MARINA 2006.

Methods	Number randomized (total and per group): 716 participants randomly assigned to study treatment: 238 to 0.3 mg ranibizumab group, 240 to 0.5 mg ranibizumab group, and 238 to sham injection group Exclusions after randomization: none Number analyzed (total and per group): all 716 participants: 238 to 0.3 mg ranibizumab group, 240 to 0.5 mg ranibizumab group, and 238 to sham injection group Unit of analysis: individuals (1 study eye per participant) Losses to follow‐up: 52 participants did not complete 12 months: 12 in the 0.3 mg ranibizumab group, 14 in the 0.5 mg ranibizumab group, and 26 in the sham injection group. Reasons included death, adverse events, loss to follow‐up, participant's decision, physician's decision, participant non‐compliance, and need for other therapeutic intervention Compliance: "more than 90% of patients in each treatment group remained in the study at 12 months, and approximately 80 to 90% remained at 24 months" Intention‐to‐treat analysis: yes; using last observation carried forward for missing data Reported power calculation: yes; sample of 720 participants for power of 95% Study design comment: following primary analyses of the study at 1 year and with recommendation of the data monitoring committee, study protocol was amended to offer treatment with 0.5 mg ranibizumab to participants still being followed in the sham control group. Study protocol was amended 4 months into the study to allow photodynamic therapy for active minimally classic or occult with classic lesions that were no larger than 4 disc areas in size and were accompanied by a 20‐letter or greater loss from baseline visual acuity confirmed at consecutive study visits. When photodynamic therapy was used, scheduled study treatment was postponed until the next scheduled monthly study visit
Participants	Country: USA Age: range 52 to 95 years; mean was 77 years in each of the 3 treatment groups Gender (per cent): 464/716 (65%) women and 252/716 (35%) men Inclusion criteria: age 50 years or older; active primary or recurrent subfoveal lesions with CNV secondary to AMD defined as (1) exhibiting at least a 10% increase in lesion size determined by comparing a fluorescein angiogram performed within 1 month before study day 0 with a fluorescein angiogram performed within 6 months preceding study day 0, (2) resulting in a visual acuity loss of greater than 1 Snellen line any time within prior 6 months, or (3) subretinal hemorrhage associated with CNV within 1 month preceding study day 0; total area of CNV encompassed within the lesion at least 50% of total lesion area; total lesion area of 12 disc areas or less in size; best‐corrected visual acuity of 20/40 to 20/320 (Snellen equivalent on ETDRS chart). Participants with lesions with an occult CNV component were included, but for participants with concomitant classic CNV, the area of classic CNV must have been less than 50% of total lesion size Exclusion criteria: prior treatment with verteporfin, external beam radiation therapy, or transpupillary thermotherapy in the study eye; previous participation in a clinical trial involving anti‐angiogenic drugs; treatment with verteporfin in non‐study eye less than 7 days before study day 0; previous intravitreal drug delivery or subfoveal focal laser photocoagulation in study eye; laser photocoagulation in study eye within 1 month preceding study day 0; history of vitrectomy surgery, submacular surgery, or other surgical intervention for AMD in study eye; participation in any studies of investigational drugs within 1 month preceding study day 0; subretinal hemorrhage in study eye involving center of the fovea if hemorrhage involves 50% or more of total lesion area or measures 1 or more disc areas in size; subfoveal fibrosis or atrophy in study eye; CNV in either eye due to other causes; retinal pigment epithelial tear involving the macula in the study eye Equivalence of baseline characteristics: yes Diagnoses in participants: 1/716 (0.1%) had predominantly classic CNV; 264/716 (37%) had minimally classic CNV; and 451/716 (63%) had occult with no classic CNV
Interventions	Intervention 1: 0.3 mg ranibizumab intravitreal injection monthly for 2 years Intervention 2: 0.5 mg ranibizumab intravitreal injection monthly for 2 years Intervention 3: sham injection monthly for 2 years In all intervention groups, verteporfin photodynamic therapy for the study eye was allowed if choroidal neovascularization converted to a predominantly classic pattern Length of follow‐up Planned: 2 years Actual: 2 years
Outcomes	Primary outcomes, as defined: proportion of participants who lost fewer than 15 letters from baseline visual acuity in study eye at 12 months Secondary outcomes, as defined: proportion of participants who gained 15 or more letters from baseline, proportion of participants with a Snellen equivalent of 20/200 or worse, and mean change from baseline (letters over time); mean change from baseline to month 12 in size of the classic CNV component and total area of leakage from CNV Exploratory efficacy endpoints: proportion of participants with visual acuity 20/40 or better and 20/20 at 12 and 24 months (Snellen equivalent), total area of and change from baseline CNV lesion, area of leakage Adverse events: include ocular and non‐ocular adverse events and proportion of participants developing immunoreactivity to ranibizumab, intraocular inflammation, and IOP Safety assessments: IOP measurement 60 minutes after each injection, incidence and severity of ocular and non‐ocular adverse events, changes and abnormalities in clinical laboratory parameters and vital signs, and immunoreactivity to ranibizumab Intervals at which outcomes assessed: 12 and 24 months
Notes	Full study name: Minimally Classic/Occult Trial of the Anti‐VEGF Antibody Ranibizumab in the Treatment of Neovascular Age‐Related Macular Degeneration Trial registration: NCT00056836 Funding sources: Genentech, USA, and Novartis Pharma, Switzerland Declarations of interest: various authors reported that they had received consulting fees from Genentech, Eyetech, Novartis Ophthalmics, Novartis, QLT, Alcon Laboratories, Pfizer, Regeneron, Theragenics, VisionCare, Protein Design Labs, Allergan, BioAxone, Tanox, Genaera, Jerini, Oxigene, Quark, Genzyme, iScience, ISTA, and Athenagen; lecture fees from Genentech, Eyetech, Pfizer, Jerini, Allergan, and Novartis Ophthalmics; grant support from Genentech, Novartis, Eyetech, Pfizer, Theragenics, and Genaera and Alcon Laboratories; and/or equity interest in Pfizer and/or were employees of Genentech and owned Genentech stock Study period: enrollment March 2003 to December 2003 Reported subgroup analyses: by baseline lesion (4 or fewer optic disc areas; more than 4), type of lesion (minimally classic; occult with no classic), and baseline VA (fewer than 55 letters; 55 or more letters) Contacting study investigators: trial authors contacted and contributed information for this review
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Eligible patients were randomly assigned in a 1:1:1 ratio, using a dynamic randomization algorithm, to receive ranibizumab (LUCENTIS®, Genentech, Inc., South San Francisco, CA) 0.3 or 0.5 mg or a sham injection monthly (30±7 days) for 2 years (24 injections). Randomization was stratified by baseline visual acuity score (< 55 letters [approximately worse than 20/80] vs. ≥ 55 letters) at day 0, by choroidal neovascularization subtype (minimally classic or occult with no classic), and by study center"
Allocation concealment (selection bias)	Low risk	"A centralized interactive voice response system (IVRS) was used to handle the randomization" (email communication with Genentech, dated October 24, 2007)
Masking of participants (performance bias)	Low risk	"All other study site personnel (except those assisting with injections), patients, and central reading center personnel were masked to treatment assignment"
Masking of study personnel (performance bias)	Low risk	"Masking of treatment assignment required at least two investigators per study site: an evaluating physician (masked to treatment assignment) and an injecting physician (unmasked regarding ranibizumab or sham treatment but masked to ranibizumab dose)"
Masking of outcome assessment (detection bias)	Low risk	"All other study site personnel (except those assisting with injections), patients, and central reading center personnel were masked to treatment assignment"
Incomplete outcome data (attrition bias) All outcomes	Low risk	"Efficacy analyses were performed on an intent‐to‐treat basis (all randomized patients) using a last observation carried forward method to handle missing data"
Selective reporting (reporting bias)	Low risk	We did not have access to the protocol. We matched all outcomes reported in publications with those reported to the FDA
Other bias	Unclear risk	Sponsored by Genentech and Novartis Pharma. Study authors disclosed financial interests and/or were paid consultants, employees, and/or shareholders of funding companies