`Author Manuscript
`Am J Ophthalmol. Author manuscript; available in PMC 2010 November 1.
`Published in final edited form as:
`Am J Ophthalmol. 2009 November ; 148(5): 725–732.e7. doi:10.1016/j.ajo.2009.06.004.
`
`SCORE Study Report 7: Incidence of Intravitreal Silicone Oil
`Droplets Associated With Staked-on Versus Luer Cone Syringe
`Design
`
`Ingrid U. Scott, MD, MPH1, Neal L. Oden, PhD2, Paul C. VanVeldhuisen, PhD2, Michael S. Ip,
`MD3, Barbara A. Blodi, MD3, and Andrew N. Antoszyk, MD [on behalf of the SCORE Study
`Investigator Group]4
`
`1Departments of Ophthalmology and Public Health Sciences, Penn State College of Medicine,
`Hershey, Pennsylvania 2The EMMES Corporation, Rockville, Maryland 3University of Wisconsin,
`Madison, Wisconsin 4Charlotte Eye Ear Nose and Throat Associates, Charlotte, North Carolina.
`
`Abstract
`PURPOSE—To evaluate the incidence of intravitreal silicone oil (SO) droplets associated with
`intravitreal injections using a staked-on versus luer cone syringe design in the Standard Care versus
`COrticosteroid in REtinal Vein Occlusion (SCORE) Study.
`DESIGN—Prospective, randomized, phase III clinical trial.
`METHODS—The incidence of intravitreal SO was compared among participants exposed to the
`staked-on syringe design, the luer cone syringe design, or both of the syringe designs in the SCORE
`Study, which evaluated intravitreal triamcinolone acetonide injection(s) for vision loss secondary to
`macular edema associated with central or branch retinal vein occlusion. Injections were given at
`baseline and 4-month intervals, based on treatment assignment and study-defined re-treatment
`criteria. Because intravitreal SO was observed following injections in some participants, investigators
`were instructed, on September 22, 2006, to look for intravitreal SO at all study visits. On November
`1, 2007, the luer cone syringe design replaced the staked-on syringe design.
`RESULTS—464 participants received a total of 1205 injections between November 4, 2004 and
`February 28, 2009. Intravitreal SO was noted in 141/319 (44%) participants exposed only to staked-
`on syringes, 11/87 (13%) exposed to both syringe designs, and 0/58 exposed only to luer cone
`syringes (p<0.0001). Among participants with first injections after September 22, 2006, intravitreal
`SO was noted in 65/114 (57%) injected only with staked-on syringes compared with 0/58 injected
`only with luer cone syringes. Differential follow-up is unlikely to explain these results.
`CONCLUSION—In the SCORE Study, luer cone syringe design is associated with a lower
`frequency of intravitreal SO droplet occurrence compared with the staked-on syringe design, likely
`due to increased residual space in the needle hub with the luer cone design.
`
`© 2009 Elsevier Inc. All rights reserved.
`Correspondence to: Paul C. VanVeldhuisen, PhD, The EMMES Corporation, 401 N. Washington St., Suite 700, Rockville, MD 20850,
`Telephone: 301-251-1161; Fax: 301-251-1355; Email: score@emmes.com.
`Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
`we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting
`proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could
`affect the content, and all legal disclaimers that apply to the journal pertain.
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`Introduction
`Intravitreal silicone oil droplets have been reported following intravitreal injections of
`pegaptanib, bevacizumab, triamcinolone acetonide, and ranibizumab,1,2 as well as in a
`participant who received intravitreal injections with amikacin, vancomycin, and triamcinolone
`acetonide.1 None of the reported agents have silicone oil in their drug vehicle; the source of
`the silicone oil droplets is believed to be the syringe and/or needle used to deliver the drug.
`Dimethicone (polymethylsiloxane) is used as a lubricant for the syringe barrel, plunger, and
`needle. The silicone oil, which coats the inside of the syringe barrel and plunger, is employed
`to reduce friction between the syringe barrel and plunger so as to permit smooth movement of
`the plunger within the barrel. Silicone oil is also employed on the outside of the needle to reduce
`friction, permitting smooth movement of the needle through tissue.
`
`Methods
`
`Because intravitreal silicone oil droplets were reported in participants treated with intravitreal
`triamcinolone acetonide injection(s) by investigators in the Standard Care versus
`COrticosteroid in REtinal Vein Occlusion (SCORE) Study (Figures 1A and 1B), the syringe
`design used in the SCORE Study was modified from a staked-on (Figure 2) to a luer cone
`(Figure 3) design in an attempt to decrease the frequency of intravitreal silicone oil occurrence.
`The rationale for syringe modification was that intravitreal silicone oil droplet formation was
`thought to result from “squeegeed” silicone oil from the inside of the syringe as the plunger
`was pushed through the barrel of the syringe. Modifying the syringe from a staked-on to a luer
`cone design created a 50 ul residual space in the needle hub, and it was hypothesized that this
`would decrease the frequency of intravitreal silicone oil droplets, since the “squeegeed”
`silicone oil would remain in the residual space rather than be injected into the vitreous cavity.
`The purpose of the current study is to evaluate the incidence of intravitreal silicone oil droplets
`associated with intravitreal injections using staked-on versus luer cone syringes in the SCORE
`Study.
`
`The design and methods of the SCORE Study, which consists of two phase 3 multicenter
`randomized clinical trials conducted at 84 clinical sites in the United States, are described in
`detail elsewhere.3–5 The 170 study investigators, all board-certified ophthalmologists with at
`least 1 year of retina fellowship training, enrolled 271 participants into the central retinal vein
`occlusion (CRVO) trial and 411 participants into the branch retinal vein occlusion (BRVO)
`trial. The eligible eye of each participant was randomized to one of three equally-sized parallel
`arms in either the CRVO trial or the BRVO trial; standard of care (SC), 1 mg intravitreal
`triamcinolone, and 4 mg intravitreal triamcinolone. Participants in the CRVO trial assigned to
`standard of care were observed. Participants in the BRVO trial assigned to standard care were
`treated with grid laser photocoagulation if a dense macular hemorrhage did not preclude
`treatment. If a dense hemorrhage was present, laser photocoagulation was postponed until
`clearing of the hemorrhage permitted laser treatment. Participants were treated with the
`randomly assigned treatment at baseline and at 4-month intervals, except when study-defined
`criteria to defer additional treatment or to employ the alternate treatment regimen were
`satisfied.
`
`Between November 4, 2004 and October 31, 2007, all syringes used in the SCORE Study had
`a staked-on 27 gauge Becton Dickinson (Franklin Lakes, NJ) or Gerresheimer (Dusseldorf,
`Germany) needle. From November 1, 2007 until February 28, 2009, the SCORE Study used
`luer cone syringes (luer-slip design) with either a 30 gauge or a 27 gauge Becton Dickinson
`needle (the choice of needle size was at the discretion of each individual investigator). Both
`syringe types were made of glass. This report is based on 464 participants (1205 injections)
`who each had at least one study injection.
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`The SCORE Study investigators were first alerted to the issue of intravitreal silicone oil
`droplets in a memorandum from the Data Coordinating Center (The EMMES Corporation,
`Rockville, MD) on September 22, 2006. The droplets were presumed to be silicone oil due to
`their appearance and because of prior reports of this finding following intravitreal injection.
`1,2 Investigators were instructed to specifically look for silicone oil droplets at each study visit
`(all participants underwent slit-lamp biomicroscopy and dilated funduscopic indirect
`ophthalmoscopy at each study visit) and to report the first date a silicone oil event was observed.
`All SCORE Study participants were informed of this issue through an addendum to their
`Informed Consent approved by each site’s IRB.
`
`When intravitreal silicone oil was observed (henceforth referred to as a “silicone oil event”)
`in a participant by a SCORE Study physician, the date of the silicone oil event was imputed
`to be the date of the last injection prior to its report, although the event could actually have
`occurred at an earlier injection, and gone unnoticed by the investigator. Before the imputed
`date, the participant is said to be "at risk" for a silicone oil event. The time period a participant
`is at risk for a silicone oil event is measured by the number of injections, because it is presumed
`that silicone oil droplets result from the injection and do not spontaneously appear between
`injections. We also assume that the silicone oil event occurs at one specific time point. If, in
`reality, small increments of silicone oil are added by each injection, then we assume the event
`occurs when the cumulated oil increments surpass a threshold of clinical detectability.
`
`Once a silicone oil event occurs, there is also a time period between that injection date and the
`date the silicone is reported. This reporting time is measured by the number of ophthalmic
`evaluation visits (either the Day 4 or Month 1 safety visits, regular 4-month evaluation, or
`supplemental visits) performed by the SCORE Study investigator since the last injection. The
`number of visits is used rather than calendar time because silicone oil cannot be reported
`between ophthalmic evaluation visits.
`
`In the Results Section we report a simulation analysis designed to discover whether the absence
`of reported oil events in the luer cone cohort (Table 1, row 11; please see the Results section
`for an explanation of Table 1) could simply be due to inadequate time to report events that
`have occurred but have not yet been reported. In this analysis, we constructed a simulated luer
`cone cohort by randomly drawing with replacement from the staked-on syringe-only cohort
`after the warning date (Table 1, rows 7–8). More specifically, for each participant in the luer
`cone cohort, we randomly chose a replacement with the same number of injections from the
`staked-on cohort (note: participants with 4 injections with the luer cone syringe were allowed
`to “match” participants with 3 injections with the staked-on syringe, because there were no
`staked-on participants with 4 injections). We then aligned the enrollment date of the chosen
`participant from the staked-on cohort with that of the replaced participant from the luer cone
`cohort. Each newly simulated luer cone participant was assigned a score of 1 if a silicone oil
`event had occurred with an aligned reporting date before April 2, 2009 (the date of database
`closure) and was assigned a silicone oil score of 0 otherwise, i.e. if either there had been no
`silicone oil event, or there had been one, but the aligned report date was after the database
`closure date. This method of simulation embodies the “null hypothesis” of the simulation,
`namely that oil event rates and reporting rates were the same in the two cohorts, but there was
`less time to report after oil events in the luer cohort. After "substituting" all participants in the
`luer cone cohort, the summed simulated silicone oil scores were calculated to represent a typical
`number of silicone oil events expected to be reported in the luer cone cohort under the null
`hypothesis. We repeated the simulation 10,000 times.
`
`For injection-specific silicone oil event probabilities reported in Table 3 and Table 4 (i.e., on
`a first injection, second injection, etc.), we assume that the probability that an event will occur
`to an individual is different at each injection. We supply Bayesian point estimates and 95%
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`Results
`
`credibility intervals for this probability assuming a binomial likelihood and a uniform prior.
`[Note: with this method, an observation of k successes in n trials leads to a point estimate of
`(k+1)/(n+2) for the probability, rather than the usual k/n.] Estimates assuming the probabilities
`are the same across injections and are derived in the same way, except the likelihood theory
`assumes that event waiting times follow a censored geometric distribution. Injections occurring
`after a reported silicone oil event are not part of the analysis.
`
`Nineteen participants (31 injections) were excluded from the analysis because the participants
`had no ophthalmic evaluation visits on or after the warning date of September 22, 2006, and
`thus were never at risk for a reported oil event. Database closure for this report was April 1,
`2009.
`
`Table 1 summarizes the history of intravitreal triamcinolone injections at risk for a silicone oil
`event, and the silicone oil droplet exposure of all SCORE Study participants who received such
`injections. Important to understanding changes in the risk of intravitreal silicone oil is the date
`the Data Coordinating Center first warned SCORE clinical centers about the possibility of
`intravitreal silicone oil (September 22, 2006) and the date of the switchover from the staked-
`on syringe to the luer cone syringes (October 31, 2007). Each row of Table 1 depicts a history
`of at-risk injections for a particular cohort relative to these dates, with the number of
`participants in the cohort specified in column 6. Rows in which column 4 is “Y” represent at-
`risk injections that culminated in a silicone oil event. Because investigators were instructed to
`report only the first silicone oil event for each participant, there is exactly one silicone oil event
`in Table 1 for each participant in such a row. Injections occurring after oil events are not shown.
`Rows in which column 4 is “N” depict all injections that did not terminate in an oil event.
`Numbers in column 10 represent the average of number of visits after the last injection in which
`the SCORE Study physician might have reported an oil event.
`
`Row (1) of Table 1 represents 90 SCORE Study participants, all of whose 174 injections
`occurred before the warning date, and did not culminate in a silicone oil event. Column 10
`shows that, on average, there were 5.6 visits after the last injection and also after the warning
`date in the cohort depicted in row (1), during which an already-alerted physician might have
`had an opportunity to observe and report intravitreal silicone oil (if it was there), but did not.
`Row (2) represents 26 participants, all of whose 61 injections occurred before the warning date
`and culminated in 26 silicone oil events. Column 10 shows that, on average, there were 2.5
`visits that occurred after the last injection and also after the warning date, but at or before the
`time of the report of the silicone oil event (inclusive). That is, among the participants of row
`(2), there were 2.5 visits that were “at risk” for reporting a silicone oil event. Thus, column 10
`depicts the time from injection to report in cases with an oil event, but time from injection to
`participant termination/database closure in cases without an oil event. When there are oil
`events, column 10 gives an idea of the shortest possible waiting times from event to report;
`these waiting times could in reality have been longer, because the oil events might actually
`have happened before their imputed event dates. When there are no reported oil events, a greater
`number in column 10 makes the absence of oil events more credible. Other rows in Table 1
`are interpreted similarly.
`
`For cohorts of participants depicted in Table 1 whose last injection culminated in a silicone oil
`event, there were an average of 1.9 to 3.0 subsequent visits necessary to identify the intravitreal
`silicone oil. For participants without a silicone oil event, “Mean Post-Injection Visits” ranged
`from 4.3 to 7.1 visits. As expected, “Mean Post Injection Visits” are more numerous when
`there are no oil events. There were 319 participants exposed only to the staked-on syringes
`(Table 1: Rows 1–4,7, and 8). Intravitreal silicone oil was noted in 141 (44%) of these
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`participants. Intravitreal silicone oil droplets were noted in 11 (13%) of the 87 participants
`exposed to both the staked-on and luer cone syringes (Rows 5, 6, 9, and 10). In this cohort,
`exposed to both types of syringes, we cannot determine whether the intravitreal silicone oil
`came from injections before or after switchover to the new syringe, although the intravitreal
`silicone oil was reported after the switch date. None of the 58 participants who were exposed
`only to the luer cone syringes (Row 11) reported intravitreal silicone oil; there were 136
`injections in these participants.
`
`Table 2 reports p-values from log-rank tests comparing time until oil events between selected
`cohorts within selected strata. The log-rank test comparing 3 cohorts of participants (staked-
`on only, luer cone only, and exposure to both staked-on and luer cone syringe designs) was
`significant at p<0.0001, as were log-rank tests comparing “staked-on only” to either “luer cone
`only” or “both staked-on and luer cone”. The log-rank test comparing “both staked-on and luer
`cone syringe” to “luer cone only”, however, was not significant (p=0.06). This pattern of
`significant and non-significant results held for log-rank tests within the following strata:
`participants in the SCORE-BRVO trial only, participants in the SCORE CRVO trial only, 1
`mg injections only, and 4 mg injections only.
`
`With respect to the “warned, staked-only” cohort (Table 1, rows 7–8), the log-rank test revealed
`no significant difference in waiting times between disease groups (p=0.70), or 1 mg versus 4
`mg treatment groups (p=0.07). Of the injections with the luer cone syringe design, the
`investigators chose the 27-gauge needle 54% of the time and the 30-gauge needle 46% of the
`time.
`
`Table 3 summarizes the timing of oil events in the 114 participants who experienced all their
`injections after the warning date, but before the switch date, when the staked-on syringe was
`still in use (Table 1: Rows 7 and 8). Of these 114 participants, 46 experienced a silicone oil
`event after their first injection, so that, for these participants, the estimated probability of
`experiencing a silicone oil event is 46/114=0.41 (95% crediblity interval: 0.37, 0.50). An
`additional 30 of the 114 participants did not experience a silicone oil event, but had no further
`injections, so that only 38 participants were at risk for an oil event following a second injection.
`Of these, 16 experienced silicone oil events, leading to an estimated probability of 0.43 for the
`silicone oil event, given that the individual was still at risk (95% credibility interval: 0.37,
`0.58). Of the 7 participants who had a third injection and therefore were at risk of a silicone
`oil event, 3 experienced a silicone oil event, leading to an estimated probability of 0.44 for the
`silicone oil event (95% credibility interval: 0.33, 0.76). Overall, 65 of the 114 participants
`originally at risk experienced an oil event, while 49 did not, leading to an estimated probability
`of experiencing an oil event equal to 0.41 (95% credibility interval: 0.38, 0.49) per injection.
`
`In the cohort of participants receiving injection with only the luer cone syringes (Table 4), there
`were 58 participants at risk of a silicone oil event after the first injection, of which 15 did not
`have further injections. Forty-three participants had a second injection, and of these, another
`26 participants had a third injection, of which 9 had a fourth injection. None of these participants
`were reported to have a silicone oil event. The 95% credibility interval for the probability of
`experiencing an oil event in this group is (0.00, 0.03). That is, the upper 95% credibility limit
`in the luer cone cohort is approximately 1/10 of the lower 95% credibility limit for the
`probability of experiencing a silicone oil event in the cohort of participants who experienced
`all their injections after the warning date, but before the switch date.
`
`The foregoing analysis finds stark differences between two cohorts; although investigators had
`been instructed to look specifically for intravitreal silicone oil droplets in both cohorts, many
`oil events were observed in the staked-on syringe cohort, while the luer cone syringe cohort
`reported no events. However, the analysis omits consideration of time from event to reporting;
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`perhaps no events were observed in the luer cohort because, even though the events have
`occurred, we did not wait long enough for their reports to come in.
`
`Table 5 shows final at-risk injections and final post-injection follow-up visits for two cohorts:
`warned, staked-on, with oil events versus luer cone. Three important aspects of this table are:
`(1) the two cohorts have about the same number of participants (65 versus 58); (2) the luer cone
`participants had longer courses of injections that were at risk for an oil event: 43 (74%) of luer
`cone participants had 2 or more injections, while only 19 (29%) of warned, staked-on, with oil
`events did. Also, luer cone participants had ample numbers of injections (136 versus 87) at
`which to experience oil events, but did not experience them; (3) fifty-four (93%) of the post-
`injection follow-up times in the luer cone cohort were at least 3 visits long, while, only 17
`(26%) of the oil reports among the warned staked-on cohort participants who experienced oil
`events were made 3 or more visits after the offending injection. Also, luer cone participants
`had ample numbers of post-injection follow-up visits (254 versus 147) at which to report oil
`events. This suggests that the luer cone cohort had ample follow-up time in which to report oil
`events, had they occurred. Thus, as judged by the experience of the warned, stake-on
`participants with oil events, the luer cone cohort had ample numbers of participants, at-risk
`injections, and follow-up time, but still experienced no events.
`
`To investigate the possibility of inadequate follow-up time further, we performed the
`simulation analysis described in the Methods section. The simulated event count from this
`analysis was never zero in any of the 10,000 iterations of this simulation (in fact, it was never
`less than 11). The 10,000 simulated oil event counts can be thought of as a prediction of the
`number of oil events that would have been reported in the luer cone cohort if that cohort had
`the staked-on oil event and reporting rates. Because the actual reported number of oil events
`in the luer cone cohort (zero) is much less than the predicted number, we can reject the
`hypothesis that the two cohorts have the same event and reporting rates. If we further accept
`that the waiting time from an event to its report (given that the event actually occurred) should
`be the same in the two cohorts, the conclusion is that the oil event rate is lower in the luer cone
`cohort. This analysis decisively rejects the null hypothesis of the simulation, providing
`additional evidence that the incidence of silicone oil in the luer cone cohort is actually lower
`than the staked-on cohort; this is not simply the result of insufficient follow-up.
`
`The complete absence of oil events in the luer cone only cohort is probably not due to
`differences in site or investigator composition in that cohort; 49 of the 58 patients in the luer
`cone only cohort came from sites that had reported oil events in the “warned, staked-on” cohort.
`Also, 75 of the 136 injections were performed by investigators who had previously injected
`patients who later experienced oil events in the “warned, staked-on” cohort. Finally, 105 of
`the 254 post-injection follow-up examinations were performed by examiners who had earlier
`reported oil events in the “warned, staked-on” cohort.
`
`The disease composition of the "warned, staked-on" and "luer cone" cohorts did not differ
`significantly (p = 0.27, chi-squared test) with 69 (61%) of 114 "warned, staked-on" participants
`and 30 (52%) of 58 luer cone participants having BRVO.
`
`Discussion
`Use of the luer cone syringe design was associated with a decreased frequency of intravitreal
`silicone oil droplets compared to the staked-on syringe design in the SCORE Study. No
`occurrence of intravitreal silicone oil droplet formation was reported in any of the participants
`exposed only to luer cone syringes. We hypothesize that this is because, with the luer cone
`syringe design, silicone oil “squeegeed” from the inside of the syringe barrel and outside of
`the plunger is trapped in the 50 ul of residual space in the needle hub and, therefore not injected
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`into the eye. In contrast, the staked-on syringe design has no such residual space, so
`“squeegeed” silicone oil is injected into the eye if the plunger is pushed all the way down the
`barrel of the syringe.
`
`A silicone oil event could be an injection that either (a) suddenly deposits a clinically evident
`amount of silicone oil where none had been before, or (b) deposits a silicone oil increment that,
`when added to increments from previous injections, finally crosses a threshold of clinical
`observation. This “increment” hypothesis suggests a risk of silicone oil that increases with
`injection number, but the relatively constant probability of intravitreal silicone oil events
`whether the injection is the first, second, or third among at risk participants (Table 3) provides
`evidence against the “increment” hypothesis.
`
`One potential source of bias in our analysis results from imputing the date of the event (i.e.
`appearance of intravitreal silicone oil) to be the date of the last injection at or before the event
`report. Even assuming that the event must happen on injection-days, this imputation may over-
`estimate the waiting time until oil events, because the event could have happened at earlier
`injections, unnoticed by the SCORE Study investigator. Thus, the rate estimates in the current
`report may be biased downward, especially for injections before the September 22, 2006
`warning date.
`
`A possible criticism of the findings in this paper is that participants who were injected with the
`luer cone syringe, which was instituted in the study more recently than the staked-on syringe,
`may have actually had many silicone oil events, but there has been insufficient follow-up to
`detect the events. The extreme form of this argument holds that silicone oil events actually
`happen with the first injection, and that all the rest of the waiting time is due to reporting delay.
`Less extreme forms of this argument allow for the hypothesis that, eventually, silicone oil
`events will be reported with the luer cone syringe design. However, Table 5 shows that, relative
`to the “staked-on, warned” cohort, the luer cone cohort had ample numbers of participants, at-
`risk injections, and follow-up time, but still experienced no events. The simulation, in which
`none of the 10,000 iterations realized a reported event count of 0, provides additional evidence
`that the luer cone syringe design reduces the incidence of silicone oil events compared with
`the staked-on syringe design.
`
`It has been reported previously that silicone oil, when left in the eye for >12–18 months, may
`be engulfed by the trabecular meshwork and Müller cells of the retina5, but we were unable to
`determine whether any silicone oil events were reversible in the SCORE Study.
`
`In conclusion, data from the SCORE Study demonstrate that intraocular silicone oil may be
`associated with intravitreal injection. The frequency of such events is dependent on the type
`of syringe used. In the SCORE Study, the frequency of intravitreal silicone oil droplet
`formation is significantly lower with syringes with a luer cone syringe design than syringes
`with a staked-on syringe design. Thus, one method of reducing the incidence of intravitreal
`silicone oil following intravitreal injection is to employ a luer cone rather than a staked-on
`syringe design.
`
`Acknowledgments
`The Standard Care vs. COrticosteroid for REtinal Vein Occlusion (SCORE) Study was supported by the National Eye
`Institute (National Institutes of Health, Department of Health and Human Services) grants 5U10EY014351,
`5U10EY014352, and 5U10EY014404. Support was also provided in part by Allergan, Inc. through donation of
`investigational drug and partial funding of site monitoring visits and secondary data analyses. Dr. Michael Ip has
`served as a consultant for QLT, Sirion and Heidelberg Engineering and Dr. Ingrid U. Scott has served as a consultant
`to Eyetech, Genentech, and Sirion. Institutional Review Board approval of the study protocol was obtained at each
`participating clinical center and all study sites are compliant with the Health Insurance Portability and Accountability
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`Act of 1996. All participants provided written, informed consent prior to participation in the study. This study is
`registered at ClinicalTrials.gov, http://www.clinicaltrials.gov (ID #NCT00105027).
`
`REFERENCES
`1. Freund KB, Laud K, Eandi CM, Spaide RF. Silicone oil droplets following intravitreal injection. Retina
`2006;26:701–703. [PubMed: 16829818]Medline. doi:10.1097/00006982-200607000-00021
`2. Bakri SJ, Ekdawi NS. Intravitreal silicone oil droplets after intravitreal drug injections. Retina
`2008;28:996–1001. [PubMed: 18698303]Medline. doi:10.1097/IAE.0b013e31816c6868
`3. Ip MS, Oden NL, Scott IU, et al. SCORE Study Investigator Group. SCORE Study Report 3: Study
`design and baseline characteristics. Ophthalmology. (Forthcoming)
`4. Manual of Policies and Procedures (MOPP) for the Standard Care vs. COrticosteroid for REtinal Vein
`Occlusion (SCORE) Study. Version 4.0. Bethesda, MD: National Eye Institute; NTIS order number
`PB2008-106870.
`5. Protocol for the Standard Care vs. COrticosteroid for REtinal Vein Occlusion (SCORE) Study. Version
`7.0. Bethesda, MD: National Eye Institute; NTIS order number PB2008-113743
`6. Suzuki M, Okada T, Takeuchi S, et al. Effect of silicone oil on ocular tissues. Jpn J Ophthalmol
`1991;35:282–291. [PubMed: 1770668]Medline
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`Am J Ophthalmol. Author manuscript; available in PMC 2010 November 1.
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`NIH-PA Author Manuscript
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`NIH-PA Author Manuscript
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`NIH-PA Author Manuscript
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`Novartis Exhibit 2019.008
`Regeneron v. Novartis, IPR2020-01317
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`Scott et al.
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`Biography
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`Ingrid U. Scott, MD, MPH, is Professor of Ophthalmology and Public Health Sciences at Penn
`State Hershey Eye Center, Penn State College of Medicine. She serves as the Co-Chair of the
`Standard Care versus COrticosteroid for REtinal Vein Occlusion (SCORE) Study sponsored
`by the National Eye Institute.
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`Am J Ophthalmol. Author manuscript; available in PMC 2010 November 1.
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`NIH-PA Author Manuscript
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`NIH-PA Author Manuscript
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`NIH-PA Author Manuscript
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`Novartis Exhibit 2019.009
`Regeneron v. Novartis, IPR2020-01317
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`Scott et al.
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`Am J Ophthalmol. Author manuscript; available in PMC 2010 November 1.
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`NIH-PA Author Manuscript
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`NIH-PA Author Manuscript
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`NIH-PA Author Manuscript
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`Novartis Exhibit 2019.010
`Regeneron v. Novar