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.

Jennifer J Arnold,Robyn H Guymer,Nicol P Kurstjens,Caroline M Markey

doi:10.1186/s12886-016-0207-3

Abstract

BackgroundWith 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/DesignThis 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.DiscussionThis 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.Trial registrationTrial registration number: NCT01972789. Date of registration: 24th October 2013.

Highlights

With increasing experience using anti-vascular endothelial growth factor (VEGF) therapy for the treatment of neovascular age-related macular degeneration, 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 advent of anti-vascular endothelial growth factor (VEGF) designed for intraocular injection has revolutionised the treatment of neovascular age-related macular degeneration, the leading cause of severe vision loss in the elderly population
With the evaluation of different injection regimens through subsequent prospective clinical trials (PIER, EXCITE, SUSTAIN) and increasing clinical experience by ophthalmologists, it became clear that less frequent ranibizumab injections could yield visual benefits in certain subgroups of patients comparable to those of monthly injections [4,5,6,7,8,9,10]

Summary

Introduction

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. In the randomised, controlled trial CATT, which evaluated monthly monitoring and a pro re nata (PRN) or ‘as needed’ treatment approach with anti-VEGF therapy, PRN ranibizumab treatment was observed to be noninferior to monthly ranibizumab in terms of visual outcome at one year, but reduced the number of injections by almost one-half, the second year results demonstrated a greater gain in visual acuity with monthly injections relative to PRN for both ranibizumab and bevacizumab treatments (p = 0.046 for regimen) [11, 12]. Individualised approaches, requiring the determination of disease activity, is widely used in protocols using all anti-VEGF agents

Objectives

Methods

Findings

Conclusion