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)

Study Overview
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Brief Summary
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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

Official Title
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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)

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

Intervention / Treatment
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* Drug: Ranibizumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intensive retinal fluid regimen<br>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<br>* 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<br>* Other names: LUCENTIS;|
| Experimental: Relaxed retinal fluid regimen<br>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<br>* 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<br>* Other names: LUCENTIS;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Subfoveal choroidal neovascularization (CNV), wet age-related macular degeneration(AMD), inject and extend, retinal fluid