Clinical trial NCT04108156: 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 Subtudy to Evaluate the Safety of Re-Implanting the PDS With Ranibizumab in Participants With DME
Official title: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Diabetic Macular Edema
Keywords: Port Delivery System
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2019-09-30
Enrollment: 634
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will evaluate the efficacy, safety, and pharmacokinetics of the PDS with Ranibizumab in participants with DME when treated every 24 weeks (Q24W) compared with intravitreal ranibizumab 0.5 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.


Eligibility criteria: 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

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

Primary outcomes:
measure: 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
timeFrame: Baseline to Week 64
measure: Substudy: Number of Participants with Ocular and Systemic (Non-ocular) Adverse Events (AEs) and Severity of Ocular and Systemic AEs
timeFrame: Baseline to Week 72
measure: Substudy: Number of Participants with Adverse Events of Special Interests (AESIs) and Severity of AESIs
timeFrame: Baseline to Week 72
measure: Substudy: Duration of AESIs
timeFrame: Baseline to Week 72
measure: Substudy: Number of Participants with Ocular AESIs and Severity of Ocular AESIs During the Post-operative Period
timeFrame: Up to Day 37 post re-implantation
measure: Substudy: Number of Participants with Ocular AESIs and Severity of Ocular AESIs During the Follow-up Period
timeFrame: > 37 days post-implantation (up to approximately 72 weeks)
measure: Substudy: Duration of Ocular AESIs During the Post-operative Period
timeFrame: Up to Day 37 post re-implantation
measure: Substudy: Duration of Ocular AESIs During the Follow-up Period
timeFrame: > 37 days post-implantation (up to approximately 72 weeks)
measure: Substudy: Number of Participants with Adverse Device Effects (ADEs) and Severity of ADEs
timeFrame: Baseline to Week 72
measure: Substudy: Number of Participants with Anticipated Serious ADEs
timeFrame: Baseline to Week 72
measure: Substudy: Duration of Serious ADEs
timeFrame: Baseline to Week 72
measure: Substudy: Number of Device Deficiencies
timeFrame: Baseline to Week 72
Secondary outcomes:
measure: 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
timeFrame: Baseline to Week 64
measure: 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
timeFrame: Baseline to Week 64
measure: Percentage of Participants with a ≥2-step Improvement from Baseline on the ETDRS-DRSS at Week 64 in the Efficacy Population
timeFrame: Baseline to Week 64
measure: Percentage of Participants with a ≥2-step Improvement from Baseline on the ETDRS-DRSS at Week 64 in the mITT population
timeFrame: Baseline to Week 64
measure: Change from Baseline in BCVA as Measured on the ETDRS Chart Over Time
timeFrame: Baseline up to Week 120
measure: Percentage of Participants Who Lose <15, <10, and <5 letters in BCVA from Baseline Over Time
timeFrame: Baseline up to Week 120
measure: Percentage of Participants Who Gain ≥15, ≥10, ≥5, ≥0 Letters in BCVA from Baseline Over Time
timeFrame: Baseline up to Week 120
measure: Percentage of Participants with a BCVA Snellen Equivalent of 20/40 or Better Over Time
timeFrame: Baseline up to Week 120
measure: Percentage of Participants with a BCVA Snellen Equivalent of 20/200 or Worse Over Time
timeFrame: Baseline up to Week 120
measure: Percentage of Participants with a ≥2-step Improvement from Baseline on the ETDRS-DRSS Over Time
timeFrame: Baseline up to Week 120
measure: Percentage of Participants with a ≥3-step Improvement from Baseline on the ETDRS-DRSS Over Time
timeFrame: Baseline up to Week 120
measure: Time to ≥2-step Worsening from Baseline on the ETDRS-DRSS
timeFrame: Baseline up to Week 120
measure: Time to ≥3-step Worsening from Baseline on the ETDRS-DRSS
timeFrame: Baseline up to Week 120
measure: Change from Baseline in ETDRS-DRSS Score Over Time
timeFrame: Baseline up to Week 120
measure: Change from Baseline in CST as Measured on SD-OCT Over Time
timeFrame: Baseline up to Week 120
measure: Change from Baseline in Total Macular Volume as Measured on SD-OCT Over Time
timeFrame: Baseline up to Week 120
measure: Percentage of Participants with Absence of Intraretinal Fluid Over Time (Intraretinal Fluid as Measured in the Central 1 mm Subfield)
timeFrame: Baseline up to Week 120
measure: Percentage of Participants with Absence of Subretinal Fluid Over Time (Subretinal Fluid as Measured in the Central 1 mm Subfield)
timeFrame: Baseline up to Week 120
measure: Percentage of Participants with Absence of Intraretinal Fluid and Subretinal Fluid Over Time
timeFrame: Baseline up to Week 120
measure: Percentage of Participants with Absence DME (Defined as CST ≥325 μm on SD-OCT) Over Time
timeFrame: Baseline up to Week 120
measure: Time to PDR (Defined as a Score ≥60 on the ETDRS-DRSS)
timeFrame: Baseline up to Week 120
measure: Percentage of Participants Who do Not Undergo Supplemental Treatment with Intravitreal Ranibizumab Within Each Refill-Exchange Interval
timeFrame: Baseline up to Week 120
measure: Percentage of Participants Who Report Preferring PDS Treatment Compared with Intravitreal Ranibizumab Treatment
timeFrame: Baseline to Week 64
measure: 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
timeFrame: Baseline to Week 64
measure: Patient-reported Vision-Related Functioning and Health-Related Quality of Life (HRQoL) Among Patients in Both Treatment Arms, as Measured by Changes from Baseline
timeFrame: , Baseline Week 48, Week 96
measure: 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
timeFrame: Baseline, Week 48, Week 96
measure: Incidence and Severity of Ocular Adverse Events
timeFrame: Baseline to Week 120
measure: Incidence and Severity of Non-ocular Adverse Events
timeFrame: Baseline up to Week 120
measure: Incidence, Severity, and Duration of Adverse Events of Special Interest
timeFrame: Baseline up to Week 120
measure: Serum Concentration of Ranibizumab Observed Over Time
timeFrame: Baseline up to Week 120
measure: PK Parameter Value Area Under the Concentration- Time Curve Over 24 weeks (AUC24W)
timeFrame: Baseline to Week 24
measure: Pharmacokinetic (PK) Parameter Maximum Serum Concentration (Cmax)
timeFrame: Baseline up to Week 120
measure: PK Parameter Minimum Serum Concentration (Cmin)
timeFrame: Baseline up to Week 120
measure: Time of Maximum Observed Serum Concentration (Tmax) After PDS Implant Insertion
timeFrame: Baseline up to Week 120
measure: Prevalence of Anti-drug Antibodies (ADAs) at Baseline and Incidence of ADAs During the Study
timeFrame: Baseline up to Week 120
measure: Prevalence of Neutralizing Antibodies at Baseline and Incidence of Neutralizing Antibodies During the Study
timeFrame: Baseline up to Week 120
measure: Reported Incidence of Device Deficiencies
timeFrame: Baseline up to Week 120
measure: Incidence and Severity of Ocular Adverse Events
timeFrame: Baseline up to Week 120
measure: 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)
timeFrame: Baseline up to Week 120
measure: Incidence and Severity of ADEs
timeFrame: Baseline up to Week 120
measure: Incidence, Causality, Severity, and Duration of Anticipated Serious Adverse Device Effects
timeFrame: Baseline up to Week 120
measure: Substudy: Number of Participants with Ocular AESIs and Severity of Ocular AESIs After Refill-exchange Procedure
timeFrame: Up to approximately 72 weeks
measure: Substudy: Duration of AESIs After Refill-exchange Procedure
timeFrame: Up to approximately 72 weeks
measure: Substudy: Number of Participants With ADEs and Severity of ADEs After Refill-exchange Procedure
timeFrame: Up to approximately 72 weeks
measure: Substudy: Number of Participants with Anticipated Serious ADEs After Refill-exchange Procedure
timeFrame: Up to approximately 72 weeks
measure: Substudy: Duration of Serious ADEs After Refill-exchange Procedure
timeFrame: Up to approximately 72 weeks
measure: Substudy: Number of Device Deficiencies After Refill-exchange Procedure
timeFrame: Up to approximately 72 weeks
Other outcomes:
Locations:
city: Mesa
country: United States
facility: Barnet Dulaney Perkins Eye Center
state: Arizona
city: Phoenix
country: United States
facility: Retinal Consultants of Arizona;Opthalmology
state: Arizona
city: Phoenix
country: United States
facility: Arizona Retina and Vitreous Consultants
state: Arizona
city: Phoenix
country: United States
facility: Associated Retina Consultants
state: Arizona
city: Bakersfield
country: United States
facility: California Retina Consultants
state: California
city: Beverly Hills
country: United States
facility: Retina-Vitreous Associates Medical Group
state: California
city: Encino
country: United States
facility: The Retina Partners
state: California
city: Fullerton
country: United States
facility: Retina Consultants of Orange County;Clinical Research
state: California
city: Los Angeles
country: United States
facility: Jules Stein Eye Institute/ UCLA
state: California
city: Mountain View
country: United States
facility: Northern California Retina-Vitreous Associates
state: California
city: Oakland
country: United States
facility: East Bay Retina Consultants
state: California
city: Pasadena
country: United States
facility: Doheny Eye Institute
state: California
city: Pasadena
country: United States
facility: California Eye Specialists Medical Group
state: California
city: Sacramento
country: United States
facility: Retina Consultants Medical Group
state: California
city: San Francisco
country: United States
facility: Zuckerberg San Francisco General Hospital and Trauma Center
state: California
city: Santa Ana
country: United States
facility: Orange County Retina Medical Group
state: California
city: Santa Barbara
country: United States
facility: California Retina Consultants;Research Department
state: California
city: Fort Collins
country: United States
facility: Eye Center of Northern Colorado
state: Colorado
city: Lakewood
country: United States
facility: Colorado Clinical Research
state: Colorado
city: Waterford
country: United States
facility: Retina Group of New England
state: Connecticut
city: Fort Lauderdale
country: United States
facility: Retina Group of Florida
state: Florida
city: Fort Myers
country: United States
facility: National Ophthalmic Research Institute
state: Florida
city: Pensacola
country: United States
facility: Retina Specialty Institute
state: Florida
city: Plantation
country: United States
facility: Fort Lauderdale Eye Institute
state: Florida
city: Saint Petersburg
country: United States
facility: Retina Vitreous Associates of Florida
state: Florida
city: Tallahassee
country: United States
facility: Southern Vitreoretinal Associates;Research
state: Florida
city: Tampa
country: United States
facility: Retina Associates of Florida;Retina Associates of Florida
state: Florida
city: Augusta
country: United States
facility: Southeast Retina Center
state: Georgia
city: Marietta
country: United States
facility: Georgia Retina
state: Georgia
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Joliet
country: United States
facility: Illinois Retina Associates
state: Illinois
city: Lemont
country: United States
facility: University Retina
state: Illinois
city: West Des Moines
country: United States
facility: Wolfe Eye Clinic
state: Iowa
city: Lenexa
country: United States
facility: Retina Associates
state: Kansas
city: Lexington
country: United States
facility: Retina & Vitreous Associates of Kentucky
state: Kentucky
city: Portland
country: United States
facility: Maine Eye Center
state: Maine
city: Baltimore
country: United States
facility: The Retina Care Center
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Hospital;Johns Hopkins Med;Wilmer Eye Inst
state: Maryland
city: Chevy Chase
country: United States
facility: The Retina Group of Washington;Retinal Disease
state: Maryland
city: Hagerstown
country: United States
facility: Cumberland Valley Retina Consultants;Clinical Research
state: Maryland
city: Towson
country: United States
facility: Retina Specialist
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Ophthalmic Consultants of Boston
state: Massachusetts
city: Worcester
country: United States
facility: Vitreo Retinal Associates
state: Massachusetts
city: Grand Rapids
country: United States
facility: Retina Specialists Of Michigan
state: Michigan
city: Royal Oak
country: United States
facility: Associated Retinal Consultants - Royal Oak
state: Michigan
city: Minneapolis
country: United States
facility: VitreoRetinal Surgery PLLC;DBA Retina Consultants of Minnesota
state: Minnesota
city: Chesterfield
country: United States
facility: Pepose Vision Institute
state: Missouri
city: Saint Louis
country: United States
facility: Retina Institute
state: Missouri
city: Reno
country: United States
facility: Sierra Eye Associates
state: Nevada
city: Bloomfield
country: United States
facility: Envision Ocular, LLC
state: New Jersey
city: Teaneck
country: United States
facility: Retina Associates of New Jersey
state: New Jersey
city: Great Neck
country: United States
facility: Long Island Vitreoretinal Consultants;Opthalmology
state: New York
city: Liverpool
country: United States
facility: Retina Vitreous Surgeons of Central New York
state: New York
city: New York
country: United States
facility: New York University (NYU)
state: New York
city: Oceanside
country: United States
facility: Ophthalmic Consultants of Long Island
state: New York
city: Asheville
country: United States
facility: Asheville Eye Associates Western Carolina Retinal Associates;Clinical Research
state: North Carolina
city: Charlotte
country: United States
facility: Charlotte Eye Ear Nose and Throat Associates- SouthPark;Retina
state: North Carolina
city: Durham
country: United States
facility: Duke Eye Center
state: North Carolina
city: Hickory
country: United States
facility: Graystone Eye;Clinical Research
state: North Carolina
city: Wilmington
country: United States
facility: Cape Fear Retinal Associates
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Eye Institute;Retina
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Ohio State Havener Eye Institute;Ophthalmology Research
state: Ohio
city: Dublin
country: United States
facility: Midwest Retina;Retina/Vitreous
state: Ohio
city: Edmond
country: United States
facility: Retina Vitreous Center - Glen Eagles
state: Oklahoma
city: Portland
country: United States
facility: Retina Northwest;Research Department
state: Oregon
city: Chambersburg
country: United States
facility: Cumberland Valley Retina Consultants
state: Pennsylvania
city: Philadelphia
country: United States
facility: Mid Atlantic Retina
state: Pennsylvania
city: Ladson
country: United States
facility: Charleston Neuroscience
state: South Carolina
city: Mount Pleasant
country: United States
facility: Carolina Eyecare Physicians
state: South Carolina
city: West Columbia
country: United States
facility: Palmetto Retina Center
state: South Carolina
city: West Columbia
country: United States
facility: Palmetto Retina Center
state: South Carolina
city: Germantown
country: United States
facility: Charles Retina Institution;Retina surgery
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Retina
state: Tennessee
city: Abilene
country: United States
facility: Retina Research Institute of Texas
state: Texas
city: Arlington
country: United States
facility: Texas Retina Associates
state: Texas
city: Austin
country: United States
facility: Austin Research Center for Retina
state: Texas
city: Austin
country: United States
facility: Austin Retina Associates;Opthalmology
state: Texas
city: Austin
country: United States
facility: Austin Clinical Research, LLC
state: Texas
city: Bellaire
country: United States
facility: Retina & Vitreous of Texas
state: Texas
city: Dallas
country: United States
facility: Texas Retina Associates;Research
state: Texas
city: Fort Worth
country: United States
facility: Texas Retina Associates
state: Texas
city: Houston
country: United States
facility: Retina Consultants of Texas
state: Texas
city: San Antonio
country: United States
facility: Medical Center Ophthalmology Associates
state: Texas
city: Murray
country: United States
facility: Rocky Mountain Retina Consultants
state: Utah
city: Salt Lake City
country: United States
facility: Retina Associates of Utah, PLLC;Clinical Research
state: Utah
city: Lynchburg
country: United States
facility: Piedmont Eye Center
state: Virginia
city: Norfolk
country: United States
facility: Wagner Kapoor Institute;Opthalmology
state: Virginia
city: Richmond
country: United States
facility: Retina Institute of Virginia
state: Virginia
city: Silverdale
country: United States
facility: Pacific Northwest Retina
state: Washington
city: Spokane
country: United States
facility: Spokane Eye Clinical Research;Spokane Eye Surgery Center
state: Washington
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: