Treatment schedules for administration of anti-vascular endothelial growth factor agents for neovascular age-related macular degeneration

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To investigate the effects of non-monthly versus monthly intravitreal injection of an anti-VEGF agent on best-corrected visual acuity (BCVA) in people with newly diagnosed nAMD at one-year follow-up.

Background

Description of the condition

Age-related macular degeneration (AMD) is a progressive, degenerative disease of the central retina, known as the macula, that can result in central vision loss. It is the leading cause of irreversible vision loss in industrialized countries and the third major cause of blindness globally (Bourne 2014; WHO 2016). The main risk factor for AMD is age (Klein 1992; Leibowitz 1980); other risk factors include cigarette smoking, Caucasian race, and genetic variation (Christen 1996; Evans 2005; Friedman 1999; Friedman 2004; Miller 2013; Seddon 1996; Swaroop 2007). There are two main forms of AMD: non-neovascular, known as 'dry' or 'non-exudative,' and neovascular, known as 'wet' or 'exudative,' types.

This review will focus on neovascular AMD (nAMD). Approximately 20% of dry AMD cases transform to exudative disease through development of choroidal neovascularization (CNV), the abnormal proliferation of blood vessels in the inner choroid layer (AAO 2010). Defects in Bruch's membrane and the retinal pigment epithelium (RPE) enable extension of choroidal blood vessels into the sub-pigment epithelial space and eventually the subretinal space. Leakage or bleeding from these vessels causes exudative or hemorrhagic retinal detachments, triggering fibrosis. The resulting scarred retina has significantly decreased visual capacity (AAO 2010; Solomon 2014).

Fluorescein angiography (FA) findings are the gold standard for diagnosing CNV. Fluorescein dye is injected into a vein and travels into the eye; characteristic patterns of hyperfluorescence and hypofluorescence outline pathology. CNV diagnosis is supported by hyperfluorescent lesions in the macula that increase in intensity and size over time. Another useful nAMD imaging modality is spectrum-domain optical coherence tomography (OCT), which provides cross-sectional views of the layers of the retina that are especially useful for monitoring disease and evaluating treatment response (AAO 2015).

CNV represents pathologic angiogenesis, the development of new capillaries, in the choroid. In nAMD, chronic exposure to hypoxia, ischemia, and/or inflammation tips the balance between angioinhibitors and angioactivators toward the formation of new blood vessels (Bressler 2009; Gunda 2013). The natural progression of nAMD without effective treatment eventually results in an end-stage subretinal disciform scar and loss of vision.

Description of the intervention

The current mainstay treatment for nAMD is intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents. VEGF is an endothelial cell-specific mitogen that promotes the proliferation of new vessels and increased vascular permeability (Ferrara 2004). It is upregulated in nAMD and is a key factor in the pathogenesis of CNV. Anti-VEGF agents, including ranibizumab, bevacizumab, and aflibercept, target this angioactivator in their treatment of nAMD (Bressler 2009; Ferrara 2004; Gunda 2013).

Ranibizumab, a monoclonal antibody fragment against VEGF-A, was approved by the United States Food and Drug Administration (FDA) for the treatment of nAMD in 2006. Its efficacy and safety were demonstrated in two pivotal trials, ANCHOR and MARINA (ANCHOR 2009; MARINA 2006). Bevacizumab, a monoclonal antibody against VEGF-A, has been used alongside ranibizumab as a cheaper anti-VEGF alternative. Although it is FDA approved only for the treatment of colorectal cancer, non-small cell lung cancer, cervical cancer, glioblastoma, and renal cell carcinoma, it is used off-label to treat nAMD. Several trials have demonstrated comparable efficacies and safeties between these two anti-VEGF agents (CATT 2012; GEFAL 2013; IVAN 2012; MANTA 2013; Moja 2014; Solomon 2014). However, the marketed dosage of bevacizumab is too large for use in the eye. The appropriate dose of bevacizumab for intravitreal injection has to be compounded by pharmacies, which introduces contamination risk. Its use in the eye is not regulated by the FDA. A third anti-VEGF intravitreal agent, aflibercept, was approved by the FDA in 2011 for the treatment of nAMD. It is a decoy receptor that blocks VEGF-A, VEGF-B, and placental growth factor (PIGF). VIEW 1 and VIEW 2 trials demonstrated the non-inferiority of aflibercept efficacy when compared to ranibizumab (Sarwar 2016; VIEW 2012).

The first FDA approved anti-VEGF drug, pegaptanib (VISION 2006), is no longer in use because of the better visual acuity results from ranibizumab, bevacizumab, and aflibercept (Sarwar 2016; Solomon 2014). Photodynamic therapy (PDT) decreases rates of visual loss from subfoveal nAMD and still has clinical application in rare cases (TAP 2001; VIP 2001; Wormald 2007; Yonekawa 2015). Our review will focus on treatment regimens using ranibizumab, bevacizumab, and aflibercept intravitreal injections.

There is currently no standard regimen for injection frequency after the initial three monthly loading doses. Ophthalmologists administer anti-VEGF injections at frequencies that vary based on physician practice and individual cases after the first three injections. Intravitreal injections of ranibizumab were administered monthly in the MARINA and ANCHOR trials (ANCHOR 2009; MARINA 2006). With a higher binding affinity and thus longer therapy window than ranibizumab, aflibercept's non-inferior effects were demonstrated with bimonthly injections after three initial monthly loading doses (VIEW 2012).

Additional studies have investigated ranibizumab, bevacizumab, and aflibercept efficacy using a variety of monthly and non-monthly injection regimens. Non-monthly dosing has included: loading doses (monthly for the first three months) followed by as needed, every eight weeks, quarterly, crossover from monthly to as needed, or formula-based (that is treat-and-extend protocol) (Abedi 2014; CATT 2012; CLEAR-IT 2 2011; EXCITE 2011; HARBOR 2014; IVAN 2012; PIER 2010; PrONTO 2009; SECURE 2013; SUSTAIN 2011; VIEW 2012). Although all investigations have supported the use of anti-VEGF agents, it is unclear which dosing regimen is superior with respect to efficacy and safety.

The ideal treatment protocol would minimize the number of injections in order to decrease side effects and maximize therapeutic outcomes. The potential side effects are rare but may have serious consequences for vision from the procedure and the drug itself. Serious risks from the injection process include endophthalmitis, retinal hemorrhage, retinal detachment, RPE detachment, retinal edema, and vitreous detachment (CATT 2012; CLEAR-IT 2 2011). Potential adverse drug events include systemic arterial thromboembolic events such as myocardial infarction and cerebral vascular accident (CATT 2012). Although Solomon et al found the occurrence of systemic adverse events to be comparable across anti-VEGF and control groups and between ranibizumab and bevacizumab when given the same injections schedules, the number of participants in the trials included in their review may have been insufficient to detect meaningful differences in adverse events (Solomon 2014). Furthermore, their review did not compare dosing regimens. Inclusion of more studies in our review may reveal other adverse systemic effects of individual anti-VEGF agents in addition to those risks posed by the injection procedure.

Delivering injections more frequently than therapeutically required also imposes an unnecessary cost burden on individuals and on national healthcare systems. Our intervention aims to evaluate the current literature to compare non-monthly with monthly injection regimens to identify the optimal anti-VEGF injection schedule for people with nAMD among those that have been implemented and reported to date.

How the intervention might work

Pivotal anti-VEGF studies followed monthly injection regimens to investigate drug efficacy. Initial trials of ranibizumab, bevacizumab, and aflibercept used monthly administration of the drugs (ANCHOR 2009; CATT 2012; CLEAR-IT 2 2011; IVAN 2012; MARINA 2006). Mean change of best-corrected visual acuity (BCVA) after two years was +8.1, +7.8, and +9 for monthly 0.5 mg ranibizumab, 1.25 mg bevacizumab, and 2.0 mg aflibercept, respectively (ANCHOR 2009; CATT 2012; CLEAR-IT 2 2011).

Subsequent studies have investigated ranibizumab, bevacizumab, and aflibercept efficacy using a variety of monthly and non-monthly injection regimens. The VIEW trials compared bimonthly injection of aflibercept 2.0 mg after three initial monthly doses with monthly injections. Results demonstrated comparable effects on BCVA due to aflibercept's longer therapy window than ranibizumab (CLEAR-IT 2 2011; VIEW 2012; Yonekawa 2015). Trials also have investigated as needed, quarterly, crossover from monthly to as needed, and formula-based (that is treat-and-extend protocol) dosing regimens. Effects on BCVA from these studies have been mixed (Abedi 2014; CATT 2012; CLEAR-IT 2 2011; EXCITE 2011; HARBOR 2014; IVAN 2012; PIER 2010; PrONTO 2009; SECURE 2013; SUSTAIN 2011; VIEW 2012). Schmucker et al performed a systematic review and meta-analysis of injections as required versus monthly injections of anti-VEGF in 2015; the review and meta-analysis, which included reports from three studies with more than 2000 participants (CATT 2012; HARBOR 2014; IVAN 2012), found that those on as-needed treatment had slightly but statistically significantly worse BCVA and an increased risk of systemic adverse events compared to those given monthly injections (Schmucker 2015). As their findings were based on only three studies, it is not known which dosing regimen satisfies therapeutic standards while minimizing injection frequency to eliminate unnecessary risk of adverse events and to control cost.

Why it is important to do this review

Although nAMD is less prevalent than non-exudative disease, it accounts for 80% of severe vision loss due to AMD (worse than 20/200 Snellen acuity) (Leibowitz 1980). Risk factors for conversion from non-exudative AMD to nAMD include a decrease in visual acuity to less than or equal to 75 Early Treatment Diabetic Retinopathy Study (ETDRS) letters from a baseline of more than 85 letters and older age (Friberg 2012).

As global populations age, the number of individuals affected by AMD is expected to rise. Approximately 1.25 million individuals with nAMD were reported in the USA in 2004. By 2020, the prevalence of nAMD is expected to increase to an estimated 1.875 million cases (Friedman 2004). AMD imposes a significant decrement in patients' quality of life, with the impact from severe AMD likened to that of end-stage cancer or a stroke requiring constant nursing care (Brown 2006). Several studies have suggested AMD as a risk factor for depression, a major cause of disability (Casten 2004). Thirty percent of people with AMD have depression, compared with 15% of adults aged 65 years and older who have clinically significant depressive symptoms in the USA and internationally (Casten 2004; Fiske 2009). Neovascular AMD not only has negative effects on individual patients, but also has negative social and economic consequences. Using utility analysis, researchers have estimated a gross domestic product (GDP) cost of USD 5.396 billion per year due to lost productivity (Brown 2005).

Previous Cochrane reviews have investigated and demonstrated the efficacy and safety of intravitreal anti-VEGF agents for the treatment of nAMD (Solomon 2014). However, ever-growing burdens on the patient and healthcare systems necessitate cost-effective therapies for nAMD. It remains unknown which treatment schedule is optimal when balancing efficacy, safety, and cost.

Objectives

To investigate the effects of non-monthly versus monthly intravitreal injection of an anti-VEGF agent on best-corrected visual acuity (BCVA) in people with newly diagnosed nAMD at one-year follow-up.

Methods

Criteria for considering studies for this review

Types of studies

We will include only randomized controlled trials.

Types of participants

We will include trials in which treatment-naive participants received a new diagnosis of nAMD as defined by study investigators.

Types of interventions

Intervention (main): Non-monthly intravitreal injection of an anti-VEGF agent including: loading doses (monthly for first three months) followed by, as needed, every eight weeks, quarterly, crossover from monthly to as needed, or formula-based (that is treat-and-extend protocol).

Comparison: Monthly intravitreal injection of an anti-VEGF agent.

Eligibility criteria for intervention and comparison include anti-VEGF doses of 0.5 mg ranibizumab, 1.25 mg bevacizumab, and 2.0 mg aflibercept.

Types of outcome measures

Primary outcomes

BCVA measured on a logMAR chart as mean change of BCVA from baseline to one year of follow-up.

Secondary outcomes
  • BCVA measured on a logMAR chart as mean change of BCVA from baseline to two years of follow-up.

  • Proportion with an improvement of BCVA by 0.3 logMAR or more (3 Snellen lines or 15 ETDRS letters) at one and two years of follow-up.

  • Change in optical coherence tomography (OCT) central subfoveal thickness in micrometers from baseline to one and two years of follow-up.

  • Quality of life measured as mean change from baseline to one and two years of follow-up using any validated questionnaire.

  • Use of resources: number of injections in the first year and within two years and their cost estimates.

Adverse events

We also will compare ocular and systemic adverse effects (e.g., all-cause death, serious systemic adverse events) within the first year of treatment and follow-up.

We will consider outcomes at '12 months' to be any observation between 9 and 15 months. If change in outcome measures between baseline and one- and two-year follow-up is not reported or calculable, we will collect data on the value at last follow-up.

Search methods for identification of studies

Electronic searches

We will search Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Eyes and Vision Trials Register (latest issue), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to present), EMBASE (January 1980 to present), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to present), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). Our search will exclude trials initiated prior to 2004. We will not use any language restrictions in the electronic search for trials.

See: Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3), LILACS (Appendix 4), ISRCTN (Appendix 5), ClinicalTrials.gov (Appendix 6), and the ICTRP (Appendix 7).

Searching other resources

We will review the reference lists of included trial reports and related systematic reviews to identify additional potentially relevant trials. We will contact pharmaceutical companies conducting studies on anti-VEGF drugs for information about any ongoing or completed clinical trials not published. We will search abstracts from the annual meetings of the Association for Research in Vision and Ophthalmology (ARVO), the European VitreoRetinal Society, the Macula Society, the Retina Society, subspecialty meetings from the American Academy of Ophthalmology, and the American Society of Retinal Surgeons for ongoing trials from 2004 onwards.

Data collection and analysis

Selection of studies

Two review authors will independently screen the titles and abstracts resulting from the searches using web-based software (Systematic Review Data Repository). We will resolve disagreements by discussion. In general, citations considered not relevant at this stage will not be documented in the review other than to note the number of these in a flow chart. We will obtain full-text copies of reports from potentially relevant studies.

Two review authors will independently assess the full-text copies for inclusion according to the 'Criteria for considering studies for this review.' We will resolve disagreements by discussion with a third review author. We will correspond with investigators to clarify study eligibility, as appropriate. We will not be masked to the names of the authors, institutions, or journal publication when we review full-text reports.

We will list all studies excluded after review of study reports and provide a brief justification for exclusion. In general, we would expect that all studies excluded after examination of full-text reports will be listed in the excluded studies table.

For potentially eligible studies identified from trials registers, we will proceed as follows:

  • If the study has a completion date more than two years earlier than our search date, we will look for publications from the study and contact the investigators as necessary to obtain published or unpublished data from the trial. If eligible, the trial will be included in the review irrespective of whether we can identify a publication.

  • If the study has a completion date within two years before the date of our search or in the future, we will document the study in the ongoing studies section.

Data extraction and management

Two review authors will independently extract study characteristics: study methods, participants, interventions, outcomes, and funding sources. We will contact the trial authors for data on primary and secondary outcomes in the individual trials when the information was not clearly presented or not available from the full-text reports. We will extract data on BCVA, adverse events, and other relevant outcomes. We will extract data from figures published in the trial reports when applicable and communicate with the authors to verify extracted data. One review author will enter data into Review Manager (RevMan 2014), and a second review author will verify the data entry.

Assessment of risk of bias in included studies

We will specifically consider and report on the following sources of bias:

  1. Selection bias (random sequence generation, allocation concealment before randomization): Was the sequence of allocation generated using a random procedure and was the allocation concealed to people recruiting/enrolling participants and to participants before randomization?

  2. Performance bias (masking of participants and researchers): Were the recipients of care unaware of their assigned intervention? Were people providing care unaware of the assigned intervention?

  3. Detection bias (masking of outcome assessors). Were people evaluating outcomes unaware of the assigned intervention?

  4. Attrition bias: Were the rates of follow-up and compliance similar in the study treatment groups? Was the analysis by intention-to-treat? Were there any postrandomization exclusions?

  5. Selective outcome reporting bias: Is there any evidence that outcomes that were measured have not been reported?

We will grade each study for each domain as being at low risk of bias, high risk of bias, or unclear (lack of information or uncertainty of potential for bias), as described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will contact trial investigators for clarification of parameters graded as 'unclear'.

Measures of treatment effect

We will calculate the mean difference for the following continuous outcomes: mean change in BCVA, mean change in retinal thickness, number of injections. We will calculate the risk ratio for the following dichotomous outcomes: proportion with BCVA improvement, adverse events.

Where possible, we will check for the skewness of continuous data by considering the ratio of the mean to the standard deviation for continuous variables with a natural ceiling, such as BCVA or retinal thickness.

We will use the standardized mean difference (SMD) whenever a continuous outcome is measured on different scales, such as quality of life scores from different questionnaires. The SMD expresses the size of the intervention effect in each study relative to the variability observed in that study. If one scale increases with severity whilst another decreases with severity, we will ensure that all the scales measure improvement in the same direction, either by multiplying the mean values of studies using one type of scale by –1 or by subtracting the mean from the maximum possible value for the scale.

Unit of analysis issues

We anticipate unit of analysis issues with respect to eyes will be found in few studies because most trials of treatment of nAMD have designated one eye of a participant as the study eye. Participants have therefore been randomized to treatment of one eye per participant and outcomes reported for study eyes. Nonetheless, if studies have included more than 10% of participants with both eyes in the analysis, regardless of whether the two eyes of a participant were assigned to the same or a different injection schedule, we will conduct a sensitivity analysis in which these studies are excluded.

Dealing with missing data

Whenever possible, we will conduct an intention-to-treat (ITT) analysis. We will use outcome data imputed by the trial investigators whenever they used an appropriate method, but we will not impute missing data ourselves.

When ITT outcome data are not available, we will do an available-case analysis. This approach assumes that data are missing at random. We will assess whether this assumption is reasonable by collecting data from each included trial on the number of participants excluded or lost to follow-up and reasons for loss to follow-up by treatment group, when reported.

Assessment of heterogeneity

We will examine the overall characteristics of the studies, in particular the type of participants and types of interventions, to assess the extent to which the studies are similar enough to make pooling outcome data sensible.

We will look at the forest plots of outcome estimates to see how consistent the results of the studies are, with particular attention to the size and direction of effects.

We will calculate I2, which is the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance, Higgins 2002). We will consider I2 values over 50% to indicate substantial statistical heterogeneity and consider the Chi2 test. As the Chi2 test has low power to identify heterogeneity when the number of studies is small, we will consider P less than 0.1 to indicate statistical significance.

Assessment of reporting biases

We will assess selective outcome reporting for each study by comparing the outcomes specified in a protocol, research plan, or clinical trial registry with the outcomes reported. When there is no pre-publication document available, we will compare the outcomes specified in the design and methods sections of study reports to the outcomes reported. When 10 or more studies are included in a meta-analysis, we will use a funnel plot to assess potential publication bias.

Data synthesis

We will pool data using a random-effects model in RevMan 5 (RevMan 2014). Whenever there are fewer than three trials in a comparison, we will use a fixed-effect model.

If there is inconsistency between individual study estimates of outcomes such that a pooled estimate may not be a good summary of the individual trial results (for example the effects are in different directions or the I2 value is more than 50% and the Chi2 P value is less than 0.1), we will not pool the data but will describe the pattern of the individual study estimates.

If there is statistical heterogeneity but all the effect estimates are in the same direction such that a pooled estimate provides a good summary of the individual trial results, we may elect to pool the data.

Subgroup analysis and investigation of heterogeneity

Our primary analysis will compare the monthly injection arm of all trials with all the reduced frequency regimens simultaneously. However, we will present subgroups of reduced frequency treatment regimens in the main analysis to explore subgroup heterogeneity. If significant subgroup heterogeneity is found, our conclusions will report on such differences and meta-regression will be used to support them.

If there are sufficient trials and outcome data, we will compare the effect of treatment regimens in the following subgroups:

  • different anti-VEGF agents;

  • different decision-making criteria, e.g. visual acuity based versus OCT based.

Sensitivity analysis

We will perform the following sensitivity analyses on the primary outcome:

  • excluding studies at high risk of bias in one or more domains;

  • excluding studies with more than 10% of participants with both eyes in primary analyses;

  • comparing fixed-effect and random-effect models (if three or more trials).

'Summary of findings' table

We will prepare a 'Summary of findings' table to present estimated relative and absolute risks. Two review authors will independently grade the overall quality of the evidence for each outcome using the GRADE classification (GRADEpro 2015). We will include the following outcomes in the 'Summary of findings' table.

  • Mean change of BCVA at one year

  • Mean change of BCVA at two years

  • Proportion of participants with 3 or more line BCVA improvement at one and two years

  • Mean change in central retinal thickness at one year

  • Mean change in quality of life at one year

  • Adverse events: all-cause death, all serious systemic adverse events

  • Cost of treatment using each regimen

Acknowledgements

The Methods section uses some text from a standard protocol template prepared by Cochrane Eyes and Vision (CEV). We thank Iris Gordon, Information Specialist for CEV, for devising the search strategy. We also thank Daniela Bacherini, Mahsa Salehi, and Barbara Hawkins for providing peer review comments to the protocol.

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Macular Degeneration] explode all trees
#2 MeSH descriptor: [Retinal Degeneration] explode all trees
#3 MeSH descriptor: [Retinal Neovascularization] explode all trees
#4 MeSH descriptor: [Choroidal Neovascularization] explode all trees
#5 MeSH descriptor: [Macula Lutea] explode all trees
#6 maculopath*
#7 (macula* or retina* or choroid*) near/3 degenerat*
#8 (macula* or retina* or choroid*) near/3 neovascul*
#9 macula* near/2 lutea
#10 AMD or AMRD or CNV
#11 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10
#12 MeSH descriptor: [Angiogenesis Inhibitors] explode all trees
#13 MeSH descriptor: [Angiogenesis Inducing Agents] explode all trees
#14 MeSH descriptor: [Endothelial Growth Factors] explode all trees
#15 MeSH descriptor: [Vascular Endothelial Growth Factors] explode all trees
#16 anti near/2 VEGF*
#17 anti near/1 angiogen*
#18 endothelial near/2 growth near/2 factor*
#19 (macugen* or pegaptanib* or lucentis* or rhufab* or ranibizumab* or bevacizumab* or avastin* or aflibercept* or conbercept*)
#20 VEGF TRAP*
#21 #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20
#22 #11 and #21

Appendix 2. MEDLINE (Ovid) search strategy

1. randomized controlled trial.pt.
2. (randomized or randomised).ab,ti.
3. placebo.ab,ti.
4. dt.fs.
5. randomly.ab,ti.
6. trial.ab,ti.
7. groups.ab,ti.
8. or/1-7
9. exp animals/
10. exp humans/
11. 9 not (9 and 10)
12. 8 not 11
13. exp macular degeneration/
14. exp retinal degeneration/
15. exp retinal neovascularization/
16. exp choroidal neovascularization/
17. exp macula lutea/
18. maculopath$.tw.
19. ((macul$ or retina$ or choroid$) adj3 degener$).tw.
20. ((macul$ or retina$ or choroid$) adj3 neovasc$).tw.
21. (macula$ adj2 lutea).tw.
22. (AMD or ARMD or CNV).tw.
23. or/13-22
24. exp angiogenesis inhibitors/
25. angiogenesis inducing agents/
26. endothelial growth factors/
27. exp vascular endothelial growth factors/
28. (anti adj2 VEGF$).tw.
29. (endothelial adj2 growth adj2 factor$).tw.
30. (anti adj1 angiogen$).tw.
31. (macugen$ or pegaptanib$ or lucentis$ or rhufab$ or ranibizumab$ or bevacizumab$ or avastin or aflibercept$ or conbercept$).tw.
32. VEGF TRAP$.tw.
33. or/24-32
34. 23 and 33
35. 12 and 34

The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville (Glanville 2006).

Appendix 3. EMBASE (Ovid) search strategy

1. exp randomized controlled trial/
2. exp randomization/
3. exp double blind procedure/
4. exp single blind procedure/
5. random$.tw.
6. or/1-5
7. (animal or animal experiment).sh.
8. human.sh.
9. 7 and 8
10. 7 not 9
11. 6 not 10
12. exp clinical trial/
13. (clin$ adj3 trial$).tw.
14. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
15. exp placebo/
16. placebo$.tw.
17. random$.tw.
18. exp experimental design/
19. exp crossover procedure/
20. exp control group/
21. exp latin square design/
22. or/12-21
23. 22 not 10
24. 23 not 11
25. exp comparative study/
26. exp evaluation/
27. exp prospective study/
28. (control$ or prospectiv$ or volunteer$).tw.
29. or/25-28
30. 29 not 10
31. 30 not (11 or 23)
32. 11 or 24 or 31
33. exp retina macula degeneration/
34. exp retinal degeneration/
35. exp subretinal neovascularization/
36. maculopath$.tw.
37. ((macul$ or retina$ or choroid$) adj3 degener$).tw.
38. ((macul$ or retina$ or choroid$) adj3 neovasc$).tw.
39. (macula$ adj2 lutea).tw.
40. (AMD or ARMD or CNV).tw.
41. or/33-40
42. angiogenesis/
43. exp angiogenesis inhibitors/
44. angiogenic factor/
45. endothelial cell growth factor/
46. monoclonal antibody/
47. vasculotropin/
48. (anti adj2 VEGF$).tw.
49. (endothelial adj2 growth adj2 factor$).tw.
50. (anti adj1 angiogen$).tw.
51. (macugen$ or pegaptanib$ or lucentis$ or rhufab$ or ranibizumab$ or bevacizumab$ or avastin or aflibercept$ or conbercept$).tw.
52. VEGF TRAP$.tw.
53. or/42-52
54. 41 and 53
55. 32 and 54

Appendix 4. LILACS search strategy

Macular Degeneration OR AMD OR ARMD and Macugen OR Pegaptanib OR Lucentis OR rhufab OR ranibizumab OR bevacizumab OR avastin OR aflibercept OR conbercept

Appendix 5. ISRCTN search strategy

(Macular Degeneration OR AMD OR ARMD) AND (Macugen OR Pegaptanib OR Lucentis OR rhufab OR ranibizumab OR bevacizumab OR avastin OR aflibercept OR conbercept)

Appendix 6. ClinicalTrials.gov search strategy

(Macular Degeneration OR AMD OR ARMD) AND (Macugen OR Pegaptanib OR Lucentis OR rhufab OR ranibizumab OR bevacizumab OR avastin OR aflibercept OR Conbercept OR KH902)

Appendix 7. ICTRP search strategy

Macular Degeneration OR AMD OR ARMD = Condition AND Macugen OR Pegaptanib OR Lucentis OR rhufab OR ranibizumab OR bevacizumab OR avastin OR aflibercept OR Conbercept = Intervention

Contributions of authors

Emily Li and Magdalena G Krzystolik conceived of, designed, and wrote this protocol. Simone Donati and Gianni Virgili designed and wrote this protocol.

Declarations of interest

Emily Li: No conflicts of interest to report.
Simone Donati: No conflicts of interest to report.
Gianni Virgili: No conflicts of interest to report.
Magdalena G Krzystolik: No conflicts of interest to report.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Methodological support provided by the Cochrane Eyes and Vision US Project, supported by cooperative agreement 1 U01 EY020522, National Eye Institute, National Institutes of Health, USA.

  • National institute for Health Research (NIHR), UK.

    • Richard Wormald, Co-ordinating Editor for Cochrane Eyes and Vision (CEV) acknowledges financial support for his CEV research sessions from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology.

    • The NIHR also funds the CEV Editorial Base in London.

    The views expressed in this publication are those of the authors and not necessarily those of the NIHR, NHS, or the Department of Health.

Ancillary