RESTORE 2011

Methods	Parallel group RCT One eye per person, eye with worse VA selected unless other eye more suitable for treatment
Participants	Country: 10 European countries, Australia, Canada, Turkey Number of people randomised: 345 (345 eyes) Average age: 63 years Sex: 42% women Inclusion criteria: 18 years or older diabetes mellitus (according to the American Diabetes Association or World Health Organization guidelines) HbA1c ≤ 10% visual impairment due to DMO stable medication for the management of diabetes within 3 months before randomisation and expected to remain stable during the study visual impairment due to focal or diffuse DMO in at least 1 eye that was eligible for laser treatment in the opinion of the investigator BCVA letter score between 78‐39, both inclusive, based on ETDRS‐like VA testing charts administered at a starting distance of 4 m (approximate Snellen equivalent 20/32‐20/160) decreased vision due to DMO and not other causes, in the investigator’s opinion (at visit 1) Exclusion criteria: concomitant conditions in the study eye that could prevent the improvement in VA on the study treatment in the investigator’s opinion active intraocular inflammation or infection in either eye uncontrolled glaucoma in either eye (e.g. IOP > 24 mmHg on medication, or from the investigator’s judgement) laser PRP (within 6 months) or focal/grid laser photocoagulation (within 3 months) before study entry treatment with antiangiogenic drugs in the study eye within 3 months before randomisation history of stroke systolic BP > 160 mmHg or diastolic BP > 100 mmHg untreated hypertension change in antihypertensive treatment within 3 months preceding baseline
Interventions	Intervention: ranibizumab (0.5 mg) plus sham laser n = 116 (116 eyes) ranibizumab (0.5 mg) plus laser n = 118 (118 eyes) Comparator laser treatment plus sham injections n = 111 (111 eyes)
Outcomes	Primary outcome: mean average change in BCVA from baseline over 12 months Secondary outcomes: VA improvement BCVA letter score 73 (20/40 Snellen equivalent) at month 12 mean change in BCVA letter score mean change in central retinal (subfield) thickness patient‐reported outcomes safety Follow‐up: 12 months
Notes	Dates participants enrolled: not reported Funding: Novartis Conflict of interest: authors reported financial support of Novartis or were Novartis employees Trial registration: NCT00906464
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"A randomization list was produced by, or under the responsibility of, Novartis Drug Supply Management using a validated system that automated the random assignment of treatment arms to randomization numbers in the specified ratio." Appendix 1
Allocation concealment (selection bias)	Low risk	Central randomisation using an electronic Case Report Form after each participant was included by study investigators
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"The masked BCVA assessor evaluated the visual acuity of the patient and provided the results to the evaluating investigator who also was masked to the treatment assignment. The evaluating investigator was responsible for all other aspects of the study, excluding the injection procedures. Based on all the performed clinical assessments and the visual acuity (VA) results received from the BCVA assessor, the evaluating investigator had to decide on the treatment requirements for the patient each month and communicated this decision to the treating investigator. The treating investigator was unmasked to the treatment assignment and performed all injections or laser treatment as well as the corresponding sham treatments. He/she was required not be involved in any other aspect of the study and not to divulge the patient’s treatment assignment to anyone. Once the designated roles were determined, the roles could not be switched at any time during the conduct of the study. Every effort was made to limit the number of unmasked study personnel to ensure the integrity of this masked study. An independent review and standardized grading of fundus photography, fluorescein angiography, and optical coherence tomography (OCT) images for the patients screened and enrolled in the study was performed at a central reading center that did not have access to any other data of the patients."Appendix 1
Blinding of outcome assessment (detection bias) All outcomes	Low risk	See above
Incomplete outcome data (attrition bias) All outcomes	Low risk	Participants randomised in each group were: 116 ranibizumab, 118 ranibizumab + laser, 111 laser At 1 year complete participants were 87.9%, 87.3% and 88.3% respectively There were 2 deaths in each of the 3 treatment arms Used ITT analysis with LOCF
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