A Study Of The Efficacy, Safety, And Pharmacokinetics Of The Port Delivery System With Ranibizumab In Chinese Patients With Neovascular Age-Related Macular Degeneration

Study Overview
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Brief Summary
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This study will evaluate the efficacy, safety, and pharmacokinetics of ranibizumab 100 mg/mL delivered Q24W via the PDS implant compared with ranibizumab 0.5 mg delivered as a Q4W intravitreal injection in Chinese patients with nAMD.

Official Title
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A Phase III, Multicenter, Randomized, Visual Assessor-Masked, Active Comparator Study Of The Efficacy, Safety, And Pharmacokinetics Of The Port Delivery System With Ranibizumab In Chinese Patients With Neovascular Age-Related Macular Degeneration

Conditions
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Neovascular Age Related Macular Degeneration, nAMD

Intervention / Treatment
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* Device: PDS with ranibizumab (100 mg/mL)
* Drug: Ranibizumab (10 mg/mL)


Participation Criteria
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Eligibility Criteria
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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 VA data prior to the first anti-VEGF treatment for nAMD up to the screening visit BCVA of 34 letters or better (20/200 or better approximate Snellen equivalent), using Early Treatment Diabetic Retinopathy Study (ETDRS) chart at a starting distance of 4 meters All subtypes of nAMD lesions are permissible Sufficiently clear ocular media and adequate pupillary dilation to allow for analysis and grading by the central reading center of FP, FA, ICGA, FAF, and OCT images Exclusion Criteria: Study Eye History of vitrectomy surgery, submacular surgery, or other surgical intervention, all for AMD Prior treatment with Visudyne, external-beam radiation therapy, or transpupillary thermotherapy Previous treatment with corticosteroid intravitreal injection Previous intraocular device implantation (not including intraocular lens implants) Previous laser (any type) used for AMD treatment Treatment with anti-VEGF agents other than ranibizumab within 1 month prior to the randomization visit Concurrent conjunctival, Tenon's capsule, and/or scleral condition in the supero temporal quadrant of the eye that may affect the implantation, subsequent tissue coverage, and refill-exchange procedure of the PDS implant 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 Retinal pigment epithelial tear Any concurrent intraocular condition 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 randomization visit History of pars plana vitrectomy surgery Aphakia or absence of the posterior capsule 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 Intraocular surgery (including cataract surgery) within 3 months preceding the randomization visit Uncontrolled ocular hypertension or glaucoma History of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma surgery History of corneal transplant Fellow (Non-Study) Eye • Non-functioning fellow eye Either Eye Prior treatment with brolucizumab (at any time prior to the screening visit) Prior participation in a clinical trial involving anti-VEGF drugs within 6 months prior to the randomization visit Choroidal neovascularization due to other causes, such as ocular histoplasmosis, trauma, central serous chorio-retinopathy, or pathologic myopia Any history of uveitis Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 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: Implant arm<br>Participants will have the implant (pre-filled intraoperatively with ranibizumab 100 mg/mL) surgically inserted on Day 1. After Day 1, patients in the implant arm will attend monthly study visits, and receive implant refill-exchanges with ranibizumab 100 mg/mL at Week 24 and Week 48. At the Week 48 study visit, patients will move to the long term extension phase of the study and continue receiving refill-exchanges Q24W until the end of study. Patients will attend monthly visits up to Week 96 and bi-monthly visits, thereafter | Device: PDS with ranibizumab (100 mg/mL)<br>* Patients randomized to the implant arm will have the implant (filled prior to implantation with approximately 20 uL 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, or at Week 48 visit for patients randomized to the intravitreal arm. After the initial fill of the implant with ranibizumab, patients will receive implant refill-exchanges at fixed 24-week intervals.<br>|
| Experimental: Intravitreal arm<br>Participants will receive intravitreal ranibizumab 0.5 mg injections starting on Day 1. Patients will receive intravitreal ranibizumab 0.5 mg Q4W until Week 44. At the Week 48 study visit, patients will receive the PDS implant (pre-filled intraoperatively with ranibizumab 100 mg/mL), move to the long-term extension phase of the study and receive Q24W refill exchanges until the end of study. If patients are unable to attend the Week 48 visit due to extenuating circumstances, they should return no later than the next scheduled visit (Week 52), when they will receive the PDS implant. Patients will attend monthly visits up to Week 96 and bi-monthly visits, thereafter. | Drug: Ranibizumab (10 mg/mL)<br>* Patients in the intravitreal arm will receive their first intravitreal injection of 50 uL of the 10 mg/mL ranibizumab (0.5 mg dose) at the Day 1 visit, which will occur at the conclusion of the randomization visit. Afterward, patients will receive intravitreal ranibizumab injections of 50 uL of the 10 mg/mL formulation Q4W at each scheduled study visit until Week 44<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 averaged over Weeks 36 and 40, as assessed using the ETDRS visual acuity chart at a starting distance of 4 meters |  | Baseline up to Week 40 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with BCVA score of 38 letters (20/200 approximate Snellen equivalent) or worse averaged over Weeks 36 and 40 |  | Baseline up to Week 40 | 
| Proportion of patients with BCVA score of 38 letters (20/200 approximate Snellen equivalent) or worse averaged over Weeks 44 and 48 |  | Baseline up to Week 48 | 
| Proportion of patients with BCVA score of 69 letters (20/40 approximate Snellen equivalent) or better averaged over Weeks 36 and 40 |  | Baseline up to Week 40 | 
| Proportion of patients with BCVA score of 69 letters (20/40 approximate Snellen equivalent) or better averaged over Weeks 44 and 48 |  | Baseline up to Week 48 | 
| Proportion of patients who gain ≥0 letters in BCVA score from baseline averaged over Weeks 36 and 40 |  | Baseline up to Week 40 | 
| Proportion of patients who gain ≥ 0 letters in BCVA score from baseline averaged over Weeks 44 and 48 |  | Baseline up to Week 48 | 
| Proportion of patients who lose < 10 or > 5 letters in BCVA score from baseline averaged over Weeks 36 and 40 |  | Baseline up to Week 40 | 
| Proportion of patients who lose < 10 or > 5 letters in BCVA score from baseline averaged over Weeks 44 and 48 |  | Baseline up to Week 48 | 
| Change from baseline in CPT at Week 36 | CPT = center point thickness | Baseline up to Week 36 | 
| Change from baseline in CST at Week 36 | CST = central subfield thickness | Baseline up to Week 36 | 
| Change from baseline in CPT at Week 44 | CPT = center point thickness | Baseline up to Week 44 | 
| Change from baseline in CST at Week 44 | CST = central subfield thickness | Baseline up to Week 44 | 
| Proportion of patients in the implant arm who do not undergo supplemental treatment with intravitreal ranibizumab 0.5 mg before the first, second, third, fourth, fifth, and sixth fixed refill exchange intervals |  | Baseline up to 144 weeks | 
| Proportion of patients in the implant arm who do not undergo a supplemental treatment that requires subsequent additional supplemental treatments during the study |  | Baseline up to 144 weeks | 
| Proportion of participants with Adverse Events |  | Baseline up to 144 weeks | 
| Incidence and severity of adverse device effects in the PDS patients |  | Baseline up to 144 weeks | 
| Incidence, causality, severity, and duration of anticipated serious adverse device effects in the PDS patients |  | Baseline up to 144 weeks | 
| Observed serum ranibizumab concentrations at specified timepoints |  | Baseline, Weeks 4, 12, 24, 28, 36, 48 | 
| Area under the concentration time curve from 0-24 weeks |  | Baseline, Weeks 4, 12, 24 | 
| Maximum serum concentration of ranibizumab |  | Baseline, Weeks 4, 12, 24, 28, 36, 48 | 
| Minimum serum concentration of ranibizumab |  | Baseline, Weeks 4, 12, 24, 28, 36, 48 | 
| Prevalence of ADAs at baseline and incidence of ADAs during the study |  | Baseline, Weeks 4, 24, 48 | 
| Incidence of treatment-emergent ADAs during the study |  | Baseline, Weeks 4, 24, 48 |