Extension Study for the Port Delivery System With Ranibizumab (Portal)

Study Overview
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Brief Summary
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This study will evaluate the long-term safety and tolerability of the Port Delivery System with ranibizumab (PDS) (100 mg/mL) in patients with neovascular age-related macular degeneration (nAMD) who have either completed Phase II Study GX28228 (Ladder), Phase III Study GR40548 (Archway), Phase IIIb Study WR42221 (Velodrome), or completed Week 24 visit in Study WR42221 but were not eligible to be randomized in WR42221.

Official Title
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A Multicenter, Open-Label Extension Study to Evaluate the Long-Term Safety and Tolerability of the Port Delivery System With Ranibizumab in Patients With Neovascular Age-Related Macular Degeneration (Portal)

Conditions
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Neovascular Age-Related Macular Degeneration

Intervention / Treatment
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* Drug: PDS Implant with Ranibizumab 100 mg/mL


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previous enrollment in and completion of Study GX28228 (Ladder) or Study GR40548 (Archway), without early treatment or study discontinuation in either study OR Previous enrollment in Study WR42221 (Velodrome) and either not eligible to be randomized in Study WR42221 at Week 24 or completed the study (from the Q24W or Q36W arm) Ability and willingness to undertake all scheduled visits and assessments For women of childbearing potential: agreement to remain abstinent or use contraceptive measures Exclusion Criteria: Pregnant or breastfeeding, or intending to become pregnant during the treatment period and for at least 28 days after the last intravitreal injection of ranibizumab or 1 year after the last Implant refill-exchange of ranibizumab History of other ocular diseases that give reasonable suspicion of a disease or condition that contraindicates the use of ranibizumab, that might affect interpretation of the results of the study or that renders the participant at high risk for treatment complications History of other diseases, metabolic dysfunction, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of ranibizumab or placement of the Implant and that might affect interpretation of the results of the study or that renders the participant at high risk of treatment complications Requirement for continuous use of any medications or treatments indicated in the Prohibited Therapy Substudy Inclusion Criteria - For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, Patients must meet the following ocular criteria for the study eye for substudy entry: Diagnosis of exudative nAMD within 2 years prior to the enrollment visit Previous treatment with at least two anti-VEGF ITV injections (e.g., ranibizumab, bevacizumab, or aflibercept) for nAMD per standard of care within 6 months prior to the enrollment visit Demonstrated response to prior anti-VEGF ITV treatment since diagnosis, as evidenced at enrollment by the following: Overall decrease in nAMD disease activity detected on SD-OCT AND Stable or improved best-corrected visual acuity (BCVA) All subtypes of nAMD lesions are permissible (i.e., type I, type II, type III, or mixed forms per optical coherence tomography (OCT) classification) nAMD lesions at the time of diagnosis must involve the macula (6 mm diameter centered at the fovea). Sufficiently clear ocular media and adequate pupillary dilation to allow for analysis and grading by the central reading center of FP and SD-OCT images. Exclusion Criteria Prior Ocular Treatments Study Eye History of vitrectomy surgery, submacular surgery, or other surgical intervention for AMD Prior treatment with Visudyne, external-beam radiation therapy, or transpupillary thermotherapy Previous treatment with corticosteroid ITV injection Previous intraocular device implantation Previous laser (any type) used for AMD treatment Either Eye Treatment with anti-VEGF agents other than ranibizumab within 1 month prior to the enrollment visit Prior participation in a clinical trial involving anti-VEGF drugs within 6 months prior to the enrollment visit, other than ranibizumab CNV Lesion Charateristics Study Eye Subretinal hemorrhage that involves the center of the fovea, if the hemorrhage is greater than 0.5 disc area (1.27 mm2 ) in size at screening Subfoveal fibrosis or subfoveal atrophy Either Eye - CNV due to other causes, such as ocular histoplasmosis, trauma, or pathologic myopia Concurrent Ocular Conditions Study Eye Retinal pigment epithelial tear Any concurrent intraocular condition (e.g., cataract, glaucoma, diabetic retinopathy, or epiretinal membrane) 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) History of vitreous hemorrhage History of rhegmatogenous retinal detachment History of rhegmatogenous retinal tears or peripheral retinal breaks within 3 months prior to the enrollment 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 Preoperative refractive error that exceeds 8 diopters of myopia, for patients who have undergone prior refractive or cataract surgery in the study eye Intraocular surgery (including cataract surgery) within 3 months preceding the enrollment visit Uncontrolled ocular hypertension or glaucoma and any such condition the investigator determines may require a glaucoma-filtering surgery during a patient's participation in the study History of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma surgery History of corneal transplant History of prior vitrectomy surgery and absence of posterior capsule Either Eye History of idiopathic or autoimmune-associated uveitis Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis Concurrent Systemic Conditions Inability to comply with study schedule or procedures as described in the study protocol Uncontrolled blood pressure History of stroke within the last 3 months prior to informed consent Uncontrolled atrial fibrillation within 3 months of informed consent History of myocardial infarction within the last 3 months prior to informed consent History of other disease, metabolic dysfunction, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of ranibizumab or placement of the implant and that might affect interpretation of the results of the study or renders the patient at high risk of treatment complications in the opinion of the investigator Current systemic treatment for a confirmed active systemic infection Use of any systemic anti-VEGF agents Chronic use of oral corticosteroids Active cancer within 12 months of enrollment 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 enrollment visit History of albinism Pregnant or breastfeeding, or intending to become pregnant during the treatment period and for at least 28 days after the last ITV injection of ranibizumab or 1 year after the last implant refill-exchange of ranibizumab

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PDS Implant Cohort 1 (US only)<br>Participants with PDS implant from Study GX28228 treated with refill-exchanges of 100 mg/mL ranibizumab Q24W. Participants will switch to an every 12 weeks (Q12W) visit schedule from Week 168 to Week 240. Eligible participants from Study GX28228 will be enrolled upon completion of their final visit. | Drug: PDS Implant with Ranibizumab 100 mg/mL<br>* Will be administered as per the schedule described in individual arm<br>|
| Experimental: PDS Implant Cohort 2 (US only)<br>Participants with PDS implant from Study GR40548 treated with refill-exchanges of 100 mg/mL ranibizumab Q24W. Participants will switch to an every 12 weeks (Q12W) visit schedule from Week 144 to Week 240. Eligible participants from Study GR40548 will be enrolled upon completion of their final visit. | Drug: PDS Implant with Ranibizumab 100 mg/mL<br>* Will be administered as per the schedule described in individual arm<br>|
| Experimental: PDS Implant Cohort 3 (US only)<br>Participants in the intravitreal ranibizumab arm of Study GX28228 who will receive the PDS implant upon study entry and refill-exchanges of 100 mg/mL ranibizumab Q24W. Participants will switch to an every 12 weeks (Q12W) visit schedule from Week 168 to Week 240. Eligible participants from Study GX28228 will be enrolled upon completion of their final visit. | Drug: PDS Implant with Ranibizumab 100 mg/mL<br>* Will be administered as per the schedule described in individual arm<br>|
| Experimental: PDS Implant Cohort 4 (US only)<br>Participants in the intravitreal ranibizumab arm of Study GR40548 who will receive the PDS implant upon study entry and refill-exchanges of 100 mg/mL ranibizumab Q24W. Participants will switch to an every 12 weeks (Q12W) visit schedule from Week 144 to Week 240. Eligible participants from Study GR40548 will be enrolled upon completion of their final visit. | Drug: PDS Implant with Ranibizumab 100 mg/mL<br>* Will be administered as per the schedule described in individual arm<br>|
| Experimental: PDS Implant Cohort 5 (ex-US only)<br>Participants from Study WR42221 who completed Week 24 but were not eligible to be randomized within WR42221 and who will be treated with refill-exchanges of ranibizumab 100 mg/mL Q24W | Drug: PDS Implant with Ranibizumab 100 mg/mL<br>* Will be administered as per the schedule described in individual arm<br>|
| Experimental: PDS Implant Cohort 6 (ex-US only)<br>Participants from Study WR42221 randomized to the Q24W arm, who will continue to be treated with refill-exchanges of ranibizumab 100 mg/mL Q24W | Drug: PDS Implant with Ranibizumab 100 mg/mL<br>* Will be administered as per the schedule described in individual arm<br>|
| Experimental: PDS Implant Cohort 7 (ex-US only)<br>Participants from Study WR42221 randomized to the Q36W arm, who will continue to be treated with refill-exchanges of ranibizumab 100 mg/mL Q36W | Drug: PDS Implant with Ranibizumab 100 mg/mL<br>* Will be administered as per the schedule described in individual arm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and Severity of Ocular and Systemic (Non-Ocular) Adverse Events (AEs) |  | Baseline up to Week 240 | 
| Incidence, Severity, and Duration of Adverse Event of Special Interest (AESIs) |  | Baseline up to Week 240 | 
| Incidence, Severity, and Duration of PDS-Associated Ocular AESIs During the Postoperative Period (Up to 37 days of Initial Implantation) and Follow-Up Period (>37 days After Implantation Surgery) for Participants who Receive the PDS Implant in the Study |  | Baseline up to Week 240 | 
| Incidence and Severity of Adverse Device Effects |  | Baseline up to Week 240 | 
| Incidence, Causality, Severity, And Duration Of Anticipated Serious Adverse Device Effects |  | Baseline up to Week 240 | 
| Substudy: Rate of vitreous hemorrhage secondary to choroidal bleeding that does not resolve by the Week 4 visit after implant insertion surgery. |  | Baseline to Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Best-Corrected Visual Acuity (BCVA) Score from Baseline Over Time, as Assessed using the ETDRS Visual Acuity Chart at a Starting Distance of 4 Meters | ETDRS = Early Treatment Diabetic Retinopathy Study A vision score of 20/20 vision is considered normal. A score of 20/200 is considered being legally blind. | Baseline up to Week 240 | 
| Percentage of Participants who Lose <15, <10, or <5 Letters in BCVA Score from Baseline Over Time |  | Baseline up to Week 240 | 
| Percentage of Participants with BCVA Score of 38 Letters (of 20/200 Approximate Snellen Equivalent) or Worse over Time |  | Baseline up to Week 240 | 
| Percentage of Participants with BCVA Score of 69 Letters (20/40 Approximate Snellen Equivalent) or Better over Time |  | Baseline up to Week 240 | 
| Change from Baseline in Center Point Thickness Over Time |  | Baseline up to Week 240 | 
| Percentage of Participants who Undergo Supplemental Treatment with Intravitreal Ranibizumab 0.5 mg During Each Refill-exchange Interval |  | Baseline up to Week 240 | 
| Substudy: Incidence of ocular adverse events and adverse events of special interest in the study eye |  | Baseline up to Week 240 | 
| Substudy: Incidence of adverse events commonly seen after TS-CPC for treatment of glaucoma in the study eye |  | Baseline up to Week 240 | 
| Substudy: Time from surgery to vitreous hemorrhage resolution in the study eye |  | Baseline up to Week 240 | 
| Substudy: Incidence of vitreous hemorrhage Grade 3 and higher in the study eye over time |  | Baseline up to Week 240 | 
| Substudy: Distribution of vitreous hemorrhage grade in the study eye over time |  | Baseline up to Week 240 | 
| Substudy: Rate of vitrectomy in the study eye |  | Baseline up to Week 240 | 
| Substudy: Percentage of Participants who Lose <15, <10, or <5 Letters in BCVA Score from Baseline Over Time |  | Baseline up to Week 240 | 
| Substudy: Change in BCVA score from baseline over time |  | Baseline up to Week 240 | 
| Substudy: Change from baseline in CPT over time |  | Baseline up to Week 240 | 
| Substudy: Change from baseline in CST over time |  | Baseline up to Week 240 |