A Variable-dosing Regimen with Intravitreal
`Ranibizumab for Neovascular Age-related Macular
`Degeneration: Year 2 of the PrONTO Study
`
`GEETA A. LALWANI, PHILIP J. ROSENFELD, ANNE E. FUNG, SANDER R. DUBOVY, STEPHEN MICHELS,
`WILLIAM FEUER, JANET L. DAVIS, HARRY W. FLYNN, JR, AND MARIA ESQUIABRO
`
`● PURPOSE: To assess the long-term efficacy of a variable-
`dosing regimen with ranibizumab in the Prospective Optical
`Coherence Tomography (OCT) Imaging of Patients with
`Neovascular Age-Related Macular Degeneration (AMD)
`Treated with intraOcular Ranibizumab (PrONTO) Study,
`patients were followed for 2 years.
`● DESIGN: A 2-year prospective, uncontrolled, variable-
`dosing regimen with intravitreal ranibizumab based on
`OCT.
`● METHODS: In this open-label, prospective, single-cen-
`ter, uncontrolled clinical study, AMD patients with
`neovascularization involving the central fovea and a
`central retinal thickness (CRT) of at least 300 ␮m as
`measured by OCT were enrolled to receive 3 consec-
`utive monthly intravitreal injections of ranibizumab
`(0.5 mg) [Lucentis; Genentech Inc, South San Fran-
`cisco, California, USA]. During the first year, retreat-
`ment with ranibizumab was performed at each monthly
`visit if any criterion was fulfilled such as an increase in
`OCT-CRT of at least 100 ␮m or a loss of 5 letters or
`more. During the second year, the retreatment criteria
`were amended to include retreatment if any qualitative
`increase in the amount of fluid was detected using
`OCT.
`● RESULTS: Forty patients were enrolled and 37 com-
`pleted the 2-year study. At month 24, the mean visual
`acuity (VA) improved by 11.1 letters (P < .001) and the
`OCT-CRT decreased by 212 ␮m (P < .001). VA
`improved by 15 letters or more in 43% of patients. These
`VA and OCT outcomes were achieved with an average of
`9.9 injections over 24 months.
`● CONCLUSIONS: The PrONTO Study using an OCT-
`guided variable-dosing regimen with intravitreal ranibi-
`zumab resulted in VA outcomes comparable with the
`outcomes from the phase III clinical studies, but fewer
`
`See accompanying Editorial on page 1.
`Accepted for publication Jan 27, 2009.
`From the Bascom Palmer Eye Institute, University of Miami Miller
`School of Medicine, Miami, Florida.
`Anne Fung is currently at the Pacific Eye Associates, California Pacific
`Medical Center, San Francisco, California. Stephen Michels is currently
`at the Department of Ophthalmology, University Hospital Zürich,
`Zürich, Switzerland.
`Inquiries to Philip J. Rosenfeld, Bascom Palmer Eye Institute, Univer-
`sity of Miami Miller School of Medicine, 900 NW 17th Street, Miami, FL
`33136; e-mail: prosenfeld@med.miami.edu
`
`(Am J Ophthal-
`intravitreal injections were required.
`mol 2009;148:43–58. © 2009 by Elsevier Inc. All rights
`reserved.)
`
`I NHIBITION OF VASCULAR ENDOTHELIAL GROWTH FAC-
`
`tor A (VEGF-A) is an effective and safe therapy for the
`treatment of neovascular age-related macular degener-
`ation (AMD).1– 6 Intravitreal injections of ranibizumab
`(Lucentis; Genentech Inc, South San Francisco, Califor-
`nia, USA), a recombinant, humanized, monoclonal anti-
`body antigen-binding fragment that inhibits all the known
`biologically active forms of VEGF, were shown to improve
`mean visual acuity (VA) in eyes with neovascular AMD
`during the phase III clinical studies. In these studies,
`monthly ranibizumab injections over the course of 2 years
`were administered to eyes with minimally classic, occult,
`and predominantly classic neovascular lesions. On average,
`the VA letter scores improved and the outcomes were
`highly statistically significant.
`While the phase III trials used monthly injections, it is
`unclear at this time if monthly dosing is the best dosing
`interval. Observations made after the earlier phase I/II
`studies with intravitreal ranibizumab suggested a role for
`optical coherence tomography (OCT) in determining the
`appropriate dosing interval for each patient. These obser-
`vations came about at the completion of the phase I/II
`studies when subjects were enrolled in an open-label
`extension study that provided continued intravitreal injec-
`tions of ranibizumab performed at the discretion of the
`investigator (Heier JS, et al. IOVS 2005;46:ARVO E-Ab-
`stract 1393). Some subjects enrolled in the extension study
`immediately on completion of the phase I/II trials, whereas
`others were delayed in their enrollment for up to 1 year
`after the completion of the phase I/II trials. During this
`period before enrollment and throughout the extension
`study, OCT was used to monitor the resolution and
`recurrence of fluid in eyes as ranibizumab therapy was
`started and stopped (Rosenfeld PJ, unpublished data,
`2003). Patients in the extension trial usually were treated
`if there was evidence of recurrent leakage from choroidal
`neovascularization (CNV) as detected using fluorescein
`angiography (FA) or if there was recurrent fluid as detected
`using OCT imaging. This recurrence of leakage or fluid in
`the macula was observed either in the presence or absence
`
`0002-9394/09/$36.00
`doi:10.1016/j.ajo.2009.01.024
`
`© 2009 BY ELSEVIER INC. ALL RIGHTS RESERVED.
`
`43
`
`Celltrion Exhibit - 1035
`Celltrion, Inc. v. Regeneron Pharmaceuticals, Inc.
`
`

`

`TABLE 1. Major Eligibility Criteria for Enrollment into the
`PrONTO Study
`
`TABLE 2. Timing of the Qualitative Change Retreatment
`Amendment in Year 2 (n ⫽ 39) of the PrONTO Study
`
`Inclusion criteria
`Age 50 years or older
`Active primary or recurrent macular neovascularization
`secondary to AMD involving the central fovea in the study
`eye with evidence of disease progression
`OCT central retinal thickness ⱖ 300 ␮m
`Best-corrected visual acuity, using ETDRS charts, of 20/40
`to 20/400 (Snellen equivalent) in the study eye
`Exclusion criteria
`More than 3 prior treatments with verteporfin photodynamic
`therapy
`Previous participation in a clinical trial (for either eye)
`involving antiangiogenic drugs (pegaptanib, ranibizumab,
`anecortave acetate, protein kinase C inhibitors)
`Previous subfoveal focal laser photocoagulation in the study
`eye
`Laser photocoagulation (juxtafoveal or extrafoveal) in the
`study eye within 1 month preceding day 0
`Subfoveal fibrosis or atrophy in the study eye
`History of vitrectomy surgery in the study eye
`Aphakia or absence of the posterior capsule in the study
`eye
`History of idiopathic or autoimmune-associated uveitis in
`either eye
`
`AMD ⫽ age-related macular degeneration; ETDRS ⫽ Early
`Treatment Diabetic Retinopathy Study; OCT⫽ optical coherence
`tomography; PrONTO ⫽ Prospective OCT Imaging of Patients with
`Neovascular AMD Treated with intraOcular Ranibizumab.
`
`of vision loss. It became apparent that the need for
`retreatment varied widely among the patients and that the
`need for retreatment was unpredictable. In addition, it was
`observed that OCT seemed to detect the earliest signs of
`reaccumulating fluid in the macula even before leakage
`could be detected reliably using FA.
`These observations from the patients in the extension
`study served as the basis for investigating whether a variable-
`dosing OCT-guided regimen with ranibizumab could result in
`fewer injections and similar clinical outcomes when com-
`pared with the phase III regimen that used monthly injec-
`tions. An investigator-sponsored, open-label, prospective
`clinical study was designed, known as the Prospective OCT
`Imaging of Patients with Neovascular AMD Treated with
`intraOcular Ranibizumab (PrONTO) Study. The 1-year re-
`sults have been published,7 and this article represents the full
`2-year results of the PrONTO Study at the Bascom Palmer
`Eye Institute.
`
`METHODS
`
`PrONTO WAS A 2-YEAR, OPEN-LABEL, PROSPECTIVE, SINGLE-
`center clinical study designed to investigate the efficacy,
`
`First Visit When Amendment Active
`
`No. of Patients
`
`Month 17
`Month 18
`Month 19
`Month 21
`Month 22
`Month 23
`Month 24
`Withdrew from study before amendment
`Completed study before amendment
`Total no. in study
`
`5
`5
`3
`4
`4
`8
`5
`1
`5
`40
`
`PrONTO ⫽ Prospective Optical Coherence Tomography Im-
`aging of Patients with Neovascular Age- Related Macular De-
`generation Treated with intraOcular Ranibizumab.
`
`durability, and safety of a variable-dosing regimen with
`intravitreal
`ranibizumab in patients with neovascular
`AMD. The PrONTO Study was an investigator-sponsored
`trial supported by Genentech Inc and performed after
`review by the Food and Drug Administration (FDA).
`Informed consent was obtained from all patients before
`determination of full eligibility.
`The major efficacy endpoints were the change from
`baseline in VA and OCT measurements and the number of
`ranibizumab injections (0.5 mg) required over 2 years. At
`the start of the study, only 1 eye of a patient was
`determined to be eligible and was assigned as the study eye.
`The major eligibility criteria are shown in Table 1. The
`major inclusion criteria were the diagnosis of neovascular
`AMD with a baseline protocol VA letter score of 20 to 70
`letters using the Early Treatment Diabetic Retinopathy
`Study (ETDRS) chart at 2 m (Snellen equivalent of 20/40
`to 20/400)8 and an OCT central retinal thickness (CRT)
`of at least 300 ␮m. There were no exclusion criteria for
`preexisting cardiovascular, cerebrovascular, or peripheral
`vascular conditions. Of note, all FA lesion types and lesion
`sizes were eligible for the study.
`Specifications for the digital fundus photography equip-
`ment and OCT equipment were described in the PrONTO
`year 1 report.7 Angiographic lesion classification, includ-
`ing the diagnosis of retinal angiomatosis proliferation
`(RAP), was independently assessed and was confirmed by
`3 study investigators as previously described.7 All 6 high-
`resolution (512 A scans per B-scan) OCT diagonal scans
`were used to evaluate whether fluid was present in the
`macula and whether retreatment was needed. For the
`purposes of this study, fluid in the macula was identified as
`intraretinal fluid (cysts) or subretinal fluid, and a fluid-free
`macula was defined by the absence of retinal cysts and
`subretinal fluid as determined by OCT. Fluid under the
`retinal pigment epithelium (RPE), otherwise known as a
`pigment epithelial detachment (PED), was recorded as an
`
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`

`

`TABLE 3. Visual Acuity of Eyes with Neovascular Age-Related Macular Degeneration Treated with a Variable-Dosing Regimen of
`Ranibizumab through 24 Months
`
`Study Eyes
`
`Baseline VA Letters
`(Snellen Equivalent), n ⫽ 40
`
`Month 12 VA Letters
`(Snellen Equivalent), n ⫽ 40
`
`Month 24 VA Letters
`(Snellen Equivalent), n ⫽ 37
`
`Change in VA Letter Scores from
`Baseline to Month 24,a n ⫽ 37
`
`Mean (P value)b
`Median (P value)c
`
`56.2 (20/80 ⫹ 1)
`57 (20/80 ⫹ 2)
`
`65.5 (20/50; P ⬍ .001)
`68 (20/40 ⫺ 2; (P ⬍ .001)
`
`67.0 (20/50 ⫹ 1; P ⬍ .001)
`68.0 (20/40 ⫺ 2; P ⬍ .001)
`
`11.1 (P ⬍ .001)
`14.0 (P ⬍ .001)
`
`VA ⫽ visual acuity.
`aChange in letter scores compares the 37 patients who completed the study at month 24 with their baseline scores.
`bPaired Student t test.
`cPaired Wilcoxon signed-rank test.
`
`TABLE 4. Central Retinal Thickness of Eyes with Neovascular Age-Related Macular
`Degeneration Treated with a Variable-Dosing Regimen of Ranibizumab through Month 24
`
`Patient Study Eyes
`
`Baseline
`CRT (␮m), n ⫽ 40
`
`Month 12 CRT (␮m),
`n ⫽ 40
`
`Month 24 CRT (␮m),
`n ⫽ 37
`
`Change in CRT (␮m) from
`Baseline to Month 24,a n ⫽ 37
`
`Mean (P value)b
`Median (P value)c
`
`393.9
`384.5
`
`216.1 (P ⬍ .001)
`199.0 (P ⬍ .001)
`
`179.3 (P ⬍ .001)
`171 (P ⬍ 0.001)
`
`⫺211.7
`⫺209.0
`
`CRT ⫽ central retinal thickness.
`aChange in letter scores compares the 37 patients who completed the study at month 24 with their
`baseline scores.
`bPaired Student t test.
`cPaired Wilcoxon signed-rank test.
`
`OCT finding in the macula, but was not included in any of
`the retreatment criteria during the first year.
`Eligible patients underwent VA testing and ophthalmo-
`scopic examination at baseline, days 14, 30, 45, and 60, and
`then monthly thereafter. Fundus photography and OCT
`imaging were performed at baseline and on days 1, 2, 4, 7, 14,
`and 30 after the first 2 injections, and then monthly there-
`after. FA was performed at baseline, months 1, 2, and 3, and
`then every 3 months thereafter. All ophthalmic photogra-
`phers and the single OCT technician involved in the study
`were previously certified to participate in FDA-approved
`clinical trials at the Bascom Palmer Eye Institute.
`Intravitreal injections of ranibizumab were administered
`to all patients at baseline, month 1, and month 2.
`Additional reinjections were given if any of the following
`changes were observed by the evaluating physician during
`the first year of the study: 1) VA loss of at least 5 letters
`with OCT evidence of fluid in the macula, 2) an increase
`in OCT CRT of at least 100 ␮m, 3) new macular
`hemorrhage, 4) new area of classic CNV, or 5) evidence of
`persistent fluid on OCT 1 month after the previous
`injection. All criteria were based on comparisons with the
`previous month’s examination or the last time a FA was
`performed. If any single criterion for reinjection was
`fulfilled, the intravitreal injection was performed using a
`standard protocol previously described.7
`
`During the second year, an amendment to the study
`changed the retreatment criteria to include any qualitative
`change in the appearance of the OCT images that sug-
`gested recurrent fluid in the macula. These qualitative
`changes included the appearance of retinal cysts or sub-
`retinal fluid or an enlargement of a PED. Any of these
`qualitative changes alone was sufficient to permit retreat-
`ment. Since this amendment was approved after comple-
`tion of the first year, the retreatment criteria were applied
`to patients at different time points in the study. Table 2
`shows when the retreatment amendment was applied to
`the patients during the study. It is important to note that
`the amendment was in addition to the initial criteria, not
`in place of them.
`At the completion of the study, an audit of drug
`shipments revealed that the vials in the first drug shipment
`received from Genentech Inc had a concentration of 6
`mg/ml, equivalent to a dose of 0.3 mg in a volume of 0.05
`ml. It was concluded that this lower dose, which was being
`used concurrently in the phase II and III clinical studies,
`mistakenly was shipped for use in the PrONTO Study. For
`this reason, the first 19 patients received some 0.3-mg
`doses rather than the per-protocol dose of 0.5 mg. The first
`7 patients received 3 monthly 0.3-mg doses, the next 7
`patients received 2 monthly 0.3-mg doses, and the next 5
`patients received one 0.3-mg dose at baseline. All subse-
`
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`

`FIGURE 1. Graph showing the mean and median change in
`visual acuity (VA) through 24 months of eyes with neovascular
`age-related macular degeneration (AMD) treated with a vari-
`able-dosing intravitreal ranibizumab regimen. Vertical lines are
`1 standard error (SE) of the means.
`
`FIGURE 2. Graph showing the mean and median change in
`optical coherence tomography (OCT) central retinal thickness
`(CRT) through 24 months of eyes with neovascular AMD
`treated with a variable-dosing intravitreal ranibizumab regimen.
`Vertical lines are 1 SE of the means.
`
`quent drug shipments and doses of drug were at the
`per-protocol concentration of 10 mg/ml, resulting in an
`intravitreal dose of 0.5 mg in 0.05 ml.
`in the
`The major 2-year outcome measurements
`PrONTO Study included ETDRS VA letter scores, OCT
`CRT measurements, the change in VA letter scores and
`OCT measurements from baseline, and the total number of
`injections received by a patient during 2 years. For pur-
`poses of analysis, a loss of VA was defined as a drop of at
`least 5 letters between baseline and the 24-month time
`point. For the mean VA letter scores and CRT measure-
`ments, the data were compared statistically with mean
`baseline values using the paired Student t test. Median
`measurements were compared with median baseline values
`using the paired Wilcoxon signed-rank test. The influence
`of baseline FA lesion types on the number of injections
`over 24 months was assessed using a one-way analysis of
`variance and the Kruskal-Wallis test. The associations
`between the number of injections and VA outcomes and
`the associations between the change in CRT and VA
`outcomes at different time points during the study were
`assessed using the Pearson correlation analysis and Spear-
`man nonparametric correlation analysis. Statistical signif-
`icance was defined as P ⬍ .05.
`
`RESULTS
`
`● STUDY COMPLIANCE: Patient demographics and en-
`rollment at baseline were described previously.7 Between
`August 23, 2004 and April 25, 2005, a total of 69 patients
`were screened for the study and 40 patients were enrolled.
`At baseline, the mean and median VA letter scores were
`56 (20/80⫹1) and 57 (20/80⫹2), respectively (Table 3).
`Baseline mean and median OCT 1-mm CRT measure-
`
`FIGURE 3. Bar graph showing the distribution of patients
`receiving a given number of ranibizumab injections through 24
`months according to the retreatment criteria used in the
`Prospective OCT Imaging of Patients with Neovascular AMD
`Treated with intraOcular Ranibizumab (PrONTO) Study.
`
`ments were 394 and 385 ␮m, respectively (Table 4). The
`characteristics of the neovascular lesions were described
`previously. Of note, the study included occult with no
`classic lesions (10 eyes; 25%), minimally classic lesions (23
`eyes; 57.5%), and predominantly classic lesions (7 eyes;
`17.5%) as characterized by FA. Overall, 10 (25%) of the
`40 lesions were categorized as RAP lesions.
`During the second year, 3 patients withdrew from the
`study. One patient developed a tear of the RPE with a
`submacular hemorrhage and experienced a VA loss of 36
`letters.3 Submacular surgery was performed for removal of
`the hemorrhage and the patient withdrew from the study.
`The second patient was unable to travel attributable to
`complications after hip surgery and withdrew at month 20.
`The third patient died of Creutzfeldt-Jakob disease at
`
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`

`FIGURE 4. Case 1: A 74-year-old woman with neovascular AMD diagnosed with a minimally classic lesion in her right eye. She
`received only the first 3 required ranibizumab injections and then was followed up for 24 months. Color fundus images with early-
`and late-phase fluorescein angiographic (FA) images are shown at baseline, month 3 (1 month after the third injection), month 12,
`and month 24 without any additional injections of ranibizumab.
`
`month 18. This death was not thought to be attributable to
`ranibizumab and the death was not deemed to be a
`drug-related adverse event. Data were analyzed from pa-
`tients who completed the study (observed data set) as well
`from all the patients who were enrolled in the study by
`carrying forward their last obtained VA and OCT data
`before their withdrawal (last observation carried forward
`data set).
`
`● VISUAL ACUITY AND OPTICAL COHERENCE TOMOG-
`RAPHY THROUGH 24 MONTHS: The 1-year results of the
`PrONTO Study were reported previously.7 Noteworthy
`outcomes included an improvement in VA detectable by
`
`day 14 and increases in mean and median VA scores at
`month 3 of 10.8 letters (P ⬍ .001) and 10.5 letters (P ⬍
`.001), respectively, after the first 3 monthly injections of
`ranibizumab. At month 12, the improvements in mean and
`median VA scores compared with baseline were 9.3 letters
`(P ⬍ .001) and 11 letters (P ⬍ .001), respectively (Table
`3; Figure 1).
`At month 24, the observed final mean and median VA
`scores for the remaining 37 patients compared with baseline
`improved by 11.1 letters (standard deviation [SD], 12.2;
`standard error, 2.0; 95% confidence interval [CI], 7.0 to 15.2;
`P ⬍ .001) and 14 letters (P ⬍ .001), respectively. Sixteen
`eyes (43%) gained at least 3 lines of vision (95% CI, 60% to
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`

`FIGURE 5. Case 1: OCT response from baseline through month 24 in an eye with neovascular AMD and a minimally classic lesion
`given a total of 3 injections through month 2, with no additional injections through month 24. (Left column) Vertical and (Right
`column) horizontal OCT scans, CRT measurements, and VA are shown of the left eye at baseline (526 ␮m; VA, 20/80), first
`ranibizumab injection; month 3 (188 ␮m; VA, 20/50), observed; month 6 (178 ␮m; VA, 20/25), observed; month 12 (198 ␮m;
`VA, 20/20), observed; month 24 (176 ␮m; VA, 20/16), observed.
`
`27%), with 3 eyes (8.1%) gaining at least 6 lines of vision.
`Twenty-nine (78%) of the 37 eyes completing the study
`avoided any loss of letters (95% CI, 89% to 61%). All 37 eyes
`completing the study avoided a loss of 3 lines or more of VA.
`When calculating VA outcomes using the last observation
`carried forward for all 40 patients, the mean and median VA
`scores improved by 10.0 letters (P ⬍ .001) and 11.5 letters
`(P ⬍ .001), respectively, and 39 eyes (97.5%) avoided a loss
`of 3 lines or more.
`The overall improvement in VA was associated with
`a decrease in CRT. At month 24, the observed mean
`
`and median thickness measurements decreased by 212
`␮m (P ⬍ .001) and 209 ␮m (P ⬍ .001), respectively
`(Figure 2). When the last observation was carried
`forward for all 40 patients, the mean and median OCT
`thickness measurements decreased by 222 ␮m (P ⬍
`.001) and 230 ␮m (P ⬍ .001), respectively. These
`results were very similar
`regardless of whether
`the
`observed data set or the last observation carried forward
`data set were used in the final analyses.
`These outcomes were achieved with a mean and median
`number of injections over 2 years of 9.9 (SD, 5.3) and 9.0
`
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`

`FIGURE 6. Case 2: A 68-year-old woman with AMD diagnosed with a minimally classic lesion and retinal angiomatous
`proliferation in her right eye. She received 24 injections over 24 months because of recurrent and persistent fluid in the macula after
`month 3. Color fundus images with early- and late-phase FA images are shown at baseline, month 3, month 12, and month 24.
`Additional ranibizumab injections were administered monthly except at month 3.
`
`(range, 3 to 25), respectively (Figure 3). Three eyes (8.1%)
`required only the first 3 injections over 2 years (Figures 4
`and 5), whereas 2 eyes (5.4%) required 24 or 25 injections
`over 2 years (Figures 6 and 7). No patient received
`anti–VEGF therapy in the fellow eye.
`The influence of baseline VA and lesion size in disc
`areas on the number of reinjections was assessed with
`both Pearson correlation and Spearman nonparametric
`correlation analyses. No correlation was found between
`number of reinjections and baseline acuity (Pearson, r ⫽
`0.14 and P ⫽ .39; Spearman, r ⫽ ⫺0.01 and P ⫽ .97) or
`lesion size (Pearson, r ⫽ 0.05 and P ⫽ .78; Spearman, r
`⫽ 0.07 and P ⫽ .67). When comparing baseline
`
`angiographic lesion types with the mean number of
`reinjections during follow-up, we did not observe statis-
`tical significance using a one-way parametric analysis of
`variance (P ⫽ .67). The variation in injection rate for
`different lesion types was less evident during the second
`year of the study as compared with the first year. Overall,
`occult with no classic component received 10.0 injections
`(SD, 5.7), minimally classic lesions received 9.4 injections
`(SD, 4.6), and predominantly classic lesions received 11.6
`injections (SD, 7.4). RAP lesions received 11.6 (SD, 5.9)
`injections. The tendency for RAP lesions to require more
`frequents retreatments during the first year was less appar-
`ent over the 2 years.
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`

`FIGURE 7. Case 2: OCT response from baseline through month 24 with a total of 24 ranibizumab injections over 24 months. (Left
`column) Vertical and (Right column) horizontal OCT scans, CRT measurements, and VA of her right eye are shown at baseline
`(345 ␮m; VA, 20/63), first ranibizumab injection; month 3 (164 ␮m; VA, 20/20), observe; month 4 (306 ␮m; VA, 20/40), fourth
`ranibizumab injection; month 5 (216 ␮m; VA, 20/32), fifth ranibizumab injection; month 12 (248 ␮m; VA, 20/25), twelfth
`ranibizumab injection; and month 24 (173 ␮m; VA, 20/25), twenty-fourth ranibizumab injection.
`
`The influence of the number of reinjections on VA
`outcomes was assessed with both Pearson parametric
`correlation and Spearman nonparametric correlation
`
`analyses. Pearson and Spearman correlations between
`the change in letter scores at month 24 and the total
`number of injections were ⫺0.12 (P ⫽ .48) and ⫺0.04
`
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`

`

`FIGURE 8. Case 3: A 96-year-old woman with neovascular AMD diagnosed with a minimally classic lesion and retinal angiomatous
`proliferation in the right eye. She developed a tear of the retinal pigment epithelium after the first injection. She was given seven
`intravitreal ranibizumab injections over 24 months. Color fundus images with early- and late-phase FA images are shown at baseline,
`month 3 (1 month after the third injection), month 12, and month 24. Four additional ranibizumab injections were given at month
`5, month 13, month 21, and month 22.
`
`(P ⫽ .082). No statistically significant correlation was
`found between the need for more frequent injections
`and VA outcomes.
`Correlation analyses between the change in OCT-CRT
`and VA measurements were performed at different time
`points in the study to examine the predictive value of these
`OCT measurements. Once again, Pearson parametric and
`Spearman nonparametric correlations were used in these
`analyses. As previously reported, statistically significant cor-
`relations were found between the OCT-CRT measurements and
`VA at months 2, 3, and 12.7 At month 24, no correlation was
`detected using either analytic technique (Pearson, r ⫽ 0.055 and
`
`P ⫽ .74; Spearman, r ⫽ 0.08 and P ⫽ .64). Another strategy was
`to examine the association between OCT changes at month 1
`with VA changes thereafter to determine if OCT improvements
`could serve as a predictor of future VA improvements. Statisti-
`cally significant correlations were detected when the OCT-CRT
`measurements at month 1 were correlated with the VA changes
`at month 2 (Pearson, r ⫽ 0.57 and P ⬍ .001; Spearman, r ⫽ 0.47
`and P ⫽ .002), month 3 (Pearson, r ⫽ 0.51 and P ⫽ .001;
`Spearman, r ⫽ 0.36 and P ⫽ .021), month 12 (Pearson, r ⫽ 0.37
`and P ⫽ .019; Spearman, r ⫽ 0.38 and P ⫽ .015), and month
`24 (Pearson, r ⫽ 0.41 and P ⫽ .011; Spearman, r ⫽ 0.36 and
`P ⫽ .031).
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`FIGURE 9. Case 3. OCT response to the first ranibizumab injection from baseline through day 14. (Left column) Vertical and
`(Right column) horizontal OCT scans and CRT measurements at baseline (382 ␮m), day 1 (400 ␮m), day 2 (321 ␮m), day 4 (295
`␮m), day 7 (585 ␮m), and day 14 (764 ␮m; VA, 20/25).
`
`● VISION LOSS: For the purposes of analysis, vision loss in
`the PrONTO Study was defined as a loss of at least 5 letters
`between baseline and month 24. Of 37 eyes with complete
`follow-up, 29 eyes (78%) avoided any loss of letters at 24
`months. Of the remaining 8 eyes, only 4 lost 5 letters or
`
`more. Of the 3 eyes that did not complete follow-up, only
`1 had lost 5 letters or more at the last follow-up. Only the
`patient who withdrew after a submacular hemorrhage lost
`more than 3 lines of vision. Therefore, a total of 5 eyes lost
`5 letters or more at their final follow-up visit.
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`FIGURE 10. Case 3: OCT response from baseline through month 24 for a total of 7 ranibizumab injections over 24 months. (Left
`column) Vertical and (Right column) horizontal OCT scans, CRT measurements, and VA are shown at baseline (382 ␮m; VA,
`20/50), month 1 (596 ␮m; VA, 20/200), month 2 (276 ␮m; VA, 20/125), month 3 (340 ␮m; VA, 20/160), month 12 (305 ␮m;
`VA, 20/125), and month 24 (220 ␮m; VA, 20/63).
`
`Vision loss in the PrONTO Study was attributable to
`tears of the RPE (2 eyes; Figures 8 to 10), progression of
`the underlying dry AMD (2 eyes; Figures 11 and 12),
`and formation of subfoveal fibrosis (1 eye). Both of the
`
`eyes which developed RPE tears had minimally classic
`lesions characterized as RAP with an associated PED.
`One eye developed the RPE tear after the first injection.
`The evolution of the tear is depicted in Figure 9. Vision
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`FIGURE 11. Case 4: An 89-year-old woman with AMD diagnosed with an occult-only lesion in her right eye. She achieved a
`fluid-free macula after the first 3 ranibizumab injections. She received a total of 9 intravitreal injections of ranibizumab over 24
`months. She showed continued progression of geographic atrophy. Color fundus images with early- and late-phase FA images are
`shown at baseline, month 3, month 12, and month 24.
`
`remained good until the subretinal fluid disappeared.
`Over the ensuing 2 years, the vision gradually improved
`after
`intermittent
`treatment with ranibizumab. The
`second eye with a tear of the RPE experienced an
`enlargement of
`the PED before the RPE tear and
`hemorrhage developed at the end of the first year. Prior
`to the hemorrhage at month 11,
`this patient had
`responded to therapy. After
`the initial 3 monthly
`injections, there was no evidence of fluid in the macula,
`and therefore no injection was given at month 3.
`Gradually, fluid reaccumulated in the macula with
`enlargement of a PED, but no injection was given until
`month 5 because none of the original quantitative
`
`retreatment criteria were fulfilled. At month 5, the
`patient was retreated because of a more than 100-␮m
`increase in the OCT-CRT measurement and a loss of 11
`letters. At month 6, the VA improved by 8 letters with
`complete resolution of the subretinal and intraretinal
`fluid and no injection was given. Injections were given
`again at month 7 and at month 9 because of reaccumu-
`lating fluid in the macula. At month 10, no fluid was
`detected in the retina or under
`the retina,
`so no
`injection was given even though the PED did show an
`increase in height. An increase in the height or size of
`a PED was not one of the retreatment criteria during the
`first year of the study. Shortly thereafter, before the
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`FIGURE 12. Case 4: OCT response in an eye with neovascular AMD from baseline through month 24 while receiving a total of
`9 ranibizumab injections over 24 months. (Left column) Vertical and (Right column) horizontal OCT scans, CRT measurements,
`and VA are shown at baseline (348 ␮m; VA, 20/63); month 3 (187 ␮m; VA, 20/32), observe; month 12 (191 ␮m; VA, 20/40);
`and month 24 (160 ␮m; VA, 20/100).
`
`month 11 visit, a submacular hemorrhage developed,
`approximately 7 weeks after the previous injection at
`month 9. Injections were then given at month 11 and
`month 12. At month 12, the VA letter score was 31
`(20/250) compared with a letter score of 80 (20/25) at
`the month 10 visit just before the hemorrhage. The
`patient subsequently elected to undergo submacular
`surgery during month 13 and withdrew from the study.
`Overall, this patient received 8 injections of ranibi-
`zumab over 12 months.
`Of the remaining 3 eyes with vision loss, 2 eyes had
`progression of geographic atrophy with gradual vision loss.
`These 2 eyes showed enlargement of their geographic
`atrophy at rates at or below 0.7 disc areas per year or
`1.8 mm2 per year. This rate was within the normal
`expected growth rate for geographic atrophy.9 –11 The fifth
`eye with vision loss had subretinal fibrosis which developed
`by month 3 after the 3 monthly injections and remained
`stable thereafter.
`
`● SAFETY: There were no ocular or systemic adverse events
`attributable to the injection of ranibizumab. A total of 386
`injections were performed without any episodes of endoph-
`thalmitis, uveitis, retinal detachment, retinal tear, vitreous
`hemorrhage, lens damage, cataract progression, or prolonged
`intraocular pressure elevation. No systemic thromboembolic
`events or deaths attributable to the medication occurred. No
`hypertension was newly diagnosed during the study.
`
`DISCUSSION
`
`IN THE PrONTO STUDY, INTRAVITREAL INJECTIONS OF
`ranibizumab were shown to improve VA and rapidly to
`reduce the amount of macular fluid in most patients
`with neovascular AMD. This decrease in retinal thick-
`ness, which was detectable within 1 day after the first
`injection, continued through the first 3 months and was
`maintained through 24 months using an OCT-guided vari-
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`able-dosing regimen. During the first year, strict quantitative
`retreatment guidelines were followed. These guidelines
`were developed to determine if more fluid continued to
`accumulate after a small amount of fluid reaccumulated
`in a dry macula. Another objective was
`to assess
`whether VA or OCT was better at determining when
`fluid was reaccumulating in the macula. It became
`evident that fluid continued to increase if left untreated
`and that