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`Cochrane Database of Systematic Reviews
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`Treatment regimens for administration of anti-vascular endothelial
`growth factor agents for neovascular age-related macular
`degeneration (Review)
`
`Li E, Donati S, Lindsley KB, Krzystolik MG, Virgili G
`
`LiE, DonatiS, LindsleyKB, KrzystolikMG, VirgiliG.
`Treatment regimens for administration of anti-vascular endothelial growth factor agents for neovascular age-related macular
`degeneration.
`Cochrane Database of Systematic Reviews 2020, Issue 5. Art. No.: CD012208.
`DOI: 10.1002/14651858.CD012208.pub2.
`
`www.cochranelibrary.com
`
`Treatment regimens for administration of anti-vascular endothelial growth factor agents for neovascular age-
`related macular degeneration (Review)
`Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
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`T A B L E O F C O N T E N T S
`HEADER.........................................................................................................................................................................................................
`ABSTRACT.....................................................................................................................................................................................................
`PLAIN LANGUAGE SUMMARY.......................................................................................................................................................................
`SUMMARY OF FINDINGS..............................................................................................................................................................................
`BACKGROUND..............................................................................................................................................................................................
`OBJECTIVES..................................................................................................................................................................................................
`METHODS.....................................................................................................................................................................................................
`RESULTS........................................................................................................................................................................................................
`Figure 1..................................................................................................................................................................................................
`Figure 2..................................................................................................................................................................................................
`Figure 3..................................................................................................................................................................................................
`Figure 4..................................................................................................................................................................................................
`Figure 5..................................................................................................................................................................................................
`DISCUSSION..................................................................................................................................................................................................
`AUTHORS' CONCLUSIONS...........................................................................................................................................................................
`ACKNOWLEDGEMENTS................................................................................................................................................................................
`REFERENCES................................................................................................................................................................................................
`CHARACTERISTICS OF STUDIES..................................................................................................................................................................
`DATA AND ANALYSES....................................................................................................................................................................................
`Analysis 1.1. Comparison 1: As needed (PRN) versus monthly injections, Outcome 1: Mean change in best-corrected visual acuity
`at 1 year.................................................................................................................................................................................................
`Analysis 1.2. Comparison 1: As needed (PRN) versus monthly injections, Outcome 2: Gain ≥ 15 letters visual acuity at 1 year......
`Analysis 1.3. Comparison 1: As needed (PRN) versus monthly injections, Outcome 3: Mean change in best-corrected visual acuity
`at 2 years...............................................................................................................................................................................................
`Analysis 1.4. Comparison 1: As needed (PRN) versus monthly injections, Outcome 4: Gain ≥ 15 letters visual acuity at 2 years......
`Analysis 1.5. Comparison 1: As needed (PRN) versus monthly injections, Outcome 5: Mean change central retinal thickness at
`1 year.....................................................................................................................................................................................................
`Analysis 1.6. Comparison 1: As needed (PRN) versus monthly injections, Outcome 6: Mean change central retinal thickness at
`2 years....................................................................................................................................................................................................
`Analysis 1.7. Comparison 1: As needed (PRN) versus monthly injections, Outcome 7: Mean number of injections during 2 years...
`Analysis 1.8. Comparison 1: As needed (PRN) versus monthly injections, Outcome 8: Endophthalmitis.......................................
`Analysis 1.9. Comparison 1: As needed (PRN) versus monthly injections, Outcome 9: Serious systemic adverse events..............
`Analysis 1.10. Comparison 1: As needed (PRN) versus monthly injections, Outcome 10: Death.....................................................
`Analysis 1.11. Comparison 1: As needed (PRN) versus monthly injections, Outcome 11: Arterial thromboembolic events...........
`Analysis 1.12. Comparison 1: As needed (PRN) versus monthly injections, Outcome 12: Mean number of injections during 1
`year.........................................................................................................................................................................................................
`Analysis 1.13. Comparison 1: As needed (PRN) versus monthly injections, Outcome 13: Sensitivity analysis excluding high-risk
`of bias: mean change in best-corrected visual acuity at 1 year.........................................................................................................
`Analysis 1.14. Comparison 1: As needed (PRN) versus monthly injections, Outcome 14: Sensitivity analysis using fixed eHects:
`mean change in best-corrected visual acuity at 1 year......................................................................................................................
`Analysis 2.1. Comparison 2: Extended-fixed versus monthly injections, Outcome 1: Mean change in best-corrected visual acuity
`at 1 year.................................................................................................................................................................................................
`Analysis 2.2. Comparison 2: Extended-fixed versus monthly injections, Outcome 2: Gain ≥ 15 letters visual acuity at 1 year........
`Analysis 2.3. Comparison 2: Extended-fixed versus monthly injections, Outcome 3: Mean change of central retinal thickness at
`1 year.....................................................................................................................................................................................................
`Analysis 2.4. Comparison 2: Extended-fixed versus monthly injections, Outcome 4: Mean change in quality of life scores at 1
`year.........................................................................................................................................................................................................
`Analysis 2.5. Comparison 2: Extended-fixed versus monthly injections, Outcome 5: Endophthalmitis..........................................
`Analysis 2.6. Comparison 2: Extended-fixed versus monthly injections, Outcome 6: Serious systemic adverse events.................
`Analysis 2.7. Comparison 2: Extended-fixed versus monthly injections, Outcome 7: Sensitivity analysis excluding high risk of
`bias: mean change in best-corrected visual acuity at 1 year.............................................................................................................
`Analysis 2.8. Comparison 2: Extended-fixed versus monthly injections, Outcome 8: Sensitivity analysis using fixed eHects: mean
`change in best-corrected visual acuity at 1 year................................................................................................................................
`
`Treatment regimens for administration of anti-vascular endothelial growth factor agents for neovascular age-related macular
`degeneration (Review)
`Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
`1
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`4
`8
`9
`9
`12
`13
`15
`16
`18
`20
`21
`23
`23
`24
`31
`70
`73
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`73
`74
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`74
`75
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`75
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`76
`76
`77
`77
`77
`78
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`Analysis 3.1. Comparison 3: As needed (PRN) or extended-fixed versus other extended-fixed injections, Outcome 1: Mean change
`in best-corrected visual acuity.............................................................................................................................................................
`Analysis 3.2. Comparison 3: As needed (PRN) or extended-fixed versus other extended-fixed injections, Outcome 2: Gain ≥ 15
`letters visual acuity...............................................................................................................................................................................
`Analysis 3.3. Comparison 3: As needed (PRN) or extended-fixed versus other extended-fixed injections, Outcome 3: Mean change
`in central retinal thickness...................................................................................................................................................................
`Analysis 4.1. Comparison 4: No loading versus loading injections, Outcome 1: Mean change in best-corrected visual acuity at
`1 year.....................................................................................................................................................................................................
`Analysis 4.2. Comparison 4: No loading versus loading injections, Outcome 2: Gain ≥ 15 letters visual acuity at 1 year................
`Analysis 4.3. Comparison 4: No loading versus loading injections, Outcome 3: Mean change in central retinal thickness............
`ADDITIONAL TABLES....................................................................................................................................................................................
`APPENDICES.................................................................................................................................................................................................
`HISTORY........................................................................................................................................................................................................
`CONTRIBUTIONS OF AUTHORS...................................................................................................................................................................
`DECLARATIONS OF INTEREST.....................................................................................................................................................................
`SOURCES OF SUPPORT...............................................................................................................................................................................
`DIFFERENCES BETWEEN PROTOCOL AND REVIEW....................................................................................................................................
`
`83
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`83
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`84
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`84
`
`84
`85
`85
`88
`90
`90
`90
`90
`90
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`Treatment regimens for administration of anti-vascular endothelial growth factor agents for neovascular age-related macular
`degeneration (Review)
`Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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`[Intervention Review]
`Treatment regimens for administration of anti-vascular endothelial
`growth factor agents for neovascular age-related macular degeneration
`
`Emily Li1, Simone Donati2, Kristina B Lindsley3, Magdalena G Krzystolik4, Gianni Virgili5
`
`1Transitional Year Residency Program, Signature Healthcare Brockton Hospital, Brockton, MA, USA. 2Department of Surgical and
`Morphological Sciences, Section of Ophthalmology, University of Insubria, Varese-Como, Varese, Italy. 3Life Sciences, Oncology, &
`Genomics, IBM Watson Health, Baltimore, Maryland, USA. 4Department of Ophthalmology, Retina Service, Mass Eye and Ear Infirmary,
`Providence, RI, USA. 5Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence,
`Florence, Italy
`
`Contact address: Gianni Virgili, gianni.virgili@unifi.it.
`
`Editorial group: Cochrane Eyes and Vision Group.
`Publication status and date: New, published in Issue 5, 2020.
`
`Citation: LiE, DonatiS, LindsleyKB, KrzystolikMG, VirgiliG. Treatment regimens for administration of anti-vascular endothelial growth
`factor agents for neovascular age-related macular degeneration. Cochrane Database of Systematic Reviews 2020, Issue 5. Art. No.:
`CD012208. DOI: 10.1002/14651858.CD012208.pub2.
`
`Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
`A B S T R A C T
`
`Background
`Age-related macular degeneration (AMD) is one of the leading causes of permanent blindness worldwide. The current mainstay of
`treatment for neovascular AMD (nAMD) is intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents: aflibercept,
`ranibizumab, and oH-label bevacizumab. Injections can be given monthly, every two or three months ('extended-fixed'), or as needed (pro
`re nata (PRN)). A variant of PRN is 'treat-and-extend' whereby injections are resumed if recurrence is detected and then delivered with
`increasing intervals. Currently, injection frequency varies among practitioners, which underscores the need to characterize an optimized
`approach to nAMD management.
`
`Objectives
`To investigate the eHects of monthly versus non-monthly intravitreous injection of an anti-VEGF agent in people with newly diagnosed
`nAMD.
`
`Search methods
`We searched CENTRAL, MEDLINE, Embase, LILACS, and three trials registers from 2004 to October 2019; checked references; handsearched
`conference abstracts; and contacted pharmaceutical companies to identify additional studies.
`
`Selection criteria
`We included randomized controlled trials (RCTs) that compared diHerent treatment regimens for anti-VEGF agents in people with newly
`diagnosed nAMD. We considered standard doses only (ranibizumab 0.5 mg, bevacizumab 1.25 mg, aflibercept 2.0 mg, or a combination
`of these).
`
`Data collection and analysis
`We used standard Cochrane methods for trial selection, data extraction, and analysis.
`
`Treatment regimens for administration of anti-vascular endothelial growth factor agents for neovascular age-related macular
`degeneration (Review)
`Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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`Main results
`We included 15 RCTs. The total number of participants was 7732, ranging from 37 to 2457 in each trial. The trials were conducted worldwide.
`Of these, six trials exclusively took place in the US, and three included centers from more than one country. Eight trials were at high risk of
`bias for at least one domain and all trials had at least one domain at unclear risk of bias.
`
`Seven trials (3525 participants) compared a PRN regimen with a monthly injection regimen, of which five trials delivered four to eight
`injections using standard PRN and three delivered nine or 10 injections using a treat-and-extend regimen in the first year. The overall
`mean change in best-corrected visual acuity (BCVA) at one year was +8.8 letters in the monthly injection group. Compared to the monthly
`injection, there was moderate-certainty evidence that the mean diHerence (MD) in BCVA change at one year for the standard PRN subgroup
`was –1.7 letters (95% confidence interval (CI) –2.8 to –0.6; 4 trials, 2299 participants), favoring monthly injections. There was low-certainty
`evidence of a similar BCVA change with the treat-and-extend subgroup (0.5 letters, 95% CI –3.1 to 4.2; 3 trials, 1226 participants).
`
`Compared to monthly injection, there was low-certainty evidence that fewer participants gained 15 or more lines of vision with standard
`PRN treatment at one year (risk ratio (RR) 0.87, 95% CI 0.76 to 0.99; 4 trials, 2299 participants) and low-certainty evidence of a similar gain
`with treat-and-extend versus monthly regimens (RR 1.11, 95% CI 0.91 to 1.36; 3 trials, 1169 participants).
`
`The mean change in central retinal thickness was a decrease of –166 m in the monthly injection group; the MD compared with standard
`PRN was 21 m (95% CI 6 to 32; 4 trials, 2215 participants; moderate-certainty evidence) and with treat-and extend was 22 m (95% CI 37 to
`–81 m; 2 trials, 635 participants; low-certainty evidence), in favor of monthly injection. Only one trial (498 participants) measured quality
`of life and reported no evidence of a diHerence between regimens, but data could not be extracted (low-certainty evidence).
`
`Both PRN regimens (standard and 'treat-and-extend') used fewer injections than monthly regimens (standard PRN: MD –4.6 injections, 95%
`CI –5.4 to –3.8; 4 trials, 2336 participants; treat-and-extend: –2.4 injections, 95% CI –2.7 to –2.1 injections; moderate-certainty evidence
`for both comparisons). Two trials provided cost data (1105 participants, trials conducted in the US and the UK). They found that cost
`diHerences between regimens were reduced if bevacizumab rather than aflibercept or ranibizumab were used, since bevacizumab was
`less costly (low-certainty evidence).
`
`PRN regimens were associated with a reduced risk of endophthalmitis compared with monthly injections (Peto odds ratio (OR) 0.13, 95%
`CI 0.04 to 0.46; 6 RCTs, 3175 participants; moderate-certainty evidence). Using data from all trials included in this review, we estimated
`the risk of endophthalmitis with monthly injections to be 8 in every 1000 people per year. The corresponding risk for people receiving PRN
`regimens was 1 in every 1000 people per year (95% CI 0 to 4).
`
`Three trials (1439 participants) compared an extended-fixed regimen (number of injections reported in only one large trial: 7.5 in one
`year) with monthly injections. There was moderate-certainty evidence that BCVA at one year was similar for extended-fixed and monthly
`injections (MD in BCVA change compared to extended-fixed group: –1.3 letters, 95% CI –3.9 to 1.3; RR of gaining 15 letters or more: 0.94,
`95% CI 0.80 to 1.10). The change in central retinal thickness was a decrease of 137 m in the monthly group; the MD with the extended-fixed
`group was 8 m (95% CI –11 to 27; low-certainty evidence). The frequency of endophthalmitis was lower in the extended-fixed regimen
`compared to the monthly group, but this estimate was imprecise (RR 0.19, 95% CI 0.03 to 1.11; low-certainty evidence). If we assumed a
`risk of 8 cases of endophthalmitis in 1000 people receiving monthly injections over one year, then the corresponding risk with extended-
`fixed regimen was 2 in 1000 people (95% CI 0 to 9).
`
`Other evidence comparing diHerent extended-fixed or PRN regimens yielded inconclusive results.
`
`Authors' conclusions
`We found that, at one year, monthly regimens are probably more eHective than PRN regimens using seven or eight injections in the first year,
`but the diHerence is small and clinically insignificant. Endophthalmitis is probably more common with monthly injections and diHerences
`in costs between regimens are higher if aflibercept or ranibizumab are used compared to bevacizumab.
`
`This evidence only applies to settings in which regimens are implemented as described in the trials, whereas undertreatment is likely to
`be common in real-world settings. There are no data from RCTs on long-term eHects of diHerent treatment regimens.
`
`P L A I N L A N G U A G E S U M M A R Y
`
`Comparing di4erent injection frequencies for neovascular age-related macular degeneration
`
`What was the aim of this review?
`The aim of this Cochrane Review was to find out if anti-vascular endothelial grown factor (anti-VEGF) injections for neovascular age-related
`macular degeneration (nAMD) can be given less frequently than every month.
`
`Key messages
`This review found that people receiving monthly injections had slightly better vision (one or two letters more on a vision test chart, less
`than half-line of vision) at one year compared with people receiving injections 'as needed' (average: seven injections), but there was no
`
`Treatment regimens for administration of anti-vascular endothelial growth factor agents for neovascular age-related macular
`degeneration (Review)
`Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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`diHerence with a modified 'as needed' regimen called treat-and-extend (average: nine injections). People receiving monthly injections had
`more injections and this increased the risk of rare, but severe side eHects such as infections.
`
`What was studied in this review?
`Neovascular age-related macular degeneration occurs in older people and aHects the central part of vision. In nAMD, new blood vessels
`grow at the back of the eye.
`
`People with nAMD can benefit from injections of medicines into the eye. These ‘anti-VEGF’ medicines block the growth of new blood vessels.
`Currently, there is variation in how oRen these injections are given. A greater number of injections may result in better vision but also
`increase harm, such as endophthalmitis, a sight-threatening infection of the eye. More injections are also more costly for the health service.
`
`What were the main results of the review?
`Cochrane researchers identified 15 studies (7732 participants) comparing non-monthly and monthly injections. Six out of 15 studies were
`funded by drug manufacturers.
`
`The review found:
`
`People who had less frequent anti-VEGF injections may have had slightly worse vision at one year compared with people having monthly
`injections when injections (seven on average) are delivered 'as needed'. This was a diHerence of 1 or 2 more letters read on a vision test
`chart and an approximate 10% increased chance of gaining 15 or more letters of vision with monthly injections. There was no evidence of
`diHerence between monthly injections and treat-and-extend (nine injections on average).
`
`There was an increased chance of endophthalmitis with monthly injections. Endophthalmitis is rare, occurring in approximately 8 in 1000
`people having monthly injections for one year, and in approximately 1 per 1000 people (range 0 to 4) having less than monthly injections
`'as needed'.
`
`How up-to-date was this review?
`The search was updated on 18 October 2019.
`
`Treatment regimens for administration of anti-vascular endothelial growth factor agents for neovascular age-related macular
`degeneration (Review)
`Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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`S U M M A R Y O F F I N D I N G S
`
`S
`
`ummary of findings 1. As needed compared to monthly injections for administration of anti-vascular endothelial growth factor agents for
`neovascular age-related macular degeneration
`
`PRN compared to monthly injections for administration of anti-vascular endothelial growth factor agents for neovascular age-related macular degeneration
`
`Patient or population: people with neovascular age-related macular degeneration
`
`Setting: eye services delivering intravitreal injections of anti-vascular endothelial growth factor agents
`
`Intervention: PRN injections
`
`Comparison: monthly injections
`
`Outcomes
`
`Anticipated absolute effects* (95% CI)
`
`Risk with monthly injections
`
`Risk with PRN
`
`Relative ef-
`fect
`(95% CI)
`
`ࡄ of partici-
`pants
`(studies)
`
`Certainty of
`the evidence
`(GRADE)
`
`Comments
`
`Change in BCVA at 1 year
`(ETDRS letters score, the
`higher the score the better)
`
`The mean change in BCVA at 1
`year was +8.8 letters
`
`Gain of ≥ 15 letters visual
`acuity at 1 year
`
`294 per 1000
`
`Standard PRN
`
`MD 1.68 letters lower
`(–2.81 to –0.55)
`
`Treat-and-extend
`
`MD 0.51 higher (–3.14 to 4.16)
`
`—
`
`—
`
`Standard PRN
`
`256 per 1000
`(223 to 291)
`
`RR 0.87
`
`(0.76 to 0.99)
`
`2299
`(4 RCTs)
`
`1226
`
`(3 RCTs)
`
`2299
`(4 RCTs)
`
`Treat-and-extend
`
`RR 1.11
`
`1169
`
`⊕⊕⊕⊝
`Moderate a
`
`⊕⊕⊝⊝
`Low a,b
`
`⊕⊕⊝⊝
`Low a,c
`
`⊕⊕⊝⊝
`Low a,c
`
`Test for sub-
`group differ-
`ences
`
`P = 0.26
`
`Test for sub-
`group differ-
`ences
`
`P = 0.04
`
`Test for sub-
`group differ-
`ences
`
`P = 0.97
`
`Change in central retinal
`thickness at 1 year ( m, the
`thinner the better on average)
`
`The mean change in central
`retinal thickness at 1 year was –
`165.5 m
`
`326 per 1000
`(268 to 400)
`
`Standard PRN
`
`MD 20.8 m higher
`(5.8 to 35.9)
`
`Treat-and-extend
`
`MD 22.0 m higher
`
`(0.91 to 1.36)
`
`(3 RCTs)
`
`—
`
`—
`
`2215
`(4 RCTs)
`
`⊕⊕⊕⊝
`Moderate a
`
`635
`
`(2)
`
`⊕⊕⊝⊝
`Low a,c
`
`Treatment regimens for administration of anti-vascular endothelial growth factor agents for neovascular age-related macular
`degeneration (Review)
`Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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`
`Change in QoL scores at 1
`year (higher was better)
`
`Data could not be extracted. Author reported that measures of QoL
`(median EuroQoL EQ-5D) did not differ to a significant degree be-
`tween monthly and PRN at 1 year.
`
`(–37.2 to –81.1)
`
`Number of injections at 1
`year
`
`The mean number of injections
`at 1 year was 11.3
`
`Standard PRN
`
`MD 4.57 lower
`(–5.38 to –3.76 lower)
`
`Treat-and extend
`
`MD 2.42 lower
`
`(–2.71 to –2.14)
`
`Cost of treatment per per-
`son at 1 year
`
`We could not estimate the difference in mean cost of treatment per
`person at 1 year for different regimens. Differences between regi-
`mens were reduced if bevacizumab was used.
`
`—
`
`—
`
`—
`
`—
`
`Endophthalmitis (ocular ad-
`verse event)
`
`8 per 1000
`
`1 per 1000
`
`(0 to 4 per 1000)
`
`Peto OR 0.13
`
`3175
`
`(0.04 to 0.46)
`
`(6 RCTs)
`
`⊕⊕⊕⊝
`Moderate a
`
`*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and
`its 95% CI).
`
`BCVA: best-corrected visual acuity; CI: confidence interval; ETDRS: Early Treatment Diabetic Retinopathy Study; MD: mean difference; OR: odds ratio; PRN: as needed;
`QoL: quality of life; RCT: randomized controlled trial; RR: risk ratio.
`
`GRADE Working Group grades of evidence
`High-certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
`Moderate-certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is
`substantially different.
`Low-certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
`Very low-certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
`
`aDowngraded one level for potential risk of bias as more than half were 'unclear' or 'high.'
`bDowngraded one level for inconsistency due to heterogeneity in the treat-and-extend subgroup
`cDowngraded one level for imprecision as no quantitative data could be extracted: "no diHerence" reported but the precision of this statement was unclear.
`dDowngraded two levels for indirectness as drug cost data available from two studies (CATT 2011; IVAN 2012b), and a full economic evaluation available from one study (IVAN
`2012b): data available from two countries (US and UK), not including measures of variation in total cost per regimen, with unknown applicability to other settings.
`
`
`
`498
`(1 RCT)
`
`2336
`(4 RCTs)
`
`1232
`
`(3 RCTs)
`
`⊕⊕⊝⊝
`Low a,c
`
`—
`
`Test for sub-
`group differ-
`ences
`
`P < 0.01
`
`⊕⊕⊕⊝
`Moderate a
`
`⊕⊕⊕⊝
`Moderate a
`
`1105
`(2 RCTs)
`
`⊕⊕⊝⊝
`Low d
`
`—
`
`—
`
`Treatment regimens for administration of anti-vascular endothelial growth factor agents for neovascular age-related macular
`degeneration (Review)
`Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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`Summary of findings 2. Extended-fixed compared to monthly injections for administration of anti-vascular endothelial growth factor agents for
`neovascular age-related macular degeneration
`
`Extended-fixed compared to monthly injections for administration of anti-vascular endothelial growth factor agents for neovascular age-related macular degener-
`ation
`
`Patient or population: people with neovascular age-related macular degeneration
`
`Setting: eye services delivering intravitreal injections of anti-vascular endothelial growth factor agents
`
`Intervention: extended-fixed injections, such as injections every 2 or 3 months
`
`Comparison: monthly injections
`
`Outcomes
`
`Anticipated absolute effects* (95% CI)
`
`Risk with monthly injections
`
`Risk with extended-fixed
`
`Relative effect
`(95% CI)
`
`ࡄ of partici-
`pants
`(studies)
`
`Change in BCVA at 1
`year (ETDRS letters
`score, the higher the
`score the better)
`
`The mean change in BCVA at 1 year
`was 9 letters' improvement
`
`MD 1.32 letters lower
`(–3.93 to 1.29)
`
`—
`
`Gain of ≥ 15 letters vi-
`sual acuity at 1 year
`
`300 per 1000
`
`280 per 1000
`(240 to 330)
`
`RR 0.94
`(0.80 to 1.10)
`
`Cochrane
`Library
`
`Trusted evidence.
`Informed decisions.
`Better health.
`
`Cochrane Database of Systematic Reviews
`
`
`
`Certainty of
`the evidence
`(GRADE)
`
`⊕⊕⊕⊝
`Moderate a
`
`⊕⊕⊕⊝
`Moderate a
`
`⊕⊕⊝⊝
`Low a,b
`
`⊕⊕⊕⊝
`Moderate a
`
`Not applica-
`ble
`
`Not applica-
`ble
`
`Comments
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`1439
`(3 RCTs)
`
`1441
`(3 RCTs)
`
`1439
`(3 RCTs)
`
`1220
`(1 RCT)
`
`Change in central reti-
`nal thickness at 1 year
`( m, the thinner the bet-
`ter on average)
`
`Change in QoL score at
`1 year (measured with
`NEI VFQ-25 question-
`naire; the higher score
`the better)
`
`Number of injections at
`1 year
`
`Cost of treatment per
`person at 1 year
`
`The mean change central retinal
`thickness at 1 year was –137 m
`
`MD 8.16 higher
`(–11.07 to 27.40)
`
`The mean change in QoL score at 1
`year was an improvement of about 5
`
`MD 0.59 lower
`(–2.22 to 1.04)
`
`—
`
`—
`
`Only 1 trial (1220 participants) comparing an extended (bimonthly) with a monthly regimen: 7.5 injections
`with the extended-fixed regimen (scheduled for 8 injections), 12.3 in the mo