`
`January 2010 Volume 94Issue 1
`
`Hy
`
`LibraryDateReceived
`FSB 0) 1 2010
`Ophthalmology
`
`Shawnee Mission Medical Center Medical Library
`
`British Journal of
`
`
`
`bjo.bmj.com
`
`BMJ|Journals
`
`CELLTRION- EXHIBIT 1030
`0001
`
`0001
`
`CELLTRION - EXHIBIT 1030
`
`

`

`.,
`Contents
`Ophthalmology
`
`__
`
`
`
`Volume 9,1 Number 1 I BJO January 2010
`
`•
`
`41
`Macular morphology and visual acuity after
`
`
`
`
`
`
`
`macular hole surgery with or without internal
`Editorial
`
`
`
`story and the never-ending 1 Ocular anaesthesia
`limiting membrane peeling
`
`I' -11l1.111as10\' r I le11daso11
`l 1 C C/,ri,re11.e11
`K J;.,�wr B S,mder,
`
`T ,II Jor1,e11st11 I' Larsm \ 1 la Cow
`
`Subretinal coapplication of recombinant tissue
`
`
`
`48
`-Cover mage Urdine and drop bottles
`Review
`
`
`
`plasminogen activator and bevacizumab for
`
`Coutesv of Mr Rtdlard Keeler. Cura,or
`2 Ranibizumab (Lucentis) in neovascular
`
`
`
`
`
`neovascular age-related macular degeneration
`
`Museum of Cle Royal College d
`
`
`
`age-related macular degeneration-evidence
`
`with submacular haemorrhage
`Oplithalmo/og SIS. See p 2li
`
`from clinical trials
`
`I-Treumer, C Klatt J Roultr J l/il/e11kamf'
`fllillNHI-C1lle
`I' ,\/11d1c/l }-/-Korol·e/111l·. 1' Lao1:::e11,1 F G Hof:::,
`
`
`
`are circulation New patterns of retinal collateral
`
`
`
`
`Harmindei S D:ia (UKI
`
`
`)' T,1110 S \\ off
`
`C Pr1,111e l 1 S.:lm11,ft-Er/1111/:
`54
`
`
`
`
`exposed by a retinal functional imager (RFI)
`
`Arun D Singh (USA
`d
`G L111.lt1
`RB Rosen
`Welooite Editor
`
`Roben Bhsotkul (USA)
`Relationship between different fluorescein and
`
`
`
`Global issues
`9
`Translatiea Editors
`
`
`
`indocyanine green angiography features in
`14 Mapping trachoma in Nasarawa and Plateau
`
`
`
`
`Evelyn Fu USA)
`
`
`multiple evanescent white dot syndrome
`
`
`States. central Nigeria
`Jose Gorres 1Braz1
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`David Pelayes Argentina)
`A comparison between microperimetry and
`
`
`
`64
`
`
`Danie de Souza Pe•e,ra IBral
`I
`
`
`
`standard achromatic penmetry of the central
`20 Increased hyperopia with ageing based on
`
`
`
`
`
`visual field in eyes with glaucomatous
`
`
`
`
`cycloplegic refractions in adults: the Tehran Eye
`fdltallal Office
`BMJ Publosh,ng Group ltd.
`
`
`
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`paracentral visual-field defects
`Study
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`The sensitivity and specificity of Heidelberg
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`68
`E bjo@llmjgloup.cont
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`
`Retina Tomograph parameters to glaucomatous
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`progression in disc photographs
`Innovations
`
`ISSN 0007-1161 (pnnt
`A I r111lc11e11 I S,111re/a I' J 4irt1l:si11w I Ft1kk,
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`ISSN. 1468 2079 (onl ne)
`24 Computer simulation-assisted rotational
`
`
`
`
`autokeratoplasty with pupillary enlargement tor
`
`Impact 2 659
`Efficacy and tolerability of bimatoprost versus
`
`
`factor:
`
`
`management of cases with partial corneal
`74
`
`
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`travoprost in patients previously on latanoprost:
`opacification
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`a 3-month, randomised, masked-evaluator,
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`T \gMu·11/, ll J/1,11111, \ ',/111,111,1, RB \',111i111'rt
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`multicentre study
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`Cover illustration
`80 Using diurnal intraocular pressure fluctuation to
`
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`26 AO for a drop: Undines and drop bottles
`
`
`
`assess the efficacy of fixed-combination
`\ D <;111gh
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`latanoprost/timolol versus latanoprost or timolol
`monotherapy
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`G \\'' Be,w R \larma .. L-j l-lmwg, J Ir Gru11de11
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`
`
`MORE CONTENTS ►
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`28 A novel Ocular Anaesthetic Scoring System,
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`0002
`
`

`

`Contents
`
`
`
`Volume 94 Number 1 I BJO January 2010
`
`115 Peripapillary retinal nerve fibre layer thickness
`
`
`
`
`
`
`85 The effect of socio-economic deprivation on
`
`
`
`
`profile 1n subjects with myopia measured using
`
`
`severity of glaucoma at presentation
`
`
`
`the Stratus optical coherence tomography
`
`\\' <; \� Pr... •\.�,1rnal. '> ::-.uliL·, I \JcKm
`
`A \:11,lr I Bl.111«
`\/ j }:., 1111 t { l eo [ If /.-1111
`.I 1 0\1'/l�lld,
`
`88 Visual training of cerebral blindness patients
`
`
`
`
`
`121 Ophthalmological findings in children
`and young
`
`
`
`adults with genetically verified mitochondrial
`
`gradually enlarges the visual field
`G ,111 .!er \\ ,I.I,
`disease
`D I' Ba!?,>111<1
`
`11 A Crc11/1111d A I.:. 5'-)'t'tlt ffon,1•1·,1,
`
`
`9 7 Scope of super-resolution in central vision
`
`
`S ,\11di!rss.i11 ti R \ b/e1111. ,-\ 0/,lfo" F. lfo/,11,:
`/. Fri,e11
`,\/ J 11/111111s. \i Dwm
`
`101 Evaluation of the impact of intracorneal ring
`
`
`
`128 A prospective comparison of fine-needle
`
`
`
`
`
`segments implantation on the quality of life of
`
`
`
`aspiration cytopathology and histopathology m
`
`
`
`patients with keratoconus using the NEI-RQL
`
`
`the diagnosis of orbital mass lesions
`
`
`
`(National Eye Institute Refractive Error Quality
`Z I K,1m,yJ11 J C. fftmmf!_. 8 <., llt11I·
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`\l I' ·\wl.1
`J de freua, S.mws P,m111/1,,,
`Education
`11 Am111Jros
`Jr P �cl,or
`
`
`131 Papilloedema and vision loss with elevated
`
`
`
`
`cerebrospinal fluid protein in a patient with
`106 Evaluation of the Lenstar LS 900 non-contact
`
`
`
`
`systemic lupus erythematosus: diagnosis and
`biometer
`
`management challenges
`i\ I Door,, f \'trbat·el.
`L P j Crn\',IW.�
`/ f- O,sd,!er \, R \Iii/a I'S Si,/•r,i,1,111i,tt1
`
`T T J ,\/ &,w,l,dt,'I, .I De Br,1/•,111.fcr
`R ,\/ H A \'w11,
`
`Postscript
`
`
`111 Endophthalmitis following open globe injury
`133 Letters
`
`) ... l:,111'" I I \ :1,,111,..., C H ),,mi,:. ) ) '"·
`K :::.1:,m.c
`
`139 Mailbox
`
`0003
`
`

`

`Head-to-head ranibizumab and bevacizumabtrials
`
`
`
`
`
`
`
`"Department of Ophthalmology,
`University of Sydney, Sydney,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`are under waybut are not scheduledto report until
`Background: Neovascular age-related macular degen-
`Australia; ? Department of
`
`
`
`
`
`
`
`
`
`
`
`2010
`(CATT
`(NCT00593450),
`VIBERA
`eration (AMD) has a poor prognosisif left untreated,
`Ophthalmology, Centre
`
`
`
`
`
`
`
`
`
`
`
`(NCT00559715), IVAN and GEFALtrials).
`frequently resulting in legal blindness. Ranibizumab is
`Hospitalier Universitaire de
`
`
`
`
`
`
`
`
`Bordeaux, Bordeaux, France;
`
`
`
`
`
`Although preliminary guidelines for anti-VEGF
`approvedfor treating neovascular AMD. However,further
`
`
`
`
`
`
`
`
`
`
`3 Department of Ophthalmology,
`
`
`
`
`
`therapies exist,'°?? more comprehensive clinical
`guidance is needed to assist ophthalmologists in clinical
`University of Udine, Udine,Italy;
`
`
`
`
`
`
`
`
`
`
`
`
`practice guidelines on applying ranibizumab are
`practice to optimise treatment outcomes.
`
`
`
`“Department of Ophthalmology,
`
`
`
`
`
`
`
`
`
`
`optimise
`patient
`outcomes.
`to
`needed
`Methods:An international retina expert pane! assessed
`University of Bonn, Bonn,
`
`
`
`Ranibizumab PhaseIII clinical trials in neovascular
`
`
`
`
`
`
`
`
`
`
`
`
`
`evidence available from prospective, multicentre studies
`Germany; ° Departmentof
`
`
`Ophthalmology and Optometry,
`
`
`
`
`
`
`
`
`
`
`
`AMDhavestudied different treatment schedules,
`
`
`evaluating different ranibizumab treatment schedules
`Medical University of Vienna,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`doses and populations, and this review applies the
`(ANCHOR, MARINA, PIER, SAILOR, SUSTAIN and EXCITE)
`
`
`
`
`Vienna, Austria; ® Department of
`trial evidence to ranibizumab use
`in clinical
`
`
`
`
`
`
`
`
`
`
`andaliterature search to generate evidence-based and
`Ophthalmology, Osaka University
`
`
`
`consensus recommendationsfor treatment indication and
`
`
`
`
`
`
`
`
`
`practice. We evaluated the licensed 0.5 mg of
`Medical School, Osaka, Japan;
`
`
`
`
`
`
`
`
`
`
`
`
`ranibizumab dose, shown to be more effective
`
`
`” Department of Ophthalmology,
`assessment, retreatment and monitoring.
`Inselspital, University of Bern,
`Results: Ranibizumab is indicated for choroidal neovas-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`than 0.3 mg in pivotal
`trials," *** and focused
`Bern, Switzerland
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`solely on ranibizumab because: pegaptanib showed
`cular lesions with active disease, the clinical parameters
`of whichare outlined. Treatmentinitiation with three
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`less visual-acuity (VA) decline than sham injection,
`
`
`
`
`
`
`
`
`
`
`
`
`although on average treated patients continued to
`consecutive monthly injections, followed by continued
`
`
`
`
`
`
`
`
`
`
`
`
`experience vision loss;'' bevacizumab use in neo-
`monthly injections, has provided the best visual-acuity
`
`
`
`
`
`
`vascular AMD currently remains off-label with
`
`
`
`
`
`
`outcomesin pivotalclinical trials.
`If continued monthly
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`relatively few reported clinical trial data and,
`to
`injections are not feasible afterinitiation, a flexible
`
`
`
`
`
`
`
`
`
`
`
`
`
`date, no completed large, prospective, randomised
`strategy appears viable, with monthly monitoring of lesion
`clinical trials."
`
`
`
`
`
`
`
`activity recommended.Initiation regimens of fewer than
`
`
`
`
`
`
`
`three injections have not been assessed. Continuous
`
`
`
`
`
`
`
`careful monitoring with flexible retreatment may help
`
`
`
`
`
`
`avoid vision loss recurring. Standardised biomarkers need
`to be determined.
`
`
`
`
`
`
`Conclusion: Evidence-based guidelines will help to
`
`
`
`
`
`optimise treatment outcomes with ranibizumabin
`neovascular AMD.
`
`
`
`
`
`
`
`
`Correspondenceto:
`
`Professor P Mitchell, Eye Clinic
`
`
`
`(B4A), Westmead Hospital,
`
`
`
`Hawkesbury Road, Westmead,
`
`
`NSW, 2145, Australia;
`
`
`paul_mitchell@wmi.usyd.edu
`au
`
`
`
`Accepted 29 April 2009
`
`
`Published Online First
`
`
`
`20 May 2009
`
`
`
`
`
`
`
`
`
`Ranibizumab (Lucentis) in neovascular age-related
`
`
`
`
`
`macular degeneration: evidence from clinicaltrials
`
`
`
`
`
`
`
`P Mitchell,' J-F Korobelnik,? P Lanzetta,? F G Holz,* C Priinte,> U Schmidt-Erfurth,°
`
`
`Y Tano,® S$ Wolf’
`
`
`
`
`
`ABSTRACT
`
`
`
`
`
`
`
`
`
`
`
`
`
`Neovascular
`age-related macular degeneration
`
`
`
`
`
`
`
`(AMD) causes severe and irreversible vision loss,
`
`
`
`
`
`
`and frequently results in legal blindness, with
`
`
`
`resulting considerable economic burden.'*
`
`
`
`
`Pharmacotherapies against vascular endothelial
`
`
`
`
`
`
`growth factor-A (VEGF-A), a key factor in the
`
`
`
`pathogenesis
`of
`choroidal
`neovascularisation
`
`
`
`
`
`
`
`(CNV), have been introduced to treat neovascular
`
`
`
`
`
`AMD.°"° Pegaptanib sodium (Macugen, EyeTech,
`
`
`
`
`New York), a selective antagonist of
`the 165
`
`
`
`
`
`
`
`isoform of VEGF-A,"' was approved by the Food
`
`
`
`
`
`
`
`and Drug Administration (FDA) in December 2004.
`
`
`
`
`Ranibizumab (Lucentis, Novartis Pharma AG,
`
`
`
`
`Basel, Switzerland and Genentech, South San
`
`
`
`
`Francisco, California), a recombinant, humanised,
`
`
`
`
`
`
`
`monoclonal antibody Fab fragment that inhibits all
`
`
`
`
`
`
`biologically active VEGF-A isoforms, was approved
`
`
`
`
`
`
`by the FDA in June 2006 (monthly 0.5 mg
`
`
`
`
`intravitreal
`injection).'*'* Bevacizumab (Avastin,
`
`
`
`
`Genentech), a full-length monoclonal antibody
`
`
`
`
`
`against all VEGF-A isoforms, was approved by
`the FDAfor colorectal cancer in 2004 and later used
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`intravitreally off-label
`in neovascular AMD." '*
`
`
`
`
`
`RANKING AND SOURCES OF EVIDENCE
`
`
`
`
`
`
`Level I indicates strong evidence(eg, well-designed,
`
`
`
`
`
`
`randomised, controlled clinical trials that address
`
`
`
`
`
`
`
`the issue in question); level II indicates substantial
`
`
`
`
`
`
`
`
`evidencethat lacks somequalities (eg, derived from
`
`
`
`
`
`
`
`randomisedclinical trials but with flaws, such as
`
`
`
`
`
`absent control group orsufficiently long follow-
`
`
`
`
`
`
`
`
`up); level III indicates relatively weak evidence(eg,
`
`
`
`
`
`derived from non-comparative studies without
`
`
`
`
`
`controls, descriptive studies, panel consensus or
`
`expert opinion).
`A PubMedliterature search on 31 October 2008
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(restricted to English literature; no date restriction)
`
`
`
`
`
`using the MeSH term macular degeneration
`
`
`
`
`
`
`
`(multi) and the words vascular endothelial growth
`
`
`
`
`
`
`
`factor, ranibizumab or Lucentis yielded 187 papers.
`
`
`
`
`
`
`
`
`The CochraneRegister of Controlled Trials and the
`
`
`
`
`
`Cochrane Database of Systematic Reviews were
`
`
`
`
`
`
`also searched, yielding 16 and four
`references,
`
`
`
`
`
`
`respectively. A total of 129 relevant articles were
`
`
`
`
`
`
`
`
`selected, from which 74 were selected for detailed
`assessment. Additional data from abstracts con-
`
`
`
`
`
`
`
`
`
`
`
`sidered relevant to this manuscript were included
`
`
`
`
`
`
`
`
`in the analysis. From this detailed literature search,
`
`
`
`
`
`
`the primary sources of data were all
`level
`I
`evidence:
`the Phase
`III
`trials MARINA’ and
`
`
`
`
`
`
`
`
`ANCHOR,” * including quality-of-life and sub-
`
`
`
`
`
`
`
`
`group analyses,*** and the PhaseIIIb trials PIER,”
`
`
`
`
`
`
`SAILOR Cohort 1,”” SUSTAIN (assigned level
`II
`
`
`
`
`
`
`
`evidence as only interim data currently available),
`
`
`
`and EXCITE.
`small,
`open-label
`A_
`study
`
`Br J Ophthalmol 2010;94:2—13. doi:10.1136/bjo.2009.159160
`
`
`
`
`
`0004
`
`0004
`
`

`

`
`
`
`Table 1 Recommendations for treatment indication with ranibizumab
`
`
`
`
`
`Parameters for recommended indication
`
`Evidence Level of evidence
`
`
`
`
`Predominantly classic, minimally classic and occult (with no All CNV types included in PIER, EXCITE, SUSTAIN, SAILOR Level | evidence (MARINA, ANCHOR,PIER, EXCITE
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`classic component) CNV*
`and PrONTO; predominantly classic CNV in ANCHOR and
`and SAILOR), supported by level Il (SUSTAIN) and Ill
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`minimally classic and occult (with no classic component)
`evidence (PrONTO)
`
`
`
`
`
`
`
`
`
`CNV in MARINA
`
`Subfoveal CNV (defined as including the foveal centre within Level | evidence (MARINA, ANCHOR,PIER, EXCITE
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the boundaries of the CNV) wasaninclusioncriteria in all
`and SAILOR), supported bylevel II (SUSTAIN) andIll
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`studies
`evidence (PrONTO)
`
`Active disease was aninclusioncriteria in the MARINA and Level | evidence (MARINA and PIER)andlevelII
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`PIER studiest
`evidence
`
`
`Subfoveal (including juxtafoveal) lesions
`
`
`
`
`Active disease
`
`
`Abnormalretinal thickness with evidenceof intraretinal or
`
`
`
`
`
`
`subretinal fluid by OCT
`
`
`
`Intraretinal or subretinal haemorrhage
`
`
`Enlargement of CNV size on FA unless solely due to dry,
`
`
`
`
`
`
`
`
`
`
`
`fibrotic staining
`
`New/persistent leakage on FA
`
`
`
`Any baseline VA
`
`
`
`Baseline VA 20/40 to 20/320 wasaninclusioncriterion in all Level | evidence (MARINA, ANCHOR,PIER and
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`SAILOR), supported by levelIl evidence (SUSTAIN)
`studiest
`
`
`
`
`
`
`_LevelIll evidence
`Baseline VA better than 20/40 or worse than 20/320: no
`
`
`
`
`
`
`
`
`
`clinical data available, expert opinion based on extrapolation
`
`
`
`
`
`
`
`
`of clinical evidence
`
`
`
`Efficacy was seen over the whole VA rangestudied in
`
`
`
`
`
`
`
`
`
`trials, so it is expected that benefit would occur
`
`
`
`
`
`
`independently of VA whenever progressive vision loss is
`
`
`
`
`
`
`expected due to an active lesion
`
`
`
`
`
`Serous PED, RAP or PCV can be considered for ranibizumab No detailed clinical trial evidence currently available
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`treatment but might not respond as well as expected from
`
`
`
`
`
`
`
`
`
`
`average trial outcomes
`
`
`“In the MARINA and PIER studies, evidence of recent disease progression was required for eyes with minimally classic or occult (with no classic) CNV.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`+Active disease was defined as meeting any of the following criteria: (1) =10% increasein lesion size by comparing a fluorescein angiogram performed within 1 month preceding
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`day 0, inclusive, compared with a fluorescein angiogram performed within 6 months preceding day 0, inclusive; (2) resulting in VA loss of >1 Snellen line (or equivalent) and
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`occurring at any time within the prior 6 months; (3) subretinal haemorrhage associated with CNV within 1 month preceding day 0; or (4) (not included in MARINAcriteria) classic
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`CNV comprised =50% of the CNV lesion area.
`
`
`
`
`
`
`
`{Snellen equivalent assessed by Early Treatment Diabetic Retinopathy Study charts; the PrONTO study included patients with baseline VA from 20/40 to 20/400.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`CNV, choroidal neovascularisation; FA, fluorescein angiography; OCT, optical coherence tomography; PCV, polypoidal choroidal vasculopathy;
`
`
`
`
`
`
`
`
`
`
`
`
`
`PED, pigment epithelial detachment; RAP, retinal angiomatousproliferation; VA, visual acuity.
`
`
`
`
`
`
`
`
`
`
`
`LevelIll evidence
`
`
`
`
`
`
`
`
`(PrONTO;level III evidence) also provided relevant informa-
`
`
`
`
`
`
`
`tion,” and appropriate abstracts covering recent PhaseIII trial
`
`
`
`findings (unpublished) were included.
`
`
`
`
`
`
`
`
`
`NATURAL HISTORY AND ASSESSMENT OF NEOVASCULAR AMD
`
`
`
`
`
`
`
`
`
`
`Whatis the naturalhistory or prognosis of untreated neovascular
`AMD?
`
`
`
`
`
`
`
`
`
`
`A systematic review covering the period 1980 to 2005 assessed
`
`
`
`
`
`
`
`studies reporting disease progression outcomes for untreated
`
`
`
`
`
`
`patients with neovascular age-related macular degeneration
`
`
`
`
`
`
`
`
`
`(AMD), by using random effects meta-analyses.‘ Of 53 studies
`
`
`
`
`
`
`
`included,
`there were 28 randomised clinical
`trials (RCTs),
`
`
`
`
`
`
`
`
`totalling 4362 patients with untreated neovascular AMD. The
`
`
`
`
`
`
`
`most recent RCTs of antivascular endothelial growth factor
`
`
`
`
`
`
`
`
`therapy (VISION,"’ MARINA” and PIER”) were not included.
`
`
`
`
`
`
`
`
`
`
`The systematic review found that, on average, one logarithm of
`
`
`
`
`
`
`
`
`
`
`the maximum angle of resolution (logMAR)line of visual acuity
`
`
`
`
`
`
`
`
`
`
`
`
`(VA) waslost by 3 months,three lines by 1 year and four lines
`
`
`
`
`
`
`
`by 2 years. This prognosis is
`relatively similar
`to that
`in
`
`
`
`
`
`
`
`
`
`MARINA,in which sham-treated eyes lost an average of two
`
`
`
`
`
`
`
`
`
`
`
`
`
`lines by 1 year and three lines by 2 years and in PIER, in which
`
`
`
`
`
`
`
`
`
`
`
`
`sham-treated eyes lost an average of three lines by 1 year. In this
`
`
`
`
`
`
`
`
`
`review, a doubling of the visual angle was foundin thefirst
`
`
`
`
`
`
`
`
`
`
`
`year. At baseline, 20% of eyes already had a VA <20/200, but
`
`
`
`
`
`
`this proportion rose to 76%by 3 years.*
`
`
`
`
`
`
`How should neovascular AMD be diagnosed?
`
`
`
`
`
`
`
`
`Accurate diagnosis and classification of neovascular AMDusing
`recommendedcriteria is critical. Assessment should include:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`history (duration and characteristics of visual symptoms); VA;
`
`
`
`
`
`
`
`stereoscopic biomicroscopicslit-lamp fundus examination (78 D
`
`Br J Ophthalmol 2010;94:2-13. doi:10.1136/bjo.2009.159160
`
`
`
`
`
`
`
`
`
`
`
`
`fluorescein angiography (FA); and, where
`lens);
`or similar
`
`
`
`
`possible, optical coherence tomography (OCT).
`
`
`
`
`
`
`
`
`
`Logarithm of the minimum angleof resolution (logMAR) VA
`
`
`
`
`
`
`
`
`
`
`
`is preferable to Snellen VA dueto its greater sensitivity, ordered
`
`
`
`
`
`
`
`
`
`
`progressionofletter size (five equally readable letters perline),
`
`
`
`
`
`
`
`reproducibility and ability to compare with published trial
`data.* The Snellen chart has several limitations such as visual
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`crowding and variable legibility of the letters. Non-geometric
`
`
`
`
`
`
`
`
`
`
`letter size progression and a variable numberofletters per line
`
`
`
`
`
`
`
`
`also prevent Snellen outcomes from being easily equated to
`
`
`
`
`
`
`letters or lines of VA change.* *
`
`
`
`
`
`
`
`
`
`Forinitial diagnosis, FA is deemed mandatory to detect CNV,
`
`
`
`
`exclude non-AMD causes
`(eg, neovascularisation due
`to
`
`
`
`
`
`myopia, pseudo-xanthomaelasticum, birdshot choroidopathy,
`
`
`
`
`
`
`etc, which could respond differently to AMD neovascularisa-
`
`
`
`
`
`
`
`
`
`
`tion) and determine CNVextent, type, size, location, degree of
`
`
`
`
`
`
`
`leakage and proportion of various lesion components.”* * OCT
`
`
`
`
`
`
`
`
`is also strongly recommendedinitially to define the extent of
`
`
`
`
`
`
`
`
`retinal
`thickening and both the localisation and qualitative
`
`
`
`
`
`pattern of extracellular
`fluid accumulation.” * Indocyanine
`
`
`
`
`
`
`
`
`
`
`Green (ICG) angiography mayalso be useful in selected cases,
`
`
`
`
`
`
`eg, when polypoidal choroidal vasculopathy (PCV)**” or
`
`
`
`
`
`
`
`retinal angiomatous proliferation (RAP)*'* is suspected, or the
`extent of CNV in occult lesions is unclear.
`
`
`
`
`
`
`
`
`
`
`
`RANIBIZUMAB THERAPY FOR NEOVASCULAR AMD:
`
`
`
`INDICATIONS AND CONTRAINDICATIONS
`
`
`
`
`
`
`
`
`Which neovascular AMD lesions should be considered for
`
`ranibizumab treatment?
`
`
`
`
`
`
`
`
`All three major CNV subtypes (predominantlyclassic, occult
`
`
`
`
`
`
`
`
`
`(with no classic component) and minimally classic) respond to
`
`
`
`
`ranibizumab” ** (table 1). Ranibizumab is primarily indicated
`
`0005
`
`0005
`
`

`

`
`
`
`
`
`
`
`whom treatmentis not generally recommended, were defined
`
`
`
`by the followingcriteria:
`
`
`
`
`
`
`
`> Structural foveal damage: advanced subretinal fibrosis or
`
`
`
`
`
`
`
`significant geographic atrophy involving the foveal centre
`
`
`
`
`
`(both particularly importantif longstanding, as any func-
`
`
`
`
`
`
`tional benefit from treatment would be unlikely).
`
`
`
`
`
`
`
`» Confounding severe ocular disease: vitreous or preretinal
`
`
`
`
`
`
`haemorrhage obscuring the central macula, or presence of
`
`
`
`
`
`rhegmatogenous retinal detachment
`(other
`forms of
`
`
`
`
`
`
`
`
`immediate therapy, eg, vitrectomy, maybeindicated before
`
`reconsidering ranibizumab).
`
`
`
`
`
`
`
`epithelial
`tears with subfoveal
`(RPE)
`Retinal pigment
`
`
`
`
`
`
`
`
`involvementhavebeen reported to occur occasionally following
`
`
`
`
`
`
`intravitreal ranibizumab,” *'** and maytherefore bea relative
`
`
`
`
`
`
`contraindication. However,
`to date, no data indicate that
`
`
`
`
`
`
`continuing ranibizumab in such cases would be deleterious
`
`
`(level III evidence).
`
`
`
`
`
`
`COMMENCING AND CONTINUING RANIBIZUMAB THERAPY
`
`
`FOR NEOVASCULAR AMD
`
`
`
`
`
`
`
`
`
`Whatare appropriate intervals for the initiation of ranibizumab
`treatment?
`Evidence
`
`
`
`
`
`
`Ranibizumabinitiation with three consecutive monthly injec-
`
`
`
`
`
`
`
`
`
`tions appears optimal as this is when the majority of patients
`
`
`
`
`
`
`
`
`
`
`
`experienced most VAgaininall studies (fig 1A-F, tables 2, 3).
`
`
`
`
`
`Improvements occurred rapidly, and the largest VA gain
`
`
`
`
`
`
`
`
`
`occurred after the first injection. Several studies indicate that
`
`
`
`
`
`
`
`
`
`untreated subfoveal CNV maygrow quickly, on average around
`
`
`
`
`
`
`
`
`
`
`
`
`10 um per day. Furthermore, after the first month in the PIER
`
`
`
`
`
`
`
`
`
`
`trial, VA deteriorated in the untreated control group by a mean
`
`
`
`
`
`
`
`
`
`
`
`offive letters (one line).” A recent study reported that delayed
`
`
`
`
`
`
`
`
`
`initiation of treatment in patients with newly diagnosed AMD
`wasassociated with substantial VA loss.”
`
`
`
`
`
`
`
`
`
`
`MARINA, ANCHOR” * and the EXCITE ranibizumab
`
`
`
`
`
`
`
`
`active control arm*! were the only Phase III studies with
`
`
`
`
`
`
`
`monthly injections throughout
`the whole treatment period.
`
`
`
`
`
`
`
`
`
`Most VA improvement was seen during the initial 3-month
`
`
`
`
`
`
`
`phase with subsequent
`injections appearing to maintain the
`
`
`
`
`
`
`achieved benefit
`(fig 2). Prospective clinical
`trials would be
`
`
`
`
`
`
`valuable for
`investigating fewer injections in the initiation
`phase.
`
`
`
`
`Clinical recommendation (level | evidence)
`
`
`
`
`
`
`
`
`least
`0.5 mg of ranibizumab should beinitiated with at
`>
`
`
`
`
`
`
`
`three consecutive monthly intravitreal injections, using an
`
`aseptic procedure.*®
`
`
`
`
`
`
`
`
`> Treatment should be commenced as soon as possible after
`
`
`
`
`
`diagnosis. As an indication of
`this time interval,
`the
`
`
`
`
`
`
`screening periods permitted before treatmentinitiation in
`
`
`
`
`
`
`
`
`the clinical studies were <14 or <28 days. Clearly,
`
`
`
`
`
`
`
`
`
`
`treatmentas early as possible, and at a maximum ofwithin
`
`
`
`
`
`
`
`2 weeks of diagnosis,
`ideal. Durations longer
`than
`is
`
`
`
`
`
`
`1 monthrisk increasing visual loss.** ©
`
`
`
`
`
`
`> Before administering ranibizumab at months 1 and 2,
`
`
`
`
`
`follow-up examination is recommended: history, VA assess-
`
`
`
`
`
`
`
`ment and slit-lamp fundus examination to identify any
`
`
`
`
`
`
`
`
`
`
`ocular side effects or major criteria for treatment failure or
`discontinuation.
`
`
`
`
`
`
`— FA is generally recommended only for patients with
`
`
`
`
`
`
`significant or unexplained vision loss, at the ophthalmol-
`
`ogist’s discretion.
`
`
`
`
`
`
`
`localises, classifies and quantifies intraretinal,
`OCT detects,
`
`
`
`
`
`
`
`subretinal and sub-RPEfluid, and is therefore recommended to
`
`
`
`Br J Ophthalmol 2010;94:2-13. doi:10.1136/bjo.2009.159160
`
`
`0006
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`for subfoveal (which could also be defined to include juxtafo-
`
`
`
`
`veal“) lesions with “active disease.”
`
`
`
`
`
`
`
`The concept of active neovascular AMDis central to these
`
`
`
`
`
`
`
`
`
`
`guidelines(level III evidence). A similar concept was proposed in
`
`
`
`
`
`developing guidelines for verteporfin photodynamic therapy
`
`
`
`
`
`
`for AMD and retreatment using specific
`(PDT)
`clinical
`
`
`
`
`parameters.” “ Anti-VEGF therapy specifically targets angio-
`
`
`
`
`
`
`
`genesis and vascular permeability,’ *’ “° and the active disease
`
`
`
`
`
`
`
`
`
`concept has evolved to encompassthe hallmarks of neovascular
`
`
`
`
`
`
`
`disease suchaspersistent or recurrent extracellular fluid.
`
`
`
`
`
`
`
`
`
`The following ‘“‘starting criteria” (level III evidence) to define
`
`
`
`
`
`
`
`active disease may assist
`in identifying suitable patients for
`ranibizumab treatment:
`
`
`
`
`
`
`
`
`abnormalretinal thickness, particularly with evidence of
`>
`
`
`
`
`
`
`intraretinal, subretinal or subpigmentepithelial fluid accu-
`
`
`
`
`mulation, optimally confirmed by OCT;
`
`
`
`presence (or
`recurrence) of
`intraretinal or subretinal
`haemorrhage;
`
`
`
`
`
`
`
`>
`new orpersistent leakage shown on FA;
`
`
`
`
`
`
`
`
`
`> CNV enlargement on FA unless solely due to dry, fibrotic
`staining;
`
`
`
`
`
`
`>» VA deterioration, considered likely to represent CNV
`activity.
`
`
`
`
`
`
`
`
`In retrospective analyses of 24-month MARINAstudydata,
`
`
`
`
`
`
`
`
`
`
`ranibizumab wassuperior to sham acrossall subgroups based on
`
`
`
`
`
`
`
`
`
`
`patient age, gender, CNVlesion type,lesion size, baseline VA
`
`
`
`
`
`
`
`
`
`and AMDduration.” VA outcomes were predicted by baseline
`
`
`
`
`
`
`VA,
`then CNV lesion size and age
`I
`evidence).
`(level
`
`
`
`
`
`
`
`
`
`Importantly, for CNV lesion size, smaller lesions had a better
`
`
`
`
`
`
`
`
`prognosis than larger lesions. A subgroup analysis of 12-month
`
`
`
`
`
`ANCHORstudy data showedsimilar results.”
`
`
`
`
`
`
`
`
`
`
`Althoughclinical data are only available for baseline VA levels
`
`
`
`
`
`
`
`
`
`
`
`
`of 20/40 (6/12) to 20/320 (6/48), the initial baseline VA was not
`
`
`
`
`
`
`
`
`a limiting factor for response to ranibizumab:all baseline VA
`
`
`
`
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`subgroups gained with treatment.” * For example, cases with
`
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`
`active subfoveal/juxtafoveal CNV and VAbetter than 20/40
`
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`
`should always be considered for treatment, as these have the
`
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`
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`potential to retain the best possible vision outcomes, particu-
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`larly for tasks such as reading anddriving.
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`Although thetrials did not include cases with the following
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`criteria, no evidence suggests that
`ranibizumab should be
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`withheld in these populations (level III evidence):'”
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`haemorrhageorserous pigmentepithelial detachment (PED)
`>
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`involving an area >50% of
`the entire CNV lesion,
`
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`particularly if any CNV can be documented before treat-
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`ment(eg, using ICG);
`
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`glaucomaorelevated intraocular pressure;
`
`
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`advanced cataract—cataract surgery should generally follow
`
`ranibizumab therapy.
`
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`Lesion characteristics such as isolated serous PED without
`
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`documented CNV,” RAP or PCV have not been investigated
`
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`sufficiently in ranibizumab trials. These cases may be con-
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`sidered for ranibizumabtherapy, but they might not respondas
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`well, or may respond more slowly,” than would be expected
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`from the average trial outcomesofother occult lesions. Current
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`trials are investigating someof these subtypes (eg, ranibizumab
`
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`
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`Phase
`IV EVEREST PCV trial;
`trials’
`identifier
`clinical
`NCT00674323).
`
`>
`
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`
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`
`
`>
`>
`
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`Whatcharacteristics suggest that ranibizumab would likely be
`futile?
`
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`
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`III evidence),'’'® and some
`Based on expert opinion (level
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`clinical
`trial evidence, patients with active disease, but
`for
`
`4
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`a) MARINA: Moothly regimen; 0.1 % PC, 63.0% MC, 36.9'1!, ONC
`15
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`15
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`b