title: The role of sub-retinal fluid in determining treatment outcomes in patients with neovascular age-related macular degeneration--a phase IV randomised clinical trial with ranibizumab: the FLUID study.
abstract: BACKGROUND
  With increasing experience using anti-VEGF therapy for the treatment of neovascular age-related macular degeneration (nAMD), ophthalmologists have shifted away from a "one size fits all" to an "individualised" approach based on disease activity with the aim of achieving a fluid-free retina. The FLUID study investigates the non-inferiority of a Treat and Extend (T&E) protocol of 0.5 mg ranibizumab, which allows treatment extension in the presence of incomplete resolution of sub-retinal fluid (SRF) ≤200 μm at the foveal centre relative to a T&E protocol that requires complete resolution of all retinal fluid (i.e., both SRF and intra-retinal fluid [IRF]) in patients with nAMD.
  
  
  METHODS
  This 24 month, randomised, phase IV trial has completed recruitment of treatment-naïve patients randomised 1:1 to ranibizumab "intensive" treatment (complete resolution of IRF and SRF) or ranibizumab "relaxed" treatment (resolution of IRF or >200 μm SRF only at foveal centre). Patients in both arms follow a T&E regimen where extension decisions are based upon assessment of lesion activity: loss of ≥5 letters of visual acuity, new haemorrhage, presence of IRF and SRF on an optical coherence tomography (OCT) scan. The determination of SRF is conducted at a reading centre while the assessment of IRF is physician-determined. The primary endpoint is the mean change in best-corrected visual acuity (BCVA) from baseline to 24 months. Secondary endpoints include the mean change in central retinal thickness (CRT) from baseline to 12 and 24 months, the number of ranibizumab injections administered at 12 and 24 months, and the pharmacogenomic assessment of AMD Gene Consortium-identified single-nucleotide polymorphisms (SNPs) and their association with treatment response. Three hundred and forty seven (347) patients have been recruited by 16 Australian sites within approximately 16 months. A protocol to adjudicate on SRF has been established by the central reading centre and is demonstrating good concordance with investigator assessment.
  
  
  CONCLUSIONS
  This study will provide important insights into retreatment criteria for managing nAMD using a T&E regimen. The current paper describes the clinical rationale for using a less intensive treatment approach using ranibizumab and details of the treatment protocol.
  
  
  BACKGROUND
  
  
  
  BACKGROUND
  NCT01972789. Date of registration: 24th October 2013.
authors.affiliation: Marsden Eye Specialists, 152 Marsden St, Parramatta, NSW, 2150, Australia. jennifer.arnold@marsdeneye.com.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Arnold
authors.affiliation: Markey Medical Consulting Pty Ltd, PO Box 136, Frenchs Forest, NSW, 1640, Australia.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Markey
authors.affiliation: Novartis Pharmaceuticals Australia, Pty Ltd, 54 Waterloo Rd, Macquarie Park, NSW, 2113, Australia.
authors.forename: Nicol P
authors.initials: NP
authors.lastname: Kurstjens
authors.affiliation: Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, 32 Gisborne St, East Melbourne, VIC, 3002, Australia.
authors.forename: Robyn H
authors.initials: RH
authors.lastname: Guymer
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D000069579:Ranibizumab / Q000627:therapeutic use*; D058471:Subretinal Fluid; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D014792:Visual Acuity / Q000502:physiology; D057135:Wet Macular Degeneration / Q000175:diagnosis* / Q000188:drug therapy*
chemical_list: D020533:Angiogenesis Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000069579:Ranibizumab
keywords: Intra-retinal fluid; Neovascular AMD; Ranibizumab; Sub-retinal fluid; Treat and extend regimen