Study of the Efficacy and Safety of the Ranibizumab Port Delivery System for Sustained Delivery of Ranibizumab in Patients With Subfoveal Neovascular Age-Related Macular Degeneration

Study Overview
=================
Brief Summary
-----------------
This is a Phase II multicenter, dose-ranging, randomized, active treatment (monthly ITV injection)-controlled study to evaluate the efficacy, safety, and pharmacokinetics of ranibizumab delivered through the Implant using three ranibizumab formulation arms (10 mg/mL, 40 mg/mL, and 100 mg/mL) compared with the control arm (0.5-mg monthly ITV injections of 10-mg/mL formulation) in participants with subfoveal neovascular age-related macular degeneration (nAMD).

Official Title
-----------------
A Phase II, Multicenter, Randomized, Active Treatment-Controlled Study of the Efficacy and Safety of the Ranibizumab Port Delivery System for Sustained Delivery of Ranibizumab in Patients With Subfoveal Neovascular Age-Related Macular Degeneration

Conditions
-----------------
Macular Degeneration

Intervention / Treatment
-----------------
* Drug: Ranibizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Newly diagnosed with wet AMD within 9 months of screening visit Participant must have received at least 2 prior ITV anti-vascular endothelial growth factor (VEGF) injections. However, the most recent anti-VEGF injection must have been ranibizumab and must have occurred at least 7 days prior to the screening visit Demonstrated response to prior ITV anti-VEGF treatment Best Corrected Visual Acuity (BCVA) using Early Treatment Diabetic Retinopathy Study (ETDRS) charts of 20/20-20/200 Snellen equivalent Exclusion Criteria: Treatment with ITV anti-VEGF agents other than ranibizumab within 1 month prior to the randomization visit in either eye Study eye treatment with ITV anti-VEGF agents other than ranibizumab within 1 month prior to the randomization visit History of laser photocoagulation, Visudyne®, ITV corticosteroid injection, vitrectomy surgery, submacular surgery, device implantation, or other surgical intervention for AMD in the study eye Prior participation in a clinical trial involving anti-angiogenic drugs, other than ranibizumab, in either eye within 2 months of the randomization visit Subretinal hemorrhage in the study eye that involves the center of the fovea Subfoveal fibrosis, or atrophy in the study eye Choroidal neovascularization (CNV) in either eye due to other causes, such as ocular histoplasmosis, trauma, or pathologic myopia Uncontrolled ocular hypertension or glaucoma in the study eye History of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma surgery in the study eye Uncontrolled blood pressure Uncontrolled atrial fibrillation within 3 months of informed consent History of myocardial infarction or stroke within the last 3 months prior to informed consent History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of ranibizumab or placement of the Implant, that might affect interpretation of the results of the study or renders the participant at high risk of treatment complications Use of oral corticosteroids Current treatment for any active systemic infection Use of anticoagulants, anti-platelets (other than aspirin), or medications known to exert similar effects Active malignancy within 12 months of randomization History of allergy to fluorescein 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
-----------------
Minimum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Port Delivery System with Ranibizumab 10mg/mL<br>Participants had the Implant (prefilled with approximately 20 μL of 10-mg/mL ,approximately 0.2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria. | Drug: Ranibizumab<br>* Ranibizumab will be administered at dose of 0.5 mg monthly ITV injections of 10-mg/mL formulation or delivered through the implant with three different formulations.<br>* Other names: Lucentis®;|
| Experimental: Port Delivery System with Ranibizumab 40mg/mL<br>Participants had the Implant (prefilled with approximately 20 μL of 40-mg/mL, approximately 0.8 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 40-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria. | Drug: Ranibizumab<br>* Ranibizumab will be administered at dose of 0.5 mg monthly ITV injections of 10-mg/mL formulation or delivered through the implant with three different formulations.<br>* Other names: Lucentis®;|
| Experimental: Port Delivery System with Ranibizumab 100mg/mL<br>Participants had the Implant (prefilled with approximately 20 μL of 100-mg/mL, approximately 2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 100-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria. | Drug: Ranibizumab<br>* Ranibizumab will be administered at dose of 0.5 mg monthly ITV injections of 10-mg/mL formulation or delivered through the implant with three different formulations.<br>* Other names: Lucentis®;|
| Active Comparator: Intravitreal Injection with Ranibizumab 0.5mg<br>Participants received ranibizumab 0.5 mg monthly ITV injections of 10 mg/mL formulation at Day 1 and every month thereafter. | Drug: Ranibizumab<br>* Ranibizumab will be administered at dose of 0.5 mg monthly ITV injections of 10-mg/mL formulation or delivered through the implant with three different formulations.<br>* Other names: Lucentis®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time Until a Participant First Requires the Implant Refill According to Protocol-Defined Refill Criteria | Protocol-Defined Refill Criteria At 1 month after initial fill: Decrease of ≥ 10 letters in BCVA at the current visit compared with the baseline BCVA, due to nAMD disease activity OR Increase in CFT of ≥ 100 um at the current visit compared with the baseline CFT, due to nAMD disease activity OR Presence of new macular hemorrhage, due to nAMD disease activity For subsequent assessments: Increase in CFT of ≥ 75 μm on SD-OCT at the current visit compared with the average CFT over the last 2 available measurements, due to nAMD disease activity OR Increase in CFT of ≥ 100 um from the lowest CFT measurement on study, due to nAMD disease activity OR Decrease of ≥ 5 letters in BCVA at the current visit compared with the average BCVA over the last 2 available measurements, due to nAMD disease activity OR Decrease of ≥ 10 letters from best recorded BCVA on study, due to nAMD disease activity OR Presence of new macular hemorrhage, due to nAMD disease activity | Baseline up to approximately 38 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Best Corrected Visual Acuity (BCVA) Averaged At Month 9 and 10 | Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. The minimum score possible is 0 and maximum possible is 100. A higher score represents better functioning. | Baseline, Months 9, 10 | 
| Change From Baseline in BCVA Over Time | Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. The minimum score possible is 0 and maximum possible is 100. A higher score represents better functioning. | Baseline up to Month 10 | 
| Adjusted Average Change From Baseline in BCVA Over Time (MMRM Analysis) | Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. The minimum score possible is 0 and maximum possible is 100. A higher score represents better functioning. Here, the adjusted mean from MMRM analysis is presented). | Baseline up to Month 10 | 
| Change From Baseline in Central Foveal Thickness (CFT) Over Time as Assessed on Spectral Domain-Optical Coherence Tomography (SD-OCT) | Central foveal thickness (CFT) is defined as the retinal thickness in the center of the fovea | Baseline up to Month 9 | 
| Number of Implant Clogging at Month 9 | Removed implants identified as meeting serum PK criteria for possible clogging were assessed via lab-based investigation (in vitro drug release testing) to determine whether there was any implant clogging. | Month 9 | 
| Observed Maximum Serum Concentration (Cmax) of Ranibizumab | The serum pharmacokinetics of ranibizumab were characterized by estimating Cmax between dose intervals. Estimates for these parameters were tabulated and summarized by descriptive statistics. | Predose (0 hour) on Day 1 up to 38 months | 
| Area Under the Concentration-Time Curve From Dosing to Last Observation (AUClast) of Ranibizumab | AUCLast is defined as area under the concentration-time curve from dosing (implant or refill) to last observation before next refill or exiting the study. The serum pharmacokinetics of ranibizumab were characterized by estimating AUC between dose intervals. Estimates for these parameters were tabulated and summarized by descriptive statistics. | Predose (0 hour) on Day 1 up to approximately 38 months (detailed timeframe is provided in description field) | 
| Time to Maximum Concentration (Tmax) of Ranibizumab | The serum pharmacokinetics of ranibizumab were characterized by estimating Tmax between dose intervals. Estimates for these parameters were tabulated and summarized by descriptive statistics. | Predose (0 hour) on Day 1 up to 38 months | 
| Terminal Half-Life (t1/2) of Ranibizumab | The serum pharmacokinetics of ranibizumab were characterized by estimating t1/2 between dose intervals. Estimates for these parameters were tabulated and summarized by descriptive statistics. | Predose (0 hour) on Day 1 up to 38 months | 
| Observed Steady-State Serum Concentration at the End of a Dosing Interval (Ctrough) of Ranibizumab |  | Predose (0 hour) on Day 1 up to 38 months | 
| Number of Participants With Ocular and Non-Ocular Adverse Events (AEs) and Serious AEs (SAEs) |  | Baseline up to approximately Month 38 | 
| Percentage of Participants With Positive Serum Antibodies to Ranibizumab |  | Baseline up to 38 months |