Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: 5-year results of two randomized clinical trials with an open-label extension
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- Kaiser, P.K. & Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study Group Graefe's Arch Clin Exp Ophthalmo (2006) 244: 1132. doi:10.1007/s00417-005-0199-9
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To report vision and safety outcomes up to 5 years from an extension of the Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Investigation evaluating verteporfin therapy in patients with subfoveal choroidal neovascularization (CNV) in age-related macular degeneration.
Patients who completed the 2-year randomized, placebo-controlled portion of the TAP Investigation could participate in the open-label extension study for an additional 3 years. Patients in the study extension received open-label verteporfin therapy in the study eye, fellow eye or both eyes, irrespective of original treatment assignment to placebo or verteporfin, if leakage from CNV was evident on fluorescein angiography. Follow-up visits occurred at 3-month intervals through to month 48, with a final follow-up visit at month 60.
Of the 402 verteporfin-treated patients in the randomized trials, 320 (80%) enrolled in the extension study; 193 (60%) of these completed the extension study up to 5 years. Patients received an average of approximately two treatments during the 3 years of the extension study. Seventy-seven (62%) of the 124 verteporfin-treated patients with predominantly classic lesions at baseline who enrolled in the extension completed the month 60 examination. Twenty-six (34%) of these 77 patients had lost 3 or more lines of visual acuity by month 24 and 27 (35%) had lost this amount of vision by month 60; the mean change in visual acuity from baseline was also similar at the month 24 and month 60 examinations (−1.5 and −1.6 lines, respectively). When visual acuity results were examined for all extension patients who received verteporfin at baseline, regardless of baseline lesion composition and extension study completion status, a similar pattern of visual acuity stabilization was evident. Few additional instances of infusion-related back pain or photosensitivity reactions were reported from month 24 to month 60. No additional safety issues were noted after bilateral treatment.
Vision outcomes remained relatively stable from month 24 to month 60 even though the treatment rate was low during this period. The TAP Study Group identified no new safety concerns to preclude repeating verteporfin therapy as described in this study through 5 years.
KeywordsAge-related macular degenerationVerteporfin therapyChoroidal neovascularization
Photodynamic therapy (PDT) with verteporfin (Visudyne®; Novartis Pharma AG, Basel, Switzerland) is approved in more than 75 countries worldwide for treatment of patients with subfoveal choroidal neovascularization (CNV) caused by age-related macular degeneration (AMD). Previous publications reported the 12- and 24-month safety and efficacy results of the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Investigation that comprised two simultaneous, randomized, multicenter clinical trials of verteporfin therapy for CNV caused by AMD with a classic CNV component [3, 4]. At the time of enrollment in the controlled trials, patients were randomly assigned to intravenous verteporfin or a placebo (5% dextrose in water) followed by application of non-thermal laser light to activate verteporfin or serve as a sham treatment. TAP Report No. 2 noted a visual acuity benefit at 24 months with respect to reducing the risk of 3 or more and 6 or more lines of visual acuity loss compared with placebo for all patients receiving verteporfin therapy in the TAP Investigation. This benefit was stronger for lesions that were predominantly classic (area of classic CNV at least 50% of area of entire lesion) .
An open-label extension of the TAP Investigation beyond 2 years of follow-up, called the TAP Extension, was designed after the beneficial 1-year outcomes were recognized . The objective of the TAP Extension was to obtain long-term follow-up information on visual acuity and safety outcomes for patients originally assigned to verteporfin therapy. In addition, patients who were originally assigned to placebo therapy and followed over the 2-year TAP Investigation were offered verteporfin therapy in the extension study. Bilateral treatment, consisting of light administration in both eyes after one verteporfin infusion, was also available for the first time to patients who entered the extension study.
The extension was initially designed to follow patients for 48 months, but was subsequently amended (before the 48-month data were analyzed) to monitor patients up to 60 months. In TAP Report No. 5 and TAP Report No. 7, the 36- and 48-month results of the TAP Extension reported that the visual outcomes for verteporfin-treated patients with predominantly classic lesions at baseline remained stable from month 24 through month 48, and no additional safety concerns were identified [5, 6].
The main purpose of this report is to provide long-term follow-up information on verteporfin therapy for physicians to use when making treatment management decisions. This paper reports detailed vision outcomes for all verteporfin-treated patients, including those who had a predominantly classic lesion at baseline, from month 24, when patients from the TAP Investigation enrolled in the extension study, to month 60, when the study was completed. Visual acuity and long-term safety are also described over the 5-year follow-up period for all patients enrolled, regardless of baseline lesion composition or original treatment assignment to verteporfin or placebo. Safety of bilateral treatment is also described.
Materials and methods
The protocol for the TAP Investigation is described in earlier reports [3, 4]. Briefly, patients eligible for treatment in the TAP Investigation must have had subfoveal CNV caused by AMD with evidence of classic CNV, a lesion in which the greatest linear dimension was no greater than 5,400 μm on the retina and a best-corrected visual acuity letter score between 73 and 34 (equivalent to an approximate Snellen acuity of 20/40 to 20/200). Patients were evaluated every 3 months (±2 weeks) for 24 months and treated with either verteporfin therapy or placebo sham therapy (whatever was assigned at baseline) at any of the 3-monthly follow-up visits if fluorescein leakage from CNV was noted by the investigator. The procedure for subsequent treatments was the same as the procedure for the initial treatment. Enrolled patients were randomly assigned (in a 2:1 ratio) to either verteporfin or placebo. Verteporfin therapy consisted of an intravenous infusion of 30 ml of verteporfin (6 mg/m2 of body surface area) over 10 min; 15 min after the start of infusion, 50 J/cm2 of light was applied to a spot size 1,000 μm greater than the lesion’s greatest linear dimension using a 689-nm diode laser light at an intensity of 600 mW/cm2 over 83 s. Placebo sham treatment included infusion of 30 ml of 5% dextrose in water with the same light application and spot size determination. All personnel involved in the 24-month TAP Investigation were masked to the treatment assignment except for the person preparing and performing the infusion, who had no role in vision measurements, light application, assessment of adverse events, clinical evaluation or evaluation of fluorescein angiograms.
The TAP 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. To enroll in the extension study, eligible patients reviewed and signed a written informed consent form accompanied by an oral consent process with a certified investigator (ophthalmologist). The extension study design was reviewed by a Study Advisory Group and the institutional review boards of all participating clinical centers. Data monitoring was continued as often as every 12 months by the same Data and Safety Monitoring Committee that oversaw the TAP Investigation. Monitoring of the clinical centers (including visual acuity examiners) and the Fundus Photograph Reading Center (Wilmer Ophthalmological Institute, Baltimore, MD) continued during the extension study.
All 22 clinical centers from the TAP Investigation could participate in the open-label TAP Extension. Patients were enrolled in the extension from 3 December 1998 to 13 January 2000.
Patients were eligible to participate in the TAP Extension if they completed the month 24 examination in the TAP Investigation, 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 could also be enrolled in the extension study.
In addition, the enrolling ophthalmologist had to determine that the patient had at least one of the following conditions at the month 24 examination: (1) evidence of fluorescein leakage from CNV in the absence of serious ocular adverse events; (2) the potential, in the opinion of the treating ophthalmologist, to benefit from verteporfin therapy if evidence of fluorescein leakage from CNV developed in the future; (3) a fellow eye with CNV that met the original TAP Investigation inclusion criteria, except that the lowest level of the visual acuity criteria for treating fellow eyes was extended from 34 letters to 24 letters (approximate Snellen equivalent of 20/320). In patients where both eyes were eligible for verteporfin treatment in the extension, bilateral treatment could be offered where the patient received one verteporfin infusion, followed by light application to the study eye 15 min after the start of the infusion, followed by light application to the fellow eye within 20 min after the start of the infusion.
Although by February 2000 patients and treating ophthalmologists were unmasked to treatment assignment in the TAP Investigation after all data had been finalized, most patients were enrolled into the TAP Extension before February 2000 and before they or their treating ophthalmologist could be informed of their treatment assignment.
TAP Extension study design
After assessments were completed for the TAP Investigation at the month 24 examination (which did not include treatment with verteporfin therapy), patients eligible to participate in the TAP Extension could receive verteporfin therapy to either the study eye or the fellow eye, or both eyes, depending on whether treatment eligibility criteria were fulfilled. Follow-up examinations were scheduled every 3 months (± 2 weeks) for an additional 24 months in the extension up to month 48, with one final visit at month 60. Patients could be treated with verteporfin therapy as often as every 3 months through to the 48-month visit if leakage from CNV had been detected on fluorescein angiography. In the final year (after month 48 and before month 60), follow-up assessments and treatment based on retreatment criteria could be continued at the discretion of the investigator; no protocol-specific study procedures were required and only reported safety information was collected and analyzed for that time period. The month 60 visit was scheduled for follow-up and study close-out purposes only; no study treatment was administered at that final visit.
Vision testing, stereoscopic color fundus photographs, fluorescein angiograms and other medical aspects were described in detail previously , with two exceptions. First, fundus photographs and fluorescein angiograms taken at every 3-month follow-up visit were evaluated by the Fundus Photograph Reading Center during the extension study only if the photographs documented specific ocular adverse events. Second, no medical history, physical examination, electrocardiogram, vital sign measurements or blood tests were performed at entry to or during the extension study.
Visual acuity and safety data were summarized from study entry of the TAP Investigation to the month 60 examination of the TAP Extension for (a) verteporfin-treated patients from the TAP Investigation who enrolled in the extension study and (b) placebo-treated patients from the TAP Investigation who enrolled in the extension study and received verteporfin therapy 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. In addition, to assess the safety of bilateral treatment, ocular adverse event data were summarized through the 90-day period after a bilateral treatment, or until the next verteporfin treatment, whichever occurred first.
Data monitoring and reporting
The database for this report includes all data through the month 60 examination of the TAP Extension and was locked as of 28 March 2003.
Of the 609 patients enrolled in the randomized, controlled TAP Investigation, 207 were assigned to placebo therapy and 402 to verteporfin. No placebo-assigned patient received verteporfin and no verteporfin-assigned patient received a placebo therapy during the 24-month follow-up in the TAP Investigation.
The 320 verteporfin-treated patients who enrolled in the TAP Extension included 124 of the initial 159 (78%) verteporfin-treated patients with lesions composed of predominantly classic CNV at baseline. Of those 124 patients with predominantly classic lesions assigned to verteporfin at baseline and enrolled into the extension study, 77 (62%) completed the month 60 examination and compose the cohort used for detailed visual acuity analyses (Fig. 1).
One hundred and thirty-four (86%) of the 156 patients from the placebo group who enrolled in the extension study were treated with verteporfin therapy at some time during the extension study by the month 60 examination (Fig. 1).
As was previously reported , at the month 24 examination verteporfin-treated patients with predominantly classic lesion composition at baseline who enrolled in the extension (n=124) were more likely to be younger, have better levels of visual acuity, have absence of leakage from classic CNV and have no evidence of progression of classic CNV than those who did not enroll.
Mean number of treatments for patients assigned to verteporfin therapy at baseline who participated in the TAP Extension
Mean number of treatmentsa
All patients (n=320)
Patients with predominantly classic CNV (n=124)
Patients with predominantly classic CNV who completed the month 60 examination (n=77)
Year 1 (0–9 months)
Year 2 (12–21 months)
Year 3 (24–33 months)
Year 4 (36–45 months)
Year 5 (48–57 months)
Patients with predominantly classic CNV originally assigned to verteporfin therapy at baseline and followed to month 60
Frequency distribution at month 24 and month 60 for patients with predominantly classic CNV originally assigned to verteporfin therapy at baseline and followed to month 60
Change in visual acuitya
Number (%) of patients
Month 24 (n=76)
Month 60 (n=77)
≥3-line to <6-line increase
≥1-line to <3-line increase
≥1-line to <3-line decrease
≥3-line to <6-line decrease
Mean lines (letters) lost
All patients originally assigned to verteporfin therapy at baseline and enrolled in the extension
Frequency distribution at month 24 and month 60 for all patients originally assigned to verteporfin therapy at baseline and followed to month 60
Change in visual acuitya
Number (%) of patients
Month 24 (n=312)b
Month 60 (n=193)
≥3-line to <6-line increase
≥1-line to <3-line increase
≥1-line to <3-line decrease
≥3-line to <6-line decrease
Mean lines (letters) lost
Safety outcomes for all participants in the extension study
Summary of adverse events judged to be clinically relevant
Number (%) of patients
Long-term verteporfin-treated patients (months 0–60)/(n=320)
Previously placebo patients treated with verteporfin in the extension/(n=134)a
Visual disturbance eventsb
Injection-site adverse eventsc
Infusion-related back pain
The cumulative rates of adverse events in patients originally assigned to placebo who then received verteporfin therapy in the TAP Extension are lower than those for long-term verteporfin-treated patients because long-term verteporfin-treated patients were exposed to active treatment for at least an additional 2 years (Table 4).
Acute severe visual acuity decrease events from the 24-month TAP Investigation have been described in detail . In the extension study, 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 the study eyes of long-term verteporfin-treated patients who participated in the extension study. However, one patient originally assigned to verteporfin therapy in the TAP Investigation who received bilateral verteporfin therapy during the extension study had acute severe visual acuity decrease in the fellow eye by month 36 . In addition, two patients originally assigned to placebo and treated with verteporfin in the extension study had acute severe visual acuity decrease in their study eye by month 36 . There were no additional acute severe visual acuity decrease events between month 36 and month 60.
The acute severe visual acuity decrease in the fellow eye after bilateral verteporfin therapy occurred after the patient’s third bilateral treatment (which also represented the 11th course of treatment in the study eye). Subretinal hemorrhage was confirmed after the event occurred. The patient’s visual acuity score returned to its pretreatment value at the next 3-month examination. The acute severe visual acuity decreases in study eyes originally assigned to placebo occurred after the first verteporfin treatment in one patient and after the second treatment in the other patient. Neurosensory detachment and subretinal hemorrhage were noted after the event for both patients. Both patients had improved visual acuity scores at the next 3-month examination compared with their score immediately after the event. The first patient improved to a score 1.6 lines higher than the pretreatment score (53 letters pretreatment visual acuity score, loss of 24 letters with the event and visual acuity score 61 letters at the next 3-month examination). The second patient’s pretreatment visual acuity score was 81 letters, the score decreased to 19 letters with the event and was 63 letters at the next 3-month examination.
Safety outcomes after bilateral treatment
Incidence of ocular treatment-emergent adverse events in eyes that received at least one bilateral treatmenta
Ocular adverse event
Number (%) of eyes
Eyes with at least one bilateral treatment (n =68)b
Total ocular adverse events
Visual field defect
The TAP Investigation reported a visual acuity benefit at 24 months for the overall population of patients receiving verteporfin therapy; this benefit was stronger in the subgroup of patients with predominantly classic lesion composition at baseline [3–5]. In the extension study, for the 77 patients who had predominantly classic CNV and received verteporfin at baseline, and who completed the month 60 examination, visual acuity showed little change between the month 24 and month 60 examinations. This stability of visual acuity was associated with an average of only 7.6 treatments of a maximum possible 20 treatments during the 5-year follow-up period. Visual acuity outcomes for all patients who received verteporfin at baseline and participated in the extension study, regardless of baseline lesion composition and extension study completion status (n=320), showed a pattern of stabilization similar to that for patients with predominantly classic CNV.
Some caution in the interpretation of the vision results is indicated. First, not all verteporfin-treated patients with a lesion composition that was predominantly classic at baseline enrolled in the extension study. As reported in TAP Report No. 5, patients who did not participate in the TAP Extension were more likely to be older, have a poorer level of visual acuity and have evidence of fluorescein leakage from classic CNV, or evidence of progression of classic CNV, at the month 24 examination than those included in the TAP Extension . These differences would be expected because one of the inclusion criteria of the extension study was the potential, in the opinion of the treating ophthalmologist, to benefit from verteporfin therapy if evidence of fluorescein leakage from CNV developed in the future. Therefore, patients without this potential would be likely to have a poorer level of visual acuity or evidence of progression of classic CNV at the month 24 examination. Because some of the patients with the worst visual acuity at the month 24 examination did not participate in the extension study, the actual visual acuity outcomes for all patients from the TAP Investigation who had a predominantly classic lesion composition at baseline and were assigned to verteporfin therapy may be worse after 5 years than those reported here. Conversely, the patients who participated in the extension study had more vision to lose because they had better mean levels of visual acuity at the month 24 examination than the patients who did not participate in the extension study (20/160 vs. 20/250+2) .
Second, only 62% of patients who enrolled in the extension study and who had predominantly classic CNV at baseline completed the month 60 visit. Consequently, the true proportion of cases that continued to lose vision from the month 24 examination through month 60 may be underestimated. A higher proportion (75%) completed the month 48 visit (Fig. 1). The high withdrawal rate between month 48 and month 60 was due to patient requests to withdraw; some patients did not consent to participate in the fifth year of the study or their study center did not participate when this additional year was added through study amendment and additional informed consent procedures.
Third, in the absence of a control group, it is unknown whether the outcomes at month 60 are better than the outcomes for patients assigned to placebo would have been, because patients originally assigned to placebo were offered verteporfin therapy, if eligible, after completing the month 24 vision assessments. However, the average visual acuity for patients assigned to placebo showed no improvement for 24 months prior to the extension study. There is little reason to suspect that improvement would have started at the month 24 examination. It is not known how patients assigned to placebo in the TAP Investigation and who subsequently received verteporfin therapy during the TAP Extension would have fared if no verteporfin therapy had been available to them during the extension study. Therefore, no conclusions can be made regarding efficacy of verteporfin therapy in eyes with fluorescein leakage from subfoveal CNV documented for at least 2 years prior to the initiation of verteporfin therapy.
The limited additional vision loss between 24 and 60 months of follow-up does not mean that the few treatments performed during this follow-up period were unnecessary. Without treatment to the cases that had fluorescein leakage from CNV during the follow-up, it is possible that the minimal change in visual outcomes between the month 24 and month 60 examinations might not have been obtained. This study was not designed to determine whether these treatments were necessary. This information could have been obtained only if patients had been randomly assigned to additional verteporfin therapy or no therapy when fluorescein leakage was noted during the extension period.
Similar to previous reports, the results suggest that almost all of the visual acuity loss in the long-term verteporfin-treated group occurred in the 6 months after enrollment into the TAP Investigation . The minimal additional visual acuity loss noted during the 4.5 years of additional 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 5 years of follow-up. In contrast, patients who were originally assigned to placebo and then were eligible to receive verteporfin therapy during the extension study continued to lose vision.
This extension study is the first study in which verteporfin therapy was given bilaterally. The analysis of bilaterally treated eyes is limited by the small number that received this treatment. Additionally, ocular events were summarized for only the 3 months after each bilateral treatment, to highlight those events most relevant to bilateral treatment and to minimize events due to other subsequent unilateral treatment or disease progression. Despite these limitations, however, analysis of ocular adverse events after bilateral treatment appears to indicate that there are no additional safety concerns. The higher incidence of mostly transient decreases in vision in bilaterally treated eyes (21%), compared with 10% in the TAP Investigation, may be explained by the more perceptible effects on vision for patients when both eyes have active disease.
In the context of a relatively low proportion of patients completing the study through 5 years, visual acuity outcomes were stable from 2 to 5 years for patients with subfoveal CNV assigned to verteporfin therapy at baseline and enrolled in the TAP Extension. Caution in the interpretation of these results is warranted in the absence of comparison with an untreated group between the month 24 and month 60 examinations. Nevertheless, the stability of visual outcomes and the lack of any additional safety concern suggest that benefits of verteporfin therapy observed in the first 2 years are likely to be maintained through the month 60 examination. On the basis of these results, the TAP Study Group recommends continuing photodynamic therapy with verteporfin beyond 24 months of initiating therapy if fluorescein leakage from CNV is noted and additional treatment is judged likely to reduce the risk of further vision loss compared with no treatment. No new safety issues arose when patients received bilateral therapy.
The Johns Hopkins University, but not Dr. N. Bressler, is paid for consulting services provided by Dr. N. Bressler to Novartis Pharma AG and QLT Inc. The terms of this institutional consulting arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies. The following authors have indicated that they are or have been paid as consultants to QLT Inc. or Novartis Pharma AG or both (which may also include travel expenses at meetings or participation in a speakers bureau): Andrea Wenkstern, MD; Jason S. Slakter, MD. The following authors have indicated support for travel expenses at meetings or participation in a speaker’s bureau: Michael J. Potter, MD; Philip J. Rosenfeld, MD, PhD; Peter K Kaiser, MD; Joan W. Miller, MD. Joan W. Miller, MD and Ursula Schmidt-Erfurth, MD, PhD have a patent interest in verteporfin under the guidelines of the Massachusetts General Hospital/Harvard Medical School. Detailed statements are on file with the Chair of the Verteporfin Study Advisory Group’s office.