This Study Will Evaluate the Efficacy, Safety, and Pharmacokinetics of the Port Delivery System With Ranibizumab in Participants With Diabetic Macular Edema Compared With Intravitreal Ranibizumab

Study Overview
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Brief Summary
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This study will evaluate the efficacy, safety, and pharmacokinetics of the Port Delivery System with Ranibizumab (PDS) in Participants with Diabetic Macular Edema (DME) when treated every 24 weeks (Q24W) compared with intravitreal ranibizumab 0.5 mg every 4 weeks (Q4W).

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 Patients With Diabetic Macular Edema (Pagoda)

Conditions
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Diabetic Macular Edema

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 ≤10% within 2 months prior to screening or at screening Study eye Macular thickening secondary to DME involving the center of the fovea with CST ≥325 um on SD-OCT at screening BCVA score of 78 to 25 letters (20/32 to 20/320 approximate Snellen equivalent) Exclusion Criteria: High-risk proliferative diabetic retinopathy Active intraocular inflammation (grade trace or above) Suspected or active ocular or periocular infection of either eye 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 Cerebrovascular accident or myocardial infarction within 6 months prior to randomization Atrial fibrillation diagnosis or worsening within 6 months prior to randomization Uncontrolled blood pressure

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 intravitreal ranibizumab injection every 4 weeks (loading phase) 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 24-weeks (Q24W) thereafter | Drug: PDS Implant Pre-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 randomized to the intravitreal arm will receive intravitreal ranibizumab injection every 4 weeks until they receive the PDS implant (pre-filled with ranibizumab). PDS implant refill-exchange procedures will be performed on a fixed interval Q24W thereafter. | 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 |
| --- | --- | --- |
| Change in BCVA score from baseline averaged over Weeks 60 and 64 as measured using the ETDRS chart in the efficacy population using a treatment policy strategy for all intercurrent events | BCVA = Best-Corrected Visual Acuity 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 to Week 64 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in BCVA score from baseline averaged over Weeks 60 and 64 as measured with use of the ETDRS chart in the modified intent-to-treat (mITT) population using a treatment policy strategy for all intercurrent events | ETDRS-DRSS = ETDRS Diabetic Retinopathy Severity Scale | Baseline to Week 64 | 
| Change in BCVA score from baseline averaged over Weeks 60 and 64 as measured with use of the ETDRS chart in the mITT population using a hypothetical strategy for all intercurrent events |  | Baseline to Week 64 | 
| Percentage of participants with a ≥2-step improvement from baseline on the ETDRS-DRSS at Week 64 in the efficacy population |  | Baseline to Week 64 | 
| Percentage of participants with a ≥2-step improvement from baseline on the ETDRS-DRSS at Week 64 in the mITT population |  | Baseline to Week 64 | 
| Change from baseline in BCVA as measured on the ETDRS chart over time |  | Baseline up to Week 120 | 
| Percentage of participants who lose <15, <10, and <5 letters in BCVA from baseline over time |  | Baseline up to Week 120 | 
| Percentage of participants who gain ≥15, ≥10, ≥5, ≥0 letters in BCVA from baseline over time |  | Baseline up to Week 120 | 
| Percentage of participants with a BCVA Snellen equivalent of 20/40 or better over time |  | Baseline up to Week 120 | 
| Percentage of participants with a BCVA Snellen equivalent of 20/200 or worse over time |  | Baseline up to Week 120 | 
| Percentage of participants with a ≥2-step improvement from baseline on the ETDRS-DRSS over time |  | Baseline up to Week 120 | 
| Percentage of participants with a ≥3-step improvement from baseline on the ETDRS-DRSS over time |  | Baseline up to Week 120 | 
| Time to ≥2-step worsening from baseline on the ETDRS-DRSS |  | Baseline up to Week 120 | 
| Time to ≥3-step worsening from baseline on the ETDRS-DRSS |  | Baseline up to Week 120 | 
| Change from baseline in ETDRS-DRSS score over time |  | Baseline up to Week 120 | 
| Change from baseline in CST as measured on SD-OCT over time |  | Baseline up to Week 120 | 
| Change from baseline in total macular volume as measured on SD-OCT over time |  | Baseline up to Week 120 | 
| Percentage of participants with absence of intraretinal fluid over time (intraretinal fluid as measured in the central 1 mm subfield) |  | Baseline up to Week 120 | 
| Percentage of participants with absence of subretinal fluid over time (subretinal fluid as measured in the central 1 mm subfield) |  | Baseline up to Week 120 | 
| Percentage of participants with absence of intraretinal fluid and subretinal fluid over time |  | Baseline up to Week 120 | 
| Percentage of participants with absence DME (defined as CST ≥325 μm on SD-OCT) over time | DME = diabetic macular edema | Baseline up to Week 120 | 
| Time to PDR (defined as a score ≥60 on the ETDRS-DRSS) | PDR = proliferative diabetic retinopathy | Baseline up to Week 120 | 
| Percentage of participants who do not undergo supplemental treatment with intravitreal ranibizumab within each refill-exchange interval |  | Baseline up to Week 120 | 
| Percentage of participants who report preferring PDS treatment compared with intravitreal ranibizumab treatment | As measured by the PDS Patient Preference Questionnaire at Week 64 among patients in the PDS arm efficacy population, mITT population | Baseline to Week 64 | 
| Percentage of participants who report preferring PDS treatment compared with intravitreal ranibizumab treatment, as measured by the PDS Patient Preference Questionnaire (PPPQ) at Week 64 | Participants in in a subset of patients with bilateral disease who are simultaneously receiving ranibizumab via study eye PDS implant and fellow eye intravitreal injection | Baseline to Week 64 | 
| Patient-reported vision-related functioning and health-related quality of life (HRQoL) among patients in both treatment arms, as measured by changes from baseline | As measured by in the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) composite score and Near Activities, Distance Activities, and Driving subscale scores | , Baseline Week 48, Week 96 | 
| Patient-reported vision-related functioning and HRQoL, as measured by the proportion of patients with a ≥ 4-point improvement from baseline in the NEI VFQ-25 composite score at Weeks 48 and 96 among patients in both treatment arms |  | Baseline, Week 48, Week 96 | 
| Incidence and severity of ocular adverse events |  | Baseline to Week 120 | 
| Incidence and severity of non-ocular adverse events |  | Baseline up to Week 120 | 
| Incidence, severity, and duration of adverse events of special interest |  | Baseline up to Week 120 | 
| Serum concentration of ranibizumab observed over time |  | Baseline up to Week 120 | 
| PK parameter value area under the concentration- time curve over 24 weeks (AUC24W) |  | Baseline to Week 24 | 
| Pharmacokinetic (PK) parameter maximum serum concentration (Cmax) |  | Baseline up to Week 120 | 
| PK Parameter minimum serum concentration (Cmin) |  | Baseline up to Week 120 | 
| Time of maximum observed serum concentration (Tmax) after PDS implant insertion |  | Baseline up to Week 120 | 
| Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during the study |  | Baseline up to Week 120 | 
| Prevalence of neutralizing antibodies at baseline and incidence of neutralizing antibodies during the study |  | Baseline up to Week 120 | 
| Reported incidence of device deficiencies |  | Baseline up to Week 120 | 
| Incidence and severity of ocular adverse events |  | Baseline up to Week 120 | 
| Incidence, severity, and duration of ocular adverse events of special interest during the postoperative period (up to 37 days after initial implantation) and follow-up period (> 37 days after implantation surgery) |  | Baseline up to Week 120 | 
| Incidence and severity of adverse device effects |  | Baseline up to Week 120 | 
| Incidence, causality, severity, and duration of anticipated serious adverse device effects |  | Baseline up to Week 120 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Port Delivery System