Subfoveal Choroidal Neovascularization CNV Secondary to Wet Age-related Macular Degeneration AMDPhase 4FLUIDNCT01972789

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)

A Phase 4 study testing Ranibizumab in people with Subfoveal Choroidal Neovascularization CNV Secondary to Wet Age-related Macular Degeneration AMD, run by Novartis Pharmaceuticals at 16 sites in Australia.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 50 years and older
Conditions the study is for: Subfoveal Choroidal Neovascularization CNV Secondary to Wet Age-related Macular Degeneration AMD
What is being tested?: Ranibizumab
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 349 participants
Where: 16 sitesAustralia
Study dates: 31 Oct 2013to 28 Feb 2017
Phase: Phase 4
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 50 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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).

Who cannot join

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.

Trial locations and contacts

16 sites in 1 country.

City, postcode or hospital

16 sites in 1 country

Australia16 sites

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

Other trials in Australia

About this study

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)

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

Conditions: Subfoveal Choroidal Neovascularization CNV Secondary to Wet Age-related Macular Degeneration AMD
Being tested: Ranibizumab
Keywords: Subfoveal choroidal neovascularization (CNV), wet age-related macular degeneration(AMD), inject and extend, retinal fluid

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

RanibizumabDrug
Also called LUCENTIS
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

Study groups in NCT01972789
Study group	Role	What they receive
Intensive retinal fluid regimen	Experimental	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. Receives: Drug: Ranibizumab
Relaxed retinal fluid regimen	Experimental	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. Receives: Drug: Ranibizumab

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: Baseline to month 24

Secondary outcomes (11)

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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Month 24

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

31 Oct 201328 Feb 2017

First posted30 Oct 2013 (estimated)
Study start31 Oct 2013
Primary completion28 Feb 2017
Study completion28 Feb 2017

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Subfoveal Choroidal Neovascularization CNV Secondary to Wet Age-related Macular Degeneration AMDStudies of the same condition, open and under way.
More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 4
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Double blind
Who is masked: Participant, Outcomes assessor
Enrolment: 349 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01972789
Sponsor's protocol ID: CRFB002AAU15
Acronym: FLUID
Status last verified: Sep 2019
First submitted: 24 Oct 2013
Last updated: 23 Oct 2019
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: No

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.
PubMed 27009515

Study at a glance

From the registry record, last updated by the sponsor on 23 Oct 2019. Recruitment status is as the sponsor reported it: confirm with the study team.

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)
ClinicalTrials.gov ID: NCT01972789
Acronym / sponsor ID: FLUID / CRFB002AAU15
Conditions: 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
Phase: Phase 4
Study type: Interventional
Recruitment status: Completed
Enrolment: 349 participants (actual)
Lead sponsor: Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
Study start: 31 Oct 2013 (actual)
Primary completion: 28 Feb 2017 (actual)
Study completion: 28 Feb 2017 (actual)
First posted: 30 Oct 2013 (estimated)
Results: Posted 23 Oct 2019

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Double blind (participant, outcomes assessor)
Number of arms: 2

Arm	Type	Receives
Intensive retinal fluid regimen	Experimental	Drug: RanibizumabRanibizumab 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.
Relaxed retinal fluid regimen	Experimental	Drug: RanibizumabRanibizumab 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.

Who may qualify

Ages: 50 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (2 listed)

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).

Key exclusion criteria (8 listed)

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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
RanibizumabAlso: LUCENTISRanibizumab 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	Drug	Intensive retinal fluid regimen, Relaxed retinal fluid regimen

Primary outcome

Mean Change in Best-corrected Visual Acuity (BCVA) From Baseline to 24 Months.
Time frame: Baseline to month 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 month 24.

11 secondary outcomes

Mean Change in BCVA From Baseline to Month 12.
Time frame: Baseline to month 12
Mean Change in Central Retinal Thickness (CRT) From Baseline to Month 12 and 24.
Time frame: Baseline to month 12 and month 24
Mean Number of Injections From Baseline to Month 12 and 24
Time frame: Baseline to month 12 to month 24.
Mean Change in Area of New and Existing Geographic Atrophy From Baseline to Month 12 and 24.
Time frame: Baseline to months 12 and 24.
Proportion of Patients Showing Newly Developed Geographic Atrophy (GA) at Months 12 and 24
Time frame: Months 12 and 24
Proportion of Patients Showing no IRF and SRF at Months 2, 12 and 24.
Time frame: 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.
Time frame: Baseline to months 12 and 24.
Proportion of Patients Showing Less Than 15 Letters ETDRS Loss From Baseline to Month 12 and 24.
Time frame: 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.
Time frame: 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
Time frame: Month 12 and 24
The Number of Times a Participant Needs to Return to Monthly Treatments During the 24 Months.
Time frame: Month 24

Results and safety

Results posted to the registry on 23 Oct 2019, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Intensive Retinal Fluid Regimen	174	134
Relaxed Retinal Fluid Regimen	175	145

Primary outcome: Mean Change in Best-corrected Visual Acuity (BCVA) From Baseline to 24 Months.

Time frame: Baseline to month 24. Mean (Standard Deviation). Unit: Letters

Measure	Intensive Retinal Fluid Regimen n = 172	Relaxed Retinal Fluid Regimen n = 173
Value	3.2 (16.51)	2.5 (16.56)

Intensive Retinal Fluid Regimen vs Relaxed Retinal Fluid Regimen: Odds Ratio (OR): 0.40 (95% CI -2.51 to 3.32), p = 0.787, Mixed Models Analysis

Population analysed: Full Analysis Set (FAS): The Full Analysis Set (FAS) compromises all subjects randomised and whom have at least one post-Baseline efficacy value for the primary endpoint

11 secondary outcomes are reported in the full results.

Adverse events

Time frame: Up to 24 month. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Intensive	58 of 173 (33.5%)	109 of 173 (63%)	7 of 173
Relaxed	58 of 174 (33.3%)	114 of 174 (65.5%)	5 of 174

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 23 Oct 2019.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 27009515Arnold 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.
Individual participant dataSharing planned: No

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Novartis Pharmaceuticals study director

Novartis Pharmaceuticals

16 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 23 Oct 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 16 sites in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 23 Oct 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Mean Change in Best-corrected Visual Acuity (BCVA) From Baseline to 24 Months. (time frame: Baseline to month 24). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01972789, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Oct 2019.