`

`The NEW ENGLAND
`JOURNAL of MEDICINE
`
`ESTABLISHED IN 1812
`
`OCTOBER 5, 2006
`
`VOL. 355 NO. 14
`
`Ranibizumab for N eovascular Age-Related
`Macular Degeneration
`
`PhilipJ. 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., and Robert Y. Kim, M.D., for the MARI NA Study Group'''
`
`ABSTRACT
`
`BACKGROUND
`a recombinant, humanized, monoclonal antibody Fab that neu(cid:173)
`Ranibizumab -
`tralizes all active forms of vascular endothelial growth factor A - has been evaluated
`for the treatment of neovascular age-related macular degeneration.
`
`METHODS
`In this multicenter, 2-year, double-blind, sham-controlled study, we randomly as(cid:173)
`signed patients with age-related macular degeneration with either minimally classic
`or occult (with no classic lesions) choroidal neovascularization to receive 24 monthly
`intravitreal injections of ranibizumab (either 0.3 mg or 0.5 mg) or sham injections.
`The primary end point was the proportion of patients losing fewer than 15 letters
`from baseline visual 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% of those given 0.5 mg lost fewer than 15 letters, as com(cid:173)
`pared with 62.2% of patients receiving sham injections (P<0.001 for both compari(cid:173)
`sons). Visual acuity improved by 15 or more letters in 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<0.001 for both doses). Mean increases in visual acuity were 6.5 letters in the
`0.3-mg group and 7.2 letters in the 0.5-mg group, as compared with a decrease ofl0.4
`letters in the sham-injection group (P<0.001 for both comparisons). The benefit in
`visual acuity was maintained at 24 months. During 24 months, presumed endoph(cid:173)
`thalmitis was identified in five patients (1.0%) and serious uveitis in six patients
`(1.3%) given ranibizumab.
`
`CONCLUSIONS
`Intravitreal administration of ranibizumab for 2 years prevented vision loss and
`-improved mean visual acuity, with low rates of serious adverse events, in patients
`with minimally classic or occult (with no classic lesions) choroidal neovascular(cid:173)
`ization secondary to age-related macular degeneration. (ClinicalTrials.gov number,
`NCT00056836.)
`
`From the Bascom Palmer Eye Institute,
`University of Miami Miller School of Med(cid:173)
`icine, Miami (P.J.R .); Vitreoretinal Con(cid:173)
`_sultants, Methodist Hospital, Houston
`(D.M.B.); Ophthalmic Consultants of
`Boston, Boston LJ.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 Ophthalmol(cid:173)
`ogy, University of Miami Miller School of
`Medicine, 900 NW 17th St., Miami, FL
`33136, or at prosenfeld@med.miami.edu.
`
`*Principal investigators in the Minimally
`Classic/Occult Trial of the Anti-VEGF
`Antibody Ranibizumab in the Treatment
`ofNeovascular Age-Related Macular De(cid:173)
`generation (MARINA) Study Group are
`listed in the Appendix.
`
`N EnglJ Med 2006;355:1419-31.
`Copyright © 2006 Massachusetts Medical Society.
`
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`The NEW ENGLAND JOURNAL of MEDICINE
`
`A GE-RELATED MACULAR DEGENERATION
`
`is a leading cause of irreversible blindness
`among people who are 50 years of age or
`older in the developed world. 1-3 The neovascular
`form of the disease usually causes severe vision
`loss and is characterized by the abnormal growth
`of new blood vessels under or within the macula,
`the central portion of the retina responsible for
`high-resolution vision.
`Neovascularization in this disease is classified
`by fluorescein angiography into major angio(cid:173)
`graphic patterns termed classic and occult, which
`may be associated with various degrees of aggres(cid:173)
`siveness of disease, vision loss, and response to
`various treatment options.4 Pharmacologic thera(cid:173)
`pies for neovascular disease that are available in
`the United States and Europe include verteporfin
`photodynamic therapys-s -
`approved by the Food
`and Drug Administration only for predominant(cid:173)
`ly classic lesions (in which 50% or more of the
`lesion consists of classic choroidal neovascular(cid:173)
`ization) and by the European Agency for the
`Evaluation of Medicinal Products for both pre(cid:173)
`dominantly classic lesions and occult disease with
`no classic lesions -
`and pegaptanib sodium. 9
`Both treatments can slow the progression of vi(cid:173)
`sion loss, but only a small percentage of treated
`patients show improvement in visual acuity.
`The age-related changes that stimulate patho(cid:173)
`logic neovascularization are incompletely under(cid:173)
`stood, but vascular endothelial growth factor A
`(VEGF-A) -
`a diffusible cytokine that promotes
`angiogenesis and vascular permeability -
`has
`been implicated as an important factor promoting
`neovascularization.10
`-15 Multiple biologically active
`forms of VEGF-A are generated by alternative
`messenger RNA splicing and proteolytic cleav(cid:173)
`age, 16 and two isoforms have been detected in
`choroidal neovascular lesions. 15
`Ranibizumab -
`a recombinant, humanized
`monoclonal antibody Fab that neutralizes all ac(cid:173)
`tive forms ofVEGF-A - was recently approved by
`the Food and Drug Administration for the treat(cid:173)
`ment of all angiographic subtypes of subfoveal
`neovascular age-related macular degeneration. In
`phase 1 and 2 clinical studies, ranibizumab dem(cid:173)
`onstrated encouraging signs of biologic activity,
`with acceptable safety, when administered intra(cid:173)
`vitreally for up to 6 months in patients with neo(cid:173)
`vascular age-related macular degeneration. 1n 9 In
`our phase 3 study, Minimally Classic/Occult Trial
`of the Anti-VEGF Antibody Ranibizumab in the
`Treatment of Neovascular Age-Related Macular
`
`Degeneration (MARINA), we evaluated ranibi(cid:173)
`zumab for the treatment of minimally classic or
`occult with no classic choroidal neovasculariza(cid:173)
`tion associated with age-related macular degen(cid:173)
`eration.
`
`METHODS
`
`STUDY DESIGN
`At 96 sites in the United States, we enrolled 716
`patients in our 2-year, prospective, randomized,
`double-blind, sham-controlled study of the safety
`and efficacy of repeated intravitreal injections of
`ranibizumab among patients with choroidal neo(cid:173)
`vascularization associated with age-related macu(cid:173)
`lar degeneration. We performed a prespecified pri(cid:173)
`mary efficacy analysis at 12 months. The primary
`efficacy end point was the proportion of patients
`who had lost fewer than 15 letters (approximate(cid:173)
`ly 3 lines) from baseline visual acuity, as assessed
`with the Early Treatment Diabetic Retinopathy
`Study (ETDRS) chart, with the use of standard(cid:173)
`ized refraction and testing protocol at a starting
`test distance of 2 m. We obtained approval from
`the institutional review board at each study site
`before the enrollment of patients; all study sites
`com_plied with the requi.rerilents of the Health
`Insurance Portability and Accountability Act. The
`eligibility of lesions was confirmed by an inde(cid:173)
`pendent central reading center with the use of
`standardized criteria and trained graders who
`were unaware of patients' treatment assignments.
`Patients provided written. informed consent be(cid:173)
`fore determination of their full eligibility. Screen(cid:173)
`ing lasted as long as 28 days.
`To be included in the study, patients had to be
`at least 50 years old; have a b~st corrected visual
`acuity of 20/40 to 20/320 (Snellen equivalent de(cid:173)
`termined with the use of an E'r;DRS chart); have
`primary or recurrent choroidal neovasculariza(cid:173)
`tion associated with age-related macular degen(cid:173)
`eration, inv1olving the foveal center; have a type of
`lesion that had been assessed with the use of
`fluorescein angiography and fundus photogra(cid:173)
`phy as minimally classic or occult with no classic
`choroidal neovascularization; have a maximum
`lesion size of 12 optic-disk areas (1 optic-disk
`area equals 2.54 mm2 on the basis ofl optic-disk
`diameter of 1.8 mm), with neovascularization
`composing 50% or more of the entire lesion; and
`have presumed recent progression of disease, as
`evidenced by observable blood, recent vision loss,
`or a recent increase in a lesion's greatest linear
`
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`RANIB[ZUMAB FOR NEQVASCULAR AGE-RELATED MACULAR DEGENERATION
`
`diameter of 10% or rnore. (For a cornplete list of
`eligibility criteria, see Table 1 of the Supplemen(cid:173)
`tary Appendix, available with the full text of this
`article at www.nejm.org.) There were no exclu(cid:173)
`sion criteria regarding preexisting cardiovascular,
`cerebrovascular, or peripheral vascular condi(cid:173)
`tions.
`
`STUDY TREATMENT
`We randomly assigned eligible patients in a 1:1:1
`ratio to receive ranibizumab (Lucentis, Genentech)
`at a dose of either 0:3 mg or 0.5 mg or a sham
`injection monthly (within 23 to 37 days) for 2 years
`(24 injections) in one eye. The evaluating physi(cid:173)
`cian was unaware of the patient's treatment as(cid:173)
`signment; the physician who administered the
`injection was aware of the patient's treatment as(cid:173)
`signment regarding ranibizumab or sham treat(cid:173)
`ment but was unaware of the dose of ranibizumab.
`Other personnel at each study site (except for those
`assisting with injections), patients, and personnel
`at the central reading center were unaware of the
`patient's treatment assignment.
`Verteporfin photodynamic therapy was allowed
`if the choroidal neovascularization in the study
`eye became predominantly classic. On the basis
`of a policy decision by the Centers for Medicare
`and Medicaid Services to reimburse photodynam(cid:173)
`ic therapy for small, minimally classic, and occult
`lesions as of April 1, 2004, the study protocol was
`amended to allow photodynamic therapy for min(cid:173)
`imally classic or occult disease with no classic le(cid:173)
`sions that were no larger than 4 optic-disk areas
`and were accompanied by a loss of 20 letters or
`more from baseline visual acuity, as confirmed
`at consecutive study visits. (A score of 55 letters
`is approximately equal to a Snellen equivalent of
`20/80 vision.)
`The study was designed and analyzed by a
`committee composed of both academic investiga(cid:173)
`tors and representatives of the industry sponsor.
`In the analysis of the data and the writing of the
`manuscript, Dr. Rosenfeld had full and unre(cid:173)
`stricted access to the data, and all the coauthors
`contributed to the interpretation of the data and
`the final version of the manuscript. All the au(cid:173)
`thors vouch for the accuracy and completeness of
`the reported data.
`
`STATISTICAL ANALYSIS
`We performed efficacy analyses on an intention(cid:173)
`to-treat basis among all patients with the use
`of a last-observation-carried-forward method for
`
`missing data. For all pairwise comparisons, the
`statistical rnodel adjusted for baseline score for
`visual acuity (<55 letters vs. ~55 letters) and sub(cid:173)
`type of choroidal neovascularization (minimally
`classic vs. occult with no classic disease). Between(cid:173)
`group comparisons for dichotomous end points
`were performed with the use of the Cochran chi(cid:173)
`square test. 2° 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-Bonfer(cid:173)
`roni multiple-comparison procedure21 was used
`to adjust for the two pairwise treatment com(cid:173)
`parisons for the primary end point. Safety analy(cid:173)
`ses included all treated patients.
`We determined the number of patients in each
`group on the basis of a 1:1:1 randomization ratio,
`Pearson's chi-square test for the two pairwise
`comparisons of the primary end point, and the
`Hochberg-Bonferroni multiple comparison pro(cid:173)
`cedure at an overall type I error of 0.0497 (adjust(cid:173)
`ing for the three planned safety interim analyses
`before the primary efficacy analysis). Monte Carlo
`simulations were used to evaluate the power of
`the study. We estimated that the enrollment of
`720 patients would provide the study with a sta(cid:173)
`tistical power of 95% to detect a significant dif..
`ference between one or both ranibizumab groups
`and the sham-injection group in the proportion of
`patients losing fewer than 15 letters at 12 months,
`assuming a proportion of 65% in each ranibi(cid:173)
`zumab group and 50% in the sham-injection
`group. (For more details, see the Methods section
`of the Supplementary Appendix.)
`
`RESULTS
`
`STUDY PATIENTS
`Between March 2003 and December 2003, 716 pa(cid:173)
`tients were enrolled and randomly assigned to
`study treatment. Groups were balanced for demo(cid:173)
`graphic and baseline ocular characteristics (Ta(cid:173)
`ble 1).
`More than 90% of patients in each treatment
`group remained in the study at 12 months, and
`approximately 80 to 90% remained at 24 months
`(Table 2 of the Supplementary Appendix). The
`percentages who were still receiving study treat(cid:173)
`ment were similarly high at 12 months and at
`the end of the study. After the unmasking of first(cid:173)
`year results and discussion with the data and
`safety monitoring committee, ranibizumab was
`
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`The NEW ENGLAND JOURNAL of MEDICINE
`
`Table I. Baseline Characteristics of the Patients.*
`
`Characteristic
`
`Sex-no.(%)
`
`Male
`
`Female
`no. (%)t
`
`Race -
`
`White
`
`Other
`
`Age-yr
`
`Mean
`
`Range
`
`Age group -
`
`no. (%)
`
`50-64 yr
`
`65-74 yr
`
`75-84 yr
`
`~85 yr
`
`Previous therapy for age-related macular degeneration
`-no.(%)
`
`Any treatment
`
`Laser photocoagulation
`
`Medication:[:
`
`Nutritional supplements
`
`Other
`
`No. of letters as measure of visual acuity§
`
`Mean
`
`<55-no. (%)
`
`~55-no. (%)
`
`Sham Injection
`(N=238)
`
`0.3 mgof
`Ranibizumab
`(N=238)
`
`0.5 mgof
`Ranibizumab
`(N=240)
`
`79 (33.2)
`
`159 (66.8)
`
`231 (97.1)
`
`7 (2.9)
`
`77±7
`
`56-94
`
`11 (4.6)
`
`67 (28.2)
`
`132 (55.5)
`
`28 (11.8)
`
`I
`85 (35.7)
`
`153 (64.3)
`
`229 (96.2)
`
`9 (3.8)
`
`77±8
`
`52-95
`
`13 (5.5)
`
`64 (26.9)
`
`130 (54.6)
`
`31 (13.0)
`
`88 (36.7)
`
`152 (63.3)
`
`232 (96.7)
`
`8 (3.3)
`
`77±8
`
`52-93
`
`16 (6.7)
`
`64 (26.7)
`
`124 (51.7)
`
`36 (15.0)
`
`135 (56.7)
`
`140 (58.8)
`
`139 (57.9)
`
`22 (9.2)
`3 (1.3)
`
`121 (50.8)
`
`8 (3.4)
`
`53.6±14.1
`
`109 (45._8)
`
`129 (54.2)
`
`13 (5.5)
`
`1 (0.4)
`
`14 (5.8)
`
`3 (1.2)
`
`134 (56.3)'
`
`127 (52.9)
`
`3 (1.3)
`
`3 (1.2)
`
`53.1±12.9
`
`llS (48.3)
`
`123 (51.7)
`
`53.7±12.8
`
`117 (48.8)
`
`123 (51.2)
`
`offered to all patients in October 2005, 2 months Of these 13 patients, 8 remained in the follow-up
`before the end of the last patient's final study group at 24 months.
`visit at 24 months. Of the patients in the sham-
`injection group, 12 were switched to receive PRIMARY AND SECONDARY END ro1NTS
`0.5 mg of ranibizumab: 5 patients (2.1%) at 22 The primary and key secondary efficacy results at
`months and 7 (2.9%) at 23 months, the last pos- 12 months (prespecified prim;ry analysis) and
`sible injection visit. During the 2-year treatment 24 months are summarized in Figures 1 and 2.
`period, 38 patients in the sham-injection group The study met its primary end point (Fig. lA) at
`(16.0%), 2 patients in the group receiving 0.3 mg 12 months: Of the patients who were treated with
`of ranibizumab (0.8%), and none in the group ranibizumab, 94.5% of the patients receiving
`receiving 0.5 mg of ranibizumab received verte- 0.3 mg and 94.6% of those receiving 0.5 mg had
`porfin photodynamic therapy at least once. In the
`lost fewer than 15 letters from baseline visual
`second year, 13 patients (5.5%) in the sham-injec- acuity, as compared with 62.2% in the sham-injec(cid:173)
`tion group (P<0.001 for the comparison of each
`tion group and none in the ranibizumab groups
`chose to discontinue study treatment and receive dose with the sham-injection group). At 24 months,
`this end point was met by 92.0% of the patients
`pegaptanib sodium, which was approved in the
`United States in December 2004 for the treatment receiving 0.3 mg of ranibizumab and 90.0% of
`of neovascular age-related macular degeneration.
`those receiving 0.5 mg, as compared with 52.9%
`
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`RANIBIZU.MAB FOR NEOVAscULAR AGE-RELATED MACULAR DEGENERATION
`
`Table 1. (Continued.)
`
`Characteristic
`
`Visual acuity (approximate Snellen equivalent) -
`
`no. (%)§
`
`20/200 or worse
`
`Better than 20/200 but worse than 20/ 40
`
`20/40 or better
`
`Type of choroid al neovascularization -
`
`no. (%)
`
`Occult with no classic lesion
`
`Minimally classic1esion
`
`_Predominantly classic lesion
`
`Missing data
`optic-disk area1
`
`Size of lesion -
`
`Mean
`
`Range
`
`Size of choroidal neovascularization -
`
`optic-disk area1
`
`Mean
`
`Range
`
`Size of leakage from choroidal neovascularization
`plus staining of retinal pigment epithelium -
`optic-disk area1
`
`Mean
`
`Range
`
`Sham Injection
`(N=238)
`
`0.3 mgof
`Ranibizumab
`(N=238)
`
`0.5 mgof
`Ranibizumab
`(N=240)
`
`32 (13.4)
`
`170 (71.4)
`
`36 (15 .1)
`
`151 (63.4)
`
`87 (36.6)
`
`0
`
`1 (0.4)
`
`4.4±2.5
`
`0.0-11.8
`
`4.3±2.4
`
`0.0-11.8
`
`35 (14.7)
`
`176 (73 .9)
`
`27 (11.3)
`
`151 (63.4)
`
`86 (36.1)
`
`1 (0.4)
`
`0
`
`4.3±2.5
`
`0.1-11.8
`
`4.1±2.5
`
`0.0-11.8
`
`31 (12.9)
`
`173 (72.1)
`
`36 (15.0)
`
`149 (62.1)
`
`91 (37.9)
`
`0
`
`0
`
`4.5±2.6
`
`0.3-12.0
`
`4.3±2.5
`
`0.1-12.0
`
`3.5±2.S
`
`0.0-12.9
`
`3.6±2.5
`
`0.0- 12.0
`
`3.5±2.6
`
`0.0-13.5
`
`* Plus-minus values are means ±SD . Percentages may not total 100 because of rounding.
`l' Race was determined by the Investigators.
`:J: Med ications Included tri amci nolone acetonide, prednisolone ophthalmic, and dlclofenac sodi um.
`§ Vis ual acu ity was mea su red with the use of ETDRS charts at a starting distance of2 m. A score of55 letters is approxi(cid:173)
`mately equa l to a Snellen equivalent of 20/80.
`1 One optic-d isk area is equal to 2.54 mm 2 on the basis of one optic-disk diameter of 1.8 mm.
`
`in the sham-injection group (P<0.001 for each
`comparison). The visual-acuity benefit associated
`with ranibizumab was independent of the size of
`the baseline lesion, the lesion type, or baseline
`visual acuity (Fig. 1B and lC).
`At·l2 and 24 months, approximately one quar(cid:173)
`ter of patients treated with 0.3 mg of ranibizu(cid:173)
`mab and one third of patients treated with 0.5 mg
`of ranibizumab had gained 15 or more letters in
`visual acuity, as compared with 5.0% or less of
`those in the sham-injection group (P<0.001 for
`each comparison) (Fig. 1D).
`At both doses of ranibizumab, the mean im(cid:173)
`provement from baseline in 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(cid:173)
`injection group declined steadily over time at each
`
`monthly assessment (P<0.001 for both compari(cid:173)
`sons) (Fig. 2A). At 12 months, mean increases in
`visual acuity were 6.5 letters in the 0.3-mg group
`and 7.2 letters in the 0.5-mg group, as compared
`with a decrease of 10.4 letters in the sham-injec(cid:173)
`tion group (P<0.001 for both comparisons). The
`benefit in visual acuity was maintained at 24
`months. The average benefit associated with
`ranibizumab over that of sham injection was
`approximately 17 letters in each dose group at
`12 months and 20 to 21 letters at 24 months.
`At baseline, the percentages of patients with
`20/40 vision or better were similar among the
`three groups (Fig. 2B). At 12 months, approxi(cid:173)
`mately 40% of patients receiving ranibizumab had
`20/40 vision or better, as compared with 11.3% in
`the sham-injection group (P<0.001). At 24 months,
`of the patients receiving ranibizumab, 34.5% of
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`The NEW ENGLAND JOURNAL of MEDICINE
`
`those in the 0.3-mg group and 42.1% in the 0.5-mg
`group had at least 20/40 vision, whereas the pro(cid:173)
`portion in the sham-injection group had dropped
`to 5.9% (P<0.001 for each comparison).
`A single patient in the sham-injection group
`had 20/20 or better vision at baseline. Among pa(cid:173)
`tients receiving ranibizumab, 3.8% in the 0.3-mg
`group and 7.9% in the 0.5-mg group had 20/20
`vision or 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(cid:173)
`injection group, only two patients (0.8%) had
`20/20 vision or better at 12 months (P<0.001 for
`the comparison with the 0.5-mg group and P=0.03
`for the comparison with the 0.3-mg group), and
`one (0.4%) had 20/20 vision or better at 24 months
`(P<0.001 for the comparison with each ranibi(cid:173)
`zumab group).
`The percentages of patients with visual acuity
`of 20/200 or worse were similar among the three
`groups at baseline (Fig. 2C). At 12 and 24 months,
`the percentages in the ranibizumab-treated groups
`remained about the same, whereas the percent(cid:173)
`ages in the sham-injection group had increased
`by 3 to 3.5 times (P<0.001 for the comparison
`with each ranibizumab dose at 12 and 24 months).
`Very few patients receiving ranibizumab had se(cid:173)
`vere vision loss (30 letters or more) from baseline
`(0.8% of the 0.3-mg group and 1.2% of the 0.5-mg
`group), as compared with 14.3% of the sham(cid:173)
`injection group at 12 months; at 24 months, 3.4%
`of the 0.3-mg group and 2.5% of the 0.5-mg group
`had severe vision loss, as compared with 22.7%
`of the sham-injection group (P<0.001 for the com(cid:173)
`parison with each dose at 12 and 24 months).
`Ranibizumab treatment was associated with
`arrested growth of and leakage from choroidal
`neovascularization (including intense, progressive
`staining of the retinal pigment epithelium) (Fig. 3A
`through Fig. 3D). The mean change from base(cid:173)
`line in each of the ranibizumab-treated groups
`differed significantly from that in the sham-i1zjec(cid:173)
`tion group at 12 and 24 months (P<0.001 for each
`comparison).
`
`ADVERSE EVENTS
`Cumulative adverse events for the 24-month study
`period are summarized in Table 2. Each of the
`key serious ocular adverse events occurred in dif(cid:173)
`ferent patients (Table 3 of the Supplementary Ap-
`
`Figure i (facing page). Rate ofloss 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 mm' on the basis of 1 optic(cid:173)
`disk diameter of 1.8 mm), baseline visual acuity (a score
`of 55 letters is approximately equal to a Snellen equiva(cid:173)
`lent of 20/80), and lesion type. Panel D shows the per(cid:173)
`centage of patients who gained 1S 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 O (<55 letters vs. 2:55 letters) and choroi(cid:173)
`dal neovascularization subtype. Pearson's chi-square
`test was used for treatment comparisons in each sub(cid:173)
`group. The last-observation -carried-forward method
`was used to handle missing data . All tests were two(cid:173)
`sided (P<0.001 for all comparisons between each ra(cid:173)
`nibizumab group and the sham-injection group). I bars
`represent 95% confidence intervals.
`
`pendix). Investigator-reported cases of endophthal(cid:173)
`mitis, as well as any case of serious uveitis treated
`with intravitreal antibiotics, were presumed to be
`endophthalmitis. The presumed endophthalmitis
`rate was 5 of 477 patients (1.0%) or, alternatively,
`a rate per injection of 0.05% (5 of 10,443 total
`injections). In four of the five presumed cases of
`endophthalmitis, neither vitreous nor aqueous
`culture showed growth.
`Slit-lamp examination revealed inflammation
`(of any cause, including endophthalmitis) through(cid:173)
`out the study in the ranibizmµab groups (Table 2,
`and Table 4 and 5 of the Supplementary Appen(cid:173)
`dix). 22
`•23 Most of the inflammation in all groups
`was designated as trace or l+.
`Ranibizumab had no long-t~rm effect on intra(cid:173)
`ocular pressure, on average, as assessed by month(cid:173)
`ly preinjection measurements during the 2-year
`follow-up. Intraocular pressure was increased on
`average 1 hour after ranibizumab injections at
`protocol-mandated intraocular-pressure assess(cid:173)
`ments; however, the absence of corresponding
`changes in preinjection measurements suggests
`the postinjection increases were transient. On
`average, postinjection inttaocular pressure in(cid:173)
`creased from the preinjection value by 1.9 to 3.5
`mm Hg in the 0.3-mg group and 2.1 to 3.4 mm Hg
`
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`

`

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`

`The NEW ENGLAND JOURNAL of MEDICINE
`
`Table 2. Adverse Events at 24 Months.*
`
`Adverse Event
`
`Serious ocular event - no. (%)
`
`Presumed endophthalmitis-j"
`
`Culture not obtained
`
`Culture negative
`
`Uveitis
`
`Rhegmatogenous retinal detachment
`
`Retinal tear
`
`Vitreous hemorrhage
`
`Lens damage
`
`Most severe ocular inflammation - no.(%),
`
`None
`
`Trace
`
`l+
`
`Sham Injection
`(N:e236)
`
`0.3 mg of
`Ranibizumab
`(N=238)
`
`0.S mg of
`Ranibizumab
`(N :e239)
`
`0
`
`0
`
`0
`
`0
`
`1 (0.4)
`
`0
`
`2 (0.8)
`
`0
`
`2 (0.8)
`
`1 (0.4)
`
`1 (0.4)
`
`3 (1.3)
`
`0
`
`1 (0.4)
`
`1 (0.4)
`
`0
`
`3 (1.3)
`
`0
`
`3 (1.3)~:
`
`3 (1.3)§
`
`0
`
`1 (0.4)
`
`1 (0.4)
`
`1 (0.4)
`
`206 (87.3)
`
`24 (10.2)
`
`6 (2.5)
`
`198 (83.2)
`
`19 (8.0)
`
`14 (5.9)
`
`189 (79.1)
`
`35 (14.6)
`
`8 (3.3)
`
`2+
`
`3+
`
`4+
`
`Nonocular adverse event
`
`Investigator-defined hypertension
`
`No. of patients (%)
`
`Mean decrease in blood pressure from baseline
`-mm Hg
`
`Key arterial thromboembolic events (nonfatal) - no. (%)
`
`Myocardial infarction
`
`Stroke
`
`Death - no. (%)
`
`Vascular cause (APTC criteria)
`
`Nonvascular cause
`
`Nonocular hemorrhage - no. (%)
`
`0
`
`0
`
`0
`
`2 (0.8)
`
`2 (0.8)
`
`3 (1.3)
`
`2 (0.8)
`
`2 (0.8)
`
`3 (1.3)
`
`38 (16.1)
`
`3.3/3.5
`
`'
`
`41 (17.2)
`
`2.6/2.5
`
`39 (16.3)
`
`4.4/1.1
`
`4 (1.7)
`
`2 (0.8J**H
`
`6 (2.5)§
`
`3 (l.3)H
`
`3 (1.3) II
`
`6 (2.smi
`
`4 (1.7),,
`
`2 (0.8)
`
`3 (l.3):j:~:1111 •
`2 (0.8)
`
`3 (1.3)***
`
`3 (1.3)
`
`Total serious and nonserious events
`
`Reported as a serious adverse event
`
`13 (5.5)
`
`2 (0.8)
`
`22 (9.2)
`
`3 (1.3)
`
`21 (8.8)
`
`5 (2.1)
`
`* APTC denotes Anti platelet Trialists' Collaboration.
`·j· Events were categorized as presumed endophthalmitis in cases in which intravitreal antibiotics were administered.
`:i: One event was reported as uveitis by an investigator.
`§ One patient had two episodes.
`, Ocular inflammation (regardless·of cause) was determined on the basis of slit-lamp examination.
`II One patient had a myocardial infarction and a hemorrhagic stroke, both nonfatal.
`** One patient in the sham-injection group received a single 0.5-mg dose of ranibizumab in error approximately
`8 months before the onset of the stroke.
`i"i" One patient had a second episode of stroke, which resulted in death.
`:i::j: One patient had a nonfatal ischemic stroke and died of an unknown cause.
`§§ One patient had a cerebral ischemic incident that was categorized as an ischemic stroke.
`11 Two patients died from stroke, one from congestive heart failure, and one from an unknown cause.
`1111 Two patients died from myocardial infarction, and one from an unknown cause.
`*** One patient died from a small-bowel infarct, and two from stroke.
`
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`

`RANJBIZUMAB FOR NEOVASCULARAGE-RELATED MACULAR DEGENERATION
`
`the study before 24 months died: one patient in
`the sham-injection group from cardiac arrest 15
`days after completing the study, one in the group
`receiving 0.3 mg of ranibizumab from lung can(cid:173)
`cer 174 days after completing the last study visit
`at 22 months, and one in the group receiving
`0.5 mg of ranibizumab from lung cancer 91 days
`after completing the last study visit at 23 months.
`The overall incidence of any serious or nonse(cid:173)
`rious nonocular (systemic) adverse event, includ(cid:173)
`ing adverse events previously associated with sys(cid:173)
`temically administered anti-VEGF therapy, such as
`arterial thromboembolic events and hypertension
`(Table 2), was similar among the groups. At 24
`months, on the basis of the classification system
`oftheAntiplateletTrialists' Collaboration (APTC),24
`which includes nonfatal myocardial infarction,
`nonfatal stroke, and death from a vascular or un(cid:173)
`known cause, the rate of arterial thromboem(cid:173)
`bolic events among patients in the sham-injection
`group was 3.8%, the rate among patients receiv(cid:173)
`ing 0.3 mg of ranibizumab was 4.6%, and the
`rate among patients receiving 0.5 mg of ranibi(cid:173)
`zumab was 4.6%; none of the differences were
`significant. The onset of these events and the
`time of study treatment appeared to be unrelated.
`No adverse events of proteinuria were reported.
`Nonocular hemorrhages occurred at similar rates
`in the first treatment year in the three groups
`(3.8% in both the sham-injection group and the
`0.3-mg group and 2.1% in the 0.5-mg group).
`Cumulative rates of nonocular hemorrhage
`increased in all groups through the second treat(cid:173)
`ment year, but more so in the ranibizumab groups
`(Table 2). By 24 months, nonocular hemorrhage
`had occurred in 5.5% of patients in the sham(cid:173)
`injection group, as compared with 9.2% of those
`receiving 0.3 mg of ranibizumab and 8.8% of
`those receiving 0.5 mg of ranibizumab; none of
`the differences were significant. (For cumulative
`rates of specific types of nonocular hemorrhage,
`see Table 6 of the Supplementary Appendix.)
`Since the study was not powered to detect small
`differences in rates, no conclusion can be drawn
`regarding whether these differences were drug(cid:173)
`related or due to chance alone. Among the 12
`patients in the sham-injection group who switched
`to ranibizumab therapy, no serious adverse events
`were reported after the switch.
`Patients in all three groups were tested for
`circulating antibodies against ranibizumab at
`baseline and at months 6, 12, and 24. A small
`
`percentage of patients in all three groups tested
`positive before study treatment, possibly owing
`to preexisting anti-Fab immunoreactivity. At base(cid:173)
`line, immunoreactivity rates were 0.9% in the
`group receiving 0.3 mg of ranibizumab, 0% in the
`group receiving 0.5 mg of ranibizumab, and 0.5%
`in the sham-injection group. During the first
`treatment year, immunoreactivity rates increased
`similarly in all treatment groups. However, by the
`end of the second year, 4.4% of patients in the
`0.3-mg group and 6.3% of those in the 0.5-mg
`group tested positive, as compared with only 1.1%
`in the sham-injection group. Exploratory subgroup
`analyses of safety and efficacy outcomes revealed
`no clinically relevant differences between patients
`with and those without immunoreactivity to ra(cid:173)
`nibizumab.
`
`DISCUSSION
`
`Our phase 3 study (MARINA) of a treatment for
`neovascular age-related macular degeneration
`demonstrated not only prevention of vision loss
`but also a mean improvement in vision in the pre(cid:173)
`specified primary analysis at 1 year. The efficacy
`outcomes for patients receiving ranibizumab at
`1 year were maintained through the second year,
`whereas vision in patients in the sham-injection
`group continued to decline.
`Most of the serious ocular adverse events were
`attributable either to the injection procedure or
`to ranibizumab. Presumed endophthalmitis was
`attributed to the injection and serious uveitis to
`ranibizumab. Although endophthalmitis could not
`be definitively distinguished from sterile serious
`uveitis in patients whose inflammation was treat(cid:173)
`ed with intravitreal antibiotics but whose vitre(cid:173)
`ous cultures were negative, the rates of these
`events were on the order of 1 to 2% during the
`2-year treatment period.
`The three treatment groups did not clearly dif-.
`fer in their rates of nonocular adverse events. The
`reported nonserious and serious nonocular ad(cid:17