CATT 2011.

Methods	Number randomized (total and per group): 1208 participants randomly assigned to study treatment; number of participants randomized per group not reported Exclusions after randomization: 1 study center (23 participants) was excluded owing to protocol violations Number analyzed (total and per group): 1105 total participants: 265 in bevacizumab monthly group, 284 in ranibizumab monthly group, 271 in bevacizumab as needed group, and 285 in ranibizumab as needed group Unit of analysis: individuals (1 study eye per participant) Losses to follow‐up: 80 total participants: 21 in bevacizumab monthly group (4 died and 17 with missing data), 17 in ranibizumab monthly group (4 died and 13 with missing data), 29 in bevacizumab as needed group (11 died and 18 with missing data), 13 in ranibizumab as needed group (5 died and 8 with missing data) Compliance: limited information given: mean of 11.9 treatments given for bevacizumab monthly group, and mean of 11.7 treatments given for ranibizumab monthly group Intention‐to‐treat analysis: no; 103 participants enrolled and randomized were not included in the analyses Reported power calculation: yes; sample of 277 participants per group for power of 90% Study design comment: non‐inferiority design, 4 arms, 6 pairwise comparisons planned; at 1 year, participants in monthly dose treatment groups were re‐randomized to continue with monthly injections or switch to as‐needed injections of the same treatment drug
Participants	Country: USA Age: mean was 80 years in bevacizumab monthly group, 79 years in ranibizumab monthly group, 79 years in bevacizumab as needed group, and 78 years in ranibizumab as needed group Gender (per cent): 732/1185 (61.8%) women and 453/1185 (38.2%) men Inclusion criteria: age 50 years or older; 1 study eye per participant with untreated active CNV due to AMD (based on presence of leakage as seen by fluorescein angiography and of fluid as seen by OCT); VA of 20/25 to 20/320 on electronic visual acuity testing Exclusion criteria: fibrosis or atrophy in center of fovea in the study eye; CNV in either eye due to other causes; retinal pigment epithelial tear involving the macula; any concurrent intraocular condition in the study eye (e.g. cataract, diabetic retinopathy) that, in the opinion of the investigator, could require medical or surgical intervention or contribute to VA loss during 3‐year follow‐up period; active or recent (within 4 weeks) intraocular inflammation; current vitreous hemorrhage in study eye; history of rhegmatogenous retinal detachment or macular hole; active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis; spherical equivalent > 8 diopters; intraocular surgery (including cataract surgery) in study eye within 2 months; uncontrolled glaucoma; participants unable to be photographed to document CNV owing to known allergy to fluorescein dye, lack of venous access, or cataract obscuring the CNV; premenopausal women not using adequate contraception; pregnancy or lactation; history of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug, or that might affect interpretation of study results or render the individual at high risk for treatment complications; current treatment for active systemic infection; uncontrolled concomitant disease such as cardiovascular disease; nervous system, pulmonary, renal, hepatic, endocrine, or gastrointestinal disorders; history of recurrent significant infection or bacterial infection; inability to comply with study or follow‐up procedures Equivalence of baseline characteristics: slightly higher percentage of participants in bevacizumab monthly group had history of transient ischemic attack (8.7% vs 4% in ranibizumab monthly group, 4% in ranibizumab as‐needed group, and 6.3% in bevacizumab as‐needed group) Diagnoses in participants: 688/1185 (58%) had active neovascular AMD with CNV in foveal center; 315/1185 (27%) had fluid in foveal center; 93/1185 (8%) had hemorrhage in foveal center; 71/1185 (6%) had other foveal center involvement; and 18/1185 (1.5%) had no CNV or not possible to grade
Interventions	Intervention 1: 1.25 mg per 0.05 mL intravitreal bevacizumab injections on a fixed schedule of every 4 weeks for 1 year; at 1 year, re‐randomization to bevacizumab every 4 weeks or as needed Intervention 2: 0.5 mg intravitreal ranibizumab injections on a fixed schedule of every 4 weeks for 1 year; at 1 year, re‐randomization to ranibizumab every 4 weeks or as needed Intervention 3: 1.25 mg intravitreal bevacizumab as needed for 2 years Intervention 4: 0.5 mg intravitreal ranibizumab as needed for 2 years Length of follow‐up Planned: 12 months for primary analysis; 24 months for secondary analyses, with modifications to 2 intervention arms, as described above Actual: 12 months for primary analysis; 24 months for secondary analyses
Outcomes	Primary outcome, as defined: change in visual acuity from baseline at 12 months with a non‐inferiority margin of 5 letters Secondary outcomes: proportion of eyes with 15‐letter change, number of injections, OCT measured change in foveal thickness, change in lesion size on OCT and also on fluorescein angiography, incidence of ocular and systemic adverse events, annual drug cost Intervals at which outcomes were assessed: weeks 4, 12, 24, 36, and 52 during first year for visual acuity; weeks 4, 8, 12, 24, and 52 for changes on OCT
Notes	Full study name: Comparison of Age‐related Macular Degeneration Treatment Trials Trial registration: NCT00593450 Funding: National Eye Institute, National Institutes of Health, USA Declarations of interest: 1 investigator reported receiving consulting fees from GlaxoSmithKline and other consulting fees from Neurotech and SurModics Study period: accrual February 2008 through December 2009; follow‐up through December 2011 Reported subgroup analyses: none, but risk factors for 2‐year VA outcomes have been reported (Ying 2015 under CATT 2011) 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	"Patients were randomly assigned to 1 of 4 study groups. Randomization schedules were stratified according to clinical center with the use of a permuted‐block method with randomly chosen block sizes"
Allocation concealment (selection bias)	Low risk	Web‐based data entry system was used to allocate participants to treatment groups
Masking of participants (performance bias)	Unclear risk	Initially, participants were masked to which drug they received, but not to the treatment schedule. Study investigators noted that "insurance and billing documents specified ranibizumab but not study‐supplied bevacizumab. Therefore, patients may have learned or deduced their assigned drug from these financial documents"
Masking of study personnel (performance bias)	Low risk	Physicians were masked to drug but not to injection schedule. Physicians were uninvolved in visual acuity testing and in secondary outcome assessments
Masking of outcome assessment (detection bias)	Low risk	Electronic Visual Acuity system (computerized testing) was used for primary outcome. Retinal center personnel were masked. Adverse event reporting was unmasked, but medical monitor who evaluated serious adverse events was masked
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	103/1208 (8.5%) participants randomized were not included in 1‐year analysis. At 2 years, outcomes were not available for all participants by their originally assigned treatment groups
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes specified a priori for 1‐year follow‐up were reported
Other bias	Low risk	None observed