Shahraki 2022.

Study characteristics
Methods	Study design: randomised, triple‐masked (participant, care provider, investigator) trial. "In bilateral cases, each eye was randomly allocated individually; however, both eyes were not allocated to the same arm". Comment: most participants received different treatments for each eye. Therefore, we considered the design as a within‐person randomised clinical trial. Unit of randomisation: eye Unit of analyses: eye Follow‐up: 12 months
Participants	Country: Iran Setting: Ophthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Number of participants: 105 participants (only reported in the published protocol) / 207 eyes (1 or 2 eyes per participant) Exclusions post‐randomisation (eyes): PRP group: 7; IVB group: 17; modified combination group: 9 Losses to follow‐up (eyes): PRP group: 9; IVB group: 5; modified combination group: 7 Age (mean (range) Total: 53 ± 7.78 years PRP group: 53.52 ± 7.25 years IVB group: 51.96 ± 9.90 years Modified combination group: 54.70 ± 5.82 years Gender: males Total: 51.6% PRP group: 47% IVB group: 55.7% Modified combination group: 52% Inclusion criteria: Age ≥ 18 years. Type 1 or type 2 diabetes. Presence of PDR. Best corrected E‐ETDRS visual acuity letter score ≥ 24 (20/320 or better) Media clarity, pupillary dilation, and individual cooperation sufficient to administer PRP and obtain wide‐field FAG and optical coherence tomography (OCT). Exclusion criteria: Significant renal disease, defined as a history of chronic renal failure requiring dialysis or kidney transplant A condition that, in the opinion of the investigator, would preclude participation (e.g. unstable medical status including blood pressure, cardiovascular disease, and glycaemic control). Blood pressure > 180 (systolic)/110 (diastolic). Myocardial infarction, other acute cardiac event requiring hospitalisation, stroke, transient ischaemic attack, or treatment for acute congestive heart failure within 4 months prior to randomisation. Systemic anti‐VEGF or pro‐VEGF treatment within 4 months prior to randomisation. Women of child‐bearing potential: pregnant or lactating or intending to become pregnant within the next 3 years. History of prior PRP, defined as ≥ 100 burns outside of the posterior pole. Traction retinal detachment involving the macula. Neovascularisation of the angle. Macular oedema due to a cause other than diabetic macular oedema that, in the opinion of the investigator, might alter visual acuity during the course of the study (e.g. retinal vein or artery occlusion, uveitis or another ocular inflammatory disease, neovascular glaucoma, etc.). Substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual acuity by 3 lines or more. History of intravitreal anti‐VEGF treatment at any time in the past 2 months Use of corticosteroid treatment (intravitreal or peribulbar) at any time in the past 4 months. Major ocular surgery (including vitrectomy, cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior 4 months or anticipated within the next 6 months following randomisation. Capsulotomy performed within 2 months prior to randomisation. Aphakia. Uncontrolled glaucoma (in the investigator’s judgment). Exam evidence of severe external ocular infection, including conjunctivitis, chalazion, or substantial blepharitis
Interventions	Modified combination group 2 intravitreal injections of 0.125 mg of bevacizumab (IVB) injections and modified laser (1 session of retinal laser delivered only to the retina anterior to the equator either by conventional or pattern modes during the first 4 months. In the cases with worsening neovascularisation or new vitreous haemorrhage at either the fourth or eighth months, four monthly IVB injections were administered. If neovascularisation persisted (not worsened) at these visits, two monthly or bimonthly IVB injections were performed. In the cases with improved neovascularisation, no further intervention was considered. One session of rescue laser was also performed if worsening of neovascularisation was still noted in the eighth month. PRP group 2 or 3 PRP sessions during 3 months either through conventional or pattern modes. At the fourth and eighth months, if the eyes demonstrated worsened neovascularisation (at iris, retina, or optic disk) or developed new vitreous haemorrhage, two rescue IVB injections were planned, either monthly or bimonthly. If neovascularisation persisted (not worsened), one rescue IVB was performed. For the eyes with improved neovascularisation at the fourth and eighth months, no further intervention was considered. IVB group 4 intravitreal injections of 0.125 mg of IVB through 4 months. At a 4‐month visit if the iris, retinal, or optic disk neovascularisation worsened or if new vitreous haemorrhage occurred, 4 monthly IVB were added. The eyes with persistent neovascularisation in the fourth month received two additional monthly or bimonthly IVB injections. In the eyes with the improved neovascularisation, no additional injection was performed. The same strategy was applied in eighth month; however, if neovascularisation worsened at that time, rescue laser was applied in addition to four monthly IVB injections. All included eyes with visual acuity (VA) ≤ 20/32 and centre‐involving DME (defined as central macular thickness ≥ 300 mm based on Heidelberg Spectralis optical coherence tomography) received IVB injection(s). Duration: 4 months
Outcomes	Primary: BCVA (logMAR) at month 12 Secondary outcomes Change in the number and area of neovessels at month 12 Changes in MD of visual field at month 12 Complications (retinal detachment needing vitrectomy, neovascular glaucoma, iris neovascularisation, new vitreous haemorrhage) Number of visits during 1 year Number of intravitreal injections needed for treating DME during 1 year
Notes	Funding: not reported Trial registration: NCT04800679 Date conducted: From February 2017 to February 2021 Conflict of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “a randomized parallel assignment with triple‐blind protocol (participant, care provider, and investigator) was used. An allocation sequence produced by computer was prepared (A.R.) to be used for enrollment of the eyes.”
Allocation concealment (selection bias)	Low risk	Quote: “a randomized parallel assignment with triple‐blind protocol (participant, care provider, and investigator) was used. An allocation sequence produced by computer was prepared (A.R.) to be used for enrollment of the eyes.”
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: “a randomized parallel assignment with triple‐blind protocol (participant, care provider, and investigator) was used. An allocation sequence produced by computer was prepared (A.R.) to be used for enrollment of the eyes.” Comment: placebo was not used. In addition, it is difficult to conceal the administration of the treatments assessed.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: “a randomized parallel assignment with triple‐blind protocol (participant, care provider, and investigator) was used. An allocation sequence produced by computer was prepared (A.R.) to be used for enrollment of the eyes.” Comment: placebo was not used. It is difficult to conceal the administration of the treatments. The masking of investigators/assessors was not described.
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: “A total of 207 eyes were randomized. After deletion of the missing data, 153 eyes were included in the final analysis” Comment: high percentage (26%) of losses to follow‐up
Selective reporting (reporting bias)	Unclear risk	Comment: the number of participants is not reported.