Table 1.

Phase 3 randomised controlled trials investigating treatment of neovascular age-related macular degeneration with intravitreal anti-vascular endothelial growth factors using a proactive capped pro re nata or treat and extend regimen

Study	Study type	Intravitreal medication and treatment	DA criteria	Treatment regimen alteration	Primary end-point and outcome	Percentage of eyes with no macular fluid at 12 months
VIEW (2012)	Multicentre phase 3 RCT N = 2419	Aflibercept 0.5 or 2 mg monthly or 2-monthly vs ranibizumab 0.5 mg monthly From week 52 to 96, IVT every 12 weeks with monthly evaluation for interim injections (capped PRN)	1. Increase in central retinal thickness of ≥ 100 μm 2. Loss of ≥ 5 ETDRS letters from best previous with recurrent fluid 3. New onset classic neovascularisation 4. New or persistent leak on fluorescein angiography 5. New macular haemorrhage Time lapse of 12 weeks since previous injections	Monthly evaluation	Non-inferiority of visual acuity At 96 weeks, gain in visual acuity (letters)  7.9 (ranibizumab)  7.6 (aflibercept)	62.0 (ranibizumab) 72.4 (2 mg aflibercept monthly) 60.3 (0.5 mg aflibercept monthly) 67.7 (2 mg aflibercept bi-monthly)
HAWK & HARRIER (2019)	Multicentre phase 3 RCT N = 1817	Brolucizumab (3 mg or 6 mg) and aflibercept 2 mg Randomised to brolucizumab at every 12 weeks after loading phase decreased to fixed 8-weekly treatment if signs of disease activity and aflibercept 2 mg (fixed bi-monthly dosing)	Week 16 1. Decrease in BCVA ≥ 5 letters compared to baseline 2. Decrease in BCVA ≥ 3 letters and CST increase of ≥ 75 compared with week 12 3. Decrease in BCVA ≥ 5 letters due to nAMD disease activity compared to week 12 4. New or worse intraretinal cysts or intraretinal fluid Weeks 20, 28, 32, 40, 44 BCVA decline compared to week 12	Brolucizumab 3-monthly injections With default 12-weekly treatment Patients assessed at week 16 and 20 visit Additional assessment week 28 and week 40 (HARRIER) If signs of disease activity, permanent switch to 8-weekly if stable	Non-inferiority of BCVA Percentage of patients attaining 12-weekly treatment Gain in visual acuity (letters) HAWK  6.1 (brolucizumab 3 mg)  6.6 (brolucizumab 6 mg)  6.8 (aflibercept) HARRIER  6.9 (brolucizumab 6 mg)  7.6 (aflibercept)	HAWK  68.9 (brolucizumab)  55.3 (aflibercept) HARRIER  74.1 (brolucizumab)  56.4 (aflibercept)
TENAYA & LUCERNE (2022)	Multicentre phase 3 RCTs N = 273	Faricimab and aflibercept 2 mg Faricimab (fixed regime 8-, 12- or 16-weekly depending on week 20 and 24 assessment) and aflibercept 2 mg (fixed dosing)	1. At discretion of masked observer 2. Increase of > 50 μm in CST compared with average CST over previous 2 visits 3. Increase of > 75 μm in CST compared with lowest CST of 2 previous visit 4. Decrease of ≥ 5 letters compared with average BCVA over previous 2 visits, due to nAMD activity 5. Decrease of ≥ 10 letters compared with highest BCVA of previous 2 visits, due to nAMD activity 6. Presence of new macular haemorrhage	Four-monthly treatments of faricimab Then disease assessments for any sign of DA Week 20: active disease, treated with 8-weekly fixed dosing until week 60 Week 24: active disease, treated with 12-weekly fixed dosing until week 60 Week 20 and 24: no disease activity, 16-weekly fixed dosing until week 60 At week 24, presence of DA that does not meet disease activity criteria but requires immediate treatment in opinion of investigator received 12-weekly treatment	Mean change in BCVA Gain in visual acuity (letters) TENAYA  5.8 (faricimab)  5.1 (aflibercept) LUCERNE  6.6 (faricimab)  6.6 (aflibercept)	Not recorded

BCVA best corrected visual acuity, CST central subfield thickness, DA disease activity, ETDRS Early Treatment of Diabetic Retinopathy Study, OCT optical coherence tomography, PRN pro re nata, RCT randomised controlled trial, RF intraretinal fluid, SRF subretinal fluid, VA visual acuity