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Photodynamic Therapy of Subfoveal Choroidal Neovascularization in Age-Related Macular Degeneration With Verteporfin
Two-Year Results of 2 Randomized Clinical Trials—TAP Report 2
Treatment of Age-Related Macular Degeneration With Photodynamic Therapy
(TAP) Study Group
Arch Ophthalmol. 2001;119:198-207.
ABSTRACT
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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.
INTRODUCTION
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  2
test.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 2 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.
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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.
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Table 1. Treatments Administered Through the Month 21 Examination*
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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.
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Table 2. Frequency Distribution of Changes in Visual Acuity From Baseline
by Treatment at the Month 24 Follow-up Examination*
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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.
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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.
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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).
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Table 3. Visual Acuity Categories in Study Eyes by Treatment at the
Month 24 Follow-Up Examination*
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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.
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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.
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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.
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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.
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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.
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Table 4. 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)
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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.
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Table 5. Visual Acuity, Contrast Sensitivity, and Fluorescein Angiography
Outcomes at Month 24 Examination for Predominantly Classic CNV Lesions at
Baseline*
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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.
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Table 6. Clinically Relevant Adverse Events Irrespective of Relationship
to Treatment
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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.
AUTHOR 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{at}jhmi.edu). Reprints:
Medical Information, CIBA Vision Corporation, 11460 Johns Creek Pkwy, Duluth,
GA 30097.
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.
REFERENCES
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