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Verteporfin Therapy for Subfoveal Choroidal Neovascularization in Age-Related Macular Degeneration
Three-Year Results of an Open-Label Extension of 2 Randomized Clinical Trials—TAP Report No. 5
Treatment of Age-Related Macular Degeneration With Photodynamic Therapy
(TAP) Study Group
Arch Ophthalmol. 2002;120:1307-1314.
ABSTRACT
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Objective To report vision and safety outcomes from an extension of a 2-year investigation
evaluating verteporfin photodynamic therapy in patients with age-related macular
degeneration with subfoveal choroidal neovascularization (CNV).
Design and Setting Open-label extension of selected patients from 2 multicenter, double-masked,
placebo-controlled, randomized clinical trials, the Treatment of Age-Related
Macular Degeneration With Photodynamic Therapy (TAP) Investigation, at 22
ophthalmology practices in Europe and North America.
Participants Patients enrolled in the TAP Investigation and followed up for at least
24 months in whom verteporfin therapy to CNV might reduce the risk of further
vision loss.
Methods Before receiving verteporfin therapy in the extension, eligible patients
signed a written informed consent form accompanied by an oral consent process
approved by local institutional review boards. Methods were similar to those
described for 1- and 2-year results, with follow-up examinations beyond 2
years continuing at 3-month intervals with a few exceptions, including that
extension patients with fluorescein leakage from CNV were to receive open-label
verteporfin therapy irrespective of their original
treatment assignment.
Results Of 402 patients in the verteporfin group, 351 (87.3%) completed the
month 24 examination; 320 (91.2%) of these enrolled in the extension study.
The enrolled participants included 124 (78.0%) of the 159 verteporfin-treated
patients with lesions composed of predominantly classic CNV at baseline, of
whom 105 (84.7%) completed the month 36 examination. Verteporfin-treated patients
with this lesion composition at baseline who participated in the extension
study, with or without a month 36 examination, appeared more likely to have
a younger age, better level of visual acuity, absence of fluorescein leakage
from classic CNV, or no progression of classic CNV beyond the baseline boundaries
of the lesion at the month 24 examination compared with those who did not
enroll in the extension. For the 105 patients with a predominantly classic
baseline lesion composition who completed the month 36 examination, an average
of 1.3 treatments were given from the month 24 examination up to, but not
including, the month 36 examination. A letter score loss in the study eye
of at least 15 from baseline for these patients occurred in 39 (37.5%) at
the month 24 examination compared with 44 (41.9%) of these patients at the
month 36 examination. Visual acuity changed little from the month 24 examination
(mean, -1.9 lines) to the month 36 examination (mean, -2.0 lines)
for these eyes. Verteporfin-treated patients had little change in the mean
visual acuity lost and few or no additional instances of infusion-related
back pain or photosensitivity reactions from month 24 to month 36. Two patients
originally assigned to placebo had acute severe vision decrease within 7 days
after verteporfin treatment during the extension. One patient originally assigned
to verteporfin had acute severe vision decrease after verteporfin treatment
of the fellow eye during the extension.
Conclusions Vision outcomes for verteporfin-treated patients with predominantly
classic lesions at baseline remained relatively stable from month 24 to month
36, although only approximately one third of the verteporfin-treated patients
originally enrolled with this lesion composition had a month 36 examination.
From these results, the TAP Study Group identified no safety concerns to preclude
repeating photodynamic therapy with verteporfin. Additional treatment was
judged likely to reduce the risk of further vision loss. Caution appears warranted
in the absence of comparison with an untreated group during the extension
and since not all patients in the TAP Investigation participated in the TAP
Extension.
INTRODUCTION
THE TREATMENT of Age-Related Macular Degeneration With Photodynamic
Therapy (TAP) Study Group reported 1-year1 and
2-year2 results from 2 randomized clinical
trials evaluating photodynamic therapy with verteporfin (Visudyne; Novartis
Ophthalmics AG, Bülach, Switzerland) among patients with subfoveal choroidal
neovascularization (CNV) caused by age-related macular degeneration (AMD)
in which the baseline lesion composition on fluorescein angiography was to
include a component of classic CNV. At the time of enrollment, patients were
assigned randomly to intravenous verteporfin or a placebo (dextrose in water)
followed by application of laser light to activate verteporfin or serve as
a sham treatment for patients given a placebo. A visual acuity benefit through
at least 2 years was demonstrated for the 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). On the basis of these outcomes, verteporfin therapy has
been recommended for treatment of patients with AMD with predominantly classic
CNV lesions, with or without occult CNV, and has received regulatory approval
for this indication in more than 50 countries, including the United States,
Canada, the European Union, and Australia.
An open-label extension of the TAP Investigation beyond 2 years of follow-up
was designed after the beneficial 1-year outcomes were recognized.1 The extension enabled longer-term visual acuity and
safety outcomes in patients originally assigned to verteporfin therapy to
be obtained and offered verteporfin therapy to selected patients originally
assigned to placebo therapy and followed up without verteporfin therapy for
2 years. The purpose of this report is 2-fold: first, to describe detailed
vision outcomes between the month 24 and month 36 follow-up examination for
verteporfin-treated patients who had a predominantly classic lesion at baseline,
a group in the TAP Investigation for whom verteporfin therapy is recommended;
and second, to describe safety information during this follow-up period for
all patients enrolled, regardless of baseline lesion composition or treatment
assignment (verteporfin or placebo).
METHODS
The highlights of the protocol for the TAP Investigation are described
in earlier reports.1-2 Patients
enrolled in the TAP Investigation had subfoveal CNV caused by AMD in which
the greatest linear dimension of the lesion was no greater than 5400 µm
on the retina and in which the lesion included a component of classic CNV
associated with a best-corrected visual acuity letter score between 73 and
34 (equivalent to an approximate Snellen acuity of 20/40 to 20/200).
Enrolled patients were randomly assigned (in a 2:1 ratio) to either
verteporfin therapy or placebo sham therapy. Verteporfin therapy included
infusion of 6 mg/m2 of body surface area of verteporfin in a 30-mL
solution during 10 minutes followed by activation with a 689-nm diode laser
light at an irradiance of 600 mW/cm2 for 83 seconds producing a
fluence of 50 J/cm2 applied to a spot size 1000 µm greater
than the lesion's greatest linear dimension. Placebo sham therapy included
infusion of 30 mL of dextrose in water with the same light application to
serve as a sham procedure.
Patients were asked to return every 3 months (±2 weeks) for 24
months and were to be retreated with either verteporfin or placebo (whatever
was assigned at baseline) at any of the 3-month follow-up visits when fluorescein
leakage from CNV was noted. The procedure for retreatment was the same as
the procedure for the initial treatment as outlined in the preceding paragraph
except that the spot size was 1000 µm greater than the greatest linear
dimension of fluorescein leakage from CNV plus any hyperfluorescence from
a serous detachment of the retinal pigment epithelium, plus any blood contiguous
to these features that was judged by the treating ophthalmologist to be thick
enough to obscure additional hyperfluorescence from these features. Hypofluorescence
not corresponding to blood (presumably from hyperpigmentation or fibrosis)
that was contiguous with leakage was included as part of the lesion to be
treated during the first application of verteporfin therapy, but was not included
as part of the area to be treated at any follow-up examination. All personnel
involved in the investigation were masked to the treatment assignment except
for the person preparing and performing the infusion who had no role in vision
measurements, light treatments, assessment of adverse events, or evaluation
of retinal photographs.
Before a patient in the TAP Investigation could be enrolled into the
extension study at a center, the extension study 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 the TAP Investigation's
data and safety monitoring committee that was independent of the study sponsors
and the TAP Study Group. The extension study was administered as protocol
amendments that allowed for extended follow-up of patients in the TAP Investigation
initially to 48 months and subsequently to 60 months. Monitoring of the clinical
centers (including visual acuity examiners) and the Fundus Photograph Reading
Center (Wilmer Ophthalmological Institute, Baltimore, Md) continued during
the extension.
PATIENT SELECTION AND ENTRY EVALUATIONS
All 22 clinical centers from the TAP Investigation could participate
in the extension. Patients were enrolled in the extension from December 3,
1998, through January 13, 2000.
Patient Selection and Patient Enrollment
Ophthalmologists at each clinical center certified to enroll and treat
study participants determined whether patients fulfilled eligibility criteria
to enroll. Patients eligible to participate in the open-label extension had
to have completed the month 24 examination in the TAP Investigation, but could
be enrolled regardless of whether the patient was assigned originally to placebo
or verteporfin, and regardless of the lesion composition at enrollment into
the TAP Investigation. Patients who missed the month 24 examination but returned
for a subsequent follow-up examination also could be enrolled in the extension
study.
In addition, the enrolling ophthalmologist had to determine that the
study eye had the following conditions: (1) met the same criteria required
to receive retreatment in the first 24 months of the TAP Investigation (specifically,
evidence of fluorescein leakage from CNV in the absence of a serious ocular
adverse event) and (2) in the investigators' opinion, had the potential to
benefit from verteporfin therapy (for example, excluding lesions that were
very large and associated with such a low level of visual acuity such that
additional treatment was judged unlikely to prevent further deterioration,
and hence unlikely to have a positive impact on the patient's quality of life),
or (3) that the study eye had a potential to benefit from verteporfin therapy
in the future (for example, a relatively small lesion not associated with
very poor vision that did not have fluorescein leakage from CNV at the month
24 examination, but might benefit from verteporfin therapy if fluorescein
leakage from CNV was noted at a follow-up examination after the month 24 examination).
In addition, patients who reached the month 24 examination could be offered
verteporfin therapy in their fellow eye if that fellow eye had a CNV lesion
that met the original TAP Investigation inclusion criteria1 except
that the lower level of the visual acuity criteria was extended to a letter
score of 24 (approximate Snellen equivalent of 20/320).
Patients eligible to participate in the TAP Extension reviewed and signed
a written informed consent form accompanied by an oral consent process with
a certified investigator (ophthalmologist) for the TAP Extension before they
received verteporfin therapy. Although patients and treating ophthalmologists
were unmasked to their treatment assignment in the TAP Investigation after
all data for these clinical trials had been finalized by February 2000, most
patients were enrolled into the TAP Extension before they or their treating
ophthalmologist knew what their treatment assignment was during the 2 years
of the TAP Investigation.
TAP Extension Design
At the month 24 examination, after assessments were completed for the
TAP Investigation (which did not include treatment
with verteporfin therapy), patients eligible to participate in the TAP Extension
who enrolled after signing a written consent form regarding the extension
then could begin to receive verteporfin therapy to either the study eye or
the fellow eye, or both eyes, depending on whether treatment or retreatment
criteria were met. Follow-up examinations were scheduled every 3 months; additional
verteporfin treatments were to be applied at those follow-up visits as often
as every 3 months for an additional 36 months if leakage from CNV was detected
on fluorescein angiography as determined by the treating ophthalmologist.
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 previously1 with
2 exceptions. First, fundus photographs and fluorescein angiograms taken at
every 3-month follow-up visit were evaluated by the Fundus Photograph Reading
Center only if the photographs documented specific ocular adverse events during
the extension study. Second, no medical history, physical examination, electrocardiogram,
vital sign measurements, or blood tests were performed at entry to or during
the extension.
STATISTICAL METHODS
Visual acuity and safety data were summarized from study entry of the
TAP Investigation to the month 36 examination of the TAP Extension for patients
who received verteporfin therapy in the TAP Investigation and continued follow-up
in the TAP Extension. Visual acuity and safety data also were summarized for
patients who received placebo therapy in the TAP Investigation and then were
enrolled in the TAP Extension and received verteporfin therapy in the TAP
Extension for either the study eye (in which verteporfin therapy was delayed
for at least 2 years from presentation with a lesion eligible to participate
in the TAP Investigation) or the fellow eye. Outcomes were not adjusted for
missing data at follow-up visits; unlike reports in the TAP Investigation,1-2 the last observation carried forward
was not used to impute for any missing values at follow-up visits during the
extension study.
DATA MONITORING AND REPORTING
Data monitoring was continued by the same Data and Safety Monitoring
Committee as often as every 12 months.1 No
safety concerns regarding this extension study were voiced by the committee
at its reviews on March 22, 2000, and February 6, 2001. The database for this
report includes all data through the month 36 examination of the TAP Extension,
which was locked as of February 27, 2001.
RESULTS
Of the 609 patients enrolled in the TAP Investigation, 207 were assigned
to placebo therapy (all received placebo therapy at baseline) and 402 to verteporfin
therapy (all received verteporfin therapy at baseline). No placebo-assigned
patient received verteporfin and no verteporfin-assigned patient received
a placebo therapy during the 24 months of follow-up in the TAP Investigation.
One hundred seventy-eight (86.0%) of the 207 patients in the placebo
group completed the month 24 examination; 156 (87.6%) of these 178 patients
enrolled in the extension study and 129 (72.5%) were treated with verteporfin
therapy at some time during the extension study by the month 36 examination.
Thus, 129 (62.3%) of the original 207 patients assigned to placebo in the
TAP Investigation were treated with verteporfin therapy in the extension study
by the month 36 examination. Three hundred fifty-one (87.3%) of the 402 patients
in the verteporfin group completed the month 24 examination; 320 (91.2%) of
these 351 patients or 79.6% of the initial 402 verteporfin-treated patients
enrolled in the extension study. These 320 verteporfin-treated patients who
enrolled in the TAP Extension Study included 124 (78.0%) of the initial 159
verteporfin-treated patients with lesions composed of predominantly classic
CNV at baseline.
Verteporfin-treated patients with a predominantly classic lesion composition
at baseline who did enroll in the extension (n = 124), with or without a month
36 examination, compared with those who did not enroll (n = 35), appeared
more likely at the month 24 examination to have a better mean change from
baseline in visual acuity letter score (P = .02),
approximate Snellen equivalent visual acuity distribution in favor of better
levels of acuity (P = .03 by Wilcoxon rank sum test),
younger age (P = .01), absence of leakage from classic
CNV (P = .01), and no evidence of progression of
classic CNV beyond the area of the lesion defined at baseline (P = .049) (Table 1).
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Table 1. Patient and Lesion Characteristics for Patients Who Did and
Did Not Enroll in the TAP Extension With Lesions Composed of Predominantly
Classic CNV at Baseline*
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VISION OUTCOMES FOR PREDOMINANTLY CLASSIC LESIONS ORIGINALLY ASSIGNED
TO VERTEPORFIN AND FOLLOWED UP TO MONTH 36
One hundred five (84.7%) of the 124 TAP Extension patients originally
assigned to verteporfin therapy who had a predominantly classic lesion at
baseline (or 66.0% of the original 159 verteporfin-treated patients with a
predominantly classic lesion at enrollment) enrolled in the extension study
and completed the month 36 examination. For the other 19 patients who did
not complete the month 36 examination, 8 (6.5%) of the 124 missed the month
36 visit but were still participating in the study, 6 (4.8%) requested to
be withdrawn, 3 (2.4%) discontinued for other reasons, 2 (1.6%) died, and
none were lost to follow-up. An average of 1.3 of a maximum possible 4 treatments
were given from the month 24 examination (inclusive) up to, but not including,
the month 36 follow-up examination. The actual number treated at each visit
during this period is shown in Figure 1.
The distribution of change in visual acuity for this group of lesions at the
month 36 examination shows very little change from the distribution at the
month 24 examination (Table 2).
At the month 36 examination, 9 (8.6%) of the 105 patients had at least moderate
visual acuity improvement ( 15-letter increase or 3-line increase over
the baseline examination). Forty-four patients (41.9%) had at least moderate
visual acuity loss (15-letter loss or 3-line loss over the baseline
examination), including 13 (12%) with severe visual acuity loss (30-letter
loss or 6-line loss over the baseline examination).
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Figure 1. Profile of participants enrolled
in the Treatment of Age-Related Macular Degeneration With Photodynamic Therapy
(TAP) Extension from the TAP Investigation who had a lesion composed of predominantly
classic choroidal neovascularization (CNV) at baseline, randomized to verteporfin
therapy at baseline, and who subsequently completed follow-up (at least a
protocol visual acuity assessment) through the month 36 examination. The percentage
of patients receiving retreatment is expressed as a percentage of the total
number of patients with lesions composed of predominantly classic (CNV) at
baseline who were enrolled in the TAP Extension. The percentage of patients
who did not receive treatment is expressed as a percentage of the total number
of patients followed up at that visit.
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Table 2. Frequency Distribution of Changes in Visual Acuity From Baseline
at the Month 24 and Month 36 Follow-up Examinations for Lesions Composed of
Predominantly Classic CNV at Baseline Assigned to Verteporfin Therapy, Participating
in TAP Extension, and Having a Month 36 Examination*
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The distribution of actual visual acuity scores at the month 36 examination
for this group of lesions shows very little change from the month 24 examination
(Table 3). At both times, 22 (21%)
of the patients had visual acuity of 20/80 or better. The percentage of eyes
with visual acuity of 20/200 or worse was similar at both times, including
41 (39.4%) of 104 eyes at the month 24 examination and 45 (42.9%) of 105 eyes
at the month 36 examination. The average visual acuity letter score also was
similar at both times, 41 (approximate Snellen equivalent of 20/160 + 1) at
the month 24 examination and 40 (approximate Snellen equivalent of 20/160)
at the month 36 examination.
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Table 3. Visual Acuity Categories in Study Eyes at the Month 24 and
Month 36 Follow-up Examinations for Lesions Composed of Predominantly Classic
CNV at Baseline Assigned to Verteporfin Therapy, Participating in TAP Extension,
and Having a Month 36 Examination*
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SAFETY BASED ON VISION OUTCOMES FOR ALL PARTICIPANTS IN EXTENSION STUDY
The mean change from baseline in visual acuity score, without last observation
carried forward, was evaluated as a safety measurement for all TAP Investigation
patients participating in the TAP Extension. For the cases enrolled in the
TAP Extension that were predominantly classic lesions at baseline, the mean
change from baseline in visual acuity score was relatively stable in the second
and third years. Specifically, these cases had an approximately 1-letter loss
between the month 15 and month 36 examinations (Figure 2). Similarly, for 162 patients in the TAP Extension originally
assigned to verteporfin therapy who had a minimally classic lesion at baseline,
the mean change from baseline in visual acuity letter score between the month
24 and month 36 examinations was relatively stable (Figure 2). Only 34 patients originally assigned to verteporfin therapy
who participated in the extension study had no classic CNV at the baseline
examination. The mean change from baseline in visual acuity letter score for
this group changed from -9.5 to -9.7 between the month 24 and
month 36 examinations.
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Figure 2. Mean change from baseline in visual
acuity scores for patients enrolled in the Treatment of Age-Related Macular
Degeneration With Photodynamic Therapy Extension who had a lesion composed
of predominantly classic choroidal neovascularization and assigned to verteporfin
therapy or a lesion composed of minimally classic choroidal neovascularization
and assigned to verteporfin therapy or placebo therapy, regardless of lesion
composition. Number of participants providing data for each group are given
below each follow-up visit.
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For the 129 patients originally assigned to placebo in the TAP Investigation
who were treated with verteporfin therapy in the TAP Extension by the month
36 examination, 103 (79.8%) received their first treatment with verteporfin
at the month 24 examination and provided 12 months of follow-up after initiation
of therapy in the extension study. The other 26 patients originally assigned
to placebo received treatment at a follow-up after the month 24 examination
and, therefore, had less than 12 months of follow-up after initiation of therapy
in the extension study. For these 129 patients assigned to placebo in the
TAP Investigation who were treated with verteporfin therapy in the TAP Extension,
again there was relatively little change in the mean change from baseline
in visual acuity score between the month 24 and month 36 examinations (Figure 2).
OTHER SAFETY OUTCOMES FOR ALL PARTICIPANTS IN EXTENSION STUDY
For the 320 patients originally assigned to verteporfin therapy who
participated in the TAP Extension, the percentage who had clinically relevant
adverse events by the month 36 examination was similar to the percentage of
these patients who had such an event at the month 24 examination2 except
for visual disturbance events. Specifically, for these 320 patients by the
month 36 examination, 57 (17.8%) had experienced an injection site adverse
event, 9 (2.8%) had experienced infusion-related back pain, and 8 (2.5%) had
experienced a photosensitivity reaction. Cumulative visual disturbance events
had increased from 89 (22.1%) of 402 patients by the month 24 examination2 to 93 (29.1%) of 320 patients by the month 36 examination.
There were no instances of acute severe visual acuity decrease (documented
loss of at least 20 letters within 7 days after treatment compared with the
visual acuity just before the treatment) in these study eyes originally assigned
to verteporfin therapy in the TAP Investigation that then participated in
the extension study. However, one of the patients originally assigned to verteporfin
therapy in the TAP Investigation who received verteporfin therapy in a fellow
eye during the extension study had an instance of acute severe visual acuity
decrease in that fellow eye.
For the 129 patients originally assigned to placebo who were treated
with verteporfin therapy in the TAP Extension, visual disturbance events were
noted in 12 (9.3%), injection site adverse events in 13 (10.1%), infusion-related
back pain in 1 (0.8%), and photosensitivity reaction in 1 (0.8%). There were
2 instances of acute severe vision decrease in the study eye of patients originally
assigned to placebo who participated in the extension study. In 1 of these
2 patients, the severe vision decrease occurred after the patient's first
verteporfin treatment during the extension study (no verteporfin treatments
were given before participation in the extension study); in the other patient,
the severe vision decrease occurred after the patient's second verteporfin
treatment during the extension study (no verteporfin treatments were given
before participation in the extension study).
COMMENT
Previous reports indicated that the vision outcomes with verteporfin
therapy1-2 in patients with subfoveal
CNV in AMD who had a lesion composed of predominantly classic CNV at baseline
enrolled in the TAP Investigation were sustained through 2 years of follow-up.
On the basis of these results, verteporfin therapy has been recommended for
the treatment of patients with AMD with predominantly classic CNV lesions.
The results from an additional year of follow-up show minimal change in vision
outcomes for these patients between the month 24 and month 36 examinations.
Furthermore, the only additional safety concern for any of the patients enrolled
in the extension study, regardless of initial lesion composition or original
assignment to verteporfin therapy or sham therapy with placebo, was the development
of acute severe vision decrease in the study eye of 2 of the patients originally
assigned to placebo and in the fellow eye of 1 patient originally assigned
to verteporfin therapy.
The data in Table 2 and Table 3 on patients who had a predominantly
classic lesion at baseline and participated in the extension study excludes
19 cases in the extension study that did not have both a month 24 and month
36 examination. This method was chosen as one way of trying to report changes
in visual acuity for patients with predominantly classic lesions at baseline
who participated in the extension study and deal with missing data between
these 2 points. The mean visual acuity change at these points in Table 2 for 105 patients with both a month
24 and a month 36 examination is similar to the mean visual acuity change
from baseline at these points in Figure 2. Figure 2 includes the
105 patients in Table 2 plus 19
patients who participated in the extension study but did not have both a month
24 and a month 36 examination. The similarity suggests that the exclusion
of these 19 patients from Table 2 and Table 3 likely did not have a large impact
on the estimates given in these tables.
Some caution in the interpretation of the vision results in Table 2 and Table 3 is indicated. Specifically, verteporfin-treated patients
with a lesion composition that was predominantly classic at baseline who did
not enroll in the extension study and are not included in these tables appeared
more likely to have a greater age, poorer level of visual acuity, evidence
of fluorescein leakage from classic CNV, or evidence of progression of classic
CNV at the month 24 examination compared with those included in these tables.
Since some of the patients with the worst visual acuity at the month 24 examination
did not participate in the extension study, the actual month 36 visual outcomes
for all patients from the TAP Investigation who had a predominantly classic
lesion at baseline and were assigned to verteporfin therapy may be somewhat
worse than that reported in these tables. On the other hand, although these
cases probably had more vision to lose during the extension study, since they
had better mean levels of visual acuity at the month 24 examination compared
with the cases that did not participate in the extension study (20/160 vs
20/250 + 2), the relatively stable visual acuity suggests an even better outcome
than might have been expected if the visual acuity had been lower. Specifically,
with lower levels of visual acuity (for example, 20/400), one might expect
that further loss of vision would be less likely than at higher levels of
acuity (for example, 20/100).
Of note, the average number of applications of verteporfin treatment
per year continued to decrease through the third year for the 105 lesions
described in Table 1 that were
predominantly classic at baseline and that had a month 36 follow-up, from
3.6 during the first year of follow-up to 2.4 during the second year of follow-up
to 1.3 during the third year of follow-up. The limited additional visual loss
in the third year of follow-up does not mean that the few retreatments performed
during this follow-up were unnecessary. Without retreatment to the cases that
had fluorescein leakage from CNV during the third year of follow-up, it is
possible that the minimal change in visual outcomes between the month 24 and
month 36 examinations might not have been obtained. This study was not designed
to determine whether these retreatments were necessary. This information could
be obtained only if outcomes with retreatments were compared with outcomes
without retreatments during this extension.
As noted in Figure 2, most
of the visual acuity loss in either the verteporfin-treated or placebo-treated
group occurred in the first year. The minimal additional visual acuity loss
noted during both the second and third years of follow-up suggests that similarly
treated patients might expect this process to stabilize within 1 year after
initiating therapy, with vision usually remaining stable at least through
3 years of follow-up. Since the average age of patients developing these lesions
may be approximately 75 years (based on the demographics of patients participating
in the TAP Investigation1 and the Macular Photocoagulation
Study of subfoveal CNV caused by AMD3), this
period of stability may represent a significant portion of the patient's remaining
lifetime.
Two additional limitations must be recognized in the interpretation
of these results. First, in the absence of a control group, it is impossible
to know for certain whether these outcomes at the month 36 examination would
have been better than the outcomes for cases assigned to placebo, since patients
originally assigned to placebo could be offered verteporfin therapy after
completing the month 24 vision assessments. However, the average visual acuity
for patients assigned to placebo showed no improvement for 24 months before
the extension study. There is little reason to suspect that improvement should
have begun at the month 24 examination.
Second, not all patients participating in the TAP Investigation participated
in the TAP Extension. The enrolling ophthalmologist had to determine that
the study eye had evidence of fluorescein leakage from CNV at the month 24
examination with a potential to benefit from additional treatment as judged
by the treating ophthalmologist, or had no fluorescein leakage from CNV at
the month 24 examination but had the potential to need treatment in the future,
again as judged by the treating ophthalmologist. For the placebo-treated patients
in the TAP Investigation who enrolled in the TAP Extension, without the last
observation carried forward to impute for missing values, visual outcomes
were marginally worse at the month 36 examination compared with the month
24 examination. However, 2 of these patients had acute severe decrease in
vision after verteporfin therapy (1 after the first treatment, 1 after the
second treatment). It is unknown how these patients assigned to placebo in
the TAP Investigation and subsequently able to receive verteporfin therapy
during the extension study would have fared if no verteporfin therapy had
been available to them during the extension study. Therefore, no conclusions
regarding efficacy of verteporfin therapy can be made in eyes with fluorescein
leakage from subfoveal CNV that has been documented for at least 2 years before
the initiation of verteporfin therapy.
CONCLUSIONS
The 3-year visual outcomes for patients with subfoveal CNV enrolled
in the TAP Extension show little change from the 2-year outcomes for patients
with lesions that were composed of predominantly classic CNV and assigned
to verteporfin therapy at baseline. Caution in the interpretation of these
results appears warranted in the absence of comparison with an untreated group
between the month 24 and month 36 examinations. Furthermore, not all patients
in the TAP Investigation participated in the TAP Extension; only approximately
one third of the verteporfin-treated patients originally enrolled with this
lesion composition had a month 36 examination. Treated patients with predominantly
classic lesions at baseline who did participate appeared more likely at the
month 24 examination to have a younger age, higher level of visual acuity,
absence of fluorescein leakage from classic CNV, and less progression of classic
CNV. Continued safety of verteporfin therapy based on mean change in visual
acuity and adverse events was maintained through the third year of follow-up
in the TAP Investigation. The results provide additional evidence that the
benefits of this therapy were sustained through at least 3 years in patients
with subfoveal CNV caused by AMD in whom additional therapy is contemplated
at the month 24 examination or at some later time beyond the month 24 examination.
On the basis of these results, the TAP Study Group identified no safety concerns
to preclude repeating photodynamic therapy with verteporfin if fluorescein
leakage from CNV was noted beyond 24 months of initiating therapy and additional
treatment was judged likely to reduce the risk of further vision loss compared
with no therapy. Caution in the interpretation of these results appears warranted
in the absence of comparison with an untreated group during the extension
and since not all patients in the TAP Investigation participated in the TAP
Extension.
AUTHOR INFORMATION
Submitted for publication December 18, 2001; final revision received
May 20, 2002; accepted June 13, 2002.
This study was supported financially by Novartis Ophthalmics AG, Bülach,
Switzerland, and QLT Inc, Vancouver, British Columbia.
Drs N. M. Bressler, Potter, and Sickenberg have been paid as consultants
to QLT Inc or Novartis Ophthalmics or both (which also may include travel
expenses at meetings or participation in a speakers bureau). The terms of
this agreement for Dr N. M. Bressler are being managed by The Johns Hopkins
University in accordance with its conflict-of-interest policies. Drs S. B.
Bressler, Monés, and Slakter have received support for travel expenses
at meetings or participation in a speakers bureau. Drs Miller and Schmidt-Erfurth
have a patent interest in verteporfin. Dr Slakter has equity ownership of
QLT Inc. Detailed statements are on file with the ARCHIVES office.
| Writing Committee for TAP Report No. 5
The following members of the TAP Investigation Study Group take authorship
responsibility for TAP Report No. 5: Mark S. Blumenkranz, MD; Neil M. Bressler,
MD; Susan B. Bressler, MD; Guy Donati, MD; Gary Edd Fish, MD; Laurie A. Haynes*;
Hilel Lewis, MD; Joan W. Miller, MD; Jordi M. Monés, MD; Michael J.
Potter, MD; Constantin Pournaras, MD; Al Reaves, PhD; Philip J. Rosenfeld,
MD, PhD; Andrew P. Schachat, MD; Ursula Schmidt-Erfurth, MD; Michel Sickenberg,
MD; Lawrence J. Singerman, MD; Jason S. Slakter, MD; H. Andrew Strong, PhD*;
Stéphane Vannier.*
*Indicates members of the writing committee who are employees of QLT
Inc or Novartis Ophthalmics AG, which sponsored the trial.
|
|
Corresponding author: Neil M. Bressler, MD, Suite 115, 550 N Broadway,
Baltimore, MD 21205-2002 (e-mail: nmboffice{at}jhmi.edu).
Reprints:
Medical Information, Novartis Ophthalmics, 11460 Johns Creek Pkwy, Duluth,
GA 30097.
A complete list of the participants in the Treatment of Age-Related
Macular Degeneration With Photodynamic Therapy Study Group was published in Arch Ophthalmol. 1999;117:1343-1344, with updates in Arch Ophthalmol. 2001;119:206.
REFERENCES
| |
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;117:1329-1345.
FREE FULL TEXT
2. 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: two-year results of 2 randomized clinical
trials—TAP Report 2. Arch Ophthalmol. 2001;119:198-207.
FREE FULL TEXT
3. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions of age-related
macular degeneration: updated findings from two clinical trials. Arch Ophthalmol. 1993;111:1200-1209.
ABSTRACT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
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Arroyo
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IOVS 2004;45:4190-4196.
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Armbrecht et al.
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Br. J. Ophthalmol. 2004;88:1180-1185.
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Hopley et al.
Br. J. Ophthalmol. 2004;88:982-987.
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Treatment of age-related macular degeneration
Browning et al.
JRSM 2004;97:166-169.
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Meads and Hyde
Br. J. Ophthalmol. 2004;88:212-217.
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