A Study Of The Effectiveness And Safety Of A 36-Week Refill Regimen For The Port Delivery System With Ranibizumab Vs Aflibercept Treat & Extend In Subjects With Neovascular Age-Related Macular Degeneration

Study Overview
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Brief Summary
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This study will evaluate the effectiveness and safety of a 36-week refill regimen for the Port Delivery System with ranibizumab 100 mg/mL (PDS Q36W) compared with intravitreal injections of aflibercept (2 mg) administered per treat-and-extend (aflibercept T&E) in subjects with neovascular (wet) age-related macular degeneration (nAMD).

Official Title
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A Phase IIIb, Multicenter, Randomized, Visual Assessor-Masked Study Of The Effectiveness And Safety Of A 36-Week Refill Regimen For The Port Delivery System With Ranibizumab Vs Aflibercept Treat & Extend In Subjects With Neovascular Age-Related Macular Degeneration

Conditions
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Neovascular Age-Related Macular Degeneration

Intervention / Treatment
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* Drug: Ranibizumab
* Drug: Aflibercept
* Device: Port Delivery System with ranibizumab (PDS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed Informed Consent Form Age ≥ 50 years, at time of signing Informed Consent Form Ability and willingness to undertake all scheduled visits and assessments For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures Ocular Inclusion Criteria: Initial diagnosis of nAMD within 9 months prior to the screening visit Previous treatment with at least three anti-VEGF intravitreal injections for nAMD per standard of care within 6 months prior to the screening visit Demonstrated response to prior anti-VEGF intravitreal treatment since diagnosis Availability of historical visual acuity data obtained at or after nAMD diagnosis and prior to the first anti-VEGF treatment for nAMD Availability of historical SD-OCT image data obtained at or after nAMD diagnosis and prior to the first anti-VEGF treatment for nAMD BCVA of 34 letters or better (20/200 or better approximate Snellen equivalent), using ETDRS chart at a starting distance of 4 meters (see the BCVA manual for additional details) at screening and randomization visits With any subtype of nAMD lesions (i.e., type I, type II, type III, or mixed forms per OCT classification, including polypoidal choroidal vasculopathy and retinal angiomatous proliferation) Sufficiently clear ocular media and adequate pupillary dilation to allow for clinical examination and analysis and grading by the central reading center of fundus photography (FP), FA, fundus autofluorescence (FAF) image, and SD-OCT images Exclusion Criteria: Prior Ocular Treatment - Study Eye History of vitrectomy surgery, submacular surgery, or other surgical intervention for AMD Prior pars plana vitrectomy surgery Prior treatment with Visudyne® (verteporfin for injection), external-beam radiation therapy, or transpupillary thermotherapy Previous treatment with corticosteroid intravitreal injection Previous intraocular device implantation (not including intraocular lens implants) Previous intraocular surgery (including cataract surgery) within 3 months of randomization Previous laser (any type) used for AMD or diabetic retinopathy treatment History of vitreous hemorrhage History of rhegmatogenous retinal detachment Concurrent conjunctival, Tenon's capsule, and/or scleral condition in the supero temporal quadrant of the eye (e.g., scarring, thinning, mass) that may affect the implantation, subsequent tissue coverage, and refill-exchange procedure of the PDS implant History of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma surgery History of corneal transplant History of conjunctival surgery in the superotemporal quadrant (including pterygium surgery) Prior Ocular Treatment Either Eye: History of a severe allergic reaction or anaphylactic reaction to a biologic agent or known hypersensitivity to any component of the ranibizumab or aflibercept injections, study-related procedure preparations (including fluorescein), dilating drops, or any of the anesthetic and antimicrobial preparations used by a subject during the study Any contraindication to aflibercept as per local label Prior participation in a clinical trial involving any anti-VEGF drugs within 6 months prior to the randomization visit Prior treatment with brolucizumab (at any time prior to the screening visit) Prior treatment with external-beam radiation therapy or brachytherapy MNV (CNV) Lesion Characteristics Study Eye: Subretinal hemorrhage that involves the center of the fovea, if the hemorrhage is greater than 0.5-disc area (1.27 mm^2) in size at screening Subfoveal fibrosis or subfoveal atrophy MNV (CNV) Lesion Characteristics Either Eye: CNV due to other causes, such as ocular histoplasmosis, trauma, central serous chorio retinopathy, or pathologic myopia CNV masquerading lesions (e.g., cone dystrophy, adult vitelliform dystrophy, pattern dystrophy) Concurrent Ocular Conditions Study Eye : Subfoveal and/or juxtafoveal retinal pigment epithelial tear Scleral pathology in the superotemporal quadrant (e.g., scleral thinning or calcification) Conjunctival pathologies (e.g., pterygium, scarring, thinning, fibrosis) in the superotemporal quadrant Any concurrent intraocular condition (e.g., cataract, glaucoma, diabetic retinopathy, epiretinal membrane, amblyopia, or strabismus) that would either require surgical intervention during the study to prevent or treat visual loss that might result from that condition or affect interpretation of study results Active intraocular inflammation (grade trace or above) Rhegmatogenous retinal tears or peripheral retinal breaks on depressed fundus exam that are untreated, or treated within 3 months prior to the randomization visit Aphakia or absence of the posterior capsule Previous violation of the posterior capsule is also an exclusion criterion unless it occurred as a result of yttrium-aluminum garnet (YAG) laser posterior capsulotomy in association with prior, posterior chamber intraocular lens implantation Spherical equivalent of the refractive error demonstrating more than 8 diopters of myopia or evidence of pathologic myopia on depressed fundus exam Preoperative refractive error that exceeds 8 diopters of myopia, for subjects who have undergone prior refractive or cataract surgery in the study eye Spherical equivalent of the refractive error demonstrating more than 5 diopters of hyperopia Preoperative refractive error that exceeds 5 diopters of hyperopia, for subjects who have undergone prior refractive or cataract surgery Uncontrolled ocular hypertension or glaucoma (defined as intraocular pressure [IOP] > 25 mmHg or a cup to disc ratio > 0.8, despite treatment with anti-glaucoma medication) and any such condition the investigator determines may require a glaucoma-filtering surgery during a subject's participation in the study History or presence of severe posterior blepharitis, recurrent chalazia or hordeolum, severe dry eye syndrome, or severe allergic conjunctivitis Ectropion, entropion, ingrowing lashes, or other impairment of the upper or lower eyelid impacting lid functionality needed to protect the ocular surface from exposure Trichiasis Corneal neuropathy Lagophthalmos or incomplete blink Active or history of facial nerve palsy/paresis Concurrent Ocular Conditions Non-Study (Fellow) Eye Non-functioning non-study eye, defined as either: BCVA of hand motion or worse No physical presence of non-study eye (i.e., monocular) Legally blind in the subject's relevant jurisdiction Concurrent Ocular Conditions Either Eye Any active or history of uveitis (e.g., idiopathic, drug-associated, or autoimmune-associated uveitis) Active or history of keratitis, scleritis, endophthalmitis, or chronic blepharitis Suspected or active ocular or periocular infectious conjunctivitis or endophthalmitis Active or history of Sjogrens syndrome or keratoconjunctivitis sicca Active or history of floppy eyelid syndrome Active or history of chronic eye rubbing Active thyroid eye disease Concurrent Systemic Conditions: Inability to comply with study schedule or procedures as described in the study protocol Uncontrolled blood pressure (defined as systolic blood pressure > 180 mmHg and/or diastolic blood pressure > 110 mmHg, while a subject is at rest) If a subject's initial measurement exceeds these values, a second reading should be taken ≥ 30 minutes after the first reading If the subject's blood pressure must be controlled by antihypertensive medication, the subject may become eligible if medication is taken continuously for at least 30 days prior to Day 1 Active or history of autoimmune diseases, for example, rheumatoid arthritis, lupus, granulomatosis with polyangiitis (Wegner's) History of stroke within the last 3 months prior to informed consent Atrial fibrillation diagnosed or worsened within the last 3 months prior to informed consent History of myocardial infarction within the last 3 months prior to informed consent History of other disease, metabolic dysfunction (including uncontrolled diabetes), or clinical laboratory finding (after reviewing the results of the screening laboratory results) giving reasonable suspicion of a disease or condition that contraindicates the use of ranibizumab, aflibercept, or placement of the implant and that might affect interpretation of the results of the study or renders the subject at high risk of treatment complications in the opinion of the investigator Confirmed active systemic infection Use of any systemic anti-VEGF agents Chronic use of oral corticosteroids (> 10 mg/day of prednisone or equivalent) Active cancer within 12 months of randomization except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, and prostate cancer with a Gleason score of ≤ 6 and a stable prostate-specific antigen for > 12 months Previous participation in any non-ocular (systemic) disease studies of investigational drugs within 1 month preceding the informed consent (excluding vitamins and minerals) Use of antimitotic or antimetabolite therapy within 30 days or 5 elimination half-lives of the randomization visit Requirement for continuous use of any medications or treatments prohibited in the study Pregnant or breastfeeding, or intending to become pregnant during the treatment period and for at least 3 months after the final intravitreal injection of ranibizumab or aflibercept, or 1 year after the last implant refill-exchange procedure

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ranibizumab<br>Subjects will have the implant (filled intra-operatively prior to implantation with approximately 20 µL of the 100-mg/mL formulation of ranibizumab [approximately 2-mg dose of ranibizumab]) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Subjects will have their implant refilled with ranibizumab at weeks 36 and 72. | Drug: Ranibizumab<br>* Ranibizumab will be administered at a dose of 100 mg/mL delivered via the PDS.<br>Device: Port Delivery System with ranibizumab (PDS)<br>* PDS is an investigation intraocular drug delivery device designed to continuously deliver anti-VEGF therapy.<br>|
| Active Comparator: Aflibercept<br>Subjects will receive intravitreal injections of aflibercept (2mg) administered in the study eye per treat-and-extend. The decision to extend, maintain, or reduce the interval until next treatment will be per investigator judgment. | Drug: Aflibercept<br>* Aflibercept will be administered at a dose of 2 mg in the study eye per treat-and-extend. The decision to extend, maintain, or reduce the interval until next treatment will be per investigator judgment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in BCVA score at week 80 as assessed using the ETDRS visual acuity chart at a starting distance of 4 meters | *Depending on the T&E schedule, some subjects in the comparator arm will have a visit at Week 76 and some at Week 78. All subjects in both arms will have a Week 80 visit | From baseline up to 80 weeks | 
| Treatment burden as assessed by the treatment frequency up to Week 80 | Treatments include injections and refills. | From baseline up to 80 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects with BCVA score of 69 letters (approximate 20/40 Snellen equivalent) or better averaged over Weeks 76 (or 78*) and 80 | *Depending on the T&E schedule, some subjects in the comparator arm will have a visit at Week 76 and some at Week 78. All subjects in both arms will have a Week 80 visit | Baseline, Week 76, Week 78, Week 80 | 
| Proportion of subjects with BCVA score of 38 letters (approximate 20/200 Snellen equivalent) or worse averaged over Weeks 76 (or 78*) and 80 | *Depending on the T&E schedule, some subjects in the comparator arm will have a visit at Week 76 and some at Week 78. All subjects in both arms will have a Week 80 visit | Baseline, Week 76, Week 78, Week 80 | 
| Proportion of subjects who lose < 15, < 10, or < 5 letters in BCVA score from baseline averaged over Weeks 76 (or 78*) and 80 | *Depending on the T&E schedule, some subjects in the comparator arm will have a visit at Week 76 and some at Week 78. All subjects in both arms will have a Week 80 visit | Baseline, Week 76, Week 78, Week 80 | 
| Change from baseline in center point thickness (CPT) at Week 80 | *CPT defined as the retinal thickness in the center point of the fovea measured between the internal limiting membrane and the inner third of the retinal pigment epithelium layer, on spectral-domain optical coherence tomography (SD-OCT) | Baseline, Week 80 | 
| Change from baseline in center subfield thickness (CST), defined as the average thickness of the central 1 mm circle of the ETDRS grid centered on the fovea measured between the internal limiting membrane and the Bruch's membrane, on SD-OCT at Week 80 |  | Baseline, Week 80 | 
| Proportion of subjects randomized to PDS Q36W who do not undergo supplemental treatment with intravitreal ranibizumab 0.5 mg before each refill-exchange procedure |  | Baseline, Week 80 | 
| Incidence and severity of ocular and systemic (non-ocular) adverse events |  | Baseline, Week 80 | 
| Incidence, severity, and duration of adverse events of special interest, including ocular adverse events of special interest |  | Baseline, Week 80 | 
| Incidence, severity, and duration of ocular adverse events of special interest during the postoperative period (≤ 37 days of initial implantation) and follow-up period (> 37 days after implantation surgery) |  | Baseline, Week 80 | 
| Incidence and severity of adverse device effects with PDS Q36W |  | Baseline, Week 80 | 
| Incidence, causality, severity, and duration of anticipated serious adverse device effects with PDS Q36W |  | Baseline, Week 80 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Wet AMD, neovascular AMD, exudative AMD