IVAN 2012b.

Study characteristics
Methods	Study design: parallel‐group randomized controlled trial Number randomized (total and per group): Drug randomization: 628 total participants; 305 in bevacizumab group and 323 in 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; 136 in continued bevacizumab group; 138 in discontinued bevacizumab group; 141 in continued ranibizumab group; and 146 in discontinued ranibizumab group At 2 years' follow‐up: 525 total participants; 127 in continued bevacizumab group; 127 in discontinued bevacizumab group; 134 in continued ranibizumab group; and 137 in discontinued ranibizumab group Unit of analysis: participant (1 study eye per participant) Losses to follow‐up: At 1 year' follow‐up: 49 total participants: 4 participants receiving treatment withdrew prior to completing 3rd 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 years' follow‐up: 85 total participants: 5 participants receiving treatment withdrew prior to completing 3rd 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: the wrong study drug was administered twice during the first year At 1 year' follow‐up: adherence was 6576/6699 (98%) scheduled injections received At 2 years' follow‐up: adherence was 12761/14640 (87%) scheduled injections received Intention‐to‐treat analysis: no, 67 participants enrolled and randomized were not included in the 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 PNR 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 (%): 366/610 (60%) women and 244/610 (40%) men Inclusion criteria: ages ≥ 50 years; previously untreated nAMD in study eye with any component of the neovascular lesion (CNV, blood, serous PED, elevated blocked fluorescence) involving the center of fovea, confirmed by FA; BCVA ≥ 25 letters on ETDRS chart (measured at 1 m) Exclusion criteria: neovascular lesion ≥ 50% fibrosis or blood; > 12 disk diameters; argon laser treatment in study eye within 6 months; presence of thick blood involving the center of fovea; presence of other active ocular disease causing concurrent vision loss; myopia ≥ 8 diopters; previous treatment with PDT or a VEGF inhibitor in study eye; women pregnant, lactating, or of child‐bearing potential; men with a spouse or partner of child‐bearing potential Equivalence of baseline characteristics: yes Diagnoses in participants: 301/610 (58%) had nAMD 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: intravitreous bevacizumab 1.25 mg in 0.05 mL injected monthly for 2 years Intervention 2: intravitreous ranibizumab 0.5 mg injected monthly for 2 years Intervention 3: after first 3 monthly intravitreous bevacizumab 1.25 mg injections, monthly treatment was discontinued, and treatment was given PNR in cycles of 3 monthly doses Intervention 4: after first 3 monthly intravitreous ranibizumab 0.5 mg injections, monthly treatment was discontinued, and treatment was given PNR in cycles of 3 monthly doses Follow‐up: 2 years Frequency of follow‐up assessments: monthly
Outcomes	Primary outcome, as defined: BCVA measured as ETDRS letters at 2 years Secondary outcomes, as defined in protocol: at 1 year' and 2 years' follow‐up: frequencies 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 VA measured by Bailey‐Love near reading cards, and reading speed measured with Belfast reading charts); lesion morphology (FA and OCT); distance VA 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 neovascularisation Trial registration: ISRCTN92166560. Type of study: published Funding sources: National Institute for Health Research Health Technology Assessment programme, UK Declarations of interest: various authors reported being principal investigators of trials sponsored by Novartis; attending and being remunerated for attendance at advisory boards for Novartis, Bayer, Neovista, Oraya, Allergan, Bausch and Lomb, or a combination; being employed by institution that has received payments from Novartis, Bayer, Neovista, Oraya, Alcon, Pfizer, or a combination; receiving honoraria from Novartis for lecture or teaching fees from Janssen‐Cilag, or both Study period: random enrollment 27 March 2008 to 15 October 2010 Reported subgroup analyses: 3 genetic polymorphisms (Lotery 2013 under IVAN 2012b) 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	Quote: "Randomized allocations were computer generated by a third party in blocks and stratified by center." Quote: "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	Quote: "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." Quote: "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."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	From study protocol: Quote: "Participants, clinicians and trial personnel will be masked to the VEGF inhibitor to which a participant is assigned." Quote: "We have chosen not to mask participants, clinicians and trial personnel to whether patients are allocated to continue or stop treatment at 3 months." Quote: "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."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "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." Quote: "Lesion morphology was assessed by independent graders masked to drug and treatment regimen." From study protocol: Quote: "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 the 1‐year analysis; 111/628 (18%) participants randomized were not included in the 2‐year analysis.
Selective reporting (reporting bias)	Unclear risk	Differences between the protocol and published 1‐year and 2‐year results papers included: 2 secondary outcomes in the protocol were not listed in paper: treatment satisfaction and survival free from treatment failure; and exploratory (serum) analysis in protocol upgraded to a secondary outcome in paper.