Photodynamic Therapy With Verteporfin for Choroidal ...

Photodynamic Therapy With Verteporfinfor Choroidal NeovascularizationCaused by Age-related Macular DegenerationResults of a Single Treatment in a Phase 1 and 2 Study

Joan W. Miller, MD; Ursula Schmidt-Erfurth, MD; Michel Sickenberg, MD; Constantin J. Pournaras, MD; Horst Laqua, MD;Irene Barbazetto, MD; Leonidas Zografos, MD; Bertrand Piguet, MD; Guy Donati, MD; Anne-Marie Lane, MPH;Reginald Birngruber, PhD; Hubert van den Berg, PhD; H. Andrew Strong, PhD; Ulrike Manjuris, PhD;Todd Gray, MSPH; Mario Fsadni, MRCOphth; Neil M. Bressler, MD; Evangelos S. Gragoudas, MD

Objective: To evaluate the safety and short-term vi-sual and fluorescein angiographic effects of a single pho-todynamic therapy treatment with verteporfin with theuse of different dosage regimens in patients with cho-roidal neovascularization (CNV) from age-related macu-lar degeneration.

Design: Nonrandomized, multicenter, open-label, clini-cal trial using 5 dosage regimens.

Setting: Four ophthalmic centers in North America andEurope providing retinal care.

Participants: Patients with subfoveal CNV caused byage-related macular degeneration.

Methods: Standardized protocol refraction, visual acu-ity testing, ophthalmic examination, color photographs, andfluorescein angiograms were used to evaluate the effectsof a single treatment of photodynamic therapy with verte-porfin. Follow-up was planned through 3 months in 97 pa-tients and for less than 3 months in 31 other patients.

Results: The mean visual acuity change (and range ofchange) from baseline at the follow-up examination at week12 after a single treatment with regimens 1 through 5 was−0.2 (−3 to +2), −0.9 (−9 to +5), −1.6 (−9 to +2), +0.4 (−8to +7), and +0.1 (−8 to +9) lines, respectively. Only thehighest light dose (150 J/cm2) in regimens 2 and 3, which

produced angiographic nonperfusion of neurosensory reti-nal vessels, caused marked vision loss. Some cessation offluorescein leakage from CNV was achieved without lossof vision when the light dose used was less than 150 J/cm2.Systemic adverse events were rare. Cessation of fluores-cein leakage from CNV was noted in all regimens by 1 weekafter photodynamic therapy. Fluorescein leakage from atleast a portion of the CNV reappeared by 4 to 12 weeksafter treatment in almost all cases. Progression of classicCNV beyond the area of CNV identified before treatmentwas noted in 42 (51%) of the 83 eyes with classic CNVfollowed up for 3 months after a single treatment. Eyes inwhich the area of any CNV leakage at 12 weeks was lessthan at baseline had a significantly better visual acuity out-come (+0.8 line) than eyes in which CNV leakage pro-gressed (−0.8 line).

Conclusions: Photodynamic therapy with verteporfinachieved short-term cessation of fluorescein leakagefrom CNV without loss of vision or growth of classicCNV in some patients with age-related macular degen-eration. Except for nonperfusion of neurosensory reti-nal vessels at a light dose of 150 J/cm2, no other adverseevents were of concern. Randomized clinical trials toinvestigate whether this new modality can preservevision in patients with CNV secondary to age-relatedmacular degeneration are justified.

Arch Ophthalmol. 1999;117:1161-1173

A GE-RELATED macular de-generation (AMD) is aleading cause of blind-ness, and neovascularAMD, characterized by

choroidal neovascularization (CNV),causes most of the severe vision loss seen

in patients with AMD.1-4 Laser photoco-agulation of neovascular AMD can re-duce the risk of severe visual acuity loss

in selected cases, but because photoco-agulation damages the overlying neuro-sensory retina, this causes marked visualloss in some patients, particularly when theCNV is subfoveal.5-10 There is also a highrecurrence rate after laser photocoagula-tion.11-13 Most patients with CNV are not

See also page 1177This article is also available on our

Web site: www.ama-assn.org/surgery.

CLINICAL SCIENCES

The affiliations of the authorsappear in the acknowledgmentsection at the end of the article.

ARCH OPHTHALMOL / VOL 117, SEP 19991161

©1999 American Medical Association. All rights reserved.Downloaded From: on 04/12/2018

eligible for laser photocoagulation, because the CNV le-sion is subfoveal and too large, or has poorly demar-cated boundaries, or has occult CNV only with no clas-sic CNV.10 Investigators seek new therapies for CNV inAMD that can be used in a larger group of patients than

conventional thermal laser therapy and that are able toimprove the visual outcome of this disease.

Oneofthesetreatments,photodynamictherapy(PDT),involvesinjectionofaphotosensitizer,usuallyintravenously,followedbyirradiationof thephotosensitizedtissuebynon-

PATIENTS AND METHODS

The study was a nonrandomized, mulitcenter, open-labeltrial that used 5 dose regimens. The protocol and all amend-ments were reviewed by the US Food and Drug Adminis-tration, the local ethics committee in Germany, and the In-terkantonale Kontrollstelle fur Heilmittel in Switzerland,and approved by an internal review board at each partici-pating institution. Each patient signed a written consentstatement after receiving a full verbal and written expla-nation of the study, including the potential benefits and risksof treatment.

STUDY POPULATION

The main inclusion and exclusion criteria are listed below.

Inclusion Criteria

• Clinical signs of CNV from any cause• CNV under the geometric center of the foveal avascular

zone (subfoveal)• Some classic CNV (occult CNV could, but need not, be

present)• Greatest linear dimension of entire CNV 5400 µm in di-

ameter or less• Nasal side of CNV at least 500 µm from temporal bor-

der of optic nerve• For CNV lesions recurring after standard laser therapy,

foveal center must not have been included in area treatedby laser

• Best-corrected visual acuity of 20/40 or worse• 50 years of age or older

Exclusion Criteria

• Tears of RPE at screening• Vitelliformlike detachment of RPE• Central serous retinopathy• Drusenoid pigment epithelial detachment alone• Additional retinovascular diseases compromising vi-

sual acuity of study eye• Use of investigational drugs, systemic corticosteroids, cy-

tokines, or photosensitive drugs in past 3 months• Substantial hepatic, renal, or neurologic disease• Class III or IV cardiovascular disease (New York Heart

Association functional status criteria)• Porphyria, porphyrin sensitivity, hypersensitivity to sun-

light or bright artificial light• Any treatment for malignant disease• Any acute illness during screening or fever on day of treat-

ment before verteporfin infusion• Uncontrolled hypertension• Ocular surgery within 3 months before study treatment

Standardized protocol refraction was performed and vi-sual acuity of each eye was determined on retroilluminatedmodified Bailey-Lovie charts29 according to a modified

protocol of the Submacular Surgery Trials.30 Color fundusphotography and fluorescein angiography were obtained ac-cording to a standardized protocol adapted from the Macu-lar Photocoagulation Study (MPS) Group.31 Photographicfeatures were identified on the basis of definitions used inMPS reports.30 Photograph Reading Center staff confirmedangiographic eligibility before enrollment for the first 61treated patients. Subsequent patients were enrolled on thebasis of the investigator’s determination of eligibility; colorphotographs and fluorescein angiograms were reviewed bythe Reading Center afterward to confirm eligibility retro-spectively. Of the 128 patients in this study, 31 received mul-tiple treatments, and data from these patients are includedup until a retreatment. Data on retreatments are includedin a separate report.32

EVALUATIONS

Standardized protocol refractions, visual acuity determina-tions, complete ophthalmic examinations, color fundus pho-tography, and fluorescein angiography were performed atbaseline (between 1 and 7 days before the day of treatment)and at follow-up weeks 1, 4, and 12. Visual acuity testingwithout refraction was also performed on the day of treat-ment and 1 day after treatment. Additional testing was car-ried out at week 2 if any ocular adverse event was noted atweek 1 or at any time between visits, if judged to be clini-cally indicated. In addition, each patient underwent mea-surement of vital signs, a physical examination, and an elec-trocardiogram at baseline and at week 12. Laboratory testing,including a complete blood cell count, measurement of se-rum cholesterol, triglyceride, urea nitrogen, creatinine, elec-trolyte, calcium, phosphorus, glucose, protein, albumin, andbilirubin levels, liver function tests, and urinalysis, was per-formed at baseline and at weeks 1 and 12.

PDT REGIMENS

The size of the treatment spot was calculated by means ofthe baseline fluorescein angiogram. The greatest linear di-mension of the neovascular lesion was measured. This di-mension was divided by 2.5 to account for the magnifica-tion of the camera systems used, to yield a size of the lesionon the retina. Initially the dimension was divided by 3.0 onthe basis of the MPS protocol, but this was found to be inerror, and the method was modified for the PDT studies. A600-µm border was added to the dimension on the retina toprovide at least a 300-µm border at all edges. In some cases,the resulting treatment border at a given edge was greaterthan 300 µm, but it was always less than 500 µm. The treat-ment spot was selected on the basis of the available laserlink settings (400-4000 µm) and magnification of the con-tact lens, according to the manufacturer of the lens.33

The initial study treatment regimen involved intra-venous infusion of verteporfin (6 mg/m2, or approxi-mately 0.15 mg/kg), followed by irradiation 30 minutesafter the start of dye infusion (regimen 1) with 689-nm



thermal light at an absorption peak of the photosensitizer.Theexcitedphotosensitizergeneratessingletoxygen,orotherreactive intermediates, which can damage cellular compo-nents, includingcellularmembranes.14-16 Inneovascular tis-sue, cellulardamage to theendotheliumcan lead to throm-

bosis of the vessel.17-21 If demonstrated to be effective forpatientswithsubfovealCNV,PDTcouldprove tobeofben-efit for a majority of patients with CNV.

Benzoporphyrin derivative, also called verteporfin,is a second-generation lipophilic photosensitizer with

light delivered by an ocular photoactivation diode and la-ser link slitlamp (Coherent Inc, Palo Alto, Calif), as de-scribed in a previous study.21 The delivered irradiance waskept constant at 600 mW/cm2. Treatment protocol amend-ments were made to evaluate different dose regimens thatmight increase the persistence of the PDT effect on fluo-rescein leakage from CNV after a single treatment. Theseregimens are summarized in Table 1. In the first 3 treat-ment regimens, the light dose (fluence) was escalated from50 to 75 to 100 to 150 J/cm2, with a minimum of 3 pa-tients at each light dose. In regimen 4, the 150-J/cm2 lightdose was not included because of nonselective neurosen-sory retinal vessel nonperfusion seen after PDT with thislight dose in regimens 2 and 3. In regimen 5, lower lightdoses of 12.5 and 25 J/cm2 were included, as well as 50 J/cm2.

On the day of treatment, the patient was weighed andthe verteporfin solution was prepared as 6 mg/m2 or 12 mg/m2. The verteporfin solution and intravenous tubing werewrapped in aluminum foil to protect the verteporfin fromlight. The verteporfin was infused by means of a syringepump followed by 5-mL flush of 5% dextrose solution. Ir-radiation was performed at a specified time after the startof verteporfin infusion with the use of the selected contactlens, and the duration of irradiation ranged from 21 to 250seconds depending on the light dose used. The first 45 par-ticipants underwent cardiac monitoring during PDT witha 2-lead rhythm strip, and vital signs were measured peri-odically. Initially, patients underwent retrobulbar injec-tion of anesthetic of the study eye to ensure akinesia. Thiswas discontinued after it was used in approximately 50 pa-tients, when it was judged to be unnecessary. After the pro-cedure, patients were instructed to avoid bright sunlightas much as possible for 7 days, and to wear special sun-glasses with a low (4%) transmittance during that time.

SHORT-TERM EFFICACY ANDSAFETY PARAMETERS

Two measures were used to assess short-term efficacy andsafety: (1) the extent of fluorescein leakage from the CNV(classic and occult) and (2) stabilization of the best-corrected visual acuity at 12-week follow-up compared withbaseline. A grading system was devised to semiquantita-tively assess the effect of PDT on the extent (area) of fluo-rescein leakage from the CNV lesions at each follow-up visitcompared with that seen at baseline. Fluorescein leakagefrom classic and occult CNV was assessed without anyknowledge of the PDT dosage. The extent of fluoresceinleakage for classic CNV and, separately, for occult CNV,was graded as (1) progression (leakage from CNV beyondthe area of the lesion noted at baseline, regardless of theamount of leakage noted within the area of the lesion iden-tified at baseline); (2) moderate leakage (area of CNV oc-cupying $50% of the area of CNV noted at baseline andno progression); (3) minimal leakage (area of CNV occu-pying ,50% of the area of CNV noted at baseline and noprogression); and (4) absence of leakage (no CNV within

the area of the lesion noted at baseline and no progres-sion). These gradings were based only on lesion area andnot on other fluorescein features such as the amount of fluo-rescence or the area of leakage extending beyond classicCNV or a fibrovascular pigment epithelial detachment. TheReading Center also graded the extent of subretinal hem-orrhage, RPE atrophy, and retinal arteriolar, venular, andcapillary nonperfusion.

Best-corrected visual acuity was obtained primarily asan indicator of safety, not efficacy, given the absence of acontrol group, the short period of follow-up, and the knownvariability in the natural course of the disease. A change invisual acuity of 3 or more lines was considered to be clini-cally significant. However, changes in visual acuity and an-giographic leakage were used to compare the results amongthe regimens. This exploratory analysis was used to selectthe treatment regimen for the subsequent randomized, pla-cebo-controlled trial.

Data on adverse ocular events were obtained from thefollowing 2 source documents: case record forms and Read-ing Center forms. Case record forms captured general sys-temic events and ocular adverse events noted by the treat-ing ophthalmologist that would not be captured by colorfundus photographs or fluorescein angiograms. The Read-ing Center forms noted adverse events observed on fun-dus photographs and fluorescein angiograms.

STATISTICAL METHODS

The different grades of cessation of fluorescein leakage fromCNV were evaluated descriptively by treatment regimen andwithin subgroups. Treatment regimens were compared byFisher exact test to assess differences in the degree of ab-sence of leakage by visit. Two-by-two contingency tableswere generated by collapsing the categories of leakage ex-tent for each treatment regimen.

The comparisons performed included the proportionof patients with absence of leakage vs the proportion of pa-tients with some leakage or progression; the proportion ofpatients with minimal leakage or absence of leakage vs theproportion of patients with moderate leakage or progres-sion; and the proportion of patients with no progression vsthe proportion of patients with progression.

Summary statistics (mean, median, and SD) were gen-erated for the change from baseline in visual acuity by treat-ment regimen and within subgroups. Further exploratorycomparisons using analysis of variance methods were per-formed to assess the relationship between visual acuity out-comes and baseline characteristics such as baseline visualacuity, baseline lesion size, baseline lesion component, andbaseline lesion status. Patients who received the 150-J/cm2 light dose in regimens 2 and 3 were excluded fromthese subgroup analyses, since this light dose was foundto be unsafe and above the maximum tolerated dose. Allsummary statistics and statistical tests were performed withthe SAS system. All tests were 2 sided, and all P values of.05 or less were considered to be statistically significant.



an absorption peak near 690 nm.22,23 It has been dem-onstrated to be an effective photosensitizer in vitro andin several in vivo systems.22-26 Photodynamic therapywith verteporfin was used for photothrombosis of ocu-lar neovascularization in different animal models andhas been shown to provide occlusion of subretinal ves-sels without significant alteration of overlying photore-ceptors.16,17 Preclinical studies have shown that verte-porfin localizes to experimental CNV,27 and that PDTwith the use of verteporfin can occlude experimentallyinduced CNV, with cessation of fluorescein leakageseen angiographically and thrombotic occlusion of ves-sels seen histologically.19,21 By controlling the vertepor-fin dose, light dose, and timing of irradiation, the effectcan be selective to the CNV, with minimal effects onthe surrounding retina and choroid.19,21 In animal mod-els, once cessation of fluorescein leakage from CNV isobserved, a fibrotic scar develops in 4 to 7 weeks.28 Theuse of PDT in normal monkey retina, with the sametherapeutic measures, showed absence of perfusion ofthe choriocapillaris acutely, followed by reperfu-sion.18,19,21,28 Similarly, the retinal pigment epitheliumRPE was damaged acutely after PDT. However, by 4 to7 weeks after PDT, the RPE had repopulated the treat-ment area, demonstrating variable pigmentation butnormal basal infoldings, indicating some degree of nor-mal function. The neural retina was essentially normalby 4 to 7 weeks after treatment.28 These preclinicalstudies established preliminary safety and efficacy ofPDT with verteporfin to treat CNV. Furthermore, theyidentified treatment parameters that could be used inclinical trials.

The present study was initially designed to assessthe safety of PDT and to determine the maximum toler-ated dose of PDT with verteporfin to treat CNV. It waslater expanded by a number of treatment protocolamendments to make comparison evaluations ondosimetry. This report presents data on the effects of asingle treatment of PDT with verteporfin on 128patients with subfoveal CNV secondary to AMD.Follow-up was planned through 3 months in 97patients and for less than 3 months in 31 patients. The

remaining 13 patients who participated in this study(not included in this report) had CNV from causesother than AMD; these data are included in a separatereport (in preparation). Photodynamic therapy withverteporfin will be known in the future as “verteporfin(Visudyne) therapy.”

RESULTS

One hundred twenty-eight patients with CNV caused byAMD were treated with at least a single course of PDT,including 31 patients who later received multiple coursesof PDT with regimen 2 or 4. In cases with multiple treat-ments, only data up to the second PDT treatment are pre-sented; retreatments are reported in a separate commu-nication. The distribution of patients and the durationof follow-up are shown in Table 1.

BASELINE PATIENT CHARACTERISTICS

The baseline characteristics of the 128 patients in the studyare given in Table2. One case in regimen 4 and two casesin regimen 5 were judged not to be subfoveal lesions bythe Photograph Reading Center. Lesion characteristics listedwere based on interpretation of the Photograph ReadingCenter, not the enrolling ophthalmologist. In the eye tobe treated, most patients (79.7%) had a baseline visual acu-ity better than or equal to 20/200. The mean and medianbaseline visual acuities were both 20/125. The mean base-line lesion size was 5.1 MPS disc areas (DAs), with a rangeof 1 to 16 MPS DAs (1 MPS DA is 1.775 mm2, assuming a32.5 magnification). Eighty-one (63.3%) of the CNV le-sions manifested classic CNV in which the area of classicCNV was 50% or more of the area of the lesion. Of theselesions, 41 (32.0%) had no occult CNV. Ten (7.8%) of thebaseline lesions were judged to have no classic CNV onreview by the Reading Center. In 93.0% of the lesions, fi-brosis was judged to be 50% of the lesion or less.

Since this trial was designed primarily as a safety trialand not as an efficacy trial, patients were not randomizedto different regimens. Baseline characteristics were com-paredamonggroups todetermineanydifferences inpatient

Table 1. Treatment Regimens 1 Through 5 and Duration of Follow-up

TreatmentRegimen, No.

VerteporfinDose, mg/m2

Planned Durationof Infusion, min

LightDoses, J/cm2

Time of LightApplication

After Start ofVerteporfin

Infusion, minNo. of

Patients

No. With4-wk Follow-up

Before AnyRetreatment

No. With12-wk Follow-up

Before AnyRetreatment

1 6 10 50, 75, 100, 150 30* 22 22 19†2 6 10 50, 75, 100, 150 20 37 28‡ 17§3 12 10 50, 75, 100, 150 30 19 19 194 6 10 50, 75, 100 15 22 22 11\

5 6 5 12.5, 25, 50 10 28 27¶ 25#

*Includes 2 patients in whom light administration was 39 and 55 minutes late.†One patient withdrew after week-4 assessment; 2 patients received multiple treatments after week 4, before week 12.‡Nine patients received multiple treatments after week 1, before week 4.§Eleven patients received multiple treatments after week 4, before week 12.\Nine patients received multiple treatments after week 4 but before week 12; two additional patients missed the week-12 follow-up visit.¶One patient withdrew before week 1.#Two patients withdrew after week 4.



characteristics thatcouldconfoundresults.Thesecompari-sons identified large differences in sex distribution amongregimens 1, 4, and 5: regimens 1 and 5 included more men(34;68%)andregimen4 includedmorewomen(17;77%).Otherwise, therewerenosignificantdifferencesamong the5 regimens in the patient variables assessed.

PROTOCOL DEVIATIONS

Withdrawals

As seen in Table 1, six patients withdrew from the studybefore their week-12 assessment or before enrolling in aretreatment protocol. One patient in regimen 1 with-drew after a single PDT treatment because of pain asso-ciated with the fluorescein injections, as well as an un-willingness to travel to the clinic for follow-up. One patientin regimen 4 withdrew between weeks 8 and 12 becauseof the death of a spouse. Another patient in regimen 4missed the final follow-up visit because of a left hip frac-ture. For regimen 5, one patient refused to return by week1; two additional patients refused to return after theweek-4 follow-up visit.

Adherence to Light Administration

Three patients assigned to regimen 2 had light adminis-tered such that regimen 1 actually was performed; theyare included under regimen 1 data. Two other patientsassigned to, and listed under, regimen 1 had light ad-ministration 39 and 55 minutes late because of techni-cal difficulties with the laser. One patient assigned to regi-men 4 had light administered such that regimen 2 wasperformed, and this patient is included under regimen 2data.

Adherence to Eligibility Criteria

Ten patients had no classic CNV and were excludedfrom the analysis of classic CNV. Three patients (seeTable 2) had CNV that was judged not to be subfovealby the Reading Center staff, but were still included inthe final analysis. One patient had a baseline visual acu-ity better than 20/40 but was still included in the finalanalysis.

CHANGES IN VISUAL ACUITYAFTER TREATMENT

The study was designed primarily as a safety trial. In eachregimen, the light dose was escalated to determine a maxi-mum tolerated dose before visual acuity changes, ocu-lar adverse events, or systemic adverse events were noted.Dose escalation in regimen 1 did not result in any signsof toxicity but also did not result in cessation of fluores-cein leakage from the CNV by week 12. Therefore, ad-ditional regimens were investigated with changes in theverteporfin dose, the rate of verteporfin infusion, or thetiming of light irradiation, to assess the effect on visionand fluorescein leakage from the CNV. At the highest lightdose used (150 J/cm2) in regimens 2 and 3, PDT-relatedvision losses were observed in 3 patients. Subsequently,

patients were not treated at this light dose. The adverseevents related to this highest light dose are discussed infurther detail in the “Safety” section below.

Table 3 summarizes the changes in visual acuityfrom baseline for treatment regimens 1 through 5. Over-all, of the 127 patients who had an assessment at week1, the mean change in visual acuity was +0.7 line. Inter-estingly, in 18 patients (14.2%) visual acuity improve-

Table 2. Baseline Characteristics*

Characteristic

1 Courseof PDT

Received(n = 97)

$2 Coursesof PDT

Received(n = 31)

Total(N = 128)

SexFemale 40 (41) 20 (65) 60 (46.8)Male 57 (59) 11 (35) 68 (53.1)

RaceWhite 96 (99) 31 (100) 127 (99.2)Asian 1 (1) 0 (0) 1 (0.8)

Age, y,60 3 (3) 1 (3) 4 (3.1)60-69 20 (21) 12 (39) 32 (25.0)70-79 47 (48) 13 (42) 60 (46.8)$80 27 (28) 5 (16) 32 (25.0)Median 75.2 73.7 74.5

Median BP, mm HgSystolic 140.0 140.0 140.0Diastolic 80.0 80.0 80.0

Type of CNVClassic only 28 (29) 13 (42) 41 (32.0)Classic and occult;

$50% classic35 (36) 5 (16) 40 (31.2)

Classic and occult;,50% classic

27 (28) 10 (32) 37 (28.9)

No classic 7 (7) 3 (10) 10 (7.8)CNV lesion location

Subfoveal 93 (96) 30 (97) 123 (96.1)Probably subfoveal 1 (1) 1 (3) 2 (1.6)Not subfoveal 3 (3) 0 (0) 3 (2.3)

CNV secondary to:AMD 92 (95) 31 (100) 123 (96.1)AMD and myopic degeneration 3 (3) 0 (0) 3 (2.3)AMD and OHS 2 (2) 0 (0) 2 (1.6)

Lesion size, MPS DAMean (SD) 5.1 (2.7) 5.3 (3.4) 5.1 (2.9)Median 5.0 4.0 5.0Minimum 1.0 1.0 1.0Maximum 12.0 16.0 16.0

Visual acuity, study eye.20/40 1 (1) 0 (0) 1 (0.8)20/40-20/80 39 (40) 14 (45) 53 (41.4)20/100-20/200 36 (37) 13 (42) 49 (38.3)20/250-20/640 21 (22) 4 (13) 25 (19.5)Mean 20/125 20/100 20/125

Fibrosis, % of lesionNo fibrosis 1 (1) 0 (0) 1 (0.8)0-25 70 (72) 27 (87) 97 (75.8)26-50 19 (20) 2 (6) 21 (16.4).50 7 (7) 2 (6) 9 (7.0)

*Unless otherwise specified, data are given as number of patients, withpercentages of patients allocated to 1, or 2 or more, courses ofphotodynamic therapy (PDT) and of the total number of patients indicated inparentheses. AMD indicates age-related macular degeneration; BP, bloodpressure; CNV, choroidal neovascularization; MPS DA, MacularPhotocoagulation Study Group disc area; and OHS, ocular histoplasmosissyndrome.



ment was 3 lines or more. Of the 118 patients with anassessment at week 4, the mean change in visual acuitywas +0.2 line, and of the 91 patients with a week-12 as-sessment, the mean change in visual acuity was −0.5 line.The difference in mean visual acuity change at week 4between regimen 3 (−1.6 lines) and regimen 4 (+1.1 lines)was statistically significant (P = .002).

At the week-12 assessment, regimen 3 showed thelargest mean visual acuity loss (1.6 lines), whereas regi-men 4 had the largest mean visual acuity improvement(0.4 line). When the patients in regimens 2 and 3 whowere treated at the highest light dose (150 J/cm2), inwhom arteriolar and venular nonperfusion hadoccurred, were excluded from the analysis, regimen 4continued to have the best mean visual acuity change atweek 4 (+1.1 lines) and week 12 (+0.4 line). Likewise,when patients who received the highest light dose wereexcluded, regimen 3 continued to have the worst meanvisual acuity change (−1.6 line) at both weeks 4 and 12.

ANGIOGRAPHIC CHANGES IN FLUORESCEINLEAKAGE AFTER PDT

Figure 1 summarizes the change in fluorescein leak-age from classic CNV for regimens 1 through 5 atweeks 1, 4, and 12 (excluding patients with no classicCNV at baseline). At week 1, some cessation of fluores-cein leakage was observed angiographically in allpatients (for example, see Figure 2). Absence of fluo-rescein leakage from classic CNV at week 1 occurred in52% (11 of 21 patients) to 100% (21 of 21 patients),depending on the regimen used. Leakage typically reap-peared in a portion of the CNV by week 4 in mostpatients in all regimens (for example, see Figure 2).

Regimen 4 resulted in the largest proportion ofcases with absence of leakage at week 1 (100%; 21patients) and week 4 (29%; 6 patients). Within regi-men 4, the 50-J/cm2 light dose was associated with thehighest percentage (57%; 4 patients) of patients withabsence of leakage at week 4. Otherwise, there was noobvious light dose–response relationship in the abilityto stop fluorescein leakage from classic CNV.

The percentages of eyes with minimal leakage andno progression (leakage from CNV beyond the originalborders) were comparable among regimens at week 4,with the exception of regimen 5, which appeared to beless effective. The rates of progression by week 4 werecomparable among the regimens and ranged from 8%(2 patients) to 23% (4 patients).

At week 12, regimen 4 had a greater percentage ofpatients (30%; 3 patients) with absence of leakage fromclassic CNV than other regimens. Regimen 4 also showedthe greatest percentage of patients (80%; 8 patients) withno leakage or minimal leakage compared with other regi-mens. The incidence of progression at week 12 rangedfrom 20% (2 patients) in regimen 4 to 62% (13 patients)in regimen 5. Cases with some leakage by week 4 weremore likely to show progression by week 12.

The effects of PDT treatment on fluorescein leak-age from occult CNV at weeks 1, 4, and 12 of follow-upare shown in Figure 3. Leakage from occult CNV wasqualitatively more difficult to grade. All eyes showedsome fluorescence of the treated fibrovascular tissue orretina immediately surrounding the CNV in the latephase of the angiogram (Figure 2). In many cases, thisstaining was difficult to distinguish from the stainingand leaking characteristics of occult CNV. Of note,some eyes with no occult CNV at baseline could be

Table 3. Visual Acuity Change From Baseline by Visit and Treatment Regimen

Visual Acuity ChangeRegimen 1

(n = 22)Regimen 2

(n = 37)Regimen 3

(n = 19)Regimen 4

(n = 22)Regimen 5

(n = 28)

Week 1$3-Line gain, No. (%) 3 (14) 6 (16) 0 (0) 5 (23) 4 (15)*No change, No. (%) 18 (81) 29 (78) 17 (89) 15 (68) 23 (85)*$3-Line loss, No. (%) 1 (5) 2 (5) 2 (11) 2 (9) 0 (0)*Mean (SD) change, lines +0.7 (1.5) +0.8 (2.6) −0.9 (2.9) +0.9 (2.5) +1.4 (2.0)Range, lines −3 to +4 −7 to +8 −12 to +2 −3 to +7 −2 to +9

Week 4$3-Line gain, No. (%) 3 (14) 5 (18)† 0 (0) 3 (14) 4 (15)No change, No. (%) 18 (81) 21 (75)† 13 (68) 18 (82) 20 (74)$3-Line loss, No. (%) 1 (5) 2 (7)† 6 (32) 1 (5) 3 (11)Mean (SD) change, lines +0.1 (1.7) +0.3 (2.3) −1.6 (3.2) +1.1 (2.4) +0.7 (2.3)Range, lines −3 to +4 −7 to +5 −9 to +2 −4 to +7 −4 to +7

Week 12$3-Line gain, No. (%) 0 (0)‡ 1 (6)§ 0 (0) 4 (36)\ 3 (12)¶No change, No. (%) 18 (95)‡ 12 (70)§ 15 (79) 4 (36)\ 19 (76)¶$3-Line loss, No. (%) 1 (5)‡ 4 (24)§ 4 (21) 3 (27)\ 3 (12)¶Mean (SD) change, lines −0.2 (1.4) −0.9 (3.3) −1.6 (3.1) +0.4 (4.5) +0.1 (3.2)Range, lines −3 to +2 −9 to +5 −9 to +2 −8 to +7 −8 to +9

*One patient withdrew before week 1.†Nine patients received multiple photodynamic therapy treatments after week 1, before week 4.‡One patient withdrew after week-4 assessment; 2 patients received multiple treatments after week 4, before week 12.§Eleven patients received multiple treatments after week 4, before week 12.\Nine patients received multiple treatments after week 4 but before week 12; two additional patients missed the week-12 follow-up visit.¶Two patients withdrew after week 4.



graded as having progression of occult CNV atfollow-up because occult CNV was identified within anarea previously occupied by classic CNV.

A number of exploratory analyses were performedto evaluate the effects of baseline lesion size, lesioncomponents, and visual acuity on visual and angio-graphic outcomes. Excluding the patients in regimens 2and 3 who were treated with the 150-J/cm2 light dose,smaller lesions (#4 MPS DAs) (n = 38) had a meanchange in visual acuity of +0.1 line at 12 weeks,whereas lesions larger than 4 MPS DAs (n = 45) had amean change in visual acuity of −0.6 line. Thirty-sixpatients with an initial visual acuity of 20/80 or bettershowed a mean change of −0.9 line compared withpatients whose initial visual acuity was 20/200 or worse(n = 21), who showed a mean change of +1.0 line ofvision. The difference between the 2 groups was signifi-cant (P = .02) despite having similar mean baselinelesion sizes (4.8 and 4.9 MPS DAs, respectively).

The CNV components at baseline also correlated withthe visual acuity outcome. At the 12-week assessment,patients with CNV, in whom 100% of the CNV was clas-sic at baseline, gained 0.6 line of vision. In comparison,patients with some occult CNV at baseline lost 0.8 lineof vision (P = .045). However, the mean baseline visualacuity was slightly worse for patients with CNV in whom100% of the CNV was classic than for patients with someoccult component (20/164 vs 20/100, respectively). Inaddition, the mean baseline lesion size was slightly smallerfor patients with 100% classic CNV (4.1 MPS DAs) thanfor patients with some occult CNV (5.1 MPS DAs). Thesedifferences may have affected the visual outcome in thesepatients.

The extent of posttreatment fluorescein leakage fromCNV relative to baseline also appeared to be correlatedwith visual acuity outcome. The 33 patients with le-sions that showed a reduced area of leakage from bothclassic and occult CNV at 12 weeks, compared with base-line, had a mean change in visual acuity of +0.8 line. Incomparison, the 49 patients with lesions that developedprogression of either classic or occult CNV by 12 weekslost 0.8 line of vision. This difference was statistically sig-nificant (P = .01).

SAFETY

Thirty-eight (29.7%) of the 128 patients receiving a singlecourse of PDT had an adverse event in the treatment eye,as reported by the treating ophthalmologists. Thirty-one of these patients had events that were judged to bepossibly, or probably, treatment related. Independent ofthe relationship to therapy, the highest incidences of ad-verse events in the treated eyes were as follows: in-creased subretinal hemorrhage (8.6%), increased fibro-sis associated with CNV (8.6%), increased RPE atrophy(3.9%), subretinal hemorrhage (3.1%), eye pain (3.1%),fibrosis (3.1%), branch retinal arteriolar or venular non-perfusion (2.3%), choroidal vessel staining (1.6%), in-creased hemorrhage (1.6%), and vitreous hemorrhage(1.6%).

Severe vision loss and associated dose-limitingocular adverse events were examined separately. Treat-

ment with PDT at 50, 75, and 100 J/cm2 was found to besafe in all regimens. However, at the highest light dose(150 J/cm2) in regimens 2 and 3, PDT resulted in clo-sure of neurosensory retinal vessels (Figure 4); there-fore, enrollment at this light dose was discontinuedpromptly. Two of the 3 patients who were treated with

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Figure 1. Grading of fluorescein leakage from classic choroidalneovascularization at week 1 (A), week 4 (B), and week 12 (C) in treatmentregimens 1 to 5 in patients with age-related macular degeneration after a firstcourse of photodynamic therapy.



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Figure 2. Baseline and follow-up of single treatment of photodynamic therapy (PDT) with verteporfin with the use of regimen 3 (light dose at 100 J/cm2). Colorfundus photograph from initial visit (visual acuity, 20/50) (A) shows fibrovascular tissue with subretinal hemorrhage. Early-phase fluorescein angiogram(B) shows a bright area of hyperfluorescence corresponding to classic choroidal neovascularization (CNV) (straight arrows), with additional hyperfluorescence(curved arrows) corresponding to occult CNV. Both areas demonstrate leakage on late-phase frame (C). One week after PDT (visual acuity, 20/64), color fundusphotograph shows darker appearance of fibrovascular tissue (D). Corresponding fluorescein angiogram, early-phase frame (E), shows a hypofluorescent area(straight arrows) corresponding to an area of fibrovascular tissue with an additional area (curved arrows) of relatively less hypofluorescence. Late-phase frame(F) shows persistence of the central hypofluorescent area (straight arrows); the relatively less hypofluorescent area seen in early phase is no longer apparent.Some additional hyperfluorescent area of staining (curved arrows) surrounds hypofluorescence. Four weeks after PDT (visual acuity, 20/50), color fundusphotograph (G) shows a central fibrous component surrounded by a reddish hue, possibly corresponding to additional hemorrhage. Corresponding fluoresceinangiogram shows some hypofluorescence within the area of previous leakage (H), with absence of leakage from classic CNV and minimal leakage from occult CNVwithin the area previously occupied by classic and occult CNV seen in the late-phase frame (I). Twelve weeks after PDT (visual acuity, 20/50), color fundusphotograph (J) shows complete clearing of subretinal hemorrhage. Corresponding fluorescein angiogram shows minimal leakage from classic CNV (straightarrows) and moderate leakage from occult CNV (curved arrows) in early-phase (K) and late-phase (L) frames, within the area occupied by classic and occult CNVat baseline (B and C).



the 150-J/cm2 light dose in regimen 2 had significantloss of vision by 12 weeks, losing 5 and 9 lines of vision,respectively. In regimen 3, two of the 5 patients treatedat 150 J/cm2 had sensory retinal vessel closure. One ofthese patients had occlusion of both branch retinal ar-teries and veins in the posterior pole, which was associ-ated with a loss of 12 lines of vision at week 1 (20/50 to20/800); visual acuity at week 12 was 20/400 (9 lineslost). The second patient had extensive capillary non-perfusion ($30% of the treated area), with minimal vi-sion loss of 1 line by 12 weeks. In addition, 1 patient in

the 75-J/cm2 group in regimen 3, and 1 patient in the100-J/cm2 group in regimen 2, experienced a vitreoushemorrhage. Both patients lost 7 lines of vision by week12. No ocular adverse events were noted in regimens 4and 5 for all light doses tested. The remaining events ofsevere vision loss were without association to any otherocular adverse event.

Adverse events for all body systems combinedwere reported by 42.2% of the 128 patients. The mostcommon adverse events, independent of the relation-ship to therapy, and other than those noted above, were

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headache in 6 patients (4.7%), asthenia in 4 patients(3.1%), and bronchitis in 4 patients (3.1%). No otheradverse events occurred in more than 3 patients (2.3%).Specifically, photosensitivity reactions were notreported by any patients. Adverse events occurring at asite other than the eye, which were considered by the

treating ophthalmologist to be possibly, or probably,treatment related, were headache in 2 patients (1.6%),with no other event being reported by more than 1patient.

COMMENT

This phase 1 and 2 study demonstrated that PDT withverteporfin can lead to cessation of fluorescein leakagefrom CNV associated with preservation or improve-ment of vision. After the results from the first few pa-tients were obtained, which showed that cessation of fluo-rescein leakage from CNV could be achieved withoutadversely affecting vision, light dose escalation was per-formed because absence of leakage did not persist at theweek 4 assessment. However, even at the highest lightdose used (150 J/cm) in regimen 1, absence of leakagedid not persist, although no ocular adverse events werenoted.

Rather than increase the light dose further in this firstregimen, which would have led to an even longer irradia-tion time than the 4.2 minutes required to deliver 150 J/cm,it was decided to increase the effective serum concentra-tion of verteporfin. This was accomplished in 2 ways: (1)by shortening the time between infusion and irradiation(regimen 2) and (2) by increasing the verteporfin dose from6 to 12 mg/m2 (regimen 3).

However, at a light dose of 150 J/cm2, appliedeither 20 minutes after a verteporfin infusion of 6mg/m2 (regimen 2) or 30 minutes after an infusion of12 mg/m2 (regimen 3), neurosensory retinal vessel non-perfusion was observed on fluorescein angiographyassociated with severe visual loss in some cases. Whileall the lesions treated involved the fovea, some caseswith retinal vessel nonperfusion did not lose vision,since the nonselective closure was patchy in its distri-bution within the treatment area. However, this nonse-lective effect was clearly undesirable and carried thepotential for treatment-associated vision loss. Accord-ingly, a light dose of 150 J/cm2 was considered to beabove the maximum tolerated dose when verteporfin, 6or 12 mg/m2, is used with irradiation 20 or 30 minutesafter the beginning of a 10-minute verteporfin infusion.Moreover, persistent cessation of fluorescein leakagefrom CNV was not achieved even at these high lightdoses when nonselective events occurred. Two of the 4patients with retinal vessel nonperfusion demonstratedprogression (CNV leakage beyond the original bordersof the CNV) by week 12.

Retinal vessel nonperfusion in regimen 2 was an un-expected finding at these treatment specifications, sinceretinal vessel damage at this dose of verteporfin had beenrare in preclinical studies with monkeys.19 The monkeystudies, which used a 10- or 30-minute intravenous in-fusion, were limited to a verteporfin dose of 0.375 mg/kg(approximating 6 mg/m2) and did not produce retinal ves-sel closure.21 However, retinal vessel closure was dem-onstrated in the same monkey model when irradiationwas applied early (within 10 minutes) after a bolus verte-porfin infusion (30 seconds) at this dose, or at higherverteporfin doses, such as 1 mg/kg (approximately 15mg/m2).18 This dose of verteporfin is only 25% higher than

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Figure 3. Grading of fluorescein leakage from occult choroidalneovascularization at week 1 (A), week 4 (B), and week 12 (C) in treatmentregimens 1 through 5 in patients with age-related macular degeneration aftera first course of photodynamic therapy.



that used in regimen 3, although the pharmacokineticsof verteporfin after bolus injection and a 10-minute in-fusion may differ.

Vitreous hemorrhage occurred in 2 patients afterPDT. In both cases, a marked increase in subretinalhemorrhage was noted before breakthrough hemor-rhage into the vitreous. This may have representednatural disease progression or may be the result of arelatively large choroidal hemorrhage (secondary tononselective choroidal vascular closure) with subse-quent breakthrough into vitreous. Alternatively, vitre-ous hemorrhage may just have occurred more often inthis study than anticipated in an untreated populationof patients with CNV. Additional ocular adverse events,including increased fibrosis and increased subretinalhemorrhage, could be attributable to the natural pro-gression of AMD and unrelated to PDT. Cases of severevision loss not associated with any other ocular adverseevent, such as nonperfusion of retinal vessels, were con-sidered to be part of the natural course of AMD. Thecausality of adverse events, both ocular and systemic,will be better assessed in the phase 3 trials, in which aplacebo group is included.

Although this study was not designed prospec-tively to compare the different treatment regimens interms of efficacy, some exploratory analyses were per-formed. They suggested that regimen 4, which used averteporfin dose of 6 mg/m2 infused over 10 minutes,with irradiation performed 15 minutes after the start ofverteporfin infusion, showed the most favorable meanchange in visual acuity at 4 weeks (+1.1 lines). Nogiven light dose had specific advantages in terms ofabsence of fluorescein leakage from CNV. However, the50-J/cm2 light dose in regimen 4 was associated withthe highest percentage of patients with absence of leak-age at 4 weeks (57%) and the lowest percentage ofpatients with progression of classic CNV at 12 weeks.When lower light doses (12.5 and 25 J/cm2) were usedin regimen 5, the angiographic outcomes were the leastfavorable and may represent a minimally effective dose.

The different outcomes among the various regi-mens with respect to change in visual acuity may repre-sent the varied natural course of this disease. However,the correlation between the extent of CNV leakage at fol-low-up and the change in visual acuity, determined in-dependently of each other, suggests that a better visual

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Figure 4. Baseline and follow-up at week 1 of a single treatment of photodynamic therapy with verteporfin with the use of regimen 3 (light dose at 150 J/cm 2)demonstrating loss of selectivity of photodynamic therapy. Color fundus photograph (A) before treatment (visual acuity, 20/50) shows fibrovascular tissue(arrows) that was beneath subretinal fluid. Corresponding late-phase fluorescein angiogram (B) shows fluorescein leakage from classic (straight arrows) andoccult (curved arrows) choroidal neovascularization. One week after treatment (visual acuity, 20/800), an early-phase fluorescein angiogram (C) showsneurosensory retinal vessel nonperfusion of both retinal arterioles and venules with persistent nonperfusion in late-phase frames (D). Visual acuity was 20/400 atweek 12.



outcome for regimen 4 may be related to an effect of thePDT on the CNV. These factors led to the selection ofthe 50-J/cm2 dose and regimen 4 for some retreatmentregimens and phase 3 trials.34

Exploratory analyses of the data also suggest thatpatients with smaller lesions (#4 MPS DAs) and worsebaseline visual acuity (#20/200) had better visual acu-ity outcomes. In addition, patients who demonstrated adecreased area of CNV leakage on fluorescein angiogra-phy at 12 weeks compared with baseline had a bettervisual outcome than patients in whom leakage fromCNV extended beyond its original borders. This findingsuggests that patients who demonstrate stabilization offluorescein leakage from CNV after PDT may have abeneficial visual outcome if this stabilization can bemaintained. Of course, these exploratory analysesshould be interpreted with caution, since this study wasnot designed prospectively to assess these effects.

Week 12 assessment data for regimen 4 may be bi-ased favorably to include the best responders to PDT, sincethis regimen allowed retreatment of some patients whoshowed fluorescein leakage from CNV at their week 4or week 8 visit. Therefore, only patients who did not showfluorescein leakage at these interim visits, and who maybe better responders, are included in the week 12 analy-sis for single treatments. However, comparisons of thevisual acuity and angiographic results of the different regi-mens at week 4 still indicate that regimen 4 has the mostfavorable mean visual acuity outcome.

In summary, PDT with verteporfin can lead to ces-sation of fluorescein leakage from CNV for 1 to 4weeks, with stabilization or improvement of vision for12 weeks. The data in the present study also suggestthat the maximum tolerated light dose is less than 150J/cm2, and that a minimally effective dose is greater than25 J/cm2. Fluorescein leakage, in at least a portion ofthe CNV, returns in most cases by 4 weeks, with pro-gression in some cases by 12 weeks. The exploratoryanalyses demonstrating an association between pre-served vision and a lesser extent of CNV leakage at 12weeks suggest that confining the growth of CNV withPDT might result in preservation of vision with PDTcompared with no treatment. If multiple courses ofPDT are required, studies would have to demonstratethat retreatment of CNV could be accomplished safely.The study presented in the accompanying article bySchmidt-Erfurth et al32 demonstrates that this is true atleast in the short term. Randomized, placebo-controlled, clinical trials with longer follow-up, cur-rently in progress by this group, will answer the ques-tion of whether PDT with verteporfin can be effective atconfining CNV growth and leakage and preserve visionin patients with neovascular AMD.

Accepted for publication April 27, 1999.From Retina Service, Massachusetts Eye and Ear In-

firmary, Harvard Medical School, Boston, Mass (DrsMiller and Gragoudas and Ms Lane); the Retina Depart-ment, University Eye Hospital, Lubeck, Germany (DrsSchmidt-Erfurth, Laqua, Barbazetto, and Birngruber);Hopital Ophtalmique Jules Gonin, Lausanne, Switzerland(Drs Sickenberg, Zografos, and Piguet); Department of

Oto-Neuro-Ophthalmology, Hopital Cantonal Universi-taire de Geneve, Geneva, Switzerland (Drs Pournaras andDonati); Laboratory of Air Pollution Studies, Departmentof Environmental Engineering, Ecole Polytechnique Feder-ale de Lausanne, Lausanne, Switzerland (Dr van denBerg); QLT PhotoTherapeutics Inc, Vancouver, BritishColumbia (Drs Strong and Manjuris); CIBA Vision Inc,Duluth, Ga (Mr Gray); CIBA Vision AG, Bulach, Switzer-land (Dr Fsadni); and The Wilmer Ophthalmological In-stitute, The Johns Hopkins University School of Medicine,Johns Hopkins Hospital, Baltimore, Md (Dr Bressler). TheMassachusetts Eye and Ear Infirmary is an owner of apatent covering the use of verteporfin. Should the Massa-chusetts Eye and Ear Infirmary receive royalties or otherfinancial remuneration related to that patent, Drs Millerand Gragoudas would receive a share of same in accor-dance with the Massachusetts Eye and Ear Infirmary’s in-stitutional Patent Policy and Procedures, which includesroyalty-sharing provisions.

This study was supported by QLT PhotoTherapeuticsInc and CIBAVision AG.

Presented in part at the annual meetings of the Asso-ciation for Research in Vision and Ophthalmology, Fort Lau-derdale, Fla, April 22, 1996, and May 11, 1997, as well asat the joint meeting of the Retina Society and Club JulesGonin, Berne, Switzerland, September 4, 1996.

Corresponding author: Joan W. Miller, MD, Laser Re-search Laboratory, Retina Service, Massachusetts Eye andEar Infirmary, 243 Charles St, Boston, MA 02114 (e-mail:[email protected]).

Reprints: Medical Information, CIBA Vision Ophthal-mics, 11460 Johns Creek Pkwy, Duluth, GA 30097 (e-mail:[email protected]).

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33. Dewey D. Corneal and retinal energy density with various laser beam deliverysystems and contact lenses. In: Puliafito CA, ed. Ophthalmic Technologies: Pro-ceedings of the Society of Photo-Optical Instrumentation Engineers, Los Ange-les, Calif, January 20-25, 1991. Vol 1423. Bellingham, Wash: The InternationalSociety for Optical Engineering; 1991:105-116.

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7. Smith SD, Katz J, Quigley HA. Analysis of progressive change in automated vi-sual fields in glaucoma. Invest Ophthalmol Vis Sci. 1996;37:1419-1428.

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13. Holmin C, Krakau CET. Visual field decay in normal subjects and in cases of chronicglaucoma. Albrech Von Graefes Arch Klin Exp Ophthalmol. 1980;213:291-298.

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CorrectionCorrection

Omission in Financial Disclosures. In the Clinical Sciences articles by Miller et al titled “Photodynamic Therapy With Verte-porfin for Choroidal Neovascularization Caused by Age-related Macular Degeneration: Results of a Single Treatment in aPhase 1 and 2 Study,” published in the September issue of the ARCHIVES (1999;117:1161-1173); by Schmidt-Erfurth et altitled “Photodynamic Therapy With Verteporfin for Choroidal Neovascularization Caused by Age-related Macular Degen-eration: Results of Retreatments in a Phase 1 and 2 Study,” published in the September issue of the ARCHIVES (1999;117:1177-1187); and by the Treatment of Age-related Macular Degeneration With Photodynamic Therapy (TAP) Study Grouptitled “Photodynamic Therapy of Subfoveal Choroidal Neovascularization in Age-related Macular Degeneration With Verte-porfin: One-Year Results of 2 Randomized Clinical Trials—TAP Report 1,” published in the October issue of the ARCHIVES

(1999;117:1329-1345), journal omissions of financial disclosure, properly reported at the time of manuscript submission,occurred in the acknowledgment sections on pages 1172, 1187, and 1344, respectively. The following statement should haveappeared in all 3 articles: “Drs Sickenberg and Bressler are consultants for CIBA Vision Inc, Duluth, Ga, and QLT Photo-therapeutics Inc, Vancouver, British, Columbia.” The journal regrets the errors.

ARCH OPHTHALMOL / VOL 118, APR 2000 WWW.ARCHOPHTHALMOL.COM488


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