A Study to Evaluate Efficacy, Safety & Pharmacokinetics of the Port Delivery System (PDS) With Ranibizumab in Participants With Diabetic Macular Edema (DME) Compared With Intravitreal Ranibizumab; A Substudy to Evaluate the Safety of Re-implanting the PDS With Ranibizumab in Participants With DME

Phase 3Active Not RecruitingNCT04108156

Hoffmann-La Roche672 enrolled

Overview

This study will evaluate the efficacy, safety, and Pharmacokinetics (PK) of the PDS with ranibizumab in participants with DME when treated every 24 weeks (Q24W) compared with intravitreal (IVT) ranibizumab 0.5 milligrams (mg) every 4 weeks (Q4W). The substudy will evaluate safety of re-implanting the updated PDS with ranibizumab and the refill-exchange procedures following re-implantation in participants with DME who were previously enrolled in the main study, GR40550. Up to 100 participants from the main study will be enrolled and followed for a maximum of 72 weeks post-re-implantation in the substudy.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Enrollment

672

Conditions

Diabetic Macular Edema

Interventions

Will be administered as per the schedule described in individual arm.

Intravitreal Ranibizumab 0.5 mg InjectionDRUG

Will be administered as per the schedule described in individual arm.

Ranibizumab refill exchangeDRUG

Will be administered as per the schedule described in individual arm.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age ≥18 years at time of signing informed consent form (ICF) * Documented diagnosis of diabetes mellitus (Type 1 or Type 2) * Glycated haemoglobin (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 micrometer (µm) on SD-OCT at screening * BCVA score of 78 to 25 letters (20/32 to 20/320 approximate Snellen equivalent) Exclusion Criteria: * High-risk PDR * 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 Substudy: Inclusion Criteria: * Having experienced a septum dislodgement in the original implant while in the main study or after exiting the main study * Sufficiently clear ocular media and adequate pupillary dilation to allow for analysis and grading by central reading center Exclusion Criteria (Cohort 1 Only): * Recent history (in the last 3 months prior to enrollment) 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 participant at high risk for treatment complications * Active cancer within the last 12 months, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or prostate cancer * Current systemic treatment for a confirmed active systemic infection * Participation in an investigational trial that involves treatment with any drug or device (with the exception of vitamins and minerals or enrollment in Study GR40550) within 6 months prior to enrollment * Use of antimitotic or antimetabolite therapy within 30 days Ocular Exclusion Criteria for Study Eye: * Any ocular condition that may render the participant at high risk for surgical or treatment complications * Intraocular surgery (including cataract surgery) within 1 month preceding the enrollment visit * Any use of medicated intraocular implants (other than the PDS implant), at any time prior to enrollment * History of rhegmatogenous retinal tears or peripheral retinal breaks within 3 months prior to the enrollment visit * Any concurrent ocular condition that would require surgical intervention during the study to prevent or treat visual loss * Concurrent conjunctival, tenon's capsule, and/or scleral condition in the supero-temporal quadrant of the eye (e.g., scarring, thinning, mass) that may affect the refill-exchange procedure of the PDS implant * Ongoing ocular complications that might affect participant safety Ocular Exclusion Criteria for Either Eye * Suspected or active ocular or periocular infection (e.g., infectious conjunctivitis or endophthalmitis) * Any history of uveitis * Active blepharitis

Locations (88)

Barnet Dulaney Perkins Eye Center

Mesa, Arizona, United States

Retinal Consultants of Arizona;Opthalmology

Phoenix, Arizona, United States

Arizona Retina and Vitreous Consultants

Phoenix, Arizona, United States

Associated Retina Consultants

Phoenix, Arizona, United States

California Retina Consultants

Bakersfield, California, United States

Outcomes

Primary Outcomes

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.

Time frame: Baseline to Week 64

Substudy: Number of Participants With Ocular and Systemic (Non-ocular) Adverse Events (AEs) and Severity of Ocular and Systemic AEs

Time frame: Baseline to Week 72

Substudy: Number of Participants With Adverse Events of Special Interests (AESIs) and Severity of AESIs

Time frame: Baseline to Week 72

Substudy: Duration of AESIs

Time frame: Baseline to Week 72

Substudy: Number of Participants With Ocular AESIs and Severity of Ocular AESIs During the Post-operative Period

Time frame: Up to Day 37 post re-implantation

Substudy: Number of Participants With Ocular AESIs and Severity of Ocular AESIs During the Follow-up Period

Time frame: > 37 days post-implantation (up to approximately 72 weeks)

Substudy: Duration of Ocular AESIs During the Post-operative Period

Time frame: Up to Day 37 post re-implantation

Substudy: Duration of Ocular AESIs During the Follow-up Period

Time frame: > 37 days post-implantation (up to approximately 72 weeks)

Substudy: Number of Participants With Adverse Device Effects (ADEs) and Severity of ADEs

Time frame: Baseline to Week 72

Substudy: Number of Participants With Anticipated Serious ADEs

Time frame: Baseline to Week 72

Substudy: Duration of Serious ADEs

Time frame: Baseline to Week 72

Substudy: Number of Device Deficiencies

Time frame: Baseline to Week 72

Secondary Outcomes

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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Baseline to Week 64

Change from Baseline in BCVA as Measured on the ETDRS Chart Over Time

Time frame: Baseline up to Week 120

Percentage of Participants Who Lose <15, <10, and <5 letters in BCVA From Baseline Over Time

Time frame: Baseline up to Week 120

Percentage of Participants Who Gain ≥15, ≥10, ≥5, ≥0 Letters in BCVA From Baseline Over Time

Time frame: Baseline up to Week 120

Percentage of Participants With a BCVA Snellen Equivalent of 20/40 or Better Over Time

Time frame: Baseline up to Week 120

Percentage of Participants With a BCVA Snellen Equivalent of 20/200 or Worse Over Time

Time frame: Baseline up to Week 120

Percentage of Participants With a ≥2-step Improvement From Baseline on the ETDRS-DRSS Over Time

Data from ClinicalTrials.gov

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Retina-Vitreous Associates Medical Group

Beverly Hills, California, United States

The Retina Partners

Encino, California, United States

Retina Consultants of Orange County;Clinical Research

Fullerton, California, United States

Jules Stein Eye Institute/ UCLA

Los Angeles, California, United States

Northern California Retina-Vitreous Associates

Mountain View, California, United States

...and 78 more locations

Time frame: Baseline up to Week 120

Percentage of Participants With a ≥3-step Improvement From Baseline on the ETDRS-DRSS Over Time

Time frame: Baseline up to Week 120

Time to ≥2-step Worsening From Baseline on the ETDRS-DRSS

Time frame: Baseline up to Week 120

Time to ≥3-step Worsening From Baseline on the ETDRS-DRSS

Time frame: Baseline up to Week 120

Change From Baseline in ETDRS-DRSS Score Over Time

Time frame: Baseline up to Week 120

Change From Baseline in Central Subfield Thickness (CST) as Measured on Spectral Domain Optical Coherence Tomography (SD-OCT) Over Time

Time frame: Baseline up to Week 120

Change From Baseline in Total Macular Volume as Measured on SD-OCT Over Time

Time frame: Baseline up to Week 120

Percentage of Participants With Absence of Intraretinal Fluid (IRF) Over Time (IRF as Measured in the Central 1 mm Subfield)

Time frame: Baseline up to Week 120

Percentage of Participants With Absence of Subretinal Fluid (SRF) Over Time (SRF as Measured in the Central 1 mm Subfield)

Time frame: Baseline up to Week 120

Percentage of Participants With Absence of IRF and SRF Over Time

Time frame: 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

Time frame: Baseline up to Week 120

Time to PDR (Defined as a Score ≥60 on the ETDRS-DRSS)

PDR = proliferative diabetic retinopathy

Time frame: Baseline up to Week 120

Percentage of Participants Who do not Undergo Supplemental Treatment With IVT Ranibizumab Within Each Refill-exchange Interval

Time frame: Baseline up to Week 120

Percentage of Participants Who Report Preferring PDS Treatment Compared With IVT Ranibizumab Treatment

As measured by the PDS patient preference questionnaire (PPPQ) at Week 64 among participants in the PDS arm efficacy population, mITT population

Time frame: Baseline to Week 64

Percentage of Participants Who Report Preferring PDS Treatment Compared With IVT Ranibizumab Treatment, as Measured by the PPPQ at Week 64

Participants in a subset of patients with bilateral disease who are simultaneously receiving ranibizumab via study eye PDS implant and fellow eye IVT injection.

Time frame: Baseline to Week 64

Participant-reported Vision-related Functioning and Health-Related Quality of Life (HRQoL) Among Participants 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

Time frame: , Baseline Week 48, Week 96

Participant-reported Vision-related Functioning and HRQoL, as Measured by the Proportion of Participants With a ≥ 4-Point Improvement From Baseline in the NEI VFQ-25 Composite Score at Weeks 48 and 96 Among Participants in Both Treatment Arms

Time frame: Baseline, Week 48, Week 96

Incidence and Severity of Ocular AEs

Time frame: Baseline to Week 120

Incidence and Severity of Non-ocular AEs

Time frame: Baseline up to Week 120

Incidence, Severity, and Duration of AEs of Special Interest

Time frame: Baseline up to Week 120

Serum Concentration of Ranibizumab Observed Over Time

Time frame: Baseline up to Week 120

PK Parameter: Value Area Under the Concentration- Time Curve Over 24 weeks (AUC24W)

Time frame: Baseline to Week 24

PK Parameter: Maximum Serum Concentration (Cmax)

Time frame: Baseline up to Week 120

PK Parameter: Minimum Serum Concentration (Cmin)

Time frame: Baseline up to Week 120

Time of Maximum Observed Serum Concentration (Tmax) After PDS Implant Insertion

Time frame: Baseline up to Week 120

Prevalence of Anti-drug Antibodies (ADAs) at Baseline and Incidence of ADAs During the Study

Time frame: Baseline up to Week 120

Prevalence of Neutralizing Antibodies at Baseline and Incidence of Neutralizing Antibodies During the Study

Time frame: Baseline up to Week 120

Reported Incidence of Device Deficiencies

Time frame: Baseline up to Week 120

Incidence and Severity of Ocular AEs

Time frame: Baseline up to Week 120

Incidence, Severity, and Duration of AESIs

Time frame: Baseline up to Week 120

Incidence, Severity, and Duration of Ocular AESIs During the Postoperative Period (up to 37 Days After Initial Implantation) and Follow-up Period (> 37 days After Implantation Surgery)

Time frame: Baseline up to Week 120

Incidence and Severity of ADEs

Time frame: Baseline up to Week 120

Incidence, Causality, Severity, and Duration of Anticipated Serious ADEs

Time frame: Baseline up to Week 120

Substudy: Number of Participants With Ocular AESIs and Severity of Ocular AESIs After Refill-exchange Procedure

Time frame: Up to approximately 72 weeks

Substudy: Duration of AESIs After Refill-exchange Procedure

Time frame: Up to approximately 72 weeks

Substudy: Number of Participants With ADEs and Severity of ADEs After Refill-exchange Procedure

Time frame: Up to approximately 72 weeks

Substudy: Number of Participants With Anticipated Serious ADEs After Refill-exchange Procedure

Time frame: Up to approximately 72 weeks

Substudy: Duration of Serious ADEs After Refill-exchange Procedure

Time frame: Up to approximately 72 weeks

Substudy: Number of Device Deficiencies After Refill-exchange Procedure

Time frame: Up to approximately 72 weeks