Study of the Efficacy and Safety of the Ranibizumab Port Delivery System for Sustained Delivery of Ranibizumab in Patients With Subfoveal Neovascular Age-Related Macular Degeneration (LADDER)

April 12, 2021 updated by: Genentech, Inc.

A Phase II, Multicenter, Randomized, Active Treatment-Controlled Study of the Efficacy and Safety of the Ranibizumab Port Delivery System for Sustained Delivery of Ranibizumab in Patients With Subfoveal Neovascular Age-Related Macular Degeneration

This is a Phase II multicenter, dose-ranging, randomized, active treatment (monthly ITV injection)-controlled study to evaluate the efficacy, safety, and pharmacokinetics of ranibizumab delivered through the Implant using three ranibizumab formulation arms (10 mg/mL, 40 mg/mL, and 100 mg/mL) compared with the control arm (0.5-mg monthly ITV injections of 10-mg/mL formulation) in participants with subfoveal neovascular age-related macular degeneration (nAMD).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

225

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Arizona
      • Mesa, Arizona, United States, 85206
        • Barnet Dulaney Perkins Eye Center
      • Phoenix, Arizona, United States, 85014
        • Retinal Research Institute, LLC
      • Phoenix, Arizona, United States, 85020
        • Associated Retina Consultants
    • California
      • Encino, California, United States, 91436
        • The Retina Partners
      • La Jolla, California, United States, 92037
        • Jacobs Retina center at the Shiley eye Institute UCSD
      • Los Angeles, California, United States, 90095-7000
        • Jules Stein Eye Institute/ UCLA
      • Mountain View, California, United States, 94040
        • N CA Retina Vitreous Assoc
      • Sacramento, California, United States, 95825
        • Retinal Consultants Med Group
      • San Francisco, California, United States, 94143
        • UCSF; Ophthalmology
      • San Francisco, California, United States, 94109
        • West Coast Retina Medical Group
      • Santa Ana, California, United States, 92705
        • Orange County Retina Med Group
      • Santa Barbara, California, United States, 93103
        • California Retina Consultants
    • Colorado
      • Colorado Springs, Colorado, United States, 80909
        • Retina Consultants of Southern
      • Lakewood, Colorado, United States, 80228
        • Colorado Retina Associates, PC
    • Florida
      • Boynton Beach, Florida, United States, 33426
        • Florida Eye Microsurgical Inst
      • Fort Myers, Florida, United States, 33912
        • National Ophthalmic Research Institute
      • Pensacola, Florida, United States, 32503
        • Retina Specialty Institute
      • Saint Petersburg, Florida, United States, 33711
        • Retina Vitreous Assoc of FL
      • Tampa, Florida, United States, 33609
        • Retina Associates of Florida, LLC
    • Georgia
      • Augusta, Georgia, United States, 30909
        • Southeast Retina Center
    • Illinois
      • Joliet, Illinois, United States, 60435
        • Illinois Retina Associates
    • Iowa
      • West Des Moines, Iowa, United States, 50266
        • Wolfe Eye Clinic
    • Kentucky
      • Lexington, Kentucky, United States, 40509
        • Retina Associates of Kentucky
      • Paducah, Kentucky, United States, 42001
        • Paducah Retinal Center
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Johns Hopkins Med; Wilmer Eye Inst
      • Chevy Chase, Maryland, United States, 20815
        • Retina Group of Washington
      • Towson, Maryland, United States, 21204
        • Retina Specialists
    • Massachusetts
      • Worcester, Massachusetts, United States, 01605
        • Vitreo-Retinal Associates, PC
    • Michigan
      • Grand Rapids, Michigan, United States, 49546
        • Foundation for Vision Research
    • Minnesota
      • Edina, Minnesota, United States, 55435
        • Vitreoretinal Surgery
    • Nevada
      • Reno, Nevada, United States, 89502
        • Sierra Eye Associates
    • New Jersey
      • Bloomfield, New Jersey, United States, 07003
        • Retina Center of New Jersey
      • Cherry Hill, New Jersey, United States, 08034
        • Mid Atlantic Retina - Wills Eye Hospital
    • New Mexico
      • Albuquerque, New Mexico, United States, 87102
        • Eye Associates of New Mexico
      • Albuquerque, New Mexico, United States, 87131
        • University of New Mexico; School of Med
    • New York
      • Rochester, New York, United States, 14620
        • Retina Assoc of Western NY
    • North Carolina
      • Charlotte, North Carolina, United States, 28210
        • Char Eye Ear &Throat Assoc
    • Ohio
      • Cincinnati, Ohio, United States, 45242
        • Cincinnati Eye Institute
      • Cleveland, Ohio, United States, 44195
        • The Cleveland Clinic Foundation
    • Oregon
      • Portland, Oregon, United States, 97221
        • Retina Northwest
      • Portland, Oregon, United States, 97239
        • Oregon HSU; Casey Eye Institute
    • South Carolina
      • Florence, South Carolina, United States, 29501
        • Palmetto Retina Center
    • Tennessee
      • Germantown, Tennessee, United States, 38138
        • Charles Retina Institute
      • Nashville, Tennessee, United States, 37203
        • Tennessee Retina PC.
    • Texas
      • Arlington, Texas, United States, 76012
        • Texas Retina Associates
      • Austin, Texas, United States, 78750
        • Retina Research Center
      • Bellaire, Texas, United States, 77401
        • Retina Consultants of Texas
      • San Antonio, Texas, United States, 78240
        • Med Center Ophthalmology Assoc
    • Utah
      • Salt Lake City, Utah, United States, 84107
        • Retina Associates of Utah
    • Virginia
      • Norfolk, Virginia, United States, 23502
        • Wagner Macula & Retina Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

50 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Newly diagnosed with wet AMD within 9 months of screening visit
  • Participant must have received at least 2 prior ITV anti-vascular endothelial growth factor (VEGF) injections. However, the most recent anti-VEGF injection must have been ranibizumab and must have occurred at least 7 days prior to the screening visit
  • Demonstrated response to prior ITV anti-VEGF treatment
  • Best Corrected Visual Acuity (BCVA) using Early Treatment Diabetic Retinopathy Study (ETDRS) charts of 20/20-20/200 Snellen equivalent

Exclusion Criteria:

  • Treatment with ITV anti-VEGF agents other than ranibizumab within 1 month prior to the randomization visit in either eye
  • Study eye treatment with ITV anti-VEGF agents other than ranibizumab within 1 month prior to the randomization visit
  • History of laser photocoagulation, Visudyne®, ITV corticosteroid injection, vitrectomy surgery, submacular surgery, device implantation, or other surgical intervention for AMD in the study eye
  • Prior participation in a clinical trial involving anti-angiogenic drugs, other than ranibizumab, in either eye within 2 months of the randomization visit
  • Subretinal hemorrhage in the study eye that involves the center of the fovea
  • Subfoveal fibrosis, or atrophy in the study eye
  • Choroidal neovascularization (CNV) in either eye due to other causes, such as ocular histoplasmosis, trauma, or pathologic myopia
  • Uncontrolled ocular hypertension or glaucoma in the study eye
  • History of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma surgery in the study eye
  • Uncontrolled blood pressure
  • Uncontrolled atrial fibrillation within 3 months of informed consent
  • History of myocardial infarction or stroke within the last 3 months prior to informed consent
  • History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of ranibizumab or placement of the Implant, that might affect interpretation of the results of the study or renders the participant at high risk of treatment complications
  • Use of oral corticosteroids
  • Current treatment for any active systemic infection
  • Use of anticoagulants, anti-platelets (other than aspirin), or medications known to exert similar effects
  • Active malignancy within 12 months of randomization
  • History of allergy to fluorescein
  • Previous participation in any non-ocular (systemic) disease studies of investigational drugs within 1 month preceding the informed consent (excluding vitamins and minerals)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: QUADRUPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Port Delivery System with Ranibizumab 10mg/mL
Participants had the Implant (prefilled with approximately 20 μL of 10-mg/mL ,approximately 0.2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.
Drug: Ranibizumab
Ranibizumab will be administered at dose of 0.5 mg monthly ITV injections of 10-mg/mL formulation or delivered through the implant with three different formulations.
Other Names:
  • Lucentis®
Experimental: Port Delivery System with Ranibizumab 40mg/mL
Participants had the Implant (prefilled with approximately 20 μL of 40-mg/mL, approximately 0.8 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 40-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.
Drug: Ranibizumab
Ranibizumab will be administered at dose of 0.5 mg monthly ITV injections of 10-mg/mL formulation or delivered through the implant with three different formulations.
Other Names:
  • Lucentis®
Experimental: Port Delivery System with Ranibizumab 100mg/mL
Participants had the Implant (prefilled with approximately 20 μL of 100-mg/mL, approximately 2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 100-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.
Drug: Ranibizumab
Ranibizumab will be administered at dose of 0.5 mg monthly ITV injections of 10-mg/mL formulation or delivered through the implant with three different formulations.
Other Names:
  • Lucentis®
Active Comparator: Intravitreal Injection with Ranibizumab 0.5mg
Participants received ranibizumab 0.5 mg monthly ITV injections of 10 mg/mL formulation at Day 1 and every month thereafter.
Drug: Ranibizumab
Ranibizumab will be administered at dose of 0.5 mg monthly ITV injections of 10-mg/mL formulation or delivered through the implant with three different formulations.
Other Names:
  • Lucentis®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time Until a Participant First Requires the Implant Refill According to Protocol-Defined Refill Criteria
Time Frame: Baseline up to approximately 38 months

Protocol-Defined Refill Criteria

At 1 month after initial fill:

  • Decrease of ≥ 10 letters in BCVA at the current visit compared with the baseline BCVA, due to nAMD disease activity OR
  • Increase in CFT of ≥ 100 um at the current visit compared with the baseline CFT, due to nAMD disease activity OR
  • Presence of new macular hemorrhage, due to nAMD disease activity

For subsequent assessments:

  • Increase in CFT of ≥ 75 μm on SD-OCT at the current visit compared with the average CFT over the last 2 available measurements, due to nAMD disease activity OR
  • Increase in CFT of ≥ 100 um from the lowest CFT measurement on study, due to nAMD disease activity OR
  • Decrease of ≥ 5 letters in BCVA at the current visit compared with the average BCVA over the last 2 available measurements, due to nAMD disease activity OR
  • Decrease of ≥ 10 letters from best recorded BCVA on study, due to nAMD disease activity OR
  • Presence of new macular hemorrhage, due to nAMD disease activity
Baseline up to approximately 38 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change From Baseline in Best Corrected Visual Acuity (BCVA) Averaged At Month 9 and 10
Time Frame: Baseline, Months 9, 10
Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. The minimum score possible is 0 and maximum possible is 100. A higher score represents better functioning.
Baseline, Months 9, 10
Change From Baseline in BCVA Over Time
Time Frame: Baseline up to Month 10
Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. The minimum score possible is 0 and maximum possible is 100. A higher score represents better functioning.
Baseline up to Month 10
Adjusted Average Change From Baseline in BCVA Over Time (MMRM Analysis)
Time Frame: Baseline up to Month 10
Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. The minimum score possible is 0 and maximum possible is 100. A higher score represents better functioning. Here, the adjusted mean from MMRM analysis is presented).
Baseline up to Month 10
Change From Baseline in Central Foveal Thickness (CFT) Over Time as Assessed on Spectral Domain-Optical Coherence Tomography (SD-OCT)
Time Frame: Baseline up to Month 9
Central foveal thickness (CFT) is defined as the retinal thickness in the center of the fovea
Baseline up to Month 9
Number of Implant Clogging at Month 9
Time Frame: Month 9
Removed implants identified as meeting serum PK criteria for possible clogging were assessed via lab-based investigation (in vitro drug release testing) to determine whether there was any implant clogging.
Month 9
Observed Maximum Serum Concentration (Cmax) of Ranibizumab
Time Frame: Predose (0 hour) on Day 1 up to 38 months
The serum pharmacokinetics of ranibizumab were characterized by estimating Cmax between dose intervals. Estimates for these parameters were tabulated and summarized by descriptive statistics.
Predose (0 hour) on Day 1 up to 38 months
Area Under the Concentration-Time Curve From Dosing to Last Observation (AUClast) of Ranibizumab
Time Frame: Predose (0 hour) on Day 1 up to approximately 38 months (detailed timeframe is provided in description field)
AUCLast is defined as area under the concentration-time curve from dosing (implant or refill) to last observation before next refill or exiting the study. The serum pharmacokinetics of ranibizumab were characterized by estimating AUC between dose intervals. Estimates for these parameters were tabulated and summarized by descriptive statistics.
Predose (0 hour) on Day 1 up to approximately 38 months (detailed timeframe is provided in description field)
Time to Maximum Concentration (Tmax) of Ranibizumab
Time Frame: Predose (0 hour) on Day 1 up to 38 months
The serum pharmacokinetics of ranibizumab were characterized by estimating Tmax between dose intervals. Estimates for these parameters were tabulated and summarized by descriptive statistics.
Predose (0 hour) on Day 1 up to 38 months
Terminal Half-Life (t1/2) of Ranibizumab
Time Frame: Predose (0 hour) on Day 1 up to 38 months
The serum pharmacokinetics of ranibizumab were characterized by estimating t1/2 between dose intervals. Estimates for these parameters were tabulated and summarized by descriptive statistics.
Predose (0 hour) on Day 1 up to 38 months
Observed Steady-State Serum Concentration at the End of a Dosing Interval (Ctrough) of Ranibizumab
Time Frame: Predose (0 hour) on Day 1 up to 38 months
Predose (0 hour) on Day 1 up to 38 months
Number of Participants With Ocular and Non-Ocular Adverse Events (AEs) and Serious AEs (SAEs)
Time Frame: Baseline up to approximately Month 38
Baseline up to approximately Month 38
Percentage of Participants With Positive Serum Antibodies to Ranibizumab
Time Frame: Baseline up to 38 months
Baseline up to 38 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Genentech, Inc.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 28, 2015

Primary Completion (Actual)

April 10, 2018

Study Completion (Actual)

March 28, 2019

Study Registration Dates

First Submitted

July 17, 2015

First Submitted That Met QC Criteria

July 27, 2015

First Posted (Estimate)

July 29, 2015

Study Record Updates

Last Update Posted (Actual)

May 6, 2021

Last Update Submitted That Met QC Criteria

April 12, 2021

Last Verified

April 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GX28228

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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