Ranibizumab for Diabetic Macular Edema
`
`Results from 2 Phase III Randomized Trials: RISE and
`RIDE
`
`
`Quan Dong Nguyen, MD, MSc,! David M. Brown, MD,? Dennis M. Marcus, MD,? David S. Boyer, MD,*
`Sunil Patel, MD, PhD,° Leonard Feiner, MD, PhD,° Andrea Gibson,’ Judy Sy, PhD,” Amy Chen Rundle, MS,”
`J. Jill Hopkins, MD,” Roman G. Rubio, MD,’ Jason S. Ehrlich, MD, PhD,’ on behalf of the RISE and RIDE
`Research Group*
`
`Purpose: To evaluate the efficacy and safety of intravitreal ranibizumab in diabetic macular edema (DME)
`patients.
`Twoparallel, methodologically identical, phase Ill, multicenter, double-masked, sham injection-
`Design:
`controlled, randomized studies.
`Participants: Adults with vision loss from DME (best-corrected visual acuity [BCVA], 20/40-20/320 Snellen
`equivalent) and central subfield thickness =275 wm on time-domain optical coherence tomography (OCT).
`Intervention: Monthlyintravitreal ranibizumab (0.5 or 0.3 mg) or sham injections. Macular laser was available
`per-protocol-specified criteria.
`Main Outcome Measures: Proportion of patients gaining =15 letters in BCVA from baseline at 24 months.
`Results:
`In RISE (NCT00473330), 377 patients were randomized (127 to sham, 125 to 0.3 mg, 125 to 0.5
`mg). At 24 months, 18.1% of sham patients gained =15 letters versus 44.8% of 0.3-mg (P<0.0001; difference
`vs sham adjusted for randomization stratification factors, 24.3%; 95% confidence interval [Cl], 13.8-34.8) and
`39.2% of 0.5-mg ranibizumab patients (P<0.001; adjusted difference, 20.9%; 95% Cl, 10.7-31.1).
`In RIDE
`(NCT00473382), 382 patients were randomized (130 to sham, 125 to 0.3 mg, 127 to 0.5 mg). Significantly more
`ranibizumab-treated patients gained =15 letters: 12.3% of sham patients versus 33.6% of 0.3-mg patients
`(P<0.0001; adjusted difference, 20.8%; 95% Cl, 11.4-30.2) and 45.7% of 0.5-mg ranibizumab patients
`(P<0.0001; adjusted difference, 33.3%; 95% Cl, 23.8—42.8). Significant improvements in macular edema were
`noted on OCT, and retinopathy wasless likely to worsen and morelikely to improve in ranibizumab-treated
`patients. Ranibizumab-treated patients underwentsignificantly fewer macular laser procedures (mean of 1.8 and
`1.6 laser procedures over 24 monthsin the sham groupsvs 0.3-0.8 in ranibizumab groups). Ocular safety was
`consistent with prior ranibizumab studies; endophthalmitis occurred in 4 ranibizumab patients. The total inci-
`denceof deaths from vascular or unknown causes,nonfatal myocardial infarctions, and nonfatal cerebrovascular
`accidents, which are possible effects from systemic vascular endothelial growth factor inhibition, was 4.9% to
`5.5% of sham patients and 2.4% to 8.8% of ranibizumab patients.
`Conclusions: Ranibizumabrapidly and sustainably improved vision, reducedtherisk of further vision loss,
`and improved macular edemain patients with DME, with low rates of ocular and nonocular harm.
`Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.
`Ophthalmology 2012;119:789-801 © 2012 by the American Academy of Ophthalmology.
`
`“Group members listed online (http://aaojournal.org).
`
`Diabetic retinopathy (DR), the most common microvas-
`cular complication of diabetes,’ is the leading cause of
`new cases of vision loss and blindness among working-
`aged adults in the United States and most developed
`countries.2’> Diabetic macular edema (DME), swelling of
`the central retina that causes vision loss, is an advanced
`complication of DR*; the prevalence of DME increases
`from 0%to 3% inindividuals with recent diagnoses of
`diabetes to 28%to 29%in those with diabetes for =20
`years.° Because the population of people with diabetes is
`~285 million worldwide® and growing rapidly, vision
`
`loss from DRis a significant public health issue, with
`considerable socioeconomic and quality-of-life impacts.”
`In 1985,
`the Early Treatment Diabetic Retinopathy
`Study (ETDRS) established macular laser as standard
`care treatment by demonstrating that patients with clini-
`cally significant DMEtreated with laser experienced a
`50% reduction in moderate vision loss over time com-
`pared with untreated patients.* However, in ETDRS and
`recent studies, relatively few patients with vision loss
`experienced significant
`improvements in best-corrected
`visual acuity (BCVA) after
`laser, and improvement
`
`© 2012 by the American Academy of Ophthalmology
`Published by Elsevier Inc.
`
`ISSN 0161-6420/12/$-see front matter
`doi:10.1016/j.ophtha.2011.12.039
`
`789
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`Ophthalmology Volume 119, Number 4, April 2012
`
`tended to occur slowly.8 –12 A treatment that rapidly and
`durably improves vision would be an important advance.
`Diabetic macular edema results from pathologically in-
`creased retinal vascular permeability.13 Recognition of vas-
`cular endothelial growth factor (VEGF) as the primary
`cytokine mediating this increase14,15 and observation of
`increased intraocular VEGF levels in DME16 led to the
`hypothesis that VEGF signaling blockade might be benefi-
`cial both in restoring normal retinal anatomy and reversing
`vision loss from macular edema. Ranibizumab is an anti-
`VEGF antibody fragment, designed for intraocular use, that
`neutralizes the biologic activity of all known active iso-
`forms of VEGF.17 Pilot studies demonstrated that intravit-
`real ranibizumab reduced macular edema and improved
`visual acuity (VA) in patients with DME.18 Subsequent
`studies demonstrated that ranibizumab was superior to laser
`at 6 months and superior to both intravitreal steroids and
`laser at 12 months.9,10,19,20 Herein, we report the results of
`two 24-month, phase III, randomized studies designed to
`evaluate long-term treatment with ranibizumab in patients
`with vision loss from DME.
`
`Methods
`
`Study Design
`RISE (registered on ClinicalTrials.gov as NCT00473330) and
`RIDE (NCT00473382) are parallel phase III multicenter, double-
`masked, sham injection– controlled, randomized studies con-
`ducted at private and university-based retina specialty clinics in
`the United States and South America (65 principal investigators
`per study). One objective was to generate confirmatory evi-
`
`thus, 2 identically designed
`dence for regulatory purposes;
`studies were carried out. Two ranibizumab doses were chosen
`for regulatory purposes. Patients were recruited from June 2007
`to January 2009, and the 24-month controlled treatment periods
`ended on November 16, 2010 (RISE), and January 12, 2011
`(RIDE). The trials adhered to the tenets of the Declaration of
`Helsinki, were Health Insurance Portability and Accountability
`Act– compliant, and protocols were approved by institutional
`review boards, ethics committees, or as applicable. Patients
`provided written, informed consent.
`
`Participants
`One eye per patient was randomized. Eligible participants were
`aged ⱖ18 years with diabetes mellitus (type 1 or 2), decreased
`vision from DME (study eye BCVA, 20/40 –20/320 Snellen equiv-
`alent using ETDRS testing), and macular edema (time-domain
`optical coherence tomography [OCT] central subfield thickness ⱖ
`275 ␮m). Key exclusion criteria were prior vitreoretinal surgery,
`or a recent history (within 3 months of screening) of panretinal or
`macular laser in the study eye,
`intraocular corticosteroids, or
`antiangiogenic drugs. Patients with uncontrolled hypertension, un-
`controlled diabetes (glycosylated hemoglobin [HbA1c] ⬎ 12%), or
`recent (within 3 months) cerebrovascular accident (CVA), or myo-
`cardial infarction (MI) were excluded.
`
`Randomization, Intervention, and Masking
`Eligible patients were randomized21 to monthly sham injections or
`intravitreal injections of 0.3 or 0.5 mg of ranibizumab. Beginning
`at month 3 all patients were evaluated monthly for the need for
`macular laser according to protocol-specified criteria: Central fo-
`veal thickness (CFT) ⱖ250 ␮m with a ⬍50-␮m change from the
`prior month, with no prior macular laser in the previous 3 months,
`and an assessment by the evaluating physician that macular laser
`
`Diabetic macular edema
`
`Screening: BCVA 20/40-20/320, OCT CST ≥ 275 µm
`
`1:1:1 Randomization (1 eye per patient)
`
`
`Sham injection (n
`
` 122a)
`
`Ranibizumab 0.3 mg (n
`
` 122a)
`
`Ranibizumab 0.5 mg (n
`
` 122a)
`
`24-month controlled treatment period
`(monthly intravitreal/sham injections; rescue laser, if eligible, beginning month 3b)
`
`Primary
`endpoint
`
`Ranibizumab 0.5mgc
`
`Ranibizumab 0.3 mg
`
`Ranibizumab 0.5 mg
`
`
`
`
`
`Long-term open-label extension with 0.5 mg ranibizumab
`
`
`
`Month 24
`
`Month 36
`
`Figure 1. Study design. BCVA ⫽ best-corrected visual acuity; CST ⫽ central subfield thickness; OCT ⫽ optical coherence tomography. aTarget
`enrollment, 122 patients per treatment group. bStarting at month 3, patients were evaluated monthly for rescue laser based on objective and subjective
`criteria as described in Methods. cAfter publication of a 12-month trial of ranibizumab, laser, and steroids for diabetic macular edema,10 and consultation
`with the data monitoring committee, the studies were amended to allow early crossover (before month 25) to ranibizumab for patients receiving sham with
`persistent edema and vision loss. One patient in RISE and 3 patients in RIDE crossed over early (before month 25). These patients were analyzed in their
`original treatment groups per the intent-to-treat principle used for efficacy analyses.
`
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`Nguyen et al
`
`䡠 Ranibizumab for Diabetic Macular Edema
`
`would be beneficial. The goal of laser treatment was to apply
`photocoagulation in a grid pattern or directly to leaky microaneu-
`rysms in areas of retinal thickening and edema, avoiding treatment
`within the foveal avascular zone. Randomization was stratified by
`study eye BCVA (ⱕ55 vs ⬎55 ETDRS letters), baseline HbA1c
`(ⱕ8% vs ⬎8%), prior DME therapy in the study eye (yes vs no),
`and study site. Dynamic randomization was used to obtain approx-
`imately a 1:1:1 ratio among groups (Fig 1). Randomization was
`done via interactive phone system. The sponsor developed the
`specifications for the randomization, and a third party programmed
`and held the randomization algorithm. The studies were unmasked
`on February 10, 2011 (RISE), and March 22, 2011 (RIDE), when
`treatment assignments were made available to the study analysis
`team of the sponsor. Ocular assessments, including the need for
`macular laser, were made by evaluating ophthalmologists masked to
`patients’ treatment assignments. Study treatments were administered
`by treating ophthalmologists unmasked to treatment assignments but
`masked to ranibizumab dose. To improve patient masking, all patients
`received subconjunctival anesthesia before sham or active injections
`(performed as previously described).22 Study site personnel (except
`treating physicians and assistants), central reading center personnel,
`and the sponsor and its agents (except drug accountability monitors)
`were masked to treatment assignment. Treating physicians were
`masked to the assigned dose of ranibizumab. An independent statis-
`tical coordinating center performed the unmasked interim analyses for
`the data monitoring committee.
`
`Assessments
`Evaluations included vital signs, safety assessments, visual func-
`tion questionnaires, and ocular assessments: BCVA measured with
`
`the ETDRS chart (4-m starting distance), contrast sensitivity,
`intraocular pressure, slit-lamp examination, indirect ophthalmos-
`copy, OCT, fluorescein angiography (FA), and fundus photogra-
`phy (FP). Study visits were scheduled every 30⫾7 days. The OCT,
`FA, and FP images were graded at a central reading center.
`
`Outcomes
`The primary efficacy measure was the proportion of patients
`gaining ⱖ15 ETDRS letters in BCVA score from baseline at 24
`months (corresponding to 3 lines on the eye chart). Secondary
`outcomes at 24 months were mean change from baseline BCVA
`score over time, proportion of patients with BCVA Snellen equiv-
`alent of ⱖ20/40, mean change from baseline BCVA score over
`time in patients with focal edema as assessed on FA, proportion of
`patients losing ⬍15 letters in BCVA score from baseline, mean
`change from baseline in OCT CFT over time, proportion of pa-
`tients with a ⱖ3-step progression from baseline in ETDRS reti-
`nopathy severity on FP, proportion of patients with resolution of
`leakage on FA, and the mean number of macular laser treatments
`over time. Certain secondary endpoints were amended after the
`studies commenced but before unmasking study results, to be more
`consistent with literature and regulatory guidance received subse-
`quent to initiation of the studies (Appendix 1; available at http://
`aaojournal.org).
`
`Analysis
`
`Efficacy Analyses. The sample size of 366 patients (122 per
`treatment group) per study provided 90% experiment-wise power
`to detect a statistically significant difference in the primary effi-
`
`Table 1. Patient Demographic and Baseline Characteristics
`
`Characteristic
`
`Mean age (SD), yrs*
`Range, yrs
`Male, n (%)
`Race, n (%)†
`Asian
`American Indian or Alaska Native
`Black or African American
`Native Hawaiian/other/Pacific Islander
`White
`Not available
`Hispanic or Latino ethnicity, n (%)
`Mean body mass index (SD)‡
`Positive history of smoking, n (%)
`Mean duration of diabetes (SD), yrs*,¶
`Mean HbA1c (SD), %**
`ⱕ8%, n (%)
`⬎8%, n (%)
`
`Sham
`(n ⫽ 127)
`
`61.8 (9.8)
`39–85
`74 (58.3)
`
`6 (4.7)
`0
`19 (15.0)
`1 (0.8)
`101 (79.5)
`0
`24 (18.9)
`31.4 (7.1)
`60 (48.0)§
`14.5 (9.9)
`7.7 (1.5)
`80 (65.0)
`43 (35.0)
`
`RISE
`
`Ranibizumab
`0.3 mg
`0 5 mg
`(n ⫽ 125)
`(n ⫽ 125)
`
`61.7 (8.9)
`38–82
`73 (58.4)
`
`7 (5.6)
`0
`18 (14.4)
`2 (1.6)
`97 (77.6)
`1 (0.8)
`20 (16.0)
`32.3 (6.8)
`64 (51.2)
`15.9 (9.9)
`7.7 (1.5)
`81 (67.5)
`39 (32.5)
`
`62.8 (10.0)
`21–87
`65 (52.0)
`
`7 (5.6)
`0
`14 (11.2)
`1 (0.8)
`97 (77.6)
`6 (4.8)
`25 (20.0)
`32.9 (8.5)
`58 (46.4)
`16.3 (8.5)
`7.7 (1.4)
`82 (68.3)
`38 (31.7)
`
`Sham
`(n ⫽ 130)
`
`63.5 (10.8)
`22–91
`66 (50.8)
`
`2 (1.5)
`1 (0.8)
`15 (11.5)
`0
`104 (80.0)
`8 (6.2)
`37 (28.5)
`32.3 (8.9)
`43 (33.6)储
`16.6 (10.6)
`7.6 (1.4)
`84 (67.2)
`41 (32.8)
`
`RIDE
`
`Ranibizumab
`0.3 mg
`0 5 mg
`(n ⫽ 125)
`(n ⫽ 127)
`
`62.7 (11.1)
`24–88
`73 (58.4)
`
`5 (4.0)
`1 (0.8)
`14 (11.2)
`1 (0.8)
`99 (79.2)
`5 (4.0)
`33 (26.4)
`32.3 (8.6)
`64 (51.6)储
`16.0 (9.8)
`7.6 (1.3)
`79 (65.8)
`41 (34.2)
`
`61.8 (10.1)
`29–84
`80 (63.0)
`
`5 (3.9)
`2 (1.6)
`13 (10.2)
`0
`105 (82.7)
`2 (1.6)
`31 (24.4)
`31.3 (7.2)
`57 (45.6)储
`15.3 (10.1)
`7.6 (1.5)
`83 (67.5)
`40 (32.5)
`
`HbA1c ⫽ glycosylated hemoglobin; SD ⫽ standard deviation.
`*At randomization.
`†Patients who are of ⬎1 race were counted for each category that they indicated.
`‡Number of patients: 124, 122, and 124 (RISE) and 128, 125, and 126 (RIDE) in the sham, 0.3-mg, and 0.5-mg groups, respectively.
`§Number of patients: 125.
`储Number of patients: 128, 124, and 125 in the sham, 0.3-mg, and 0.5-mg groups, respectively.
`¶Number of patients: 123, 118, and 118 (RISE) and 122, 119, and 124 (RIDE) in the sham, 0.3-mg, and 0.5-mg groups, respectively.
`**Number of patients: 123, 120, and 120 (RISE) and 125, 120, and 123 (RIDE) in the sham, 0.3-mg, and 0.5-mg groups, respectively.
`
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`Ophthalmology Volume 119, Number 4, April 2012
`
`Table 2. Study Eye Characteristics at Baseline
`
`Characteristic
`
`Mean ETDRS letter score (SD)
`Mean approximate Snellen equivalent
`ⱕ20/200, n (%)
`⬎20/200 but ⬍20/40, n (%)
`ⱖ20/40, n (%)
`Mean CFT (SD), ␮m
`Mean time from first known CSME diagnosis to
`randomization (SD), yrs*
`Active or previously treated PDR present, n (%)†
`Previous treatment for CSME, n (%)
`Any
`Focal/grid laser
`Steroids‡
`Other
`
`RISE
`Ranibizumab
`0.3 mg
`0 5 mg
`(n ⫽ 125)
`(n ⫽ 125)
`
`54.7 (12.6)
`20/80
`17 (13.6)
`91 (72.8)
`17 (13.6)
`474.5 (174.8)
`2.1 (2.2)
`
`56.9 (11.6)
`20/80⫹2
`10 (8.0)
`91 (72.8)
`24 (19.2)
`463.8 (144.0)
`2.1 (2.1)
`
`RIDE
`Ranibizumab
`0.3 mg
`0 5 mg
`(n ⫽ 125)
`(n ⫽ 127)
`
`57.5 (11.6)
`20/80⫹2
`9 (7.2)
`92 (73.6)
`24 (19.2)
`482.6 (149.3)
`1.6 (2.0)
`
`56.9 (11.8)
`20/80⫹2
`11 (8.7)
`91 (71.1)
`25 (19.7)
`463.8 (175.5)
`1.9 (2.4)
`
`Sham
`(n ⫽ 130)
`
`57.3 (11.2)
`20/80⫹2
`10 (7.7)
`95 (73.1)
`25 (19.2)
`447.4 (154.4)
`2.4 (3.2)
`
`Sham
`(n ⫽ 127)
`
`57.2 (11.1)
`20/80⫹2
`10 (7.9)
`92 (72.4)
`25 (19.7)
`467.3 (152.0)
`2.3 (3.0)
`
`34 (26.8)
`
`28 (22.4)
`
`32 (25.6)
`
`28 (21.5)
`
`31 (24.8)
`
`34 (26.8)
`
`94 (74.0)
`86 (67.7)
`35 (27.6)
`21 (16.5)
`
`94 (75.2)
`86 (68.8)
`39 (31.2)
`20 (16.0)
`
`102 (81.6)
`90 (72.0)
`50 (40.0)
`21 (16.8)
`
`92 (70.8)
`84 (64.6)
`36 (27.7)
`21 (16.2)
`
`86 (68.8)
`72 (57.6)
`32 (25.6)
`27 (21.6)
`
`88 (69.3)
`79 (62.2)
`37 (29.1)
`25 (19.7)
`
`CFT ⫽ central foveal thickness; CSME ⫽ clinically significant macular edema; ETDRS ⫽ Early Treatment Diabetic Retinopathy Study; PDR ⫽
`proliferative diabetic retinopathy; SD ⫽ standard deviation.
`*Number of patients: 127, 124, and 123 in the sham, 0.3-mg, and 0.5-mg groups, respectively, in RISE and 126 in the 0.5-mg group in RIDE.
`†Active PDR was a study enrollment exclusion criterion.
`‡Intraocular or subtenon injection.
`
`cacy measure between 1 or both ranibizumab groups and the
`control (expecting percentages of 35% for 0.5-mg ranibizumab-
`treated patients, 25% for 0.3-mg, and 13% for sham patients). The
`studies were not designed or powered to compare the 2 selected
`doses of ranibizumab, but rather to compare each ranibizumab
`dose against the sham comparator (2 doses were used for regula-
`tory purposes). The intent-to-treat principle was used for efficacy
`analyses, with missing data imputed using the last observation
`carried forward method. To account for potential differences in
`baseline characteristics between treatment groups that may affect
`the outcome measures, efficacy analyses were stratified by the
`randomization stratification factors baseline BCVA (ⱕ55, ⬎55
`
`letters), baseline HbA1c (ⱕ8%, ⬎8%), and prior therapy for DME
`(yes or no); reported differences and 95% confidence intervals
`were also adjusted for these baseline variables. For the primary
`endpoint and secondary efficacy endpoints based on binary vari-
`ables, a comparison between each ranibizumab group and the
`control group was made using the Cochran-Mantel-Haenszel chi-
`square test stratified (adjusted) by the randomization stratification
`factors. For secondary efficacy endpoints that were continuous in
`nature (e.g., mean change from baseline in BCVA score), com-
`parisons were made by fitting either an analysis of variance or
`analysis of covariance model, adjusting for the randomization
`stratification factors. For the secondary efficacy endpoint of mean
`
`Outcomes at Month 24
`
`Number of macular focal/grid rescue laser treatments, mean (SD)
`Difference vs sham (95% CI)†
`Test for treatment difference vs sham‡
`Median
`Range
`Received macular laser treatment, n (%; 95% CI)
`Difference vs sham (95% CI)†
`Test for treatment difference vs sham§
`Proportion of patients who received PRP laser, n (%)储
`
`Sham
`(n ⫽ 127)
`
`1.8 (1.8)
`
`1.0
`0–6
`94 (74.0; 66.4–81.6)
`
`14 (11.0)
`
`RISE
`
`0.3 mg
`(n ⫽ 125)
`
`0.8 (1.2)
`⫺1.0 (⫺1.4 to ⫺0.7)
`P⬍0.0001
`0
`0–7
`49 (39.2; 30.6–47.8)
`⫺35.0 (⫺46.4 to ⫺23.7%)
`P⬍0.0001
`0
`
`Table 4. Use of Macular and
`
`Ranibizumab
`
`0.5 mg
`(n ⫽ 125)
`
`0.8 (1.3)
`⫺1.1 (⫺1.5 to ⫺0.7)
`P⬍0.0001
`0
`0–6
`44 (35.2; 26.8–43.6)
`⫺39.3 (⫺50.7 to ⫺28.0)
`P⬍0.0001
`1 (0.8)
`
`CI ⫽ confidence interval; PRP ⫽ panretinal photocoagulation; SD ⫽ standard deviation.
`The last-observation-carried-forward method was used to impute missing data. The mean number of macular lasers is reported with no imputation.
`*Starting at month 3, patients were evaluated monthly for macular focal/grid laser based on the objective and subjective criteria as described in the
`†Difference is adjusted for baseline visual acuity (ⱕ55, ⬎55 Early Treatment Diabetic Retinopathy Study [ETDRS] letters), baseline glycosylated
`‡Wilcoxon test stratified by baseline visual acuity (ⱕ55, ⬎55 ETDRS letters), baseline HbA1c (ⱕ8%, ⬎8%), and prior treatment for diabetic macular
`§Cochran-Mantel-Haenszel ␹2 (stratified by baseline visual acuity [ⱕ55, ⬎55 ETDRS letters], baseline HbA1c [ⱕ8%, ⬎8%], and prior treatment for
`储Not a prespecified endpoint; no statistical testing performed. Data are reported in context of safety outcomes and laser treatments performed for diabetic
`
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`Nguyen et al
`
`䡠 Ranibizumab for Diabetic Macular Edema
`
`change from baseline in CFT over time up to 24 months, the
`respective baseline CFT value was included as a continuous vari-
`able (covariate) in the analysis of covariance model. The mean
`number of macular laser treatments during 24 months was com-
`pared between each ranibizumab group and sham using a stratified
`Wilcoxon test. Additional details are in the supplemental material
`(Appendix 1; available at http://aaojournal.org).
`Safety Analyses. Safety was assessed through collection and
`summary of ocular and nonocular adverse events (AEs), serious
`AEs (SAEs), ocular assessments, deaths,
`laboratory results,
`vital signs, and antibodies to ranibizumab. At each study visit,
`nondirective questioning was used to elicit AE reports from
`patients. All AEs and SAEs, whether volunteered by the patient,
`discovered by study site personnel during questioning, or de-
`tected by examination, laboratory testing, or other means, were
`recorded in the patient record and case report forms. Safety
`analyses included all patients receiving ⱖ1 ranibizumab or
`sham injection. Patients were analyzed according to actual
`treatment received before optional crossover for patients ran-
`domized to the sham group.
`All data analyses occurred after all patients completed the
`month 24 visit or discontinued early. A Data Monitoring Commit-
`tee (3 ophthalmologists and 1 biostatistician) was established to
`monitor safety and study conduct by periodically reviewing un-
`masked data. Each interim safety analysis was allocated a type I
`error ␣ ⫽ 0.0001 to account for review of VA data forming the
`basis of the primary efficacy endpoint.
`
`Results
`
`In total, 759 patients were enrolled and randomized to study
`treatment (377 in RISE and 382 in RIDE; Fig 2, available at
`http://aaojournal.org). Randomized groups were generally well-
`balanced for baseline demographic (Table 1) and study eye
`characteristics, including history of prior treatment (Table 2);
`however, in RISE, more patients in the 0.3-mg ranibizumab
`group had a BCVA ⬍20/200, and more patients in the 0.5-mg
`ranibizumab group in both studies had previously received
`
`Panretinal Photocoagulation*
`
`intraocular or periocular steroids for DME. The 2-year study
`period was completed by 83.3% of patients in RISE and by
`84.6% in RIDE. The median number of ranibizumab injections
`was 24 (Table 3, available at http://aaojournal.org). The mean
`number of macular laser treatments over 24 months was 1.8
`and 1.6 in the sham groups and 0.3 to 0.8 in the ranibizumab
`groups (Table 4). Substantially more sham-treated patients re-
`ceived macular laser under the protocol-specified criteria or
`underwent panretinal photocoagulation for proliferative DR
`(PDR; Table 4).
`
`Visual Acuity Outcomes
`In both studies, statistically significantly greater numbers of pa-
`tients randomized to ranibizumab gained ⱖ15 ETDRS letters from
`baseline at 24 months. In RISE, 44.8% of patients receiving 0.3 mg
`ranibizumab and 39.2% of patients receiving 0.5 mg ranibizumab
`gained ⱖ15 letters compared with 18.1% of sham-treated pa-
`tients (Table 5, available at http://aaojournal.org; Fig 3). In RIDE,
`corresponding proportions were 33.6%, 45.7%, and 12.3%, respec-
`tively (Table 5; Fig 3). Ranibizumab treatment led to rapid vision
`improvements, with statistically significant changes versus sham
`observed as early as 7 days after the first injection (Fig 4). Mean
`BCVA in ranibizumab groups continued to improve steadily, with
`patients experiencing an average benefit over sham (adjusted for
`baseline variables) of 8.5 to 9.9 ETDRS letters at month 24 (Table
`5; Fig 4). Fewer ranibizumab-treated patients experienced signif-
`icant (ⱖ15 ETDRS letters) vision loss (Tables 5 and 6; Fig 3 and
`Fig 5 [available at http://aaojournal.org]). More patients in the
`ranibizumab groups achieved Snellen BCVA of ⱖ20/40 at month
`24 compared with sham (P⬍0.0001 for each ranibizumab group vs
`sham; Table 5; Fig 3).
`The effects of demographic and baseline ocular characteristics
`on efficacy outcomes were examined in prespecified subgroup
`analyses. As expected, baseline BCVA impacted efficacy23; pa-
`tients with worse baseline BCVA experienced greater improve-
`ments, and patients with better baseline BCVA (and less ability to
`gain letters) experienced lesser improvements (Table 7, available
`at http://aaojournal.org). No prespecified subgroup was identified
`
`Sham
`(n ⫽ 130)
`
`1.6 (1.6)
`
`1.0
`0–7
`91 (70.0; 62.1–77.9)
`
`16 (12.3)
`
`Ranibizumab
`
`RIDE
`
`0.3 mg
`(n ⫽ 125)
`
`0.7 (1.4)
`⫺0.9 (⫺1.3 to ⫺0.5)
`P⬍0.0001
`0
`0–7
`45 (36.0; 27.6–44.4)
`⫺32.8 (⫺44.2 to ⫺21.4)
`P⬍0.0001
`2 (1.6)
`
`methods. Panretinal laser was available as clinically indicated.
`hemoglobin (HbA1c; ⱕ8%, ⬎8%), and prior treatment for DME (yes, no).
`edema (DME; yes, no).
`DME [yes, no]).
`retinopathy during these studies.
`
`0.5 mg
`(n ⫽ 127)
`
`0.3 (0.7)
`⫺1.3 (⫺1.6 to ⫺1.0)
`P⬍0.0001
`0
`0–5
`25 (19.7; 12.8–26.6)
`⫺49.8 (⫺60.1 to ⫺39.6)
`P⬍0.0001
`2 (1.6)
`
`793
`
`Regeneron Pharmaceuticals, Inc. Exhibit 2057 Page 5
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
`

`

`Ophthalmology Volume 119, Number 4, April 2012
`
`RISE
`
`RIDE
`
`B
`
`100
`
`80
`
`P 0.0002
`
`P<0,0001
`
`
`
`Sham
`(n
`127)
`
`0.5 mg
`0.3 mg
`(@m
`125)
`(n
`125)
`Ranibizumab
`
`Sham
`(n
`130)
`
`0.5 mg
`0.3 mg
`(n_
`127)
`(nm
`125)
`Ranibizumab
`
`P 0.0126
`
`P 0.0086
`
`D
`
`P 0.1384
`
`P 0.0119
`-——_
`
`A
`
`x z
`
`e
`vo
`
`32A
`
`la
`
`° 4o
`
`O
`
`C
`
`x £
`
`2
`
`2 Y
`
`=
`
`° Z
`
`4
`
`80
`60
`
`40
`20
`0
`
`Sham
`(n
`127)
`
`80
`60
`
`40
`20
`0
`
`Sham
`(n
`130)
`
`0.5mg
`03mg
`(n_
`125)
`(n
`125)
`Ranibizumab
`
`0.5 mg
`0.3 mg
`(mn
`127)
`(mn
`125)
`Ranibizumab
`
`
`
`Snellenequivalentof20/40©
`
`100
`
`P<0.0001
`
`P<0.0001
`
`F
`100
`
`P<0,0001
`
`P 0.0002
`
`Sham
`(n
`127)
`
`0.5 mg
`0.3 mg
`(n_
`125)
`(@@
`125)
`Ranibizumab
`
`Sham
`(n
`130)
`
`0.5 mg
`0.3 mg
`(n_
`127)
`(m
`125)
`Ranibizumab
`
`Figure 3. Visual acuity outcomes at 24 months. Primary efficacy endpoint: percentage of patients who gained =15 Early Treatment Diabetic Retinopathy Study
`(ETDRS)letters from baseline at 24 months in RISE (A) and in RIDE (B). Secondary efficacy endpoints were (i) percentage of patients who lost <15 ETDRS
`letters from baseline visual acuity at 24 months in RISE (C) and in RIDE (D); and (ii) percentage of patients with vision of the Snellen equivalent of =20/40
`in RISE (E) and in RIDE(F). The proportionsofpatients with baseline Snellen equivalent of =20/40 are in Table 2, Vertical bars are 95% confidence intervals
`(Cls) for the percentage. Outcomesonbar charts are unadjusted. P values (treatment comparisons) are based on the Cochran-Mantel-Haenszel chi-square test
`stratified according to the baseline visual acuity (=55, >55letters), baseline glycosylated hemoglobin (=8%, >8%), and prior treatment for diabetic macular
`edema (yes, no). See Table 5 for 95% Cls for the differences.
`
`in which sham patients experienced better visual outcomes. Pa-
`tients with predominantly focal DME on angiography had mean
`BCVAimprovements at month 24 similar to the overall population
`(Table 5).
`
`Anatomic Outcomes
`
`Improvements in VA among ranibizumab-treated patients were
`paralleled by rapid reductions in macular edema measured with
`
`794
`
`Page6
`Exhibit2057
`Regeneron Pharmaceuticals, Inc.
`SamsungBioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc.
`IPR2023-00884
`
`

`

`Nguyen et al
`
`+ Ranibizumab for Diabetic Macular Edema
`
`Meanchangeinvisualacuity,ETDRSletters>
`
`
`
`
`
`
`MeanchangeinCFT,pm
`
`Day 7
`
`Month
`
` RIDE
`23
` 0123
`
`0123
`Day7
`
`6
`
`12
`Menth
`
`18
`
`24
`
`Day7
`
`6
`
`12
`Month
`
`12.0*
`
`18
`
`24
`
`-—O Sham
`
`Ranibizumab 0.3 mg
`
`—®- Ranibizumab 0.5 mg
`
`Figure 4. Changes in (A) visual acuity and (B) central foveal thickness (CFT) from baseline through 24 months. Numberof patients: 127, 125, and 125 (RISE)
`and 130, 125, and 127 (RIDE)in the sham,0.3-mg, and 0.5-mg groups, respectively. Vertical bars are +1 standard error of the mean. The last-observation-
`carried-forward imputation method was used. *P<0,0001 versus sham (analysis of variancettest [stratified]). Differences were statistically significant starting at
`the first posttreatment observation (day 7) and at each pointthereafter; a hierarchical testing strategy controlled for multiple comparisons. ETDRS = Early
`Treatment Diabetic Retinopathy Study.
`
`OCT (Fig 4). Differences between ranibizumab and sham
`groupswerestatistically significant at day 7 (first posttreatment
`measurement) and at each point thereafter. Resolution of leak-
`age on FA and of macular edema on OCTboth werestatistically
`significantly more common amongranibizumab-treated patients
`(Table 5; Fig 6).
`Patients randomized to ranibizumab wereless likely to develop
`PDR(Table 8, available at http://aaojournal.org; Fig 6). Notably,
`we observed lower rates of retinopathy progression and higher
`rates of retinopathy improvement
`in ranibizumab-treated eyes,
`measured by the ETDRSretinopathy severity scale (Table 8).
`
`Ocular Harm
`
`Serious AEs affecting study eyes are summarized in Table 9.
`Overall, the most common SAEwasvitreous hemorrhage, which
`occurred in 4 sham-treated and 2 ranibizumab-treated eyes in RISE
`and in 3 sham-treated eyes in RIDE. Serious intraocular inflam-
`mation was uncommon amongranibizumab-treated patients, oc-
`curring only once. Serious AEsarising from the injection proce-
`dure were also uncommon; | case of endophthalmitis occurred in
`RISEand3 in RIDE,along with 3 cases of traumatic cataract and
`1 rhegmatogenous retinal detachment out of 10 584 intravitreal
`injections (Table 10, available at http://aaojournal.org).
`Ocular AEs in the study eye are summarized in Table 11
`(available at http://aaojournal.org). Most were reported as mild
`or moderate. Rates of cataract, intraocular inflammation, and
`glaucoma AEs were similar among the sham and ranibizumab
`
`groups. Increased intraocular pressure after the injection was
`morelikely in ranibizumab-treated patients, as expected, be-
`cause sham-treated patients did not receive actual injections. In
`ranibizumab-treated patients, AEs related to worsening of DR,
`such as retinal neovascularization and vitreous hemorrhage,
`were less common. Threetraction retinal detachments occurred
`
`in sham-treated patients.
`
`Systemic Harm
`
`Systemic safety was ascertained through analysis of overall sys-
`temic AEs and events potentially related to systemic VEGFinhi-
`bition. The most frequent systemic SAEs were those common to
`patients with advanced diabetes, such as MI, pneumonia, and
`congestive heart failure, with similar rates across treatment groups
`(Table 12, available at http://aaojournal.org). Analysis of arterial
`thromboembolic events, a subgroup of events potentially related to
`systemic VEGFinhibition, can be challenging because of varia-
`tions in the definition, assessment, and reporting of events. Anti-
`platelet Trialists’ Collaboration (APTC) criteria mitigate some of
`these issues by focusing on a more restricted but well-defined
`spectrum of SAEs: Vascular deaths, deaths of unknown cause,
`nonfatal MIs, and nonfatal cerebrovascular accidents (CVAs).?*
`Systemic SAEs potentially related to VEGFinhibition and cate-
`gorized by APTC definitions are summarized in Table 13. Among
`APTC SAEs,deaths of vascular or unknown cause and CVAs were
`slightly more commoninpatients treated with ranibizumab. Over-
`all, SAEs potentially related to systemic VEGFinhibition occurred
`
`795
`
`Page 7
`Regeneron Pharmaceuticals, Inc.
`Exhibit 2057
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc.
`IPR2023-00884
`
`

`

`Ophthalmology Volume 119, Number 4, April 2012
`
`RISE
`
`76.0
`
`433
`
`RIDE
`
`P<0.0001
`————4—M#_!__
`P<0.0001
`-—+—_
`76.0
`|
`
`81.1
`
`46.2
`
`B
`
`100
`
`"
`60
`
`40
`
`20
`
`0
`
`P<0.0001
`|A
`P<0.0001
`-——_
`74.4
`,
`
`100
`
`80
`
`660
`
`Ee
`oO
`G x>
`= g
`ER 40
`Z uM
`S
`Aa
`
`20
`0
`
`Sham
`(n=127)
`
`0.5 mg
`0.3 mg
`(n=125)
`(n=125)
`Ranibizumab
`
`Sham
`(n=130)
`
`0.5 mg
`0.3 mg
`(n=127)
`(n=125)
`Ranibizumab
`
`D S
`
`Sham
`(n= 126)
`
`0.5 mg
`0.3 mg
`(n=123)
`(n=123)
`Ranibizumab
`
`100
`
`80
`
`P 0.0114
`
`
`
`Sham
`(n=127)
`
`0.5 mg
`0.3 mg
`(n=125)
`(n=125)
`Ranibizumab
`
`ham
`(n=129)
`
`0.5 mg
`0.3 mg
`(n=127)
` (n=123)
`Ranibizumab
`
`
`
`Sham
`(n=130)
`
`0.5 mg
`0.3 mg
`(n=127)
`(n=125)
`Ranibizumab
`
`
`
`leakageof0DA,%Patientswithtotalareaof©fluorescein
`
`
`
`PatientsprogressingtoPDR,%
`
`E
`
`Figure 6. Exploratory analysis: proportion of patients withoutresidual edema in (A) RISE and in (B) RIDE; secondary outcome measure: proportion of patients with
`resolution of leakage in (C) RISE and in (D) RIDE; proportion of patients progressing to proliferative diabetic retinopathy (PDR) in (E) RISE and in (F) RIDE. A patient
`was considered to have progressed t