A Phase III Study to Evaluate the Port Delivery System With Ranibizumab Compared With Monthly Ranibizumab Injections in Participants With Wet Age-Related Macular Degeneration

Study Overview
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Brief Summary
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Study GR40548 is a Phase III, randomized, multicenter, open-label (visual assessor [VA]-masked), active-comparator study designed to assess the efficacy, safety, and pharmacokinetics (PK) of 100mg/ml delivered via the Port Delivery System with ranibizumab (PDS) compared with ranibizumab intravitreal injections at 0.5 mg (10 mg/mL) in participants with neovascular age-related macular degeneration (nAMD).

Official Title
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Phase III, Multicenter, Randomized, Visual Assessor-Masked, Active-Comparator Study of the Efficacy, Safety, and Pharmacokinetics of the Port Delivery System With Ranibizumab in Patients With Neovascular Age-Related Macular Degeneration

Conditions
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Neovascular Age-Related Macular Degeneration

Intervention / Treatment
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* Drug: PDS Implant filled with 100 mg/mL Ranibizumab
* Drug: Intravitreal Injections of 10 mg/mL Ranibizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥50 years, at time of signing Informed Consent Form Initial diagnosis of exudative neovascular age-related macular degeneration (nAMD) within 9 months prior to the screening visit Previous treatment with at least three anti-vascular endothelial growth factor (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 Best-corrected visual acuity (BCVA) of 34 letters or better Exclusion Criteria: Subfoveal fibrosis or subfoveal atrophy in study eye Subretinal hemorrhage that involves the center of the fovea in study eye History of vitrectomy surgery, submacular surgery, or other surgical intervention for AMD in study eye Prior treatment with Visudyne®, external-beam radiation therapy, or transpupillary thermotherapy in study eye Previous intraocular device implantation in study eye Previous laser (any type) used for AMD treatment in study eye Treatment with anti-VEGF agents other than ranibizumab within 1 month prior to the randomization visit in either eye Prior participation in a clinical trial involving anti-VEGF drugs within 6 months prior to the randomization visit, other than ranibizumab in either eye CNV due to other causes, such as ocular histoplasmosis, trauma, or pathologic myopia in either eye 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 participant at high risk of treatment complications in the opinion of the investigator Current systemic treatment for a confirmed active systemic infection Chronic use of oral corticosteroids Active cancer within 12 months of randomization Previous participation in any non-ocular (systemic) disease studies of investigational drugs within 1 month preceding the informed consent (excluding vitamins and minerals)

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: PDS Implant Arm<br>Participants will receive ranibizumab delivered through the PDS implant with 100 mg/mL in the study eye on Day 1 and receive refill-exchanges at fixed 24-week intervals | Drug: PDS Implant filled with 100 mg/mL Ranibizumab<br>* Will be administered as per the schedule described in individual arm.<br>|
| Active Comparator: Intravitreal Arm<br>Participants will receive ranibizumab 0.5 mg monthly intravitreal injections of 10 mg/mL formulation at Day 1 and every month thereafter. | Drug: Intravitreal Injections of 10 mg/mL Ranibizumab<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 |
| --- | --- | --- |
| Change From Baseline in Best-Corrected Visual Acuity (BCVA) Score at the Average of Week 36 and Week 40, as Assessed Using the ETDRS Visual Acuity Chart at a Starting Distance of 4 Meters | The primary efficacy endpoint is the change in BCVA score from baseline averaged over Weeks 36 and 40 with BCVA assessed using the ETDRS chart at a starting distance of 4 meters. ETDRS = Early Treatment Diabetic Retinopathy Study. The primary objective is to determine the NI and equivalence between the two treatment groups, as measured by the primary efficacy endpoint with a NI margin of 4.5 letters and equivalence margins of ± 4.5 letters. A vision score of 20/20 vision is considered normal. A score of 20/200 is considered being legally blind. | Baseline, and the average of Week 36 and Week 40 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in BCVA Score Averaged Over Week 60 and Week 64 |  | Baseline, Week60, Week 64 | 
| Change From Baseline in BCVA Score Over Time |  | Baseline up to Week 96 | 
| Percentage of Participants With BCVA Score of 38 Letters (20/200 Approximate Snellen Equivalent) or Worse at the Average Over Week 36 and Week 40 |  | Baseline, and the average of Week 36 and Week 40 | 
| Percentage of Participants With BCVA Score of 38 Letters (20/200 Approximate Snellen Equivalent) or Worse Over Time |  | Baseline up to Week 96 | 
| Percentage of Participants With BCVA Score of 69 Letters (20/40 Approximate Snellen Equivalent) or Better at the Average Over Week 36 and Week 40 |  | Baseline, and the average of Week 36 and Week 40 | 
| Percentage of Participants With BCVA Score of 69 Letters (20/40 Approximate Snellen Equivalent) or Better Over Time |  | Baseline up to Week 96 | 
| Percentage of Participants Who Lose <10 or <5 Letters in BCVA Score From Baseline to the Average Over Week 36 and Week 40 |  | Baseline, and the average of Week 36 and Week 40 | 
| Percentage of Participants Who Lose <10 or <5 Letters in BCVA Score From Baseline Over Time |  | Baseline up to Week 96 | 
| Percentage of Participants Who Gain ≥0 Letters in BCVA Score From Baseline to the Average Over Week 36 and Week 40 |  | Baseline up to Week 40 | 
| Percentage of Participants Who Gain ≥0 Letters in BCVA Score From Baseline Over Time |  | Baseline up to Week 96 | 
| Change From Baseline in Center Point Thickness (CPT) at Week 36 |  | Baseline to Week 36 | 
| Change From Baseline in CPT Over Time |  | Baseline up to Week 96 | 
| Percentage of Participants in the PDS Implant Arm Who Undergo Supplemental Treatment With Intravitreal Ranibizumab 0.5 mg Before the First, Second, Third, and Fourth Fixed Refill-Exchange Intervals |  | Day 1 to Week 24, Week 25 to Week 48, Week 49 to Week 72, Week73 to Week 96 | 
| Percentage of Participants in the PDS Implant Arm Who Undergo a Supplemental Treatment That Requires Subsequent Additional Supplemental Treatments During the Study |  | Week 16 to Week 92 | 
| Percentage of Participants With Ocular and Systemic (Non-Ocular) AEs |  | Randomization to Week 96 | 
| Percentage of Participants With Adverse Events of Special Interest | Percentage of Participants with Adverse Events of Special Interest | Randomization to Week 96 | 
| Observed Serum Ranibizumab Concentrations at Specified Timepoints |  | Randomization to Week 96 | 
| Estimated PK Parameter Values AUC0-6M | AUC0-6M = Area Under the Concentration-Time Curve From 0 to 6 Months | Randomization to Week 96 | 
| Estimated PK Parameter Value t1/2 After PDS Implant Insertion | Apparent terminal half-life | Randomization to Week 96 | 
| Estimated PK Parameter Value Cmin | Cmin = Minimum Serum Concentration | Randomization to Week 96 | 
| Estimated PK Parameter Value Cmax | Cmax = Maximum Serum Concentration | Randomization to Week 96 | 
| Baseline Prevalence and Incidence of Treatment-Emergent ADA |  | Randomization to Week 96 |