RESOLVE 2010

Methods	Parallel group RCT One eye per person, eye with worse VA selected
Participants	Country: unclear exactly where conducted. Investigators from Australia, Denmark, Austria, France, Germany, Italy, Korea, Portugal, Spain, Switzerland, UK Number of people randomised: 151 (151 eyes) Average age: 64 years (range 32 to 85) Sex: 46% women Inclusion criteria: 18 years or older diabetes mellitus stable HbA1c levels (≤ 12%) DMO with centre involvement in at least one eye (study eye) CRT ≥ 300 μm (Stratus Zeiss Meditec) BCVA score between 73‐39 letters inclusively, using ETDRS charts at a testing distance of 4 m (approximate Snellen equivalent of 20/40‐20/160) decreased vision attributed to foveal thickening from DMO, that was not explained by any other causes in the opinion of the investigator laser photocoagulation, additional or first treatment, could be withheld for at least 3 months after randomisation Exclusion criteria: PRP (focal peripheral laser photocoagulation) performed within 6 months prior to study entry. Grid/central laser photocoagulation was excluded except for participants with only mild laser burns at least 1000 µm from the centre of the fovea performed more than 6 months before the trial commenced PDR in the study eye, with the exception of tufts of neovascularization < 1 disc area with no vitreous haemorrhage. As well as those with area of retinal ischaemia ≥ 500 µm and located ≤ 500 µm from the centre of the macula of the study eye as assessed by fluorescein angiography at visit 1 and confirmed by a central reading centre participants with unstable medical conditions such as poor glycaemic or BP control participants with hypertension for whom a change in antihypertensive treatment was initiated within 2 months preceding start of trial were not enrolled unless BP was maintained below 160/100 mmHg for at least 1 month prior to the first day of the trial by antihypertensive treatment history of treatment with systemic corticosteroids within 4 months prior to randomisation or topical, rectal or inhaled corticosteroids in current use more than 2 times per week previous participation in a study on antiangiogenic drugs ocular disorders and history of any condition that might confound the interpretation of study results or might render participant at high risk for treatment complications ocular inflammation in either eye or history of cataract surgery in the study eye within 6 months before study initiation pre‐menopausal women not using adequate contraception and pregnant or nursing women
Interventions	Intervention: ranibizumab (0.3 mg or 0.5 mg) n = 102 (102 eyes) Comparator: sham injection n = 49 (49 eyes)
Outcomes	Primary outcome: mean change in BCVA from baseline at 1 month and 12 months Secondary outcomes: mean change in BCVA and CRT from baseline at 12 months categorised BCVA outcome safety
Notes	Dates participants enrolled: not reported Funding: Novartis Conflict of interest: authors served on advisory boards for Novartis and received honoraria and travel and accommodation payments; Novartis employees assisted with the analysis, interpretation and writing Trial registration:NCT00284050
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Eligible patients were randomised 1:1:1 to either ranibizumab (0.3 mg or 0.5 mg) or sham treatment according to a computer‐generated randomised allocation schedule" Online appendix page 1
Allocation concealment (selection bias)	Low risk	"...allocation schedule (kept at a secure site and accessible only to the injecting physician" Online appendix page 1 "Based on the patient strata the injecting physician would take the treatment allocation card and tear‐off the cover and follow instructions to choose vial from the box as indicated (3 boxes, randomisation block size 3). The randomisation data were kept strictly confidential until database lock; not accessible to anyone involved in the study with the exception of injecting physician(s) and drug accountability monitor." Online appendix page 1
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Sham injection for masking participants
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	"Masking was maintained through appointment of a minimum of 2 investigators at each study site; unmasked injecting physician and a masked evaluating physician (roles could not be switched)." Online appendix page 1
Incomplete outcome data (attrition bias) All outcomes	Low risk	Participants who completed the trial at 1 year: 92/102 ranibizumab and 40/49 sham. Causes of missingness were balanced ITT analysis with LOCF was used
Selective reporting (reporting bias)	Low risk	We could not find a protocol, but primary outcomes were stated in the methods and were those routinely used in the field
Other bias	Low risk	No other source of bias identified
Overall risk of bias	Low risk	Low risk of bias for most items