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 (PAVILION)

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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Diabetic Retinopathy
• Intervention / Treatment: Drug: PDS Implant Pre-Filled with 100 mg/mL Ranibizumab; Drug: Intravitreal Ranibizumab 0.5 mg Injection

• Study Type: Interventional
• Enrollment (Actual): 174
• Phase: Phase 3

Contacts and Locations

Study Locations

• Puerto Rico
  • Arecibo, Puerto Rico, 00612
    • Emanuelli Research and Development Center LLC
• United States
  • Arizona
    • Mesa, Arizona, United States, 85206
      • Barnet Dulaney Perkins Eye Center
    • Phoenix, Arizona, United States, 85020
      • Associated Retina Consultants
  • California
    • Bakersfield, California, United States, 93309
      • California Retina Consultants
    • Encino, California, United States, 91436
      • The Retina Partners
    • Fullerton, California, United States, 92835-3424
      • Retina Consultants of Orange County
    • Pasadena, California, United States, 91107
      • California Eye Specialists Medical group Inc.
    • Riverside, California, United States, 92505
      • Kaiser Permanente Riverside Medical Center
    • Sacramento, California, United States, 95825
      • Retinal Consultants Med Group
    • Santa Ana, California, United States, 92705
      • Orange County Retina Med Group
    • Santa Barbara, California, United States, 93103
      • California Retina Consultants
  • Colorado
    • Durango, Colorado, United States, 81303
      • Southwest Retina Consultants
    • Lakewood, Colorado, United States, 80228
      • Colorado Retina Associates, PC
  • Connecticut
    • Waterford, Connecticut, United States, 06385
      • Retina Group of New England
  • Florida
    • Pensacola, Florida, United States, 32503
      • Retina Specialty Institute
    • Plantation, Florida, United States, 33324
      • Fort Lauderdale Eye Institute
    • Tampa, Florida, United States, 33609
      • Retina Associates of Florida, LLC
  • Georgia
    • Augusta, Georgia, United States, 30909
      • Southeast Retina Center
    • Marietta, Georgia, United States, 30060-1137
      • Georgia Retina PC
  • Hawaii
    • 'Aiea, Hawaii, United States, 96701
      • Retina Consultants of Hawaii
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Medical Group/Northwestern University
    • Joliet, Illinois, United States, 60435
      • Illinois Retina Associates
  • Iowa
    • West Des Moines, Iowa, United States, 50266
      • Wolfe Eye Clinic
  • Kansas
    • Lenexa, Kansas, United States, 66215
      • Retina Associates
  • Maine
    • Portland, Maine, United States, 04101
      • Maine Eye Center
  • Maryland
    • Baltimore, Maryland, United States, 21209
      • The Retina Care Center
    • Hagerstown, Maryland, United States, 21740
      • Cumberland Valley Retina Associates
    • Towson, Maryland, United States, 21204
      • Retina Specialists
  • Michigan
    • Royal Oak, Michigan, United States, 48073
      • Associated Retinal Consultants PC
  • Minnesota
    • Minneapolis, Minnesota, United States, 55435
      • Vitreo Retinal Surgery
  • Missouri
    • Chesterfield, Missouri, United States, 63017
      • Midwest Vision Research Foundation
  • Nevada
    • Reno, Nevada, United States, 89502
      • Sierra Eye Associates
  • New Jersey
    • Bloomfield, New Jersey, United States, 07003
      • Envision Ocular, LLC
    • Teaneck, New Jersey, United States, 07666
      • Retina Associates of NJ
  • New York
    • Liverpool, New York, United States, 13088
      • Retina Vit Surgeons/Central NY
    • New York, New York, United States, 10017
      • New York University
  • North Carolina
    • Asheville, North Carolina, United States, 28803
      • Western Carolina Retinal Associate PA
    • Charlotte, North Carolina, United States, 28210
      • Char Eye Ear &Throat Assoc
    • Durham, North Carolina, United States, 27705
      • Duke Eye Center
    • Wilmington, North Carolina, United States, 28401
      • Cape Fear Retinal Associates
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
  • Oklahoma
    • Edmond, Oklahoma, United States, 73013
      • Retina Vitreous Center
  • Pennsylvania
    • Chambersburg, Pennsylvania, United States, 17201
      • Cumberland Valley Retina Consultants; Chambersburg
    • Philadelphia, Pennsylvania, United States, 19107
      • Mid Atlantic Retina - Wills Eye Hospital
  • South Carolina
    • Ladson, South Carolina, United States, 29456
      • Charleston Neuroscience Inst
    • West Columbia, South Carolina, United States, 29169
      • Palmetto Retina Center
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Charles Retina Institute
    • Knoxville, Tennessee, United States, 37923
      • Southeastern Retina Associates
    • Nashville, Tennessee, United States, 37203
      • Tennessee Retina PC
  • Texas
    • Austin, Texas, United States, 78705-1169
      • Austin Retina Associates
    • Bellaire, Texas, United States, 77401
      • Retina & Vitreous of Texas
    • Dallas, Texas, United States, 75231
      • Texas Retina Associates
    • San Antonio, Texas, United States, 78240
      • Med Center Ophthalmology Assoc
    • Southlake, Texas, United States, 76092
      • Retina Center of Texas
    • The Woodlands, Texas, United States, 77384-4167
      • Retina Consultants of Texas
  • Utah
    • Salt Lake City, Utah, United States, 84107
      • Rocky Mountain Retina
  • Virginia
    • Lynchburg, Virginia, United States, 24502
      • Piedmont Eye Center
    • Richmond, Virginia, United States, 23235
      • Retina Institute of Virginia
  • Washington
    • Silverdale, Washington, United States, 98383
      • Retina Center Northwest
    • Spokane, Washington, United States, 99204
      • Spokane Eye Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PDS Arm; 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; Will be administered as per the schedule described in individual arm.; Drug: Intravitreal Ranibizumab 0.5 mg Injection; Will be administered as per the schedule described in individual arm.
Other: Comparator Arm; 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; Will be administered as per the schedule described in individual arm.; Drug: Intravitreal Ranibizumab 0.5 mg Injection; Will be administered as per the schedule described in individual arm.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): August 10, 2020
• Primary Completion (Actual): October 3, 2022
• Study Completion (Estimated): May 7, 2024

Study Registration Dates

• First Submitted: August 5, 2020
• First Submitted That Met QC Criteria: August 5, 2020
• First Posted (Actual): August 7, 2020

Study Record Updates

• Last Update Posted (Actual): September 13, 2023
• Last Update Submitted That Met QC Criteria: September 7, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Port Delivery System; ranibizumab; Diabetic Retinopathy; anti-VEGF, nonproliferative diabetic retinopathy, retina, vision loss, retinal disease, eye disease
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Eye Diseases; Endocrine System Diseases; Diabetic Angiopathies; Diabetes Complications; Diabetes Mellitus; Retinal Diseases; Diabetic Retinopathy; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Ranibizumab
• Other Study ID Numbers: GR41675

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here ( https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No