A Multicenter, Randomized Study in Participants With Diabetic Retinopathy Without Center-involved Diabetic Macular Edema To Evaluate the Efficacy, Safety, and Pharmacokinetics of Ranibizumab Delivered Via the Port Delivery System Relative to the Comparator Arm

Study Overview
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Brief Summary
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Study GR41675 is a Multicenter, Randomized Study in Participants with Diabetic Retinopathy (DR) Without Center-Involved Diabetic Macular Edema (CI-DME) to Evaluate the Efficacy, Safety of the Port Delivery System with Ranibizumab (PDS) Relative to the Comparator Arm

Official Title
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A Phase III, Multicenter, Randomized Study of the Efficacy, Safety, and Pharmacokinetics of the Port Delivery System With Ranibizumab in Patients With Diabetic Retinopathy

Conditions
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Diabetic Retinopathy

Intervention / Treatment
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* Drug: PDS Implant Pre-Filled with 100 mg/mL Ranibizumab
* Drug: Intravitreal Ranibizumab 0.5 mg Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years at time of signing Informed Consent Form Documented diagnosis of diabetes mellitus (Type 1 or Type 2) HbA1c level of ≤12% within 2 months prior to screening or at screening Inclusion Criteria for Study Eye Moderately severe or severe NPDR (ETDRS-DRSS level 47 or 53) BCVA score of ≥ 69 letters (20/40 approximate Snellen equivalent or better) Exclusion Criteria: Uncontrolled blood pressure Cerebrovascular accident or myocardial infarction within 6 months prior to randomization Atrial fibrillation diagnosis or worsening within 6 months prior to randomization Current systemic treatment for a confirmed active systemic infection Renal failure requiring renal transplant, hemodialysis, or peritoneal dialysis, or anticipated to require hemodialysis or peritoneal dialysis at any time during the study History of other disease, other non-diabetic metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a condition that contraindicates the use of ranibizumab or surgical placement of the PDS implant; that might affect interpretation of the results of the study; or that renders the patient at high risk for treatment complications in the opinion of the investigator or Sponsor Ocular Exclusion Criteria for Study Eye: Presence of center-involved diabetic macular edema (defined as CST ≥325 µm) Any intravitreal anti-VEGF treatment at any time prior to randomization Any use of medicated intraocular implants, including Ozurdex® or Iluvien® implants at any time prior to randomization Any intravitreal corticosteroid treatment at any time prior to randomization Any periocular (e.g., subtenon) corticosteroid treatment at any time prior to randomization Any PRP at any time prior to randomization Any macular laser photocoagulation (such as micropulse and focal or grid laser) at any time prior to randomization Active intraocular inflammation (grade trace or above) Clinically significant abnormalities of the vitreous-retinal interface involving the macular area or disrupting the macular architecture, such as vitreous-retinal traction or epiretinal membrane (assessed by the investigator and confirmed by the central reading center) Uncontrolled ocular hypertension or glaucoma and any such condition the investigator determines may require a glaucoma-filtering surgery during a participant's participation in the study History of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma surgery Any concurrent ocular condition (e.g., cataract, epiretinal membrane) that would require surgical intervention during the study to prevent or treat visual loss that might result from that condition Any concurrent ocular condition (e.g., amblyopia, strabismus) that may affect interpretation of study results History of other ocular diseases that gives reasonable suspicion of a disease or condition that contraindicates the use of ranibizumab, that might affect interpretation of study results, or that renders the participant at high risk for treatment complications Ocular Exclusion Criteria for Either Eye Suspected or active ocular or periocular infection of either eye Any history uveitis including idiopathic, drug-associated or autoimmune-associated uveitis

Ages Eligible for Study
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Minimum Age: 18 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 Arm<br>Participants randomized to the PDS arm will receive two intravitreal ranibizumab injections and will then have the PDS implant (pre-filled with ranibizumab) surgically inserted. PDS implant refill-exchange procedures will be performed on a fixed interval every 36-weeks (Q36W) thereafter | Drug: PDS Implant Pre-Filled with 100 mg/mL Ranibizumab<br>* Will be administered as per the schedule described in individual arm.<br>Drug: Intravitreal Ranibizumab 0.5 mg Injection<br>* Will be administered as per the schedule described in individual arm.<br>|
| Other: Comparator Arm<br>Participants randomized to the comparator arm will undergo study visits every 4 weeks (Q4W) for comprehensive clinical monitoring until they receive the PDS implant (pre-filled with ranibizumab). PDS implant refill-exchange procedures will be performed on a fixed interval Q36W thereafter. Participants will be eligible to receive intravitreal ranibizumab 0.5 mg injections if treatment eligibility criteria are met. | Drug: PDS Implant Pre-Filled with 100 mg/mL Ranibizumab<br>* Will be administered as per the schedule described in individual arm.<br>Drug: Intravitreal Ranibizumab 0.5 mg Injection<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 |
| --- | --- | --- |
| Percentage of participants with a ≥2-step improvement from baseline on the ETDRS-DRSS at Week 52 | ETDRS = Early Treatment Diabetic Retinopathy Study DRSS = Diabetic Retinopathy Severity Scale The ETDRS-DRSS includes 13 score levels, ranging from the absence of retinopathy to PDR, including neovascularization and/or vitreous/preretinal hemorrhage. | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of participants developing a vision-threatening complication (defined as PDR, ASNV, or CI-DME [defined as central foveal thickness [CST] ≥325 μm on spectral-domain optical coherence tomography [SD-OCT]) through Week 52 | PDR = proliferative diabetic retinopathy ASNV = Anterior segment neovascularization | From baseline through 52 weeks | 
| Rate of participants developing PDR or ASNV through Week 52 |  | From baseline through 52 weeks | 
| Rate of participants developing CI-DME through Week 52 |  | From baseline through 52 weeks | 
| Rate of participants developing a ≥ 2-step worsening from baseline on the ETDRS-DRSS through Week 52 |  | From baseline through 52 weeks | 
| Percentage of participants with a ≥ 3-step improvement from baseline on the ETDRS-DRSS at Week 52 |  | Week 52 | 
| Rate of participants developing a ≥ 3-step worsening from baseline on the ETDRS-DRSS through Week 52 |  | Baseline up to 52 weeks | 
| Percentage of participants with a ≥ 2-step improvement from baseline on the ETDRS-DRSS over time |  | Baseline up to Week 112 | 
| Percentage of participants with a ≥ 3-step improvement from baseline on the ETDRS-DRSS over time |  | Baseline up to Week 112 | 
| Time to first development of either PDR, ASNV, or CI-DME |  | Baseline up to Week 112 | 
| Time to first development of PDR or ASNV |  | Baseline up to Week 112 | 
| Time to first development of CI-DME |  | Baseline up to Week 112 | 
| Time to first development of a ≥ 2-step worsening from baseline on the ETDRS-DRSS |  | Baseline up to Week 112 | 
| Time to first development of a ≥ 3-step worsening from baseline on the ETDRS-DRSS |  | Baseline up to Week 112 | 
| Change from baseline in Best-Corrected Visual Acuity (BCVA) as measured on the ETDRS chart over time | A vision score of 20/20 vision is considered normal. A score of 20/200 is considered being legally blind. | Baseline up to Week 112 | 
| Percentage of participants who lose <15, < 10 and < 5 letters in BCVA from baseline over time |  | Baseline up to Week 112 | 
| Percentage of participants with a BCVA score of 69 letters (20/40 approximate Snellen equivalent) or better over time |  | Baseline up to Week 112 | 
| Change from baseline in CST as measured on SD-OCT over time |  | Baseline up to Week 112 | 
| Change from baseline in total macular volume as measured on SD-OCT over time |  | Baseline up to Week 112 | 
| Incidence and severity of ocular adverse events |  | Baseline up to Week 112 | 
| Incidence and severity of non-ocular adverse events |  | Baseline up to Week 112 | 
| Incidence, severity, and duration of adverse events of special interest |  | Baseline up to Week 112 | 
| Incidence, severity, and duration of ocular adverse events of special interest during the postoperative period (≤ 37 days after initial implant insertion) and follow-up period (> 37 days after implant insertion surgery) |  | Baseline up to Week 112 | 
| Serum concentration of ranibizumab observed over time |  | Baseline up to Week 112 | 
| Pharmacokinetic (PK) parameter value area under the concentration- time curve |  | Baseline up to Week 112 | 
| PK Parameter minimum serum concentration (Cmin) |  | Baseline up to Week 112 | 
| PK parameter half-life (t1/2) after PDS implant insertion |  | Baseline up to Week 112 | 
| Prevalence of anti-drug antibodies (ADAs) prior to study treatment and incidence of ADAs after study treatment |  | Baseline up to Week 112 | 
| Prevalence of neutralizing antibodies at baseline and incidence of neutralizing antibodies during the study |  | Baseline up to Week 112 | 
| Percentage of participants who do not undergo supplemental treatment with intravitreal ranibizumab within each refill-exchange interval |  | Baseline up to Week 112 | 
| Percentage of participants with adverse device effects |  | Baseline up to Week 112 | 
| Percentage of participants with serious adverse device effects |  | Baseline up to Week 112 | 
| Percentage of participants with absence of intraretinal fluid, subretinal fluid or both (as measured in the central 1 mm subfield) over time |  | Baseline up to Week 112 | 
| Percentage of participants who report preferring PDS treatment to intravitreal ranibizumab treatment, as measured by the PPPQ at Week 52 |  | Week 52 | 
| Reported incidence of device deficiencies |  | Baseline up to Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Port Delivery System; ranibizumab; Diabetic Retinopathy; anti-VEGF, nonproliferative diabetic retinopathy, retina, vision loss, retinal disease, eye disease