IVAN 2013.

Methods	Number randomized (total and per group) Drug randomization: 628 total participants: 305 to bevacizumab group and 323 to ranibizumab group Regimen randomization: 294/305 in bevacizumab group and 312/323 in ranibizumab group completed first 3 injections and were randomized to continue or discontinue treatment: 149 continued bevacizumab; 145 discontinued bevacizumab; 157 continued ranibizumab; and 155 discontinued ranibizumab Exclusions after randomization: 18 participants did not receive treatment and were excluded after randomization to drug treatment (9 in bevacizumab group and 9 in ranibizumab group) Number analyzed (total and per group) At 1‐year follow‐up: 561 total participants at 1 year: 136 in continued bevacizumab group; 138 in discontinued bevacizumab group; 141 in continued ranibizumab group; and 146 in discontinued ranibizumab group At 2‐year follow‐up: 525 total participants at 1 year: 127 in continued bevacizumab group; 127 in discontinued bevacizumab group; 134 in continued ranibizumab group; and 137 in discontinued ranibizumab group Unit of analysis: individuals (1 study eye per participant) Losses to follow‐up At 1‐year follow‐up: 49 total participants: 4 participants receiving treatment withdrew before completing third injection (2 in bevacizumab group and 2 in ranibizumab group); 45 participants randomized to regimen groups exited trial before 1 year (13 in continued bevacizumab group; 7 in discontinued bevacizumab group; 16 in continued ranibizumab group; and 9 in discontinued ranibizumab group) At 2‐year follow‐up: 85 total participants: 5 participants receiving treatment withdrew before completing third injection (3 in bevacizumab group and 2 in ranibizumab group); 80 participants randomized to regimen groups exited trial before 2 years (21 in continued bevacizumab group; 18 in discontinued bevacizumab group; 23 in continued ranibizumab group; and 18 in discontinued ranibizumab group) Compliance: wrong study drug was administered twice during first year At 1‐year follow‐up: adherence was 6576/6699 (98%) scheduled injections received At 2‐year follow‐up: adherence was 12761/14,640 (87%) scheduled injections received Intention‐to‐treat analysis: no; 67 participants enrolled and randomized were not included in analyses at 1 year and 103 at 2 years Reported power calculation: yes; sample of 600 participants per group for power of 90% to detect non‐inferiority Study design comment: non‐inferiority design; 2 × 2 factorial design – randomization in 2 stages: first randomized to drug treatment (bevacizumab or ranibizumab), then to treatment regimen (continue monthly injections or discontinue monthly injections and switch to as‐needed injections given in 3‐month cycles); results reported only as bevacizumab vs ranibizumab and continuous vs discontinuous
Participants	Country: UK (23 study centers) Age: mean age for 610 participants receiving treatment was 78 years Gender (per cent): 366/610 (60%) women and 244/610 (40%) men Inclusion criteria: age 50 years or older; previously untreated neovascular AMD in study eye with any component of neovascular lesion (CNV, blood, serous pigment epithelial detachment, elevated blocked fluorescence) involving center of the fovea, confirmed by fluorescein angiography; best‐corrected VA of 25 or more letters on ETDRS chart (measured at 1 m) Exclusion criteria: neovascular lesion of 50% or more fibrosis or blood; more than 12 disc diameters; argon laser treatment in study eye within 6 months; presence of thick blood involving center of the fovea; presence of other active ocular disease causing concurrent vision loss; myopia ≥ 8 diopters; previous treatment with PDT or VEGF inhibitor in study eye; women pregnant, lactating, or of child‐bearing potential; men with spouse or partner of child‐bearing potential Equivalence of baseline characteristics: yes Diagnoses in participants: 301/610 (58%) had neovascular AMD with CNV in foveal center; 308/610 (54%) had fluid in foveal center; 90/610 (16%) had hemorrhage in foveal center; 75/610 (13%) had other foveal center involvement; and 15/610 (3%) had no CNV or not possible to grade
Interventions	Intervention 1: 1.25 mg in 0.05 mL intravitreal bevacizumab injected monthly for 2 years Intervention 2: 0.5 mg intravitreal ranibizumab injected monthly for 2 years Intervention 3: after first 3 monthly 1.25 mg intravitreal bevacizumab injections, monthly treatment was discontinued and treatment was given as needed in cycles of 3 monthly doses Intervention 4: after first 3 monthly 0.5 mg intravitreal ranibizumab injections, monthly treatment was discontinued and treatment was given as needed in cycles of 3 monthly doses Follow‐up Planned length: 2 years Actual length: 2 years Frequency of follow‐up assessments: monthly
Outcomes	Primary outcome, as defined: best‐corrected distance visual acuity measured as ETDRS letters at 2 years Secondary outcomes, as defined in protocol: at 1‐year and 2‐year follow‐up: frequency of adverse effects of treatment; generic and vision‐specific health‐related quality of life; treatment satisfaction; cumulative resource use/cost and cost‐effectiveness; clinical measures of vision (contrast sensitivity measured with Pelli‐Robson charts, near visual acuity measured by Bailey‐Love near reading cards, and reading speed measured with Belfast reading charts); lesion morphology (fluorescein angiography and OCT); distance visual acuity at 1 year; survival free from treatment failure Exploratory analysis: association between serum markers and cardiovascular serious adverse events Intervals at which outcomes were assessed: monthly through 24 months; various data were collected at every visit depending on assessment schedule and regimen group
Notes	Full study name: alternative treatments to inhibit VEGF in age‐related choroidal neovascularization Trial registration: ISRCTN92166560 Funding sources: National Institute for Health Research Health Technology Assessment Program, UK Declarations of interest: various study authors reported that they were principal investigators of trials sponsored by Novartis; attending and had been remunerated for attending advisory boards for Novartis, Bayer, Neovista, Oraya, Allergan, and/or Bausch and Lomb; were employed by institution that has received payments from Novartis, Bayer, Neovista, Oraya, Alcon, and/or Pfizer; and had received honoraria from Novartis for lecture and/or teaching fees from Janssen‐Cilag Study period: random enrollment March 27, 2008, to October 15, 2010 Reported subgroup analyses: 3 genetic polymorphisms (Lotery 2013) Contacting study investigators: trial authors not contacted as data were available in published reports
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomized allocations were computer generated by a third party in blocks and stratified by center" "Randomisation was stratified by centre and was blocked to ensure roughly equal numbers of participants per group within a centre"
Allocation concealment (selection bias)	Low risk	"Research teams at sites recruited participants and accessed a password‐protected website to randomize participants. Allocations were concealed until participants’ eligibility and identities were confirmed" "Allocations were computer generated and concealed with an internet‐based system (Sealed Envelope, London, UK). Staff in participating centres accessed the website and, on entering information to confirm a participant’s identity and eligibility, were provided with the unique study number"
Masking of participants (performance bias)	Low risk	From study protocol: "Participants, clinicians and trial personnel will be masked to the VEGF inhibitor to which a participant is assigned" "We have chosen not to mask participants, clinicians and trial personnel to whether patients are allocated to continue or stop treatment at 3 months"
Masking of study personnel (performance bias)	Low risk	"We intended that drug allocation should be concealed by having separate masked assessment and unmasked treating teams. This system was achieved by 14 sites. At the other 9 sites, staffing levels could not support this system and an unmasked staff member prepared ranibizumab in a syringe identical to those containing bevacizumab and did not perform assessments" From study protocol: "We have chosen not to mask participants, clinicians and trial personnel to whether patients are allocated to continue or stop treatment at 3 months"
Masking of outcome assessment (detection bias)	Low risk	"We intended that drug allocation should be concealed by having separate masked assessment and unmasked treating teams. This system was achieved by 14 sites. At the other 9 sites, staffing levels could not support this system and an unmasked staff member prepared ranibizumab in a syringe identical to those containing bevacizumab and did not perform assessments" "Lesion morphology was assessed by independent graders masked to drug and treatment regimen" From study protocol: "We have chosen not to mask participants, clinicians and trial personnel to whether patients are allocated to continue or stop treatment at 3 months"
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	67/628 (11%) participants randomized were not included in 1‐year analysis; 111/628 (18%) participants randomized were not included in 2‐year analysis
Selective reporting (reporting bias)	Unclear risk	Differences between protocol and published 1‐year and 2‐year results papers included the following: • 2 secondary outcomes in the protocol were not listed in paper: treatment satisfaction and survival free from treatment failure • Exploratory (serum) analysis in protocol upgraded to a secondary outcome in paper
Other bias	Low risk	None observed