`Critical Stimulus for Diabetic Macular Edema
`
`QUAN DONG NGUYEN, MD, MSC, SINAN TATLIPINAR, MD, SYED MAHMOOD SHAH,
`MBBS, JULIA A. HALLER, MD, EDWARD QUINLAN, MD, JENNIFER SUNG, MD,
`INGRID ZIMMER-GALLER, MD, DIANA V. DO, MD,
`AND PETER A. CAMPOCHIARO, MD
`
`● PURPOSE: The role of vascular endothelial growth
`factor (VEGF) in diabetic macular edema (DME) was
`tested with ranibizumab, a specific antagonist of VEGF.
`● DESIGN: A nonrandomized clinical trial.
`● METHODS: Ten patients with chronic DME received
`intraocular injections of 0.5 mg of ranibizumab at base-
`line and at one, two, four, and six months. The primary
`outcome was change in foveal thickness between baseline
`and seven months, and the secondary outcome measures
`were changes from baseline in visual acuity and macular
`volume.
`● RESULTS: Mean values at baseline were 503 m for
`foveal thickness, 9.22 mm3 for macular volume, and
`28.1 letters (20/80) read on an Early Treatment Diabetic
`Retinopathy Study (ETDRS) visual acuity chart. At
`seven months (one month after the fifth injection), the
`mean foveal thickness was 257 m, which was a reduc-
`tion of 246 m (85% of the excess foveal thickness
`present at baseline; P ⴝ .005 by Wilcoxon signed-rank
`test for likelihood that this change is due to ranibizumab
`rather than chance). The macular volume was 7.47 mm3,
`which was a reduction of 1.75 mm3 (77% of the excess
`macular volume at baseline; P ⴝ .009). Mean visual
`acuity was 40.4 letters (20/40), which was an improve-
`ment of 12.3 letters (P ⴝ .005). The injections were
`well-tolerated with no ocular or systemic adverse events.
`● CONCLUSION: Intraocular injections of ranibizumab
`significantly reduced foveal thickness and improved vi-
`sual acuity in 10 patients with DME, which demon-
`strated that VEGF is an important therapeutic target for
`
`Supplemental Material available at AJO.com.
`Accepted for publication Jun 29, 2006.
`From the The Wilmer Eye Institute, The Johns Hopkins University
`School of Medicine, Baltimore, Maryland.
`Supported by the Innovative Grant Award from the Juvenile Diabetes
`Research Foundation; by a scholarship from the Scientific and Techno-
`logical Research Council of Turkey (S.T.); and by a K23 Career
`Development Award (EY 13552) from the National Eye Institute
`(Q.D.N.). The study drug was provided by Genentech, Inc.
`Inquiries to Peter A. Campochiaro, MD, Maumenee 719, The Wilmer
`Eye Institute, The Johns Hopkins University School of Medicine, 600
`North Wolfe St, Baltimore, MD 21287–9277; e-mail: pcampo@jhmi.edu
`
`DME. A randomized, controlled, double-masked trial is
`needed to test whether intraocular injections of ranibi-
`zumab provide long-term benefit to patients with DME.
`(Am J Ophthalmol 2006;142:961–969. © 2006 by
`Elsevier Inc. All rights reserved.)
`
`D IABETIC RETINOPATHY IS THE MOST PREVALENT
`
`cause of vision loss in working aged individuals in
`developed countries.1 Severe vision loss occurs
`because of traction retinal detachments that complicate
`retinal neovascularization, but the most common cause of
`moderate vision loss is macular edema. Macular edema
`occurs from the leakage of plasma into the central retina,
`which causes it to thicken because of excess interstitial
`fluid. The excess interstitial fluid is likely to disrupt ion
`fluxes and the thickening of the macula results in stretch-
`ing and distortion of neurons. There is reversible reduction in
`visual acuity, but over time the perturbed neurons die, which
`results in permanent visual loss.
`The leakage of plasma in patients with diabetic macular
`edema (DME) is visualized by fluorescein angiography and
`may be focal because of leakage from microaneurysms or
`diffuse. Microaneurysms are thought to occur because of
`hyperglycemia-induced pericyte death, which weakens the
`walls of retinal vessels and results in the small aneurysms in
`which endothelial cells are perturbed causing them to lose
`their barrier qualities and leak.2 However, diffuse leakage
`from retinal capillaries that do not show visible structural
`changes (such as microaneurysms) is also a common feature
`of DME. This could be due to microscopic damage to
`retinal vessels that are not visible in images that are
`obtained during fluorescein angiography but could also be
`due the presence of excessive amounts of pro-permeability
`factors.
`Recently, retinal hypoxia has been implicated in the
`pathogenesis of DME.3 Hypoxia causes increased expres-
`sion of vascular endothelial growth factor (VEGF), which
`is a potent inducer of vascular permeability that has been
`shown to cause leakage from retinal vessels.4,5 Thus, it is
`reasonable to hypothesize that VEGF contributes to DME.
`
`0002-9394/06/$32.00
`doi:10.1016/j.ajo.2006.06.068
`
`© 2006 BY ELSEVIER INC. ALL RIGHTS RESERVED.
`
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`Ranibizumab is a Fab fragment of an antibody that specif-
`ically binds all isoforms of VEGF-A with high affinity.
`Intraocular injections of ranibizumab provide benefit for
`patients with choroidal neovascularization because of age-
`related macular degeneration, which confirms studies in
`animal models that suggest that VEGF is an important
`stimulus for choroidal neovascularization (reported at the
`meeting of the American Society of Retina Specialists,
`Montreal, Canada, July 2005). In this study, we tested the
`hypothesis that VEGF is also an important stimulus for
`DME by assessing the effect of multiple intraocular injec-
`tions of ranibizumab in patients with DME.
`
`METHODS
`
`AN OPEN-LABEL STUDY TO INVESTIGATE THE EFFECT OF
`intraocular injections of 0.5 mg of ranibizumab in 10
`patients with DME was approved by the Federal Drug
`Administration and the institutional review board of the
`Johns Hopkins Medical Institutions. The study was de-
`signed to give patients an intraocular injection of 0.5 mg of
`ranibizumab at study entry and at one, two, four, and six
`months after entry. The dose was selected because 0.5 mg
`is the highest dose available and because it is reasonable to
`start with the highest dose and investigate other doses in
`future studies, if indicated. The regimen was selected to
`assess the effect of three monthly injections and then to
`determine the impact of increasing the time between injec-
`tions to two months for the last two injections. The primary
`outcome measure was foveal thickness that was measured by
`optical coherence tomography (OCT)6,7 at seven months,
`compared with baseline. Secondary outcome measures were
`macular volume that was measured by OCT and visual acuity
`that was measured by the protocol of the Early Treatment
`Diabetic Retinopathy Study (ETDRS)8 at seven months,
`compared with baseline.
`
`● PATIENT ELIGIBILITY AND EXCLUSION CRITERIA:
`Patients (18 or older) were eligible if they had reduction in
`visual acuity between 20/40 and 20/320 and met the
`following criteria: (1) baseline foveal thickness by OCT
`was 250 m or greater, (2) serum HbA1c ⱖ6% for 12
`months before randomization, (3) no potential contribut-
`ing causes to reduced visual acuity other than DME, and
`(4) reasonable expectation that laser photocoagulation
`would not be required for the next six months. If both eyes
`were eligible, the eye with the greater foveal thickness was
`entered.
`
`● STUDY PROTOCOL: Consenting patients were screened
`for the study with a medical history, physical examination,
`measurement of best-corrected visual acuity by an experi-
`enced examiner who used the ETDRS protocol,8 a com-
`plete eye examination, an OCT, a fluorescein angiogram,
`and laboratory tests on blood and urine. Eligible patients
`
`received an intraocular injection of 0.5 mg of ranibizumab.
`Patients returned one week later for a repeat examination
`and OCT. Subsequent return visits occurred every month
`through seven months, which was the primary end point of
`the study. Additional injections of ranibizumab were per-
`formed at one, two, four, and six months. This protocol
`was selected to determine the effect of monthly injections
`for the first three months and then to try to determine
`whether less frequent injections would be feasible. Safety
`evaluations, measurement of best-corrected visual acuity,
`eye examinations, and OCTs were done at all study visits;
`fluorescein angiograms were done at three and six months.
`Measurements of HbA1C were done at baseline and three
`and six months. Hematologic and blood chemistry tests
`were done at baseline and six months.
`
`● ADMINISTRATION OF STUDY DRUG: Povidone iodine
`was used to clean the lids, and a lid speculum was inserted.
`Topical anesthesia was applied; in some patients, a sub-
`conjunctival injection of 2% lidocaine was given. The
`conjunctiva was irrigated with 5% povidone iodine. A
`30-gauge needle was inserted through the pars plana, and
`0.05 ml containing 0.5 mg of ranibizumab was injected
`into the vitreous cavity. Funduscopic examination was
`performed to confirm retinal perfusion, and patients were
`observed for one hour or until intraocular pressure returned
`to normal. Patients were called the day after each injection
`and asked whether they had decreased vision, eye pain,
`unusual redness, or any new symptoms.
`
`● OCT: OCT scans were performed by an experienced
`investigator with a StratusOCT3 (Carl Zeiss Meditec,
`Dublin, California, USA) that used the fast macular scan
`protocol. This protocol consists of 6 line scans that are
`6.0-mm long, centered on fixation, and spaced 30 degrees
`apart around the circumference of a circle. Each line
`consists of 128 A-scan measurements. With each A-scan,
`the OCT software measures the distance between the
`inner surface of the retina and the anterior border of the
`retinal pigment epithelium choriocapillaris complex on
`the basis of changes in reflectivity. The center point
`thickness, also known as the foveolar thickness, is a mean
`value that is generated by the StratusOCT software from
`the 6 central A-scan thickness values of each of the radial
`lines comprising the fast macular thickness map. We did
`not use this value generated from only 6 data points for our
`primary measure of central retinal thickness but instead
`used the foveal or central 1 mm thickness, which is an
`average generated value based on central 21 scans of each
`of the 6 lines that pass through the patient’s fixation. The
`number of data points that are used to compute this value
`is 21 ⫻ 6 ⫽ 126, which provides a better representation of
`the thickness of the central retina than a value that is
`generated from only 6 points around fixation. Macular
`volume throughout the entire 6-mm zone is calculated
`with extrapolated values between the line scans. Excess
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`FIGURE 1. Horizontal cross sectional optical coherence tomography (OCT) scans at all time points for patients 3 and 9 with
`diabetic macular edema that was treated with ranibizumab to illustrate two patterns of response over time. Seven days after the first
`intraocular injection of 0.5 mg of ranibizumab (day seven), patient 3 showed a marked improvement in the appearance of the OCT
`scan with the elimination of several large cysts and the return of a normal macular contour that included a foveal depression. At
`month one (M1), one month after the first injection, and M2 and M3, one month after the second and third injections, respectively,
`the scans for patient 3 were worse than the scan at day seven, which suggests a loss of effect of ranibizumab or transient effects that
`are lost by one month after injection. At M4, two months after the third injection, the scan showed substantial deterioration, but
`seven days after the fourth injection (M4 ⴙ seven days) there was marked improvement supporting transient effect. However, there
`was less deterioration one month after the fourth injection (M5) than there had been one month after each of the first three
`injections. This was followed by deterioration at M6, two months after the fourth injection, but then at M7, the primary end point
`and one month after the fifth injection, there was improvement to the point that the scan looked more like the two previous scans
`that had been performed seven days after an injection than like those scans that had been performed one month after an injection.
`Like patient 3, patient 9 also showed substantial improvement at day seven compared with baseline, with resolution of several large
`cysts. However, unlike patient 3, patient 9 showed continued improvement and then stability at subsequent time points, regardless
`of the time after the injection that the scan was performed. This suggests that the beneficial effects of ranibizumab were more
`sustained in patient 9 than in patient 3. BL ⴝ baseline.
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`FIGURE 2. Excess foveal thickness was measured by optical coherence tomography (OCT) at each study visit in all patients with diabetic
`macular edema that was treated with ranibizumab. Each bar represents the foveal thickness above the normal mean value of 212 m, which is
`set to zero. The arrows show intraocular injections of 0.5 mg of ranibizumab. The bars for baseline and month seven are shaded to allow quick
`comparison between baseline and the primary end point. The foveal thickness is less at the primary end point than at baseline for all patients.
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`FIGURE 3. The mean excess foveal thickness at each study visit in all patients with diabetic macular edema that was treated with
`ranibizumab. Each bar represents the mean value for excess foveal thickness for all patients at the designated study visit (data for
`eight of 10 patients at month nine). The arrows show when intraocular injections of 0.5 mg of ranibizumab were administered.
`Compared with baseline, foveal thickness was reduced by 246 m at the primary end point of the study, which constituted the
`elimination of 85% of the excess foveal thickness that had been present at baseline.
`
`foveal thickness was calculated by subtraction of the
`measured foveal thickness value from the normal mean
`value of 212 m that was calculated from measurements
`on a large population of subjects.9 Excess macular volume
`was determined by subtraction of the upper limit of the
`normal range of 6.94 ⫾ 0.37 mm3 from the measured
`value.
`
`● STATISTICAL ANALYSIS: Statistical analyses were per-
`formed with Statistical Package for the Social Sciences
`software (SPSS Inc, Chicago, Illinois, USA). The likeli-
`hood that the change in foveal thickness, macular volume,
`and visual acuity from baseline to month seven was due to
`ranibizumab rather than to chance was determined by the
`Wilcoxon signed-rank test.
`
`RESULTS
`● CHARACTERISTICS OF THE STUDY POPULATION: There
`were five men and five women in the study, with a median
`age of 60 years. Eight of the 10 patients were insulin-
`dependent diabetics. The median and mean HbA1C values
`at enrollment were 7.50% and 7.64%, respectively, and
`were 7.90% and 7.91%, respectively, at month 6 (P ⫽
`
`.240). Four patients had diabetic neuropathy, and three
`patients had diabetic nephropathy with modest renal
`insufficiency that did not require dialysis. Eight patients
`were receiving treatment for hypertension, which was
`well-controlled; seven patients had hypercholesterolemia,
`five of whom were receiving treatment. There was no
`significant change in mean systolic or diastolic blood
`pressure during the study. The mean duration of DME was
`4.75 ⫾ 1.22 years with a median duration of 3.5 years and
`a range of six months to 10 years. Nine of the 10 patients
`with DME had received previous treatment in the study
`eye; eight of the patients had received at least two sessions
`of focal/grid laser photocoagulation not less than 5 months
`before study entry (range, five to 120 months), and three
`patients had received intraocular corticosteroids not less
`than 10 months before entry (range, 10 to 20 months).
`Despite these treatments, the mean foveal thickness at
`baseline was 503 ⫾ 115 m (range, 326 to 729 m).
`Therefore, this patient population had severe, chronic
`DME that was poorly responsive to standard therapies.
`
`● EFFECT OF RANIBIZUMAB ON FOVEAL THICKNESS:
`Several patients had a large reduction in foveal thickness
`by seven days after the first intraocular injection of 0.5 mg
`of ranibizumab (median, 88 m; mean, 130 m). OCT scans
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`FIGURE 4. Mean and median change in visual acuity from baseline at each study visit in all patients with diabetic macular edema
`that was treated with ranibizumab. The black line shows the mean change in visual acuity measured in the number of letters that
`were read on an Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart, and the white line shows the median
`change in visual acuity. The arrows show times of intraocular injection of 0.5 mg of ranibizumab. At the primary end point, month
`seven, there was an improvement of 12.3 letters in mean visual acuity and 11 letters in median visual acuity.
`
`from two patients whose condition showed such an immedi-
`ate, dramatic response are shown in Figure 1. Patient 3 had
`several
`large cysts within the retina at baseline that
`resolved within a week of the first injection with return of
`a normal contour that included a foveal depression. Much
`of the improvement was lost at one month, just before the
`second injection. Substantial thickening and cystic changes
`were also seen at months two and three, which was one
`month after the second and third injections, respectively.
`To determine whether this patient had become refractory
`to ranibizumab, an OCT scan was done seven days after
`the month four injection. There was a marked improve-
`ment, with resolution of cysts and a normal foveal contour
`that indicated that the patient was continuing to respond
`well to ranibizumab, but the drug effect quickly dissipated
`and was not apparent by one month after each injection.
`The subsequent course showed that, when injections were
`given two months apart, there might be a longer duration
`of effect from a single injection. Like patient 3, patient 9
`also showed substantial improvement at day seven, com-
`pared with baseline, with resolution of several large cysts.
`However, unlike patient 3, patient 9 showed continued
`improvement and then stability at subsequent time
`
`points, regardless of the time after the injection that the
`scan was done. This suggests that the beneficial effects
`of ranibizumab were more sustained in patient 9 than in
`patient 3.
`Excess foveal thickness is shown for each visit for all 10
`patients in Figure 2. Patient 9, whose scans are shown in
`Figure 1, experienced the disappearance of excess foveal
`thickness after the first injection, with a persistent effect at
`each subsequent time point that included the primary end
`point at seven months. Patient 4 had a similar pattern.
`Patient 3 (Figure 1) experienced a dramatic reduction in
`foveal thickness at day seven, but fluctuation occurred
`because of the dissipation of drug effect over the course of
`one month and further worsening when injections were
`delayed for two months. This same profile is shown to some
`extent for patients 1, 2, 5, 7, and 10. Patients 6 and 8 had
`a different pattern of more gradual, steady improvement,
`regardless of the alteration of the injection interval.
`Regardless of the different patterns that were exhibited,
`all patients appeared to have a beneficial response to
`ranibizumab. The magnitude of the beneficial response is
`substantial, which is shown by the change from baseline in
`median and mean excess foveal thickness for the entire
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`FIGURE 5. Scatter plot of reduction in foveal thickness vs gain in visual acuity at each study visit for all patients with diabetic
`macular edema treated with ranibizumab. The reduction in foveal thickness in micrometers on the y-axis is plotted against the
`improvement in visual acuity, which was measured by the numbers of letters that were read on an Early Treatment Diabetic
`Retinopathy Study (ETDRS) visual acuity chart. There is a strong correlation with an R2 value of 0.78.
`
`group of 10 patients (Figure 3). There was a substantial
`drop seven days after the first injection, with further
`improvement to a plateau between months one and three.
`After an injection was skipped at month three, the foveal
`thickening was slightly worse at month four but, after the
`month four injection,
`improved beyond the previous
`plateau level. After an injection was skipped at month five,
`thickening was worse at month six, but after the month six
`injection, thickening improved to the best level of the
`study at the primary end point (month seven) when there
`were median and mean reductions in foveal thickness
`from baseline of 261 and 246 m, respectively, which
`represented a resolution of 85% of the edema. At month
`nine (three months after the last injection), there was
`some increase in excess foveal thickness, compared with
`the seven-month time point, but not back to the
`baseline level.
`
`● EFFECT OF RANIBIZUMAB ON MACULAR VOLUME:
`Mean macular volume was 9.22 mm3 at baseline and was
`reduced to 7.47 mm3 at seven months, which was a
`reduction of 1.75 mm3 (Supplementary Figures 1S and 2S).
`This is a significant reduction (P ⫽ .009), which consti-
`tutes 77% of the excess macular volume that was present at
`
`baseline. This large effect indicates that the reduction in
`thickening that occurred in the center of the macula was
`accompanied by global reduction in edema throughout the
`entire macula.
`
`● EFFECT OF RANIBIZUMAB ON VISUAL ACUITY: Be-
`cause of the chronicity of the DME and lack of response to
`other treatments, we did not expect a large improvement
`in visual acuity. However, mean and median visual acuities
`were better than the acuities at baseline at all time points
`and improved by 12.3 and 11 letters, respectively, at the
`seven-month time point (Figure 4). This is an improve-
`ment of a little more than two lines. A scatter plot of
`reduction in foveal thickness vs improvement in visual
`acuity at each visit is shown in Figure 5. There is a strong
`correlation with an R2 value of 0.78. This indicates that,
`even for these patients with chronic macular edema, for
`the group as a whole improvement in foveal thickening
`correlates well with improvement in visual acuity at each
`study visit. However, the rate of change of these two
`outcome measures is different. A comparison of Figures 3
`and 4 shows that change in visual acuity occurs more
`slowly than change in foveal thickness. There was rapid
`improvement in foveal thickness after the first injection of
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`ranibizumab, with more gradual improvement in visual
`acuity. The marked fluctuations in foveal thickness that
`depended on time after the last injection of the OCT scan
`was not accompanied by fluctuations in visual acuities,
`which tended to show gradual improvement (this was the
`first clue that patient 3 had not become refractory to
`ranibizumab because, despite the prominent foveal thick-
`ening seen on sequential scans that were done one month
`after injections, visual acuity showed progressive improve-
`ment). In view of this, it is not surprising that there was
`good maintenance of the improvement in visual acuity
`between seven and nine months, despite substantial wors-
`ening of foveal thickness, which indicates that return of
`thickening precedes loss of visual acuity.
`
`● SAFETY: Intraocular injections of ranibizumab were tol-
`erated well with no inflammation or other problems. The
`mean systolic blood pressures at baseline, months one, two,
`four, and six were 131.6, 139.0, 142.0, 138.4, and 135.0
`mm Hg, respectively. The mean diastolic blood pressures at
`baseline, months one, two, four, and six were 72.3, 75.1,
`78.2, 78.2, and 76.8 mm Hg, respectively. One patient
`received intraocular corticosteroids in the nonstudy eye for
`DME, and severe intractable glaucoma developed that
`required filtration surgery. There were no systemic adverse
`events, no thromboembolic events, cerebral vascular acci-
`dents, or myocardial infarctions. Capillary nonperfusion
`was measured by image analysis on baseline and month six
`fluorescein angiograms, with the investigator masked with
`respect to time point. The mean area of nonperfusion was
`0.19812 disk areas at baseline and 0.19525 disk areas at six
`months. Thus, there was no significant change in capillary
`nonperfusion throughout the study.
`
`DISCUSSION
`
`THE DEVELOPMENT OF OCT HAS PROVIDED AN EXTREMELY
`useful tool for the study and management of DME. It
`allows noninvasive cross-sectional imaging of the retina
`that provides reproducible measurements of retinal thick-
`ness with a resolution of 10 m.6 OCT provides an objective
`assessment of treatment response that is not influenced by
`observer or patient bias. Because reproducibility is high
`and sudden changes in DME are unusual, spontaneous
`short-term changes of more than 30 m are rarely seen.9
`One week after a single injection of 0.5 mg of ranibizumab
`(a specific antagonist of VEGF) in 10 patients with chronic
`DME, there were median and mean reductions in foveal
`thickness of 88 and 130 m, respectively. This strongly
`suggests that VEGF is a stimulus for retinal thickening, which
`is a conclusion that is supported by the added improvement
`in foveal thickness that is achieved with four additional
`injections of ranibizumab that result in median and mean
`reductions in foveal thickness of 261 and 246 m, respec-
`tively, at seven months, which was the primary end point
`
`of the study. This was an 85% reduction of the excess
`foveal thickening that was present at baseline. There was
`a strong correlation between the change in foveal thick-
`ness over time and the change in macular volume over
`time, which provided added confidence that the results are
`reliable and meaningful. Visual acuity measurements are most
`reliable when both patients and examiners are masked to
`whether a treatment was actually administered, but the
`anatomic evidence of improvement and the strong corre-
`lation between reduction in foveal thickening and im-
`provement in vision support the reliability of the measured
`gains in median and mean visual acuity of 11 and 12.3
`letters, respectively.
`Previous studies have also suggested that VEGF may
`play a role in DME. An orally administered kinase inhib-
`itor that blocks VEGF receptor signaling caused a dose-
`dependent reduction in foveal thickness in patients with
`DME, but because of other activities of this drug, the
`improvement in DME could not be attributed solely to
`inhibition of VEGF receptors.10 Recently, intraocular in-
`jections of pegaptanib, an aptamer that selectively binds
`VEGF165, combined with focal
`laser photocoagulation
`when considered needed, was found to cause a possible
`small beneficial effect in patients with DME.11 Patients
`who were randomly assigned to receive intraocular injec-
`tions of 0.3 mg of pegaptanib had a median visual acuity of
`20/50 at the primary end point, compared with 20/63 at
`baseline, which was an improvement of approximately one
`line. This was no different from the sham injection group,
`which showed improvement of approximately one line
`from 20/80 at baseline to 20/63. Change in foveal thick-
`ness from baseline was ⫺68.0, ⫺22.7, and ⫺5.3 m in the
`0.3-, 1-, and 3-mg pegaptanib treatment groups compared
`with ⫹3.7 m in the sham injection group. These results
`are confounded by the concomitant use of focal laser
`photocoagulation in this study;
`fewer patients in the
`0.3-mg treatment group (11/44 patients) compared with
`the sham injection group (20/42 patients) were treated
`with focal laser photocoagulation. The small benefit in the
`0.3-mg treatment group cannot be attributed solely to the
`inhibition of VEGF165, but rather to the combination of
`VEGF165 blockade and focal laser compared with focal
`laser alone in the sham injection group. Also, the rela-
`tively small effect of this combination therapy on foveal
`thickness in patients with DME suggests that VEGF165
`plays a relatively small role in DME and/or that pegaptanib
`is an inefficient inhibitor. Although the current study
`included only 10 patients, it is not confounded by any
`concomitant treatments and demonstrates that a specific
`VEGF antagonist that is given over seven months causes
`reductions in median and mean retinal thickening of 261
`and 246 m, respectively which results in the resolution of
`most excess thickening (85%). This supports the conclu-
`sion that VEGF-A (probably multiple isoforms) plays a
`major role in DME.
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`
`This study raises several questions. Are the different
`patterns of response to intraocular injections of ranibi-
`zumab in different patients because of different levels of
`VEGF production in these patients? What is the optimal
`timing for injections? There appeared to be a plateau in the
`amount of reduction of foveal thickening during the first
`three months of the study when monthly injections of
`ranibizumab were given, with additional benefit achieved
`by switching to injections every other month. It is impor-
`tant to determine whether this is a valid observation that
`can be confirmed or simply random variation. If it is a valid
`observation, it suggests that there may be some compen-
`satory response during the monthly injection phase, such as
`increased expression of VEGF that is circumvented by less
`frequent injections. The most important question raised by
`the study is whether intraocular injections of ranibizumab can
`provide long-term benefit in patients with DME. The mean
`improvement of 12.3 letters of visual acuity over seven
`months is suggestive, but a larger double-masked, randomized,
`controlled trial that will span several years is needed to
`determine the ultimate value of ranibizumab for patients with
`DME. Such a trial is being planned.
`
`REFERENCES
`
`1. Klein R. Retinopathy in a population-based study. Trans Am
`Ophthalmol Soc 1992;90:561–594.
`
`2. Moore J, Bagley S, Ireland G, et al. Three dimensional
`analysis of microaneurysms in the human diabetic retina.
`J Anat 1999;194:89 –100.
`3. Nguyen QD, Shah SM, van Anden E, et al. Supplemental
`inspired oxygen improves diabetic macular edema: a pilot
`study. Invest Ophthalmol Vis Sci 2003;45:617– 624.
`4. Ozaki H, Hayashi H, Vinores SA, et al. Intravitreal sustained
`release of VEGF causes retinal neovascularization in rabbits
`and breakdown of the blood-retinal barrier in rabbits and
`primates. Exp Eye Res 1997;64:505–517.
`5. Derevjanik NL, Vinores SA, Xiao W-H, et al. Quantitative
`assessment of the integrity of the blood-retinal barrier in
`mice. Invest Ophthalmol Vis Sci 2002;43:2462–2467.
`6. Huang D, Swanson EA, Lin CP, et al. Optical coherence
`tomography. Science 1991;254:1178 –1181.
`7. Hee MR, Izatt JA, Swanson EA, et al. Optical coherence
`tomography of the human retina. Arch Ophthalmol 1995;
`113:325–332.
`8. The Early Treatment Diabetic Retinopathy Study Research
`Group. Photocoagulation for diabetic macular edema, ETDRS
`Report No. 1. Arch Ophthalmol 1985;103:1644 –1652.
`9. Chan A, Duker JS, Ko TH, et al. Normal macular thickness
`measurements in healthy eyes using Stratus optical coher-
`ence tomography. Arch Ophthalmol 2006;124:193–198.
`10. Campochiaro PA, C99-PKC412-003 Study Group. Reduc-
`tion of diabetic macular edema by oral administration of the
`kinase inhibitor PKC412. Invest Ophthalmol Vis Sci 2004;
`45:922–931.
`11. Macugen Diabetic Retinopathy Study Group. A phase II
`randomized double-masked study of pegaptanib, an anti-
`vascular endothelial growth factor aptamer,
`for diabetic
`macular edema. Ophthalmology 2005;112:1747–1757.
`
`VOL. 142, NO. 6
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`RANIBIZUMAB FOR DIABETIC MACULAR EDEMA
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`969
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`Quan Dong Nguyen, MD, MSc, is an Assistant Professor of Ophthalmology at Johns Hopkins, Baltimore, Maryland. A
`graduate of Phillips Exeter Academy, Yale University, and University of Pennsylvania School of Medicine, Dr Nguyen
`completed his residency and fellowships in Uveitis and Retina and Vitreous at the Massachusetts Eye and Ear Infirmary
`and the Schepens Eye Research Institute, and a fellowship in Ocular Immunology at Wilmer. Dr Nguyen focuses his
`research on early clinical trials of pharmacologic treatments for macular degeneration, macular edema, and ocular
`inflammatory diseases.
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`969.e1
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`AMERICAN JOURNAL OF OPHTHALMOLOGY
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`DECEMBER 2006
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`Syed Mahmood Ali Shah, MBBS, is a Research Scientist managing the Retinal Imaging Research an