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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)

Primary Purpose

Subfoveal Choroidal Neovascularization CNV Secondary to Wet Age-related Macular Degeneration AMD

Status
Completed
Phase
Phase 4
Locations
Australia
Study Type
Interventional
Intervention
Ranibizumab
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Subfoveal Choroidal Neovascularization CNV Secondary to Wet Age-related Macular Degeneration AMD focused on measuring Subfoveal choroidal neovascularization (CNV), wet age-related macular degeneration(AMD), inject and extend, retinal fluid

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Intensive retinal fluid regimen

Relaxed retinal fluid regimen

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.

Full Information

First Posted
October 24, 2013
Last Updated
September 30, 2019
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01972789
Brief Title
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)
Acronym
FLUID
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2019
Overall Recruitment Status
Completed
Study Start Date
October 31, 2013 (Actual)
Primary Completion Date
February 28, 2017 (Actual)
Study Completion Date
February 28, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Subfoveal Choroidal Neovascularization CNV Secondary to Wet Age-related Macular Degeneration AMD
Keywords
Subfoveal choroidal neovascularization (CNV), wet age-related macular degeneration(AMD), inject and extend, retinal fluid

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantOutcomes Assessor
Allocation
Randomized
Enrollment
349 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Intensive retinal fluid regimen
Arm Type
Experimental
Arm Description
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.
Arm Title
Relaxed retinal fluid regimen
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Ranibizumab
Other Intervention Name(s)
LUCENTIS
Intervention Description
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
Primary Outcome Measure Information:
Title
Mean Change in Best-corrected Visual Acuity (BCVA) From Baseline to 24 Months.
Description
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.
Time Frame
Baseline to month 24
Secondary Outcome Measure Information:
Title
Mean Change in BCVA From Baseline to Month 12.
Description
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.
Time Frame
Baseline to month 12
Title
Mean Change in Central Retinal Thickness (CRT) From Baseline to Month 12 and 24.
Description
Central retinal thickness will be measured by Optical Coherence Tomography (OCT) at every visit.
Time Frame
Baseline to month 12 and month 24
Title
Mean Number of Injections From Baseline to Month 12 and 24
Description
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.
Time Frame
Baseline to month 12 to month 24.
Title
Mean Change in Area of New and Existing Geographic Atrophy From Baseline to Month 12 and 24.
Description
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.
Time Frame
Baseline to months 12 and 24.
Title
Proportion of Patients Showing Newly Developed Geographic Atrophy (GA) at Months 12 and 24
Description
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
Time Frame
Months 12 and 24
Title
Proportion of Patients Showing no IRF and SRF at Months 2, 12 and 24.
Description
Assessed by Optical Coherence Tomography (OCT) and confirmed by a central reading centre.
Time Frame
Months 2, 12 and 24.
Title
Proportion of Patients Showing Greater Than or Equal to 15 Letters Early Treatment Diabetic Retinopathy (ETDRS) Gain From Baseline to Month 12 and 24.
Description
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.
Time Frame
Baseline to months 12 and 24.
Title
Proportion of Patients Showing Less Than 15 Letters ETDRS Loss From Baseline to Month 12 and 24.
Description
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.
Time Frame
Baseline to months 12 and 24
Title
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.
Description
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.
Time Frame
Baseline or following consent
Title
Proportion of Patients With Both SRF (Sub-retinal Fluid) and IRF (Intra-retinal Fluid) Who Despite Monthly Treatment do Not Resolve Their SRF
Description
Assessed by Optical Coherence Tomography (OCT) and confirmed by a central reading centre.
Time Frame
Month 12 and 24
Title
The Number of Times a Participant Needs to Return to Monthly Treatments During the 24 Months.
Description
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.
Time Frame
Month 24

10. Eligibility

Sex
All
Minimum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. 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: Any active periocular or ocular infection or inflammation (e.g., blepharitis, conjunctivitis, keratitis, scleritis, uveitis, endophthalmitis) at the time of Screening or Baseline. Uncontrolled glaucoma (intraocular pressure [IOP] ≥30 mm Hg on medication) at the time of Screening or Baseline. Neovascularisation of the iris or neovascular glaucoma at the time of Screening or Baseline. 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. 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. Treatment with any anti-angiogenic drugs (including any anti-VEGF agents) prior to Baseline in study eye (allowed in fellow eye). 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Albury
State/Province
New South Wales
ZIP/Postal Code
2640
Country
Australia
Facility Name
Novartis Investigative Site
City
Chatswood
State/Province
New South Wales
ZIP/Postal Code
2067
Country
Australia
Facility Name
Novartis Investigative Site
City
Eastwood
State/Province
New South Wales
ZIP/Postal Code
2122
Country
Australia
Facility Name
Novartis Investigative Site
City
Hurtsville
State/Province
New South Wales
ZIP/Postal Code
2220
Country
Australia
Facility Name
Novartis Investigative Site
City
Liverpool
State/Province
New South Wales
ZIP/Postal Code
2170
Country
Australia
Facility Name
Novartis Investigative Site
City
North Ryde
State/Province
New South Wales
ZIP/Postal Code
2109
Country
Australia
Facility Name
Novartis Investigative Site
City
Parramatta
State/Province
New South Wales
ZIP/Postal Code
2150
Country
Australia
Facility Name
Novartis Investigative Site
City
Strathfield
State/Province
New South Wales
ZIP/Postal Code
2135
Country
Australia
Facility Name
Novartis Investigative Site
City
Sydney
State/Province
New South Wales
ZIP/Postal Code
2000
Country
Australia
Facility Name
Novartis Investigative Site
City
Westmead
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
Facility Name
Novartis Investigative Site
City
Adelaide
State/Province
South Australia
ZIP/Postal Code
5000
Country
Australia
Facility Name
Novartis Investigative Site
City
Hobart
State/Province
Tasmania
ZIP/Postal Code
7000
Country
Australia
Facility Name
Novartis Investigative Site
City
South Launceston
State/Province
Tasmania
ZIP/Postal Code
7249
Country
Australia
Facility Name
Novartis Investigative Site
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3000
Country
Australia
Facility Name
Novartis Investigative Site
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3002
Country
Australia
Facility Name
Novartis Investigative Site
City
Nedlands
State/Province
Western Australia
ZIP/Postal Code
6009
Country
Australia

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
27009515
Citation
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.
Results Reference
derived

Learn more about this trial

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)

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