Comparison of Treatment Regimens Using Ranibizumab: Intensive (Resolution of Intra- and Sub-retinal Fluid) vs Relaxed (Resolution of Intra-retinal Fluid and/or Sub-retinal Fluid >200µm at the Foveal Centre) (FLUID)

A Phase IV, Randomised, Single Masked Study Investigating the Efficacy and Safety of Ranibizumab "Inject and Extend" Using an Intensive Retinal Fluid Retreatment Regimen Compared to a Relaxed Retinal Fluid Retreatment Regimen in Patients With Wet Age-related Macular Degeneration (AMD)

To evaluate and compare two individualised ranibizumab treatment regimens, differentiated by the definition of disease activity, which determines the treatment interval until the next injection. The results will be used to generate recommendations about ranibizumab treatment when using an 'inject and extend' approach to maximise patient outcomes, while reducing the need for potentially unnecessary intravitreal injections. This study will also investigate if genotypic expression influences response to intravitreal injections of ranibizumab between the two treatment arms.

The study hypothesis is that intravitreal ranibizumab when administered to resolve IRF (and/or SRF >200 μm at the foveal centre) results in visual acuity benefit that is not clinically worse than intravitreal ranibizumab when administered to completely resolve both IRF and SRF in patients with wet AMD

Study Overview

• Status: Completed
• Conditions: Subfoveal Choroidal Neovascularization CNV Secondary to Wet Age-related Macular Degeneration AMD
• Intervention / Treatment: Drug: Ranibizumab

• Study Type: Interventional
• Enrollment (Actual): 349
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Albury, New South Wales, Australia, 2640
      • Novartis Investigative Site
    • Chatswood, New South Wales, Australia, 2067
      • Novartis Investigative Site
    • Eastwood, New South Wales, Australia, 2122
      • Novartis Investigative Site
    • Hurtsville, New South Wales, Australia, 2220
      • Novartis Investigative Site
    • Liverpool, New South Wales, Australia, 2170
      • Novartis Investigative Site
    • North Ryde, New South Wales, Australia, 2109
      • Novartis Investigative Site
    • Parramatta, New South Wales, Australia, 2150
      • Novartis Investigative Site
    • Strathfield, New South Wales, Australia, 2135
      • Novartis Investigative Site
    • Sydney, New South Wales, Australia, 2000
      • Novartis Investigative Site
    • Westmead, New South Wales, Australia, 2145
      • Novartis Investigative Site
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Novartis Investigative Site
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Novartis Investigative Site
    • South Launceston, Tasmania, Australia, 7249
      • Novartis Investigative Site
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Novartis Investigative Site
    • Melbourne, Victoria, Australia, 3002
      • Novartis Investigative Site
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Diagnosis of subfoveal CNV secondary to wet AMD without restriction of lesion size, with visual impairment being exclusively due to an active wet AMD lesion. Active lesions will be characterised by any of the following: abnormal retinal thickness, with evidence of intraretinal, subretinal or sub-pigment epithelial fluid accumulation, confirmed by OCT; presence of intraretinal or subretinal haemorrhage; new leakage shown on a FA; CNV enlargement on FA unless solely due to dry, fibrotic staining; visual acuity deterioration considered likely to represent CNV.
2. BCVA score at both Screening and Baseline must be 23 letters or more as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) logMAR charts (a Snellen visual acuity or equivalent of 20/320 or more may be used as an alternative at Screening).

Exclusion Criteria:

1. Any active periocular or ocular infection or inflammation (e.g., blepharitis, conjunctivitis, keratitis, scleritis, uveitis, endophthalmitis) at the time of Screening or Baseline.
2. Uncontrolled glaucoma (intraocular pressure [IOP] ≥30 mm Hg on medication) at the time of Screening or Baseline.
3. Neovascularisation of the iris or neovascular glaucoma at the time of Screening or Baseline.
4. Visually significant cataract, aphakia, severe vitreous haemorrhage, rhegmatogenous retinal detachment, proliferative diabetic retinopathy or CNV of any cause other than wet AMD at the time of screening and baseline.
5. Structural damage within 0.5 disc diameter of the centre of the macula (e.g., vitreomacular traction, epiretinal membrane, scar, laser burn, foveal atrophy) at the time of screening that in the investigator's opinion could preclude visual function improvement with treatment.
6. Treatment with any anti-angiogenic drugs (including any anti-VEGF agents) prior to Baseline in study eye (allowed in fellow eye).
7. Any intraocular procedure (including Ytrium-Aluminium- Garnet capsulotomy) within 2 months prior to Baseline or anticipated within the next 6 months following Baseline in th study eye (allowed in fellow eye).

Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intensive retinal fluid regimen; Ranibizumab 0.5mg is given monthly for the first 3 months followed by an individualised treatment regimen as determined by disease activity defined by a loss of ≥5 letters, new retinal haemorrhage, presence of any IRF or SRF on OCT.	Drug: Ranibizumab; Ranibizumab solution for injection is commercially supplied in two presentations: as a pre-filled syringe (containing 1.65 mg of ranibizumab in 0.165 mL solution) and as a vial (containing 2.3 mg of ranibizumab in 0.23 mL solution) corresponding to a recommended dose of 0.5 mg (0.05 mL) given as a single intravitreal injection. It will be prescribed and administered by the investigator or designee; Other Names: LUCENTIS
Experimental: Relaxed retinal fluid regimen; Ranibizumab 0.5mg is given monthly for the first 3 months followed by an individualised treatment regimen as determined by disease activity defined by a loss of ≥5 letters, new retinal haemorrhage, presence of IRF or SRF >200 um on OCT.	Drug: Ranibizumab; Ranibizumab solution for injection is commercially supplied in two presentations: as a pre-filled syringe (containing 1.65 mg of ranibizumab in 0.165 mL solution) and as a vial (containing 2.3 mg of ranibizumab in 0.23 mL solution) corresponding to a recommended dose of 0.5 mg (0.05 mL) given as a single intravitreal injection. It will be prescribed and administered by the investigator or designee; Other Names: LUCENTIS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in Best-corrected Visual Acuity (BCVA) From Baseline to 24 Months.	Best-corrected visual acuity (BCVA) with refraction will be taken using a logMAR chart at a distance of 3 metres in the study eye at baseline and month 24.	Baseline to month 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in BCVA From Baseline to Month 12.	Best-corrected visual acuity (BCVA) with refraction will be taken using a logMAR chart at a distance of 3 metres in the study eye at baseline and month 12.	Baseline to month 12
Mean Change in Central Retinal Thickness (CRT) From Baseline to Month 12 and 24.	Central retinal thickness will be measured by Optical Coherence Tomography (OCT) at every visit.	Baseline to month 12 and month 24
Mean Number of Injections From Baseline to Month 12 and 24	The number of injections will be determined by the individual patient response to ranibizumab therapy and potential for extension between injections based on specific criteria: loss of visual acuity, new retinal haemorrhage, and presence of IRF or SRF on OCT.	Baseline to month 12 to month 24.
Mean Change in Area of New and Existing Geographic Atrophy From Baseline to Month 12 and 24.	Autofluorescence will be measured by multimodal imaging to assess the presence and development of geographic atrophy in the study at baseline, and month 12 and 24.	Baseline to months 12 and 24.
Proportion of Patients Showing Newly Developed Geographic Atrophy (GA) at Months 12 and 24	A multimodal imaging approach will be used to assess the presence of new geographic atrophy (defined as incorporating both geographic atrophy and atrophy associated with the CNV) in the study eye at baseline, and month 12 and 24. Image modalities will include fundus autofluorescence (AF) imaging, infrared imaging, OCT and colour fundus (CF) photographs. Atrophy will be diagnosed if FA and one other modality confirm the presence of macular atrophy	Months 12 and 24
Proportion of Patients Showing no IRF and SRF at Months 2, 12 and 24.	Assessed by Optical Coherence Tomography (OCT) and confirmed by a central reading centre.	Months 2, 12 and 24.
Proportion of Patients Showing Greater Than or Equal to 15 Letters Early Treatment Diabetic Retinopathy (ETDRS) Gain From Baseline to Month 12 and 24.	Best-corrected visual acuity (BCVA) with refraction will be taken using a logMAR chart at a distance of 3 metres in the study eye at baseline and months 2, 12 and 24.	Baseline to months 12 and 24.
Proportion of Patients Showing Less Than 15 Letters ETDRS Loss From Baseline to Month 12 and 24.	Best-corrected visual acuity with refraction will be taken using a logMAR chart at a distance of 3 metres in the study eye at baseline and months 2, 12 and 24.	Baseline to months 12 and 24
Number of Participants With the Genotypes Associated With Age-Related Macular Degeneration (AMD) and Response to Treatment at Baseline; Correlation With Visual Acuity (VA) Outcome and Ability to Dry the Retina.	DNA will be extracted from saliva and genotyping performed on the significantly associated single nucleotide polymorphisms (SNPs) identified by the AMD Gene Consortium (Nature Genetics, March 2013). Genotypes will be derived through the use of a Sequenom Iplex protocol. No correlation analyses were performed.	Baseline or following consent
Proportion of Patients With Both SRF (Sub-retinal Fluid) and IRF (Intra-retinal Fluid) Who Despite Monthly Treatment do Not Resolve Their SRF	Assessed by Optical Coherence Tomography (OCT) and confirmed by a central reading centre.	Month 12 and 24
The Number of Times a Participant Needs to Return to Monthly Treatments During the 24 Months.	Treatment requirements will be determined by the individual patient disease activity as measured by OCT, BCVA, colour fundus photography and fluorescein angiography (FA). Analysis was not performed.	Month 24

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Arnold JJ, Markey CM, Kurstjens NP, Guymer RH. 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. BMC Ophthalmol. 2016 Mar 24;16:31. doi: 10.1186/s12886-016-0207-3.

Study record dates

Study Major Dates

• Study Start (Actual): October 31, 2013
• Primary Completion (Actual): February 28, 2017
• Study Completion (Actual): February 28, 2017

Study Registration Dates

• First Submitted: October 24, 2013
• First Submitted That Met QC Criteria: October 24, 2013
• First Posted (Estimate): October 30, 2013

Study Record Updates

• Last Update Posted (Actual): October 23, 2019
• Last Update Submitted That Met QC Criteria: September 30, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: inject and extend; Subfoveal choroidal neovascularization (CNV); wet age-related macular degeneration(AMD); retinal fluid
• Additional Relevant MeSH Terms: Pathologic Processes; Eye Diseases; Retinal Degeneration; Retinal Diseases; Uveal Diseases; Choroid Diseases; Metaplasia; Macular Degeneration; Choroidal Neovascularization; Neovascularization, Pathologic; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Ranibizumab
• Other Study ID Numbers: CRFB002AAU15

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No