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Improved Vision-Related Function After Ranibizumab Treatment of Neovascular Age-Related Macular DegenerationResults of a Randomized Clinical Trial
Tom S. Chang, MD;
Neil M. Bressler, MD;
Jennifer T. Fine, ScD;
Chantal M. Dolan, PhD;
James Ward, PhD;
Todd R. Klesert, MD, PhD; for the MARINA Study Group
Arch Ophthalmol. 2007;125(11):1460-1469.
ABSTRACT
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Objective To examine the effects of ranibizumab on patient-reported visual function using the National Eye Institute Visual Function Questionnaire 25 (NEI VFQ-25) in patients with neovascular age-related macular degeneration (AMD).
Design In MARINA, a randomized, double-masked clinical trial, 716 patients with AMD with recent disease progression and minimally classic or occult with no classic lesion component were randomized 1:1:1 to monthly intravitreal ranibizumab (0.3 or 0.5 mg) or sham injections. The NEI VFQ-25 was administered at 0, 1, 2, 3, 6, 9, 12, 18, and 24 months.
Main Outcome Measure Mean change from baseline in NEI VFQ-25 scores at 12 and 24 months.
Results At 12 months, ranibizumab-treated patients (0.3 mg [n = 238] and 0.5 mg [n = 240]) had mean improvements in NEI VFQ-25 composite scores of +5.2 (95% confidence interval [CI], 3.5 to 6.9) and +5.6 (95% CI, 3.9 to 7.4), respectively; sham-injected patients (n = 238) had a mean decline of –2.8 (95% CI, –4.6 to –1.1; P < .001 vs each dose). Ranibizumab-treated patients were more likely to improve in near activities, distance activities, and vision-specific dependency through 24 months.
Conclusions In MARINA, ranibizumab-treated patients were more likely than sham-treated patients to report visual function improvements at 12 and 24 months.
Application to Clinical Practice Treatment of neovascular AMD with ranibizumab can improve patient-reported visual function in a meaningful way compared with sham treatments.
Trial Registration clinicaltrials.gov Identifier: NCT00056836
INTRODUCTION
Age-related macular degeneration (AMD) was reported to be the leading cause of blindness in adults in the industrialized world, affecting more than 1.75 million individuals in the Unites States with approximately 200 000 new cases diagnosed each year.1-2 Neovascular (wet) AMD affects central, high-acuity vision, profoundly impacting an individual's ability to perform even the most basic activities of daily living,3 such as reading, writing, cooking, or driving, leading to a progressive loss of independence and decreased vision-related function. Although most physicians and patients make decisions based on functional parameters such as a patient's ability to read, drive, and function independently, the primary outcome measure in ophthalmology clinical trials evaluating treatments for neovascular AMD recently has been visual acuity in the treated eye.4-5 While changes in visual acuity on an eye chart are important in the clinical trial setting, measures of visual acuity do not always fully capture the degree of visual function. Clinicians may assume that visual function or patient's perception of visual function improves along with visual acuity; however, this is not always the case.6 To our knowledge to date, no neovascular AMD clinical trials have reported clinically meaningful improvement in patient-reported vision-related function more often than no treatment. Recently, 2 pharmacologic therapies have received Food and Drug Administration approval for treatment of neovascular AMD based on their visual acuity results.4-5 The studies supporting these therapies did not publish outcomes on vision-related function. The inclusion of patient-reported outcomes in clinical trials provides information on these critical functional parameters that is an important supplement to traditional clinical measures of vision.7-8
The National Eye Institute Visual Function Questionnaire 25 (NEI VFQ-25) was developed to measure a patient's subjective assessment of vision-related function.9-10 The NEI VFQ-25 has been validated in patients with AMD, age-related cataracts, diabetic retinopathy, primary open-angle glaucoma, cytomegalovirus retinitis, and low vision from any cause.10 Recent major clinical trials sponsored by the NEI, such as the Age Related Eye Disease Study,11-13 the Submacular Surgery Trials (SST),6, 14-17 and the Complications of Age-Related Macular Degeneration Prevention Trial,18 have used the NEI VFQ-25 to assess vision-related function. The SST confirmed that neovascular AMD can have a profound impact on the NEI VFQ-25 overall composite scores and most subscales19 and that individuals with neovascular AMD often rate their health status as low20 as patients with symptomatic AIDS21 or patients with chronic renal failure receiving home dialysis.22 To determine whether patient-reported vision-related function in neovascular AMD could be improved with intervention, we describe the results of prespecified vision-related function end points (near activities, distance activities, and vision-specific dependency subscales of the NEI VFQ-25) from a randomized clinical trial comparing monthly intraocular injections of ranibizumab (Lucentis; Genentech, Inc, South San Francisco, California) at 2 different doses compared with a sham injection. This trial, designated MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab In the Treatment of Neovascular AMD), demonstrated that intravitreal ranibizumab, administered for 2 years, markedly decreased the risk of visual acuity loss, improved mean visual acuity, and improved the chance of visual acuity gain in patients with subfoveal choroidal neovascularization (CNV) secondary to AMD and recent disease progression with a lesion composition on fluorescein angiography that was minimally classic or occult with no classic. At 12 months, 94.5% and 94.6% of patients given 0.3-mg and 0.5-mg ranibizumab, respectively, lost fewer than 15 letters as compared with 62.2% of patients receiving sham injections (P < .001 for both comparisons). Visual acuity improved by at least 15 letters in 24.8% and 33.8% of patients receiving 0.3-mg and 0.5-mg ranibizumab, respectively, as compared with 5.0% of the sham-injection group (P < .001 for both doses). This visual acuity benefit was maintained at 24 months.23
METHODS
Institutional review board approval was obtained before patient enrollment began, and Health Insurance Portability and Accountability Act compliance was achieved at all 96 participating study sites. All patients provided signed consent for their study participation before enrollment and random treatment assignment.
SYNOPSIS OF THE PROTOCOL
Between March 2003 and December 2003, 716 patients with minimally classic or occult with no classic subfoveal CNV secondary to AMD were enrolled in the study. The eligibility requirements for patients and eyes, clinical evaluation procedures, and clinical data collection methods and schedules are described in detail elsewhere.23 Eligible patients were 50 years or older and had a diagnosis of primary or recurrent subfoveal CNV secondary to AMD. Requirements for the study eye included an AMD lesion no larger than 12 disc areas, a neovascular component that was at least 50% of the AMD lesion, and a lesion composition that was minimally classic or occult with no classic; evidence of recent disease progression; and best-corrected visual acuity of 20/40 to 20/320 (Snellen equivalent). Only 1 eye per patient was chosen as the study eye and only the study eye received either ranibizumab or sham injection. If both eyes of the patient were eligible for enrollment, the evaluating physician (along with the patient) determined which eye would be designated the study eye.
Patients were randomized in a 1:1:1 ratio to receive monthly intravitreal 0.3-mg ranibizumab, 0.5-mg ranibizumab, or sham injections and stratified by visual acuity at day 0 (letter score  55 [approximately 20/80] or  54 [approximately <20/80]), CNV lesion composition (minimally classic or occult without classic CNV), and study center. Patients received monthly injections (within 23-37 days) for 2 years (24 injections) in the study eye. All patients were scheduled for follow-up interviews at 1, 2, 3, 6, 9, 12, 18, and 24 months after the initial interview and treatment with best-corrected visual acuity measured at 2 and 4 m at each visit.
NEI VFQ-25 METHODS
The interview instrument selected for the MARINA trial was the NEI VFQ-25, which was developed to measure a patient's subjective assessment of vision-related function.10 The NEI VFQ-25 consists of a 25-item base set of questions, which measure different aspects of visual function, as well as 6 additional items to enhance the reliability of both the near and distance visual subscales.9-10,24 The instrument includes 12 subscales: 1 general health subscale and 11 vision subscales, including general vision, difficulty with near- and distance-vision activities, difficulty with driving, vision-specific dependency, social functioning, role difficulties, limitation in peripheral and color vision, ocular pain, and mental health issues related to vision.
The NEI VFQ-25 scores were calculated using the recommendations of the developers and according to published guidelines for the NEI VFQ-25 to yield an overall composite score as well as scores on the general health subscale and the 11 other subscales that address different aspects of visual function.25 The mean of all the NEI VFQ-25 subscales, excluding the general health question, is used to calculate the overall composite score. The general health question is treated as a stand-alone item because it is frequently used as an indicator of overall health status in many population-based studies. The NEI VFQ-25 subscale scores are a mean of the items included in a given subscale transformed to a scale from 0 (worst score) to 100 (best score), where higher scores indicate better vision-related function. Items left blank are not taken into account when calculating scores. At least 1 item in the subscale must be answered to calculate a subscale score.
Although no minimum important difference has been established for the NEI VFQ-25, several studies have now shown that a 10-point difference in NEI VFQ-25 scores roughly corresponds to a 3-line change in visual acuity—a magnitude of visual acuity change that is deemed clinically important.6, 13-14 Thus, in the current study, a 10-point change in the NEI VFQ-25 overall composite or subscale scores was considered a clinically meaningful change across the range of enrolling visual acuities. The NEI VFQ-25 interview was administered by trained study-site personnel who were masked to treatment assignment.
DATA ANALYSIS AND STATISTICAL METHODS
In the MARINA study, the primary efficacy outcome measure was the proportion of patients who lost fewer than 15 letters of visual acuity at 12 months relative to baseline visual acuity. Secondary efficacy outcome measures included mean change from baseline in NEI VFQ-25 scores for the near activities, distance activities, and vision-specific dependency subscales over time (up to 12 months and at 24 months). These subscales were previously identified as important to patients with AMD.6, 14 The overall composite score and the remaining subscales of the NEI VFQ-25 were prespecified as end points (but not as secondary efficacy outcomes) in the analysis plan.
All efficacy analyses were performed on the intent-to-treat patient population. Missing values were imputed using the last-observation-carried-forward method (data not shown). The results were similar when there was no imputation of the missing NEI VFQ-25 scores using the last-observation-carried-forward approach (data not shown).
Mean changes in NEI VFQ-25 subscale scores from baseline to follow-up interviews were compared between treatment groups using t tests from analysis of covariance models that adjusted for baseline visual acuity (54 or 55 letter score), CNV classification, and relevant baseline subscale score as covariates. Patients achieving a 10-point or greater gain on NEI VFQ-25 subscales at 12 or 24 months were compared using descriptive statistics (percentages and corresponding 95% confidence intervals [CIs]). Times for achieving a 10-point or greater gain over 24 months were also descriptively compared with Kaplan-Meier time-to-event curves.
In this report, the study eye was categorized as the better-seeing eye when the visual acuity letter score in the study eye was higher than the other eye; the study eye was the worse-seeing eye when the letter score in the study eye was worse than the other eye. Eyes were excluded from the analyses by better- or worse-seeing eye in the rare cases where the letter score was the same in both eyes at baseline or when baseline visual acuity was not assessed in the other eye.
Data from all interviews completed by December 8, 2005, were analyzed. We used SAS software (SAS, Inc, Cary, North Carolina) for data analyses.
RESULTS
DEMOGRAPHIC AND CLINICAL CHARACTERISTICS
Of the 716 patients enrolled in MARINA, 238 were randomized to sham injections, 238 to 0.3-mg ranibizumab monthly, and 240 to 0.5-mg ranibizumab monthly. The mean age of the patients at baseline was 77 years (range, 52-95 years). As had been reported previously,23 the treatment arms were well balanced with regard to the baseline demographic characteristics, visual acuity, and other characteristics of the eyes and CNV lesions. More patients received treatment in their worse-seeing eye: 62.4% in the sham arm, 55.9% in the 0.3-mg ranibizumab arm, and 53.6% in the 0.5-mg ranibizumab arm. Of the enrolled patients, 42.4% in the sham arm, 47.1% in the 0.3-mg ranibizumab arm, and 47.5% in the 0.5-mg ranibizumab arm had evidence of having had CNV in the fellow eye (thus, these patients had CNV in the study eye and CNV in the fellow eye that had developed sometime prior to baseline enrollment in MARINA). The treatment groups were balanced in the distribution of visual acuity whether their study was the better- or worse-seeing eye at baseline, regardless of which eye was treated (Table 1). Subjects who had the same visual acuity letter score in both eyes (2 in the sham group, 2 in the 0.3-mg group, and 5 in the 0.5-mg group) or whose visual acuity in the nontreated eye was not assessed (1 in the sham group, 2 in the 0.3-mg group, and 1 in the 0.5-mg group) were excluded from the better- and worse-eye information in Table 1. The baseline NEI VFQ-25 overall composite and subscale scores for the entire cohort are shown in Table 2.
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Table 1. Selected Characteristics Relevant to Patient-Reported Vision-Related Outcomes and Visual Acuity Distribution According to Better- or Worse-Seeing Eye at Baseline
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Table 2. Change in NEI VFQ-25 Scores From Baseline to Month 12 and Month 24
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INTERVIEW COMPLETION
The percentage of patients completing month 12 was high in each treatment group (89.1% for sham, 95.0% for 0.3 mg, and 94.2% for 0.5 mg at 12 months, and approximately 80%-90% among the 3 arms at 24 months). Interview completion rates during follow-up were also high in all treatment arms. After 12 months of follow-up, all patients completing month 12 also completed the NEI VFQ-25 interview with the exception of 1 patient in the 0.3-mg ranibizumab arm. Interview completion rates were fairly well sustained at 24 months, although there was some variability between the groups: 79.0% of sham-injected patients, 87.8% of 0.3-mg ranibizumab–treated patients, and 88.8% of 0.5-mg ranibizumab–treated patients completed the NEI VFQ-25 interview.
NEI VFQ-25 SCORES DURING FOLLOW-UP
Ranibizumab-treated patients had mean changes in NEI VFQ-25 scores that were higher than those in sham-injected patients at every follow-up visit through month 24 (Figure 1). For the entire cohort, the mean changes from baseline in the overall composite scores after 12 months of follow-up were improvements of +5.2 (95% CI, 3.5 to 6.9) and +5.6 (95% CI, 3.9 to 7.4) for patients treated with 0.3-mg and 0.5-mg ranibizumab, respectively, compared with a decline of –2.8 (95% CI, –4.6 to –1.1) for sham-injected patients (Table 2). These mean improvements in vision-related function were sustained for up to 24 months in ranibizumab-treated patients, whereas on average, vision-related function in sham-injected patients continued to decline.
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Figure 1. Mean change from baseline through 24 months in National Eye Institute Visual Function Questionnaire 25 (NEI VFQ-25) score by treatment group for overall (composite) score (A), near activities (B), distance activities (C), and dependency (D). P values for comparison of ranibizumab dose groups with control are as follows. (A) Overall score, 0.3 mg vs sham: P = .01 at month 1, P < .001 at months 2 through 24; 0.5 mg vs sham: P > .05 at month 1, P = .04 at month 2, P < .001 at months 3 through 24. (B) Near activities, 0.3 mg vs sham: P = .05 at month 1, P = .004 at month 2, P < .001 at months 3 through 24; 0.5 mg vs sham: P = .04 at month 1, P = .03 at month 2, P < .001 at months 3 through 24. (C) Distance activities, 0.3 mg vs sham: P = .008 at month 1, P < .001 at months 2 through 24; 0.5 mg vs sham: P > .05 at month 1, P = .01 at month 2, P < .001 at months 3 through 24. (D) Dependency, 0.3 mg vs sham: P > .05 at month 1, P = .009 at month 2, P = .006 at month 3, P = .005 at month 6, P = .001 at month 9, P < .001 at months 12 through 24; 0.5 mg vs sham: P > .05 at month 1, P = .02 at month 2, P = .001 at month 3, P < .001 at months 6 through 24.
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The mean change from baseline to month 12 and month 24 in the predefined NEI VFQ-25 subscale scores (near activities, distance activities, and vision-specific dependency) indicated improvement at both time points in ranibizumab-treated patients receiving either dose, but a decline was seen at each time point in sham-injected patients (Table 2). For the entire cohort after 12 months of follow-up, the mean improvements from baseline in the near-activities subscale, distance-activities subscale, and vision-specific dependency were +9.4 (95% CI, 6.8 to 12.0) and +10.4 (95% CI, 8.1 to 12.8); +6.7 (95% CI, 4.3 to 9.2) and +7.0 (95% CI, 4.8 to 9.2); and +3.6 (95% CI, 0.6 to 6.6) and +6.8 (95% CI, 4.1 to 9.6) for 0.3-mg and 0.5-mg ranibizumab-treated patients, respectively. Sham-injected patients had a mean decline in these subscales of –2.6 (95% CI, –4.9 to –0.2), –5.9 (95% CI, –8.2 to –3.6), and –4.7 (95% CI, –7.8 to –1.6), respectively. These benefits in the specified subscale scores were sustained for up to 24 months in ranibizumab-treated patients, whereas vision-related function in sham-injected patients continued to decline. The earliest time point for all 3 specified subscales where there was a difference with a P value <.05 between the ranibizumab arms and the sham arm was month 2 for both the 0.3-mg and the 0.5-mg ranibizumab arms (Figure 1).
Patient scores in each ranibizumab arm were more likely to improve by at least 10 points and less likely to decrease by at least 10 points compared with the sham arm in both the overall composite score and the 3 subscales specified as secondary end points at both 12 and 24 months (Figure 2). Kaplan-Meier analysis of patients by the first time to improvement of 10 or more points by treatment arm showed that such improvements could be seen by month 1 in any of the treatment arms, but the percentage that improved by 10 or more points was always greater for ranibizumab-treated patients than for sham-treated patients for the overall score as well as for the 3 subscale scores (Figure 3). The cumulative percentage of patients with these improvements was generally twice as high as sham-treated patients at 3 months. Additional ranibizumab-treated and sham-treated patients had an improvement of 10 or more points at 6 months, with the percentage continuing to be generally twice as high in ranibizumab-treated patients. The increase in the cumulative percentage between 3 and 6 months indicates that not all patients who have an improvement of 10 or more points will have this improvement within 3 months. Even after 6 months, additional patients achieved this outcome for the first time. Most of the ranibizumab-treated patients maintained the clinically meaningful improvement of 10 or more points at 12 and 24 months as shown in Figure 2 by the percentage with these outcomes at these time points.
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Figure 2. Percentage with improvement of 10 or more points (left side) or loss of 10 or more points from baseline to 12 months (light gray bars) or 24 months (dark gray bars) on the National Eye Institute Visual Function Questionnaire 25 (NEI VFQ-25) overall (composite) score (A), near activities (B), distance activities (C), and dependency (D) by treatment group. P values for comparison of ranibizumab dose groups with control are from Pearson  2 tests as follows: P < .001 for all comparisons of 0.3 mg or 0.5 mg vs sham with the single exception of dependency, 10 or greater point loss at month 12, 0.3 mg vs sham: P = .02.
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Figure 3. Time to first gain of at least 10 or more points from baseline sustained at the next or last qualifying visit (Kaplan-Meier estimates) by treatment group for National Eye Institute Visual Function Questionnaire 25 (NEI VFQ-25) overall (composite) score (A), near activities (B), distance activities (C), and dependency (D) by treatment group.
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COMMENT
The MARINA study, to our knowledge, is the first randomized, controlled clinical trial to demonstrate a marked improvement in patient-reported vision-related function in patients receiving a treatment for neovascular AMD compared with a control (sham) treatment. Ranibizumab-treated patients showed greater improvement from baseline than did sham-injected patients in the NEI VFQ-25 composite score and all 3 NEI VFQ-25 subscales specified as secondary end points (near activities, distance activities, vision-related dependency). These outcomes in vision-related function were sustained at 12 and 24 months in ranibizumab-treated patients, whereas mean vision-related function in sham-injected patients continued to decline so that the treatment differences in mean change from baseline for ranibizumab compared with sham patients for both dose groups were even greater at 24 months (11-16 points) than at 12 months (8-13 points). These clinically meaningful improvements (gains of 10 or more points) were detected as early as 1 month after treatment initiation.
Among 6 of the remaining 9 NEI VFQ-25 subscales not specified as secondary end points (driving, role differences, mental health, social functioning, peripheral vision, and general vision), ranibizumab-treated patients had at least a 5-point benefit in mean change from baseline score compared with sham-injected patients at 12 and 24 months. Of note, the driving subscale showed that a larger proportion of ranibizumab-treated patients than sham-injected patients reporting driving at the 24-month visit, providing additional objective evidence that patients with neovascular AMD treated with ranibizumab may be more likely than sham-injected patients to retain functional independence.
Although color vision did not meet this 5-point threshold, other studies have also suggested that patient-reported perception of visual function with respect to color vision as measured as a subscale with the NEI VFQ-25 is not affected greatly by neovascular AMD.6, 14, 26 The ocular pain subscale and the general health subscale did not show significant differences between ranibizumab-treated and sham-injected patients, a finding consistent with other studies in similar populations,6, 19 and that could be expected because AMD is a painless disease that does not directly affect general health. These results further support the validity of the treatment effect of ranibizumab on patient-reported vision-related function in patients participating in the MARINA study.
In a recent prospective study of macular translocation with 360° peripheral retinectomy in 50 patients with bilateral advanced AMD and relatively low levels of visual acuity,26 at 12 months an improvement of 10.6 from baseline was reported in mean NEI VFQ-25 scores (P < .001, 95% CI not reported). This study was limited, however, by the lack of a comparative observational or control arm. The clinical relevance of these results is therefore difficult to assess.
The current study has several major strengths that minimize bias and facilitate detection of treatment effects. Specifically, the strengths are a large sample size and masking, with both patients and study personnel administering the NEI VFQ-25 interviews masked to treatment assignment. The study is limited in part by the lower completion rates of the questionnaire at follow-up in the control group compared with the ranibizumab-treated groups. Because visual acuity can decline over time, it is likely that NEI VFQ-25 scores will decline over time; thus, if last observation carried forward is used for missing values, it is possible that the lower completion rates in the control group may lead to falsely higher values for the control group and underestimate the benefits for ranibizumab at later time points. Other potential limitations include the difficulty in generalizing these results to the entire neovascular AMD population that would meet the criteria of the MARINA study because the patients were participating in a clinical trial with regular follow-up planned for at least 2 years. Study participants may be healthier and better able to cope with the visual disabilities accompanying neovascular AMD than the general AMD population.
Patient-reported vision-related outcomes are designed to measure visual function, which is a binocular phenomenon. In prior studies, correlation analysis determined that patient-reported vision-related function results are more dependent on changes in visual acuity of the "better-seeing eye,"27 a situation in which one might expect that a treatment that can improve visual acuity would more profoundly affect the NEI VFQ-25 scores. In the MARINA trial, only 1 eye of any participant in the trial was treated. We observed clinically meaningful changes in the vision-related function scores even though the better-seeing eye was treated in less than half of the patients in any of the treatment groups. Future analyses are under way that will examine the impact of ranibizumab treatment on vision-related function according to whether the study eye was the better-seeing eye or the worse-seeing eye at the time of randomization.
In summary, we describe the first treatment for neovascular AMD that provides a demonstrable and clinically meaningful improvement in patient-reported vision-related function relative to sham injection. These results were observed consistently across the NEI VFQ-25 composite score and the 3 prespecified secondary end-point subscales of near activities, distance activities, and dependency, noted as early as 1 month after initiating treatment in some cases. Improvements in patient-reported vision-related function in ranibizumab-treated patients in this trial were incremental over time, with mean improvements through 1 year appearing to be maintained through 2 years. This finding was consistent across all relevant subscales and paralleled objective improvements in visual acuity, consistent with a genuine treatment effect. Although previous clinical trials in neovascular AMD have reported effects on visual acuity, they have not shown improvements in patient-reported visual function.4-5 We believe evidence of patient-reported functional improvements will play an increasingly important role in understanding the effects of treatments on this devastating condition and in addressing growing public health concern.
AUTHOR INFORMATION
Correspondence: Tom S. Chang, MD, Retina Institute of California, 800 S Fairmount Ave, Ste 312, Pasadena, CA 91105 (tomschang{at}hotmail.com).
Submitted for Publication: March 23, 2007; final revision received June 22, 2007; accepted June 28, 2007.
Financial Disclosure: This study was supported financially by Genentech, Inc, South San Francisco, California, and by Novartis Pharma AG, Basel, Switzerland. As of March 1, 2007, Dr Bressler's employer, the Johns Hopkins University (JHU), but not Dr Bressler, received funding from Acucela, Athenagen, Bausch & Lomb, Carl Zeiss Meditec, Fovea, Genentech, Notal Vision Inc, Novartis, (OSI) Eyetech, Othera, QLT, Regeneron, and TargeGen for sponsored projects by the Department of Ophthalmology for the efforts of Dr Bressler. Dr Bressler receives salary support for these sponsored projects; the terms of these projects are negotiated and administered by JHU's Office of Research Administration. Under JHU's policy, receiving support for the costs of research administered by the institution does not constitute a conflict of interest. In addition, Dr Bressler's spouse is a paid consultant to Genentech. The terms of this arrangement are being managed by JHU in accordance with its conflict-of-interest policies. Dr Chang is a consultant for Genentech; Novartis; iScience Interventional; and Regeneron Pharmaceuticals and has received honoraria from Genentech, Inc; iScience Interventional; and Regeneron Pharmaceuticals. He is also an investor in iScience Interventional. Dr Klesert is contracted to consult with Genentech. Dr Fine is a Genentech employee, has received stock options, and owns Genentech stock. Dr Dolan is a paid consultant for Genentech, owns Genentech stock, and has received stock options as a Genentech employee in the past 5 years. Dr Ward is a paid consultant for Genentech.
Additional Contributions: The design and conduct of the study as well as the data collection, management, and analysis and interpretation of the data were supported by Genentech, Inc, and Novartis Pharma AG. Medical writing assistance for the preparation and review of this article was provided by Genentech.
| MARINA Study Group Principal Investigators
Thomas Aaberg, Associated Retinal Consultants, Grand Rapids, Michigan; Prema Abraham, BH Regional Eye Institute, Rapid City, South Dakota; D. Virgil Alfaro, III, Retina Consultants of Charleston, Charleston, South Carolina; Andrew Antoszyk, Southeast Clinical Research Associates, Charlotte, North Carolina; Carl Awh, Retina Vitreous Associates, Nashville, Tennessee; Gaetano Barile, Edward Harkness Eye Institute, New York, New York; Charles Barr, Louisville, Kentucky; Wendall Bauman, Department of Ophthalmology, Brooke Army Medical Center, Fort Sam Houston, Texas; Paul Beer, Lions Eye Institute, Albany, New York; Brian Berger, Austin, Texas; Abdhish Bhavsar, Retina Center, PA, Minneapolis, Minnesota; Robert Bhisitkul, Department of Ophthalmology, School of Medicine, University of California at San Francisco; H. Culver Boldt, Department of Ophthalmology, University of Iowa Hospital and Clinics, Iowa City; David Boyer, Retina-Vitreous Associates, Beverly Hills, California; William Bridges, Western Carolina Retinal Associates, Asheville, North Carolina; Roy Brod, Lancaster, Pennsylvania; David Brown, Vitreoretinal Consultants, Houston, Texas; J. Shepard Bryan, Associated Retinal Consultants, Ltd, Phoenix, Arizona; Robert Chambers, Retinal Consultants, Inc, Columbus, Ohio; Thomas Ciulla, Indianapolis, Indiana; Thomas Connor, Medical College of Wisconsin, Milwaukee; Scott Cousins, Bascom Palmer Eye Institute, Palm Beach Gardens, Florida; Richard Dreyer, Northwest Retina, PC, Portland, Oregon; William Dunn, Florida Retina Institute, Daytona Beach; Dean Eliott, Kresge Eye Institute, Detroit, Michigan; Philip Ferrone, Long Island Vitreoretinal Consultants, Great Neck, New York; Bradley Foster, New England Retina Consultants, West Springfield, Massachusetts; William Freeman, University of California at San Diego, Jacobs Retina Center, La Jolla; Wayne Fung, Pacific Eye Associates, San Francisco, California; Ronald Gentile, The New York Eye and Ear Infirmary, New York; Bert Glaser, National Retina Institute, Chevy Chase, Maryland, and Towson, Maryland; David Glaser, Retina Associates of St. Louis, Florissant, Missouri; Louis Glazer, Vitreo-Retinal Associates, Grand Rapids; Victor Gonzalez, Valley Retina Institute, PA, McAllen, Texas; Roy Goodart, Rocky Mountain Retina Consultants, Salt Lake City, Utah; Julia Haller, Johns Hopkins University, Baltimore, Maryland; Mark Hammer, Retina Associates of Florida, PA, Tampa; Jeffrey Heier, Ophthalmic Consultants of Boston, Boston, Massachusetts; Baker Hubbard, Emory University, Atlanta, Georgia; Henry Hudson, Retina Centers, PC, Tucson, Arizona; Darma Ie, Delaware Valley Retina Associates, Lawrenceville, New Jersey; Mark Johnson, University of Michigan, Ann Arbor; Robert Johnson, West Coast Retina Medical Group, Inc, San Francisco; Daniel Joseph, Barnes Retina Institute, St. Louis, Missouri; Peter Kaiser, Cleveland Clinic Foundation, Cole Eye Institute, Cleveland, Ohio; Richard Kaiser, Retina Diagnostic and Treatment Associates, LLC, Philadelphia, Pennsylvania; Randy Katz and Kevin T. Kelly, Palm Beach Eye Foundation, Lake Worth, Florida; Ronald Kingsley, Dean A. McGee Eye Institute, Oklahoma City, Oklahoma; Gregg Kokame, Retina Consultants of Hawaii, Aiea; Baruch Kuppermann, University of California at Irvine; Steven Leff, Retina-Vitreous Center, Lakewood, New Jersey, and New Brunswick, New Jersey; Craig Leong, Bay Area Retina Associates, Walnut Creek, California; Louis Lobes, Retina Vitreous Consultants, Pittsburgh, Pennsylvania; Mark Lomeo, Midwest Retina, Columbus; Christopher MacDonald, Department of Ophthalmology, University of Texas Health Science Center, San Antonio; Dennis Marcus, Southeast Retina Center, Augusta, Georgia; Linda Marouf, Retina Associates of South Texas, PA, San Antonio; Randy Adam Martidis, Retina Diagnostic and Treatment Associates, LLC, Philadelphia; Jose Martinez, Austin Retina Associates, Austin; Donald Maxwell Jr, Retinal Associates of Oklahoma, Oklahoma City; Colin McCannel, Mayo Clinic, Rochester, Minnesota; Tod McMillan, Southeastern Retina Associates, PC, Knoxville, Tennessee; Lawrence Morse, University of California at Davis Medical Center, Sacramento; Thomas Oei, Braverman-Terry-Oei Eye Associates, San Antonio; Robert Park, University of Arizona, Tucson; Matthew Paul, Danbury Eye Physicians and Surgeons, Danbury, Connecticut; Peter Pavan, Department of Ophthalmology, University of South Florida, Tampa; Dante Pieramici, California Retina Consultants, Santa Barbara; Jay Prensky, Pennsylvania Retina Specialists, PC, Camphill; David Quillen, Penn State Hershey Medical Center, Hershey, Pennsylvania; Elias Reichel, New England Eye Center, Boston; William Rodden, Retina and Vitreous Center of Southern Oregon, Ashland, Oregon; Philip J. Rosenfeld, Bascom Palmer Eye Institute, Miami, Florida; Juan Rubio, Retina Associates of South Texas, PA, San Antonio; Paul Runge, Ophthalmic Consultants, Sarasota, Florida; Srinivas Sadda, Doheny Eye Institute, Los Angeles, California; George Sanborn, Virginia Eye Institute, Richmond; Reginald Sanders, Retina Group of Washington, Chevy Chase; Steven Sanislo, California Vitreoretinal Research Center, Menlo Park; Stephen G. Schwartz, Bascom Palmer Eye Institute, Palm Beach Gardens, Florida; Michael Singer, Medical Center Ophthalmology Associates, San Antonio; Lory Snady-McCoy, Rhode Island Eye Institute, Providence; Scott Sneed, Retinal Consultants of Arizona, Phoenix; Jay Stallman, Georgia Retina, PC, Decatur, Georgia; Walter Stern, Northern California Retina-Vitreous Associates, San Mateo, California, and Mountain View, California; Glenn Stoller, Ophthalmic Consultants of Long Island, Rockville Centre, New York; Barry Taney, Retina Vitreous Consultants, Ft. Lauderdale, Florida; John Thompson, Retina Specialists, Towson; David Tom, New England Retina Associates, Hamden, Connecticut; Michael Trese, Associated Retinal Consultants, PC, Royal Oak, Michigan; Thierry Verstaeten, Allegheny General Hospital, Pittsburgh; Cuong Vu, Retina Associates, PC, Annapolis, Maryland; Joseph Walker, Retina Consultants of Southwest Florida, Fort Myers; Harold Weiss, Retina Consultants of Michigan, Southfield, Michigan; Jeffrey Weiss, Retina Associates of South Florida, Margate; Craig Wells, Vitreoretinal Associates, Seattle, Washington; Harold Woodcome, Ophthalmology Consultants, Providence; Marco Zarbin, Department of Ophthalmology, New Jersey Medical School, Newark; Kang Zhang, John Moran Eye Center, University of Utah, Salt Lake City.
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Author Affiliations: Retina Institute of California, Pasadena (Dr Chang); Retina Division, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland (Dr Bressler); Genentech, Inc, South San Francisco, California (Drs Fine, Dolan, and Ward); and Doheny Retina Institute, University of Southern California, Los Angeles (Dr Klesert).
REFERENCES
| |
1. Friedman DS, O’Colmain BJ, Munoz B; et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 2004;122(4):564-572.
FREE FULL TEXT
2. Bressler NM. Age-related macular degeneration is the leading cause of blindness. JAMA. 2004;291(15):1900-1901.
FREE FULL TEXT
3. Williams RA, Brody BL, Thomas RG, Kaplan RM, Brown SI. The psychosocial impact of macular degeneration. Arch Ophthalmol. 1998;116(4):514-520.
FREE FULL TEXT
4. 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. Arch Ophthalmol. 1999;117(10):1329-1345.
FREE FULL TEXT
5. Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR, VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351(27):2805-2816.
FREE FULL TEXT
6. Miskala PH, Bass EB, Bressler NM; et al. Surgery for subfoveal choroidal neovascularization in age-related macular degeneration: quality-of-life findings: SST report No. 12. Ophthalmology. 2004;111(11):1981-1992.
FULL TEXT
|
ISI
| PUBMED
7. Wilson IB, Cleary PD. Linking clinical variables with health-related quality of life: a conceptual model of patient outcomes. JAMA. 1995;273(1):59-65.
FREE FULL TEXT
8. Margolis MK, Coyne K, Kennedy-Martin T, Baker T, Schein O, Revicki DA. Vision-specific instruments for the assessment of health-related quality of life and visual functioning: a literature review. Pharmacoeconomics. 2002;20(12):791-812.
FULL TEXT
|
ISI
| PUBMED
9. Mangione CM, Lee PP, Pitts J, Gutierrez P, Berry S, Hays RD. Psychometric properties of the National Eye Institute Visual Function Questionnaire (NEI-VFQ). Arch Ophthalmol. 1998;116(11):1496-1504.
FREE FULL TEXT
10. Mangione CM, Lee PP, Gutierrez PR, Spritzer K, Berry S, Hays RD. Development of the 25-item National Eye Institute Visual Function Questionnaire. Arch Ophthalmol. 2001;119(7):1050-1058.
FREE FULL TEXT
11. Bressler NM, Bressler SB, Congdon NG; et al. Potential public health impact of Age-Related Eye Disease Study results: AREDS report No. 11. Arch Ophthalmol. 2003;121(11):1621-1624.
FREE FULL TEXT
12. Clemons TE, Chew EY, Bressler SB, McBee W. National Eye Institute Visual Function Questionnaire in the Age-Related Eye Disease Study (AREDS): AREDS Report No. 10. Arch Ophthalmol. 2003;121(2):211-217.
FREE FULL TEXT
13. Lindblad AS, Clemons TE. Responsiveness of the National Eye Institute Visual Function Questionnaire to progression to advanced age-related macular degeneration, vision loss, and lens opacity: AREDS report No. 14. Arch Ophthalmol. 2005;123(9):1207-1214.
FREE FULL TEXT
14. Miskala PH, Hawkins BS, Mangione CM; et al. Responsiveness of the National Eye Institute Visual Function Questionnaire to changes in visual acuity: findings in patients with subfoveal choroidal neovascularization: SST report No. 1. Arch Ophthalmol. 2003;121(4):531-539.
FREE FULL TEXT
15. Childs AL, Bressler NM, Bass EB; et al. Surgery for hemorrhagic choroidal neovascular lesions of age-related macular degeneration: quality-of-life findings: SST report No. 14. Ophthalmology. 2004;111(11):2007-2014.
FULL TEXT
|
ISI
| PUBMED
16. Dong LM, Childs AL, Mangione CM; et al. Health- and vision-related quality of life among patients with choroidal neovascularization secondary to age-related macular degeneration at enrollment in randomized trials of submacular surgery: SST report No. 4. Am J Ophthalmol. 2004;138(1):91-108.
FULL TEXT
|
ISI
| PUBMED
17. Hawkins BS, Miskala PH, Bass EB; et al. Surgical removal vs observation for subfoveal choroidal neovascularization, either associated with the ocular histoplasmosis syndrome or idiopathic: II, Quality-of-life findings from a randomized clinical trial: SST Group H Trial: SST report No. 10. Arch Ophthalmol. 2004;122(11):1616-1628.
FREE FULL TEXT
18. Maguire M. Baseline characteristics, the 25-Item National Eye Institute Visual Functioning Questionnaire, and their associations in the Complications of Age-Related Macular Degeneration Prevention Trial (CAPT). Ophthalmology. 2004;111(7):1307-1316.
FULL TEXT
|
ISI
| PUBMED
19. Submacular Surgery Trials Research Group. Health- and vision-related quality of life among patients with ocular histoplasmosis or idiopathic choroidal neovascularization at enrollment in a randomized trial of submacular surgery: Submacular Surgery Trials report No. 5. Arch Ophthalmol. 2005;123(1):78-88.
FREE FULL TEXT
20. Bass EB, Marsh MJ, Mangione CM; et al. Patients' perceptions of the value of current vision: assessment of preference values among patients with subfoveal choroidal neovascularization: the Submacular Surgery Trials Vision Preference Value Scale: SST report No. 6. Arch Ophthalmol. 2004;122(12):1856-1867.
FREE FULL TEXT
21. Morimoto T, Fukui T. Utilities measured by rating scale, time trade-off, and standard gamble: review and reference for health care professionals. J Epidemiol. 2002;12(2):160-178.
PUBMED
22. Torrance GW, Feeny D. Utilities and quality-adjusted life years. Int J Technol Assess Health Care. 1989;5(4):559-575.
PUBMED
23. Rosenfeld PJ, Brown DM, Heier JS; et al, MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431.
FREE FULL TEXT
24. Mangione CM. The National Eye Institute 25-item Visual Function Questionnaire (VFQ-25) version 2000. http://www.nei.nih.gov/resources/visionfunction/manual_cm2000.pdf. Accessed October 6, 2006.25. Published guidelines for the NEI VFQ-25. http://www.rand.org/health/surveys_tools/vfq/. Accessed September 1, 2006.26. Cahill MT, Stinnett SS, Banks AD; et al. Quality of life after macular translocation with 360° peripheral retinectomy for age-related macular degeneration. Ophthalmology. 2005;112(1):144-151.
FULL TEXT
|
ISI
| PUBMED
27. Linder M, Chang TS, Scott IU; et al. Validity of the visual function index (VF-14) in patients with retinal disease. Arch Ophthalmol. 1999;117(12):1611-1616.
FREE FULL TEXT
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