Ranibizumab for Neovascular Age-Related Macular Degeneration
Philip J. Rosenfeld, M.D., Ph.D., David M. Brown, M.D., Jeffrey S. Heier, M.D., David S. Boyer, M.D., Peter K. Kaiser, M.D., Carol Y. Chung, Ph.D., Robert Y. Kim, M.D., for the MARINA Study Group
Background Ranibizumab — a recombinant, humanized, monoclonalantibody Fab that neutralizes all active forms of vascular endothelialgrowth factor A — has been evaluated for the treatmentof neovascular age-related macular degeneration.
Methods In this multicenter, 2-year, double-blind, sham-controlledstudy, we randomly assigned patients with age-related maculardegeneration with either minimally classic or occult (with noclassic lesions) choroidal neovascularization to receive 24monthly intravitreal injections of ranibizumab (either 0.3 mgor 0.5 mg) or sham injections. The primary end point was theproportion of patients losing fewer than 15 letters from baselinevisual acuity at 12 months.
Results We enrolled 716 patients in the study. At 12 months,94.5% of the group given 0.3 mg of ranibizumab and 94.6% ofthose given 0.5 mg lost fewer than 15 letters, as compared with62.2% of patients receiving sham injections (P<0.001 forboth comparisons). Visual acuity improved by 15 or more lettersin 24.8% of the 0.3-mg group and 33.8% of the 0.5-mg group,as compared with 5.0% of the sham-injection group (P<0.001for both doses). Mean increases in visual acuity were 6.5 lettersin the 0.3-mg group and 7.2 letters in the 0.5-mg group, ascompared with a decrease of 10.4 letters in the sham-injectiongroup (P<0.001 for both comparisons). The benefit in visualacuity was maintained at 24 months. During 24 months, presumedendophthalmitis was identified in five patients (1.0%) and seriousuveitis in six patients (1.3%) given ranibizumab.
Conclusions Intravitreal administration of ranibizumab for 2years prevented vision loss and improved mean visual acuity,with low rates of serious adverse events, in patients with minimallyclassic or occult (with no classic lesions) choroidal neovascularizationsecondary to age-related macular degeneration. (ClinicalTrials.govnumber, NCT00056836
[ClinicalTrials.gov]
.)
Age-related macular degeneration is a leading cause of irreversibleblindness among people who are 50 years of age or older in thedeveloped world.1,2,3 The neovascular form of the disease usuallycauses severe vision loss and is characterized by the abnormalgrowth of new blood vessels under or within the macula, thecentral portion of the retina responsible for high-resolutionvision.
Neovascularization in this disease is classified by fluoresceinangiography into major angiographic patterns termed classicand occult, which may be associated with various degrees ofaggressiveness of disease, vision loss, and response to varioustreatment options.4 Pharmacologic therapies for neovasculardisease that are available in the United States and Europe includeverteporfin photodynamic therapy5,6,7,8 — approved bythe Food and Drug Administration only for predominantly classiclesions (in which 50% or more of the lesion consists of classicchoroidal neovascularization) and by the European Agency forthe Evaluation of Medicinal Products for both predominantlyclassic lesions and occult disease with no classic lesions —and pegaptanib sodium.9 Both treatments can slow the progressionof vision loss, but only a small percentage of treated patientsshow improvement in visual acuity.
The age-related changes that stimulate pathologic neovascularizationare incompletely understood, but vascular endothelial growthfactor A (VEGF-A) — a diffusible cytokine that promotesangiogenesis and vascular permeability — has been implicatedas an important factor promoting neovascularization.10,11,12,13,14,15Multiple biologically active forms of VEGF-A are generated byalternative messenger RNA splicing and proteolytic cleavage,16and two isoforms have been detected in choroidal neovascularlesions.15
Ranibizumab — a recombinant, humanized monoclonal antibodyFab that neutralizes all active forms of VEGF-A — wasrecently approved by the Food and Drug Administration for thetreatment of all angiographic subtypes of subfoveal neovascularage-related macular degeneration. In phase 1 and 2 clinicalstudies, ranibizumab demonstrated encouraging signs of biologicactivity, with acceptable safety, when administered intravitreallyfor up to 6 months in patients with neovascular age-relatedmacular degeneration.17,18,19 In our phase 3 study, MinimallyClassic/Occult Trial of the Anti-VEGF Antibody Ranibizumab inthe Treatment of Neovascular Age-Related Macular Degeneration(MARINA), we evaluated ranibizumab for the treatment of minimallyclassic or occult with no classic choroidal neovascularizationassociated with age-related macular degeneration.
Methods
Study Design
At 96 sites in the United States, we enrolled 716 patients inour 2-year, prospective, randomized, double-blind, sham-controlledstudy of the safety and efficacy of repeated intravitreal injectionsof ranibizumab among patients with choroidal neovascularizationassociated with age-related macular degeneration. We performeda prespecified primary efficacy analysis at 12 months. The primaryefficacy end point was the proportion of patients who had lostfewer than 15 letters (approximately 3 lines) from baselinevisual acuity, as assessed with the Early Treatment DiabeticRetinopathy Study (ETDRS) chart, with the use of standardizedrefraction and testing protocol at a starting test distanceof 2 m. We obtained approval from the institutional review boardat each study site before the enrollment of patients; all studysites complied with the requirements of the Health InsurancePortability and Accountability Act. The eligibility of lesionswas confirmed by an independent central reading center withthe use of standardized criteria and trained graders who wereunaware of patients' treatment assignments. Patients providedwritten informed consent before determination of their fulleligibility. Screening lasted as long as 28 days.
To be included in the study, patients had to be at least 50years old; have a best corrected visual acuity of 20/40 to 20/320(Snellen equivalent determined with the use of an ETDRS chart);have primary or recurrent choroidal neovascularization associatedwith age-related macular degeneration, involving the fovealcenter; have a type of lesion that had been assessed with theuse of fluorescein angiography and fundus photography as minimallyclassic or occult with no classic choroidal neovascularization;have a maximum lesion size of 12 optic-disk areas (1 optic-diskarea equals 2.54 mm2 on the basis of 1 optic-disk diameter of1.8 mm), with neovascularization composing 50% or more of theentire lesion; and have presumed recent progression of disease,as evidenced by observable blood, recent vision loss, or a recentincrease in a lesion's greatest linear diameter of 10% or more.(For a complete list of eligibility criteria, see Table 1 ofthe Supplementary Appendix, available with the full text ofthis article at www.nejm.org.) There were no exclusion criteriaregarding preexisting cardiovascular, cerebrovascular, or peripheralvascular conditions.
Study Treatment
We randomly assigned eligible patients in a 1:1:1 ratio to receiveranibizumab (Lucentis, Genentech) at a dose of either 0.3 mgor 0.5 mg or a sham injection monthly (within 23 to 37 days)for 2 years (24 injections) in one eye. The evaluating physicianwas unaware of the patient's treatment assignment; the physicianwho administered the injection was aware of the patient's treatmentassignment regarding ranibizumab or sham treatment but was unawareof the dose of ranibizumab. Other personnel at each study site(except for those assisting with injections), patients, andpersonnel at the central reading center were unaware of thepatient's treatment assignment.
Verteporfin photodynamic therapy was allowed if the choroidalneovascularization in the study eye became predominantly classic.On the basis of a policy decision by the Centers for Medicareand Medicaid Services to reimburse photodynamic therapy forsmall, minimally classic, and occult lesions as of April 1,2004, the study protocol was amended to allow photodynamic therapyfor minimally classic or occult disease with no classic lesionsthat were no larger than 4 optic-disk areas and were accompaniedby a loss of 20 letters or more from baseline visual acuity,as confirmed at consecutive study visits. (A score of 55 lettersis approximately equal to a Snellen equivalent of 20/80 vision.)
The study was designed and analyzed by a committee composedof both academic investigators and representatives of the industrysponsor. In the analysis of the data and the writing of themanuscript, Dr. Rosenfeld had full and unrestricted access tothe data, and all the coauthors contributed to the interpretationof the data and the final version of the manuscript. All theauthors vouch for the accuracy and completeness of the reporteddata.
Statistical Analysis
We performed efficacy analyses on an intention-to-treat basisamong all patients with the use of a last-observation-carried-forwardmethod for missing data. For all pairwise comparisons, the statisticalmodel adjusted for baseline score for visual acuity (<55letters vs. 55 letters) and subtype of choroidal neovascularization(minimally classic vs. occult with no classic disease). Between-groupcomparisons for dichotomous end points were performed with theuse of the Cochran chi-square test.20 Change from baseline visualacuity was analyzed with the use of analysis-of-variance models.For end points for lesion characteristics, analysis-of-covariancemodels adjusting for the baseline value were used. The Hochberg–Bonferronimultiple-comparison procedure21 was used to adjust for the twopairwise treatment comparisons for the primary end point. Safetyanalyses included all treated patients.
We determined the number of patients in each group on the basisof a 1:1:1 randomization ratio, Pearson's chi-square test forthe two pairwise comparisons of the primary end point, and theHochberg–Bonferroni multiple comparison procedure at anoverall type I error of 0.0497 (adjusting for the three plannedsafety interim analyses before the primary efficacy analysis).Monte Carlo simulations were used to evaluate the power of thestudy. We estimated that the enrollment of 720 patients wouldprovide the study with a statistical power of 95% to detecta significant difference between one or both ranibizumab groupsand the sham-injection group in the proportion of patients losingfewer than 15 letters at 12 months, assuming a proportion of65% in each ranibizumab group and 50% in the sham-injectiongroup. (For more details, see the Methods section of the Supplementary Appendix.)
Results
Study Patients
Between March 2003 and December 2003, 716 patients were enrolledand randomly assigned to study treatment. Groups were balancedfor demographic and baseline ocular characteristics (Table 1).
Table 1. Baseline Characteristics of the Patients.
More than 90% of patients in each treatment group remained inthe study at 12 months, and approximately 80 to 90% remainedat 24 months (Table 2 of the Supplementary Appendix). The percentageswho were still receiving study treatment were similarly highat 12 months and at the end of the study. After the unmaskingof first-year results and discussion with the data and safetymonitoring committee, ranibizumab was offered to all patientsin October 2005, 2 months before the end of the last patient'sfinal study visit at 24 months. Of the patients in the sham-injectiongroup, 12 were switched to receive 0.5 mg of ranibizumab: 5patients (2.1%) at 22 months and 7 (2.9%) at 23 months, thelast possible injection visit. During the 2-year treatment period,38 patients in the sham-injection group (16.0%), 2 patientsin the group receiving 0.3 mg of ranibizumab (0.8%), and nonein the group receiving 0.5 mg of ranibizumab received verteporfinphotodynamic therapy at least once. In the second year, 13 patients(5.5%) in the sham-injection group and none in the ranibizumabgroups chose to discontinue study treatment and receive pegaptanibsodium, which was approved in the United States in December2004 for the treatment of neovascular age-related macular degeneration.Of these 13 patients, 8 remained in the follow-up group at 24months.
Primary and Secondary End Points
The primary and key secondary efficacy results at 12 months(prespecified primary analysis) and 24 months are summarizedin Figure 1 and Figure 2. The study met its primary end point(Figure 1A) at 12 months. Of the patients who were treated withranibizumab, 94.5% of the patients receiving 0.3 mg and 94.6%of those receiving 0.5 mg had lost fewer than 15 letters frombaseline visual acuity, as compared with 62.2% in the sham-injectiongroup (P<0.001 for the comparison of each dose with the sham-injectiongroup). At 24 months, this end point was met by 92.0% of thepatients receiving 0.3 mg of ranibizumab and 90.0% of thosereceiving 0.5 mg, as compared with 52.9% in the sham-injectiongroup (P<0.001 for each comparison). The visual-acuity benefitassociated with ranibizumab was independent of the size of thebaseline lesion, the lesion type, or baseline visual acuity(Figure 1B and 1C).
Figure 1. Rate of Loss or Gain of Visual Acuity at 12 and 24 Months Associated with Ranibizumab, as Compared with Sham Injection.
Panel A shows the percentage of patients in each group who lost fewer than 15 letters from baseline visual acuity at 12 months (the primary efficacy end point) and at 24 months. Panels B and C summarize the percentage of patients who lost fewer than 15 letters at 12 and 24 months, respectively, according to lesion size (1 optic-disk area is equal to 2.54 mm2 on the basis of 1 optic-disk diameter of 1.8 mm), baseline visual acuity (a score of 55 letters is approximately equal to a Snellen equivalent of 20/80), and lesion type. Panel D shows the percentage of patients who gained 15 or more letters from baseline at 12 and 24 months. For the study overall, treatment comparisons were based on the Cochran chi-square test stratified according to the visual-acuity score at day 0 (<55 letters vs. 55 letters) and choroidal neovascularization subtype. Pearson's chi-square test was used for treatment comparisons in each subgroup. The last-observation-carried-forward method was used to handle missing data. All tests were two-sided (P<0.001 for all comparisons between each ranibizumab group and the sham-injection group). I bars represent 95% confidence intervals.
Figure 2. Mean Changes from Baseline in Visual Acuity and Snellen Equivalents at 12 and 24 Months.
Panel A shows the mean changes from baseline in visual acuity during a 24-month period. At each monthly assessment, P<0.001 for the comparison between each ranibizumab group and the sham-injection group. On day 7, P=0.006 for patients receiving 0.3 mg of ranibizumab and P=0.003 for those receiving 0.5 mg. Panels B and C show the change from baseline in the percentage of patients with a Snellen equivalent of 20/40 or better and the percentage of patients with 20/200 or worse, respectively, at 12 and 24 months (P<0.001 for the comparison between each ranibizumab group and the sham-injection group at 12 and 24 months). Treatment comparisons use pairwise models adjusted for visual-acuity scores at day 0 (<55 letters vs. 55 letters) and for the type of choroidal neovascularization. Analysis of variance was used to assess the change in visual acuity from baseline at each monthly assessment. The Cochran chi-square test was used for the comparison of percentages. The last-observation-carried-forward method was used to handle missing data. All statistical tests were two-sided. I bars represent SE in Panel A and 95% confidence intervals in Panels B and C.
At 12 and 24 months, approximately one quarter of patients treatedwith 0.3 mg of ranibizumab and one third of patients treatedwith 0.5 mg of ranibizumab had gained 15 or more letters invisual acuity, as compared with 5.0% or less of those in thesham-injection group (P<0.001 for each comparison) (Figure 1D).
At both doses of ranibizumab, the mean improvement from baselinein visual-acuity scores was evident 7 days after the first injection(P=0.006 for the 0.3-mg dose and P=0.003 for the 0.5-mg dose),whereas mean visual acuity in the sham-injection group declinedsteadily over time at each monthly assessment (P<0.001 forboth comparisons) (Figure 2A). At 12 months, mean increasesin visual acuity were 6.5 letters in the 0.3-mg group and 7.2letters in the 0.5-mg group, as compared with a decrease of10.4 letters in the sham-injection group (P<0.001 for bothcomparisons). The benefit in visual acuity was maintained at24 months. The average benefit associated with ranibizumab overthat of sham injection was approximately 17 letters in eachdose group at 12 months and 20 to 21 letters at 24 months.
At baseline, the percentages of patients with 20/40 vision orbetter were similar among the three groups (Figure 2B). At 12months, approximately 40% of patients receiving ranibizumabhad 20/40 vision or better, as compared with 11.3% in the sham-injectiongroup (P<0.001). At 24 months, of the patients receivingranibizumab, 34.5% of those in the 0.3-mg group and 42.1% inthe 0.5-mg group had at least 20/40 vision, whereas the proportionin the sham-injection group had dropped to 5.9% (P<0.001for each comparison).
A single patient in the sham-injection group had 20/20 or bettervision at baseline. Among patients receiving ranibizumab, 3.8%in the 0.3-mg group and 7.9% in the 0.5-mg group had 20/20 visionor better at 12 months, and 6.7% in the 0.3-mg group and 7.9%in the 0.5-mg group had 20/20 vision or better at 24 months.In the sham-injection group, only two patients (0.8%) had 20/20vision or better at 12 months (P<0.001 for the comparisonwith the 0.5-mg group and P=0.03 for the comparison with the0.3-mg group), and one (0.4%) had 20/20 vision or better at24 months (P<0.001 for the comparison with each ranibizumabgroup).
The percentages of patients with visual acuity of 20/200 orworse were similar among the three groups at baseline (Figure 2C).At 12 and 24 months, the percentages in the ranibizumab-treatedgroups remained about the same, whereas the percentages in thesham-injection group had increased by 3 to 3.5 times (P<0.001for the comparison with each ranibizumab dose at 12 and 24 months).Very few patients receiving ranibizumab had severe vision loss(30 letters or more) from baseline (0.8% of the 0.3-mg groupand 1.2% of the 0.5-mg group), as compared with 14.3% of thesham-injection group at 12 months; at 24 months, 3.4% of the0.3-mg group and 2.5% of the 0.5-mg group had severe visionloss, as compared with 22.7% of the sham-injection group (P<0.001for the comparison with each dose at 12 and 24 months).
Ranibizumab treatment was associated with arrested growth ofand leakage from choroidal neovascularization (including intense,progressive staining of the retinal pigment epithelium) (Figure 3A through Figure 3D).The mean change from baseline in each of the ranibizumab-treatedgroups differed significantly from that in the sham-injectiongroup at 12 and 24 months (P<0.001 for each comparison).
Figure 3. Mean (±SE) Changes in Choroidal Neovascularization and Leakage.
Leakage refers to that associated with choroidal neovascularization plus intense, progressive staining of the retinal pigment epithelium. One optic-disk area is equal to 2.54 mm2. Pairwise analysis of covariance was adjusted for the visual-acuity score at day 0 (<55 letters vs. 55 letters), the subtype of choroidal neovascularization, and the baseline value of the end point. Missing data were imputed according to the last-observation-carried-forward approach. P<0.001 for the comparison between each ranibizumab group and the sham-injection group at 12 and 24 months. All statistical tests were two-sided.
Adverse Events
Cumulative adverse events for the 24-month study period aresummarized in Table 2. Each of the key serious ocular adverseevents occurred in different patients (Table 3 of the Supplementary Appendix).Investigator-reported cases of endophthalmitis, as well as anycase of serious uveitis treated with intravitreal antibiotics,were presumed to be endophthalmitis. The presumed endophthalmitisrate was 5 of 477 patients (1.0%) or, alternatively, a rateper injection of 0.05% (5 of 10,443 total injections). In fourof the five presumed cases of endophthalmitis, neither vitreousnor aqueous culture showed growth.
Slit-lamp examination revealed inflammation (of any cause, includingendophthalmitis) throughout the study in the ranibizumab groups(Table 2, and Tables 4 and 5 of the Supplementary Appendix).22,23Most of the inflammation in all groups was designated as traceor 1+.
Ranibizumab had no long-term effect on intraocular pressure,on average, as assessed by monthly preinjection measurementsduring the 2-year follow-up. Intraocular pressure was increasedon average 1 hour after ranibizumab injections at protocol-mandatedintraocular-pressure assessments; however, the absence of correspondingchanges in preinjection measurements suggests the postinjectionincreases were transient. On average, postinjection intraocularpressure increased from the preinjection value by 1.9 to 3.5mm Hg in the 0.3-mg group and 2.1 to 3.4 mm Hg in the 0.5-mggroup, as compared with 0.8 to 1.5 mm Hg in the sham-injectiongroup. Postinjection intraocular pressure of 30 mm Hg or moreoccurred in approximately 13.0% of patients in the 0.3-mg groupand 17.6% of those in the 0.5-mg group, as compared with 3.4%of those in the sham-injection group. Intraocular pressure of40 mm Hg or more occurred in 2.3% of patients in each ranibizumabgroup and in no patients in the sham-injection group. A postinjectionintraocular pressure of 50 mm Hg or more occurred in 0.6% ofeach ranibizumab group.
Ranibizumab was not associated with an increased frequency ofcataracts (15.7% of patients in the sham-injection group, ascompared with 15.5% in each ranibizumab group). However, lensstatus did change in a few patients during the 2-year treatmentperiod. Of patients whose study eye was phakic at baseline andwhose lens status was known at 24 months, the study eye of 6of 117 patients in the 0.3-mg group (5.1%) and 8 of 111 patientsin the 0.5-mg group (7.2%) had become pseudophakic by 24 months,as compared with no patients in the sham-injection group. At24 months, ranibizumab-treated patients whose study eye hadbeen phakic and then became pseudophakic during the course ofthe study had visual acuity similar to that of ranibizumab-treatedpatients overall.
Seventeen deaths occurred during the 2-year study. In the sham-injectiongroup, six patients (2.5%) died: two from strokes, one fromcongestive heart failure, one from renal failure, one from acuterespiratory failure, and one of an unknown cause. In the groupreceiving 0.3 mg of ranibizumab, five patients (2.1%) died:two from myocardial infarction, one from complications of non-Hodgkin'slymphoma, one from pneumonia, and one from an unknown cause.In the group receiving 0.5 mg of ranibizumab, six patients (2.5%)died: two from stroke, one from a small-bowel infarct, one fromtraumatic injury from an automobile accident, one from sepsis,and one from chronic asthma and chronic obstructive pulmonarydisease. An additional three patients who had completed thestudy or had withdrawn from the study before 24 months died:one patient in the sham-injection group from cardiac arrest15 days after completing the study, one in the group receiving0.3 mg of ranibizumab from lung cancer 174 days after completingthe last study visit at 22 months, and one in the group receiving0.5 mg of ranibizumab from lung cancer 91 days after completingthe last study visit at 23 months.
The overall incidence of any serious or nonserious nonocular(systemic) adverse event, including adverse events previouslyassociated with systemically administered anti-VEGF therapy,such as arterial thromboembolic events and hypertension (Table 2),was similar among the groups. At 24 months, on the basis ofthe classification system of the Antiplatelet Trialists' Collaboration(APTC),24 which includes nonfatal myocardial infarction, nonfatalstroke, and death from a vascular or unknown cause, the rateof arterial thromboembolic events among patients in the sham-injectiongroup was 3.8%, the rate among patients receiving 0.3 mg ofranibizumab was 4.6%, and the rate among patients receiving0.5 mg of ranibizumab was 4.6%; none of the differences weresignificant. The onset of these events and the time of studytreatment appeared to be unrelated. No adverse events of proteinuriawere reported. Nonocular hemorrhages occurred at similar ratesin the first treatment year in the three groups (3.8% in boththe sham-injection group and the 0.3-mg group and 2.1% in the0.5-mg group).
Cumulative rates of nonocular hemorrhage increased in all groupsthrough the second treatment year, but more so in the ranibizumabgroups (Table 2). By 24 months, nonocular hemorrhage had occurredin 5.5% of patients in the sham-injection group, as comparedwith 9.2% of those receiving 0.3 mg of ranibizumab and 8.8%of those receiving 0.5 mg of ranibizumab; none of the differenceswere significant. (For cumulative rates of specific types ofnonocular hemorrhage, see Table 6 of the Supplementary Appendix.)Since the study was not powered to detect small differencesin rates, no conclusion can be drawn regarding whether thesedifferences were drug-related or due to chance alone. Amongthe 12 patients in the sham-injection group who switched toranibizumab therapy, no serious adverse events were reportedafter the switch.
Patients in all three groups were tested for circulating antibodiesagainst ranibizumab at baseline and at months 6, 12, and 24.A small percentage of patients in all three groups tested positivebefore study treatment, possibly owing to preexisting anti-Fabimmunoreactivity. At baseline, immunoreactivity rates were 0.9%in the group receiving 0.3 mg of ranibizumab, 0% in the groupreceiving 0.5 mg of ranibizumab, and 0.5% in the sham-injectiongroup. During the first treatment year, immunoreactivity ratesincreased similarly in all treatment groups. However, by theend of the second year, 4.4% of patients in the 0.3-mg groupand 6.3% of those in the 0.5-mg group tested positive, as comparedwith only 1.1% in the sham-injection group. Exploratory subgroupanalyses of safety and efficacy outcomes revealed no clinicallyrelevant differences between patients with and those withoutimmunoreactivity to ranibizumab.
Discussion
Our phase 3 study (MARINA) of a treatment for neovascular age-relatedmacular degeneration demonstrated not only prevention of visionloss but also a mean improvement in vision in the prespecifiedprimary analysis at 1 year. The efficacy outcomes for patientsreceiving ranibizumab at 1 year were maintained through thesecond year, whereas vision in patients in the sham-injectiongroup continued to decline.
Most of the serious ocular adverse events were attributableeither to the injection procedure or to ranibizumab. Presumedendophthalmitis was attributed to the injection and seriousuveitis to ranibizumab. Although endophthalmitis could not bedefinitively distinguished from sterile serious uveitis in patientswhose inflammation was treated with intravitreal antibioticsbut whose vitreous cultures were negative, the rates of theseevents were on the order of 1 to 2% during the 2-year treatmentperiod.
The three treatment groups did not clearly differ in their ratesof nonocular adverse events. The reported nonserious and seriousnonocular adverse events reflect common medical conditions inan elderly population. In regard to potential systemic anti-VEGFside effects, the rates of hypertension were not imbalanced,and no adverse events associated with proteinuria were reported.Nonocular hemorrhages were more frequent in the ranibizumabgroups than in the sham-injection group. During the 2-year treatmentperiod, the rates of arterial thromboembolic events (on thebasis of APTC criteria) were similar in the three treatmentgroups. However, our study was not powered to detect small differencesbetween groups in the rates of uncommon adverse events. Additionalongoing clinical trials may provide further information on therates of key nonocular adverse events. For example, elsewherein this issue of the Journal, Brown et al. report data fromthe first year of the phase 3 Anti-VEGF Antibody for the Treatmentof Predominantly Classic Choroidal Neovascularization in Age-RelatedMacular Degeneration (ANCHOR) study,25 which compares verteporfinphotodynamic therapy with ranibizumab treatment at the samedoses used in our study. The results of the ANCHOR study areconsistent with those of the first year of our study for bothsafety and efficacy outcomes in the ranibizumab-treated groups.
The clinical significance of the increased rate of systemicimmunoreactivity with ranibizumab treatment, which was not presentat 1 year but emerged at 2 years, is unclear. Exploratory analysesfailed to reveal any effect of immunoreactivity on efficacyor safety.
In conclusion, ranibizumab therapy was associated with clinicallyand statistically significant benefits with respect to visualacuity and angiographic lesions during 2 years of follow-upin patients with minimally classic or occult lesions with noclassic choroidal neovascularization. These efficacy outcomeswere achieved with a low rate of serious ocular adverse eventsand with no clear difference from the sham-treated group inthe rate of nonocular adverse events.
Supported by Genentech and Novartis Pharma.
Dr. Rosenfeld reports having received consulting fees from Genentech,Eyetech, Novartis Ophthalmics, Protein Design Labs, Allergan,BioAxone, Tanox, Genaera, Jerini, Quark, and Athenagen; lecturefees from Genentech, Eyetech, and Novartis Ophthalmics; andgrant support from Genentech, Eyetech, and Alcon Laboratories.Dr. Brown reports having received consulting fees from Genentech,Eyetech, Alcon Laboratories, and Allergan; having an equityinterest in Pfizer; and having received lecture fees from Eyetechand Pfizer. Dr. Heier reports having received consulting feesfrom Genentech, Eyetech, Jerini, Oxigene, Allergan, Genzyme,iScience, ISTA, Pfizer, Regeneron, Theragenics, VisionCare,and Novartis; lecture fees from Genentech, Eyetech, Jerini andAllergan; and grant support from Genentech, Eyetech, Pfizer,Theragenics, and Genaera. Dr. Boyer reports having receivedconsulting fees from Genentech, Eyetech, Pfizer, Novartis, QLT,and Regeneron. Dr. Kaiser reports having received consultingfees, lecture fees, and grant support from Genentech and Novartis.Dr. Chung and Dr. Kim report being employees of Genentech andreport owning Genentech stock. No other potential conflict ofinterest relevant to this article was reported.
We are indebted to the patients who participated in this study,their families, and the research teams at each site; to themembers of the data and safety monitoring committee: FrederickL. Ferris III, M.D. (chair), Susan B. Bressler, M.D., StuartL. Fine, M.D., and Marian Fisher, Ph.D.; to the members of theUniversity of Wisconsin Fundus Photograph Reading Center; tothe members of the data-coordinating center (Statistics Collaborative);and to Genentech personnel Charles Semba, M.D. and Steven Butler,Ph.D., for their critical comments and review throughout thedesign, conduct, and analysis of the study; to Susan Schneider,M.D., Nisha Acharya, M.D., and Angele Singh, M.D., for theircritical comments and review of the second-year results; andto staff members for their assistance in the preparation ofthe manuscript.
* Principal investigators in the Minimally Classic/Occult Trialof the Anti-VEGF Antibody Ranibizumab in the Treatment of NeovascularAge-Related Macular Degeneration (MARINA) Study Group are listedin the Appendix.
Source Information
From the Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami (P.J.R.); Vitreoretinal Consultants, Methodist Hospital, Houston (D.M.B.); Ophthalmic Consultants of Boston, Boston (J.S.H.); Retina Vitreous Associates Medical Group, Los Angeles (D.S.B.); the Cole Eye Institute, Cleveland Clinic Foundation, Cleveland (P.K.K.); and Genentech, South San Francisco, CA (C.Y.C., R.Y.K.).
Address reprint requests to Dr. Rosenfeld at the Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, 900 NW 17th St., Miami, FL 33136, or at prosenfeld{at}med.miami.edu.
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Appendix
The following principal investigators were members of the MARINAStudy Group: T. Aaberg, Associated Retinal Consultants, GrandRapids, MI; P. Abraham, Black Hills Regional Eye Institute,Rapid City, SD; D. Alfaro III, Retina Consultants of Charleston,Charleston, SC; A. Antoszyk, Southeast Clinical Research Associates,Charlotte, NC; C. Awh, Retina Vitreous Associates, Nashville;G. Barile, Edward Harkness Eye Institute, New York; C. Barr,Louisville, KY; W. Bauman, Brooke Army Medical Center, FortSam Houston, TX; P. Beer, Lions Eye Institute, Albany, NY; B.Berger, Austin, TX; A. Bhavsar, Retina Center, Minneapolis;R. Bhisitkul, University of California at San Francisco, Schoolof Medicine, San Francisco; H. Boldt, University of Iowa Hospitaland Clinics, Iowa City; D. Boyer, Retina–Vitreous Associates,Beverly Hills, CA; W. Bridges, Western Carolina Retinal Associates,Asheville, NC; R. Brod, Lancaster, PA; D. Brown, VitreoretinalConsultants, Houston; J. Bryan, Associated Retinal Consultants,Phoenix, AZ; R. Chambers, Retinal Consultants, Columbus, OH;T. Ciulla, Midwest Eye Institute, Indianapolis; T. Connor, MedicalCollege of Wisconsin, Milwaukee; S. Cousins, Bascom Palmer EyeInstitute, Palm Beach Gardens, FL; R. Dreyer, Northwest Retina,Portland, OR; W. Dunn, Florida Retina Institute, Daytona Beach,FL; D. Eliott, Kresge Eye Institute, Detroit; P. Ferrone, LongIsland Vitreoretinal Consultants, Great Neck, NY; B. Foster,New England Retina Consultants, West Springfield, MA; W. Freeman,University of California at San Diego, Jacobs Retina Center,La Jolla; W. Fung, Pacific Eye Associates, San Francisco; R.Gentile, New York Eye and Ear Infirmary, New York; B. Glaser,National Retina Institute, Chevy Chase, MD, and Towson, MD;D. Glaser, Retina Associates of St. Louis, Florissant, MO; L.Glazer, Vitreo-Retinal Associates, Grand Rapids, MI; V. Gonzalez,Valley Retina Institute, McAllen, TX; R. Goodart, Rocky MountainRetina Consultants, Salt Lake City; J. Haller, Johns HopkinsUniversity, Baltimore; M. Hammer, Retina Associates of Florida,Tampa; J. Heier, Ophthalmic Consultants of Boston, Boston; B.Hubbard, Emory University, Atlanta; H. Hudson, Retina Centers,Tucson, AZ; D. Ie, Delaware Valley Retina Associates, Lawrenceville,NJ; M. Johnson, University of Michigan, Ann Arbor; R. Johnson,West Coast Retina Medical Group, San Francisco; D. Joseph, BarnesRetina Institute, St. Louis; P. Kaiser, Cleveland Clinic Foundation,Cole Eye Institute, Cleveland; R. Kaiser, Retina Diagnosticand Treatment Associates, Philadelphia; R. Katz, K. Kelly, PalmBeach Eye Foundation, Lake Worth, FL; R. Kingsley, Dean A. McGeeEye Institute, Oklahoma City; G. Kokame, Retina Consultantsof Hawaii, Aiea, HI; B. Kuppermann, University of Californiaat Irvine, Irvine; S. Leff, Retina-Vitreous Center, Lakewood,NJ, and New Brunswick, NJ; C. Leong, Bay Area Retina Associates,Walnut Creek, CA; L. Lobes, Retina Vitreous Consultants, Pittsburgh;M. Lomeo, Midwest Retina, Columbus, OH; C. MacDonald, Universityof Texas Health Science Center, San Antonio; D. Marcus, SoutheastRetina Center, Augusta, GA; L. Marouf, Retina Associates ofSouth Texas, San Antonio; R. Martidis, Retina Diagnostic andTreatment Associates, Philadelphia; J. Martinez, Austin RetinaAssociates, Austin, TX; D. Maxwell, Jr., Retinal Associatesof Oklahoma, Oklahoma City; C. McCannel, Mayo Clinic, Rochester,MN; T. McMillan, Southeastern Retina Associates, Knoxville,TN; L. Morse, University of California at Davis Medical Center,Sacramento; T. Oei, Braverman-Terry-Oei Eye Associates, SanAntonio, TX; R. Park, University of Arizona, Tucson; M. Paul,Danbury Eye Physicians and Surgeons, Danbury, CT; P. Pavan,University of South Florida, Tampa; D. Pieramici, CaliforniaRetina Consultants, Santa Barbara, CA; J. Prensky, PennsylvaniaRetina Specialists, Camp Hill, PA; D. Quillen, Penn State HersheyMedical Center, Hershey; E. Reichel, New England Eye Center,Boston; W. Rodden, Retina and Vitreous Center of Southern Oregon,Ashland; P. Rosenfeld, Bascom Palmer Eye Institute, Miami; J.Rubio, Retina Associates of South Texas, San Antonio; P. Runge,Ophthalmic Consultants, Sarasota, FL; S. Sadda, Doheny Eye Institute,Los Angeles; G. Sanborn, Virginia Eye Institute, Richmond; R.Sanders, Retina Group of Washington, Chevy Chase, MD; S. Sanislo,California Vitreoretinal Research Center, Menlo Park, CA; S.Schwartz, Bascom Palmer Eye Institute, Palm Beach Gardens, FL;M. Singer, Medical Center Ophthalmology Associates, San Antonio,TX; L. Snady-McCoy, Rhode Island Eye Institute, Providence;S. Sneed, Retinal Consultants of Arizona, Phoenix; J. Stallman,Georgia Retina, Decatur, GA; W. Stern, Northern California Retina–VitreousAssociates, San Mateo and Mountain View; G. Stoller, OphthalmicConsultants of Long Island, Rockville Centre, NY; B. Taney,Retina Vitreous Consultants, Ft. Lauderdale, FL; J. Thompson,Retina Specialists, Towson, MD; D. Tom, New England Retina Associates,Hamden, CT; M. Trese, Associated Retinal Consultants, RoyalOak, MI; T. Verstaeten, Allegheny General Hospital, Pittsburgh;C. Vu, Retina Associates, Annapolis, MD; J. Walker, Retina Consultantsof Southwest Florida, Fort Myers; H. Weiss, Retina Consultantsof Michigan, Southfield; J. Weiss, Retina Associates of SouthFlorida, Margate; C. Wells, Vitreoretinal Associates, Seattle;H. Woodcome, Ophthalmology Consultants, Providence, RI; M. Zarbin,New Jersey Medical School, Newark; and K. Zhang, John MoranEye Center, University of Utah, Salt Lake City.
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Marneros, A. G., She, H., Zambarakji, H., Hashizume, H., Connolly, E. J., Kim, I., Gragoudas, E. S., Miller, J. W., Olsen, B. R.
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21: 3809-3818
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Izumi-Nagai, K., Nagai, N., Ohgami, K., Satofuka, S., Ozawa, Y., Tsubota, K., Umezawa, K., Ohno, S., Oike, Y., Ishida, S.
(2007). Macular Pigment Lutein Is Antiinflammatory in Preventing Choroidal Neovascularization. Arterioscler. Thromb. Vasc. Bio.
27: 2555-2562
[Abstract][Full Text]
Madhusudhana, K C, Hannan, S R, Williams, C P R, Goverdhan, S V, Rennie, C, Lotery, A J, Luff, A J, Newsom, R S B
(2007). Intravitreal bevacizumab (Avastin) for the treatment of choroidal neovascularization in age-related macular degeneration: results from 118 cases. Br. J. Ophthalmol.
91: 1716-1717
[Full Text]
Fu, Y., Ponce, M. L., Thill, M., Yuan, P., Wang, N. S., Csaky, K. G.
(2007). Angiogenesis Inhibition and Choroidal Neovascularization Suppression by Sustained Delivery of an Integrin Antagonist, EMD478761. IOVS
48: 5184-5190
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Chang, T. S., Bressler, N. M., Fine, J. T., Dolan, C. M., Ward, J., Klesert, T. R., for the MARINA Study Group,
(2007). Improved Vision-Related Function After Ranibizumab Treatment of Neovascular Age-Related Macular Degeneration: Results of a Randomized Clinical Trial. Arch Ophthalmol
125: 1460-1469
[Abstract][Full Text]
Chong, E. W-T, Wong, T. Y, Kreis, A. J, Simpson, J. A, Guymer, R. H
(2007). Dietary antioxidants and primary prevention of age related macular degeneration: systematic review and meta-analysis. BMJ
335: 755-755
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Submacular Surgery Trials Research Group,
(2007). Incident Choroidal Neovascularization in Fellow Eyes of Patients With Unilateral Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration: SST Report No. 20 From the Submacular Surgery Trials Research Group. Arch Ophthalmol
125: 1323-1330
[Abstract][Full Text]
Bashshur, Z. F., Schakal, A., Hamam, R. N., El Haibi, C. P., Jaafar, R. F., Noureddin, B. N.
(2007). Intravitreal Bevacizumab vs Verteporfin Photodynamic Therapy for Neovascular Age-Related Macular Degeneration. Arch Ophthalmol
125: 1357-1361
[Abstract][Full Text]
Lima e Silva, R., Shen, J., Hackett, S. F., Kachi, S., Akiyama, H., Kiuchi, K., Yokoi, K., Hatara, M. C., Lauer, T., Aslam, S., Gong, Y. Y., Xiao, W.-H., Khu, N. H., Thut, C., Campochiaro, P. A.
(2007). The SDF-1/CXCR4 ligand/receptor pair is an important contributor to several types of ocular neovascularization. FASEB J.
21: 3219-3230
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Bopp, S.
(2007). Anti-VEGF for neovascular ARMD: visual improvement as the goal of therapy?. Br. J. Ophthalmol.
91: 1259-1260
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Lux, A., Llacer, H., Heussen, F. M A, Joussen, A. M
(2007). Non-responders to bevacizumab (Avastin) therapy of choroidal neovascular lesions. Br. J. Ophthalmol.
91: 1318-1322
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Koto, T., Nagai, N., Mochimaru, H., Kurihara, T., Izumi-Nagai, K., Satofuka, S., Shinoda, H., Noda, K., Ozawa, Y., Inoue, M., Tsubota, K., Oike, Y., Ishida, S.
(2007). Eicosapentaenoic Acid Is Anti-Inflammatory in Preventing Choroidal Neovascularization in Mice. IOVS
48: 4328-4334
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Mori, F., Eguchi, S.
(2007). Polypoidal choroidal vasculopathy. Br. J. Ophthalmol.
91: 1104-1105
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Raftery, J., Clegg, A., Jones, J., Tan, S. C., Lotery, A.
(2007). Ranibizumab (Lucentis) versus bevacizumab (Avastin): modelling cost effectiveness. Br. J. Ophthalmol.
91: 1244-1246
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Takeda, A L, Colquitt, J, Clegg, A J, Jones, J
(2007). Pegaptanib and ranibizumab for neovascular age-related macular degeneration: a systematic review. Br. J. Ophthalmol.
91: 1177-1182
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Mohamed, Q., Gillies, M. C., Wong, T. Y.
(2007). Management of Diabetic Retinopathy: A Systematic Review. JAMA
298: 902-916
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Aisenbrey, S, Gelisken, F, Szurman, P, Bartz-Schmidt, K U
(2007). Surgical treatment of peripapillary choroidal neovascularisation. Br. J. Ophthalmol.
91: 1027-1030
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(2007). A view on new drugs for macular degeneration. DTB
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Scott, I. U., Flynn, H. W. Jr
(2007). The Role of Topical Antibiotic Prophylaxis for Intravitreal Injections. Arch Ophthalmol
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D'Amore, P. A.
(2007). Vascular Endothelial Cell Growth Factor-A: Not Just for Endothelial Cells Anymore. Am. J. Pathol.
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Nakazawa, T., Takeda, M., Lewis, G. P., Cho, K.-S., Jiao, J., Wilhelmsson, U., Fisher, S. K., Pekny, M., Chen, D. F., Miller, J. W.
(2007). Attenuated Glial Reactions and Photoreceptor Degeneration after Retinal Detachment in Mice Deficient in Glial Fibrillary Acidic Protein and Vimentin. IOVS
48: 2760-2768
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Fine, H. F
(2007). Photodynamic therapy in the anti-VEGF era. Br. J. Ophthalmol.
91: 707-708
[Full Text]
Izumi-Nagai, K., Nagai, N., Ozawa, Y., Mihara, M., Ohsugi, Y., Kurihara, T., Koto, T., Satofuka, S., Inoue, M., Tsubota, K., Okano, H., Oike, Y., Ishida, S.
(2007). Interleukin-6 Receptor-Mediated Activation of Signal Transducer and Activator of Transcription-3 (STAT3) Promotes Choroidal Neovascularization. Am. J. Pathol.
170: 2149-2158
[Abstract][Full Text]
Peters, S., Julien, S., Heiduschka, P., Grisanti, S., Ziemssen, F., Adler, M., Schraermeyer, U., Bartz-Schmidt, K.-U., the Tuebingen Bevacizumab Study Group,
(2007). Antipermeability and antiproliferative effects of standard and frozen bevacizumab on choroidal endothelial cells. Br. J. Ophthalmol.
91: 827-831
[Abstract][Full Text]
Potter, M. J, Szabo, S. M
(2007). Recurrence of choroidal neovascularisation after photodynamic therapy in patients with age-related macular degeneration. Br. J. Ophthalmol.
91: 753-756
[Abstract][Full Text]
55 letters) and subtype of choroidal neovascularization (minimally classic vs. occult with no classic disease). Between-group comparisons for dichotomous end points were performed with the use of the Cochran chi-square test.20 Change from baseline visual acuity was analyzed with the use of analysis-of-variance models. For end points for lesion characteristics, analysis-of-covariance models adjusting for the baseline value were used. The Hochberg–Bonferroni multiple-comparison procedure21 was used to adjust for the two pairwise treatment comparisons for the primary end point. Safety analyses included all treated patients. 
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