity loss and contrast sensitivity loss in this group during the second 12 months suggests that the photodynamic therapy selectively avoided substantial damage to the photoreceptors and underlying retinal pigment epithelium. Recent studies have indicated that decreased levels of contrast sensitivity in patients with decreased visual acuity from AMD are associated with decreased levels of visual function.8

The minimal worsening of vision outcomes during the second 12 months of follow-up was noted despite the relatively low proportion of study eyes treated with verteporfin that had absence of leakage from classic CNV (18.8%) at the month 12 examination as judged by the Photograph Reading Center. The average number of applications of verteporfin treatment in the second year(2.2) was lower than the average number of applications in the first year(3.4). The limited additional vision loss in the verteporfin-treated group in the second 12 months does not necessarily suggest that retreatments were unnecessary during this period. Without retreatment of study eyes with fluorescein leakage from CNV during the second 12 months of follow-up, the favorable outcomes at the month 24 examination might not have been attained.

Angiographic outcomes provide further evidence to the visual acuity information that the lesions were stabilizing on verteporfin therapy, because the proportion of study eyes treated with verteporfin that had progression of classic CNV decreased from 43% to 23% between the month 12 and month 24 examination. Similarly, the difference in percentage of verteporfin-treated patients with absence of classic CNV increased from 23% to 51.2%, a much greater jump than in patients given placebo, which increased only from 13% to 28.5%.

As was noted at the month 12 examination, the treatment benefit at the month 24 examination was stronger not only for the subgroup of eyes with predominantly classic lesions but also for the subgroup of eyes composed of classic CNV with no occult CNV at baseline. However, in an exploratory retrospective analysis, even when study eyes with classic but no occult CNV were removed from the subgroup with predominantly classic CNV, visual acuity and contrast sensitivity benefits for predominantly classic with occult CNV were noted and were even stronger than at the month 12 examination.

For lesions judged to be minimally classic at the baseline examination by the Photograph Reading Center, contrast sensitivity and fluorescein angiography outcomes at both the month 12 and month 24 examinations were significantly better in verteporfin-treated patients compared with those given placebo. These positive outcomes were not accompanied by significantly better visual acuity outcomes than in placebo-treated cases. These results also confirm that using fluorescein angiographic outcomes to predict those for visual acuity may not always work, because significantly better angiographic results do not always correlate with better outcomes for visual acuity.

The favorable outcomes for verteporfin therapy noted for the small number of patients whose eyes had no classic CNV at baseline (according to the Photograph Reading Center) were less evident at the month 24 examination, when the difference between the percentage of verteporfin-treated patients and placebo-treated patients who lost less than 15 letters only approached statistical significance. The Verteporfin in Photodynamic Therapy (VIP) Trial, which was to enroll patients with subfoveal lesions caused by AMD with occult CNV but no classic CNV, will provide more precise data regarding the benefits and risks of verteporfin therapy in such cases.

CONCLUSIONS

The 2-year outcomes from the TAP Investigation strengthen the evidence from the 1-year results that verteporfin therapy can safely reduce the risk of vision loss in patients with predominantly classic subfoveal CNV caused by AMD, with or without occult CNV, and that verteporfin should be prescribed for this type of lesion. For AMD patients with minimally classic subfoveal lesions, there is insufficient evidence at this time to make a recommendation regarding the use of verteporfin therapy.

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Article Information

Accepted for publication November 2, 2000.

This study was financially supported by CIBA Vision AG, Bülach, Switzerland, and QLT Inc, Vancouver, British Columbia.

The Wellman Laboratories of Photomedicine, Massachusetts General Hospital, are an owner of a patent covering the use of verteporfin. Should the Wellman Laboratories of Photomedicine receive royalties or other financial remuneration related to that patent, Dr Schmidt-Erfurth would receive a share of the same in accordance with the Wellman Laboratories of Photomedicine's institutional Patent Policy and Procedures, which includes royalty-sharing provisions. The Massachusetts Eye and Ear Infirmary is a co-owner of a patent covering the use of verteporfin. In addition, the Massachusetts Eye and Ear Infirmary is the sole owner of claims in patent applications relating to the selective destruction of subretinal choroidal neovasculature for the treatment of macular degeneration and other disorders. Should the Massachusetts Eye and Ear Infirmary receive royalties or other financial remuneration related to the patent and patent filing, Drs Miller and Gragoudas would receive a share of the same in accordance with the Massachusetts Eye and Ear Infirmary's institutional Patent Policy and Procedures, which includes royalty-sharing provisions.

The following authors have indicated a financial interest as follows: paid consultants of Novartis Ophthalmics or QLT, Inc, or both: Mark S. Blumenkranz, MD, Neil M. Bressler, MD, Michael J. Potter, MD; support for scientific presentations at meetings and travel expenses: Susan B. Bressler, MD, Jordi M. Monés, MD; ownership of QLT stock: Patricia Harvey, MD, Lawrence J. Singerman, MD; patent interest in verteporfin: Evangelos S. Gragoudas, MD, Joan W. Miller, MD, Ursula Schmidt-Erfurth, MD. Detailed statements are on file with the ARCHIVES office.

Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group

Clinical Centers

The Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Md: Ann Eager.

Cole Eye Institute, The Cleveland Clinical Foundation, Cleveland, Ohio: Stephen Burke.

Texas Retina Associates, Dallas: Jean Arnwine, Rubye Collins, Hank Aguado.

St. Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, England: Salim Natha.

Medizinische Universität zu Lübeck, Klinik für Augenheilkunde, Lübeck, Germany: Hanno Elsner, Kai Honnicke, Verena Wintzer.

Zweng Memorial Retinal Research Foundation, Menlo Park, Calif: Kathy Honeycutt, Lora Lamborn.

Bascom Palmer Eye Institute, University of Miami, Miami, Fla: Jael Gosdenovich, Linda Duria.

Vitreous-Retina-Macula Consultants of New York, New York, NY: Maria Scolaro.

Devers Eye Institute, Portland, Ore: Harold Crider, Milton Johnson.

Associated Retina Consultants, Royal Oak, Mich: Kristi Cumming.

CIBA Vision AG, Bülach, Switzerland: Alain Bobillier.

CIBA Vision Corp, Duluth, Ga: Leann McAlister, Roberta Birch.

QLT Inc, Vancouver, British Columbia: Marcia Mason, Ursula McCurry, Terri So.

Writing Committee for TAP Report 2

Jennifer Arnold, MD, Irene Barbazetto, MD, Reginald Birngruber, MD, Mark S. Blumenkranz, MD, Susan B. Bressler, MD, Neil M. Bressler, MD, Guy Donati, MD, Gary Edd Fish, MD, Evangelos S. Gragoudas, MD, Patricia Harvey, MD, Peter K. Kaiser, MD, Hilel Lewis, MD, Joan W. Miller, MD, Jordi M. Monés, MD, Michael J. Potter, MD, Constantin J Pournaras, MD, Andrew P. Schachat, MD, Ursula Schmidt-Erfurth, MD, Lawrence J. Singerman, MD, H. Andrew Strong, PhD, Hubert van den Berg, PhD, George A. Williams, MD.

A complete list of the participants in the TAP Study Group is available in Arch Ophthalmol. 1999;117:1343-1344, with updates as of January 11, 2000, above.

Corresponding author: Neil M. Bressler, MD, Suite 115, 550 N Broadway, Baltimore, MD 21205-2005 (e-mail: pstaflin@jhmi.edu). Reprints: Medical Information, CIBA Vision Corporation, 11460 Johns Creek Pkwy, Duluth, GA 30097.

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