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)
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| ClinicalTrials.gov Identifier: NCT02510794 |
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Recruitment Status :
Completed
First Posted : July 29, 2015
Results First Posted : May 6, 2021
Last Update Posted : May 6, 2021
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Sponsor:
Genentech, Inc.
Information provided by (Responsible Party):
Genentech, Inc.
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Brief Summary:
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).
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Macular Degeneration | Drug: Ranibizumab | Phase 2 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 225 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Primary Purpose: | Treatment |
| Official Title: | 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 |
| Actual Study Start Date : | September 28, 2015 |
| Actual Primary Completion Date : | April 10, 2018 |
| Actual Study Completion Date : | March 28, 2019 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Age-related macular degeneration
MedlinePlus related topics:
Macular Degeneration
Drug Information available for:
Ranibizumab
| Arm | Intervention/treatment |
|---|---|
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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.
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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 Name: Lucentis® |
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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 Name: 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 Name: 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 Name: Lucentis® |
Primary Outcome Measures :
- 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
Secondary Outcome Measures :
- 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.
- 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.
- 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).
- 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
- 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.
- 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.
- 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.
- 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.
- 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.
- 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 ]
- Number of Participants With Ocular and Non-Ocular Adverse Events (AEs) and Serious AEs (SAEs) [ Time Frame: Baseline up to approximately Month 38 ]
- Percentage of Participants With Positive Serum Antibodies to Ranibizumab [ Time Frame: Baseline up to 38 months ]
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| Ages Eligible for Study: | 50 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
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)
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02510794
Locations
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Sponsors and Collaborators
Genentech, Inc.
Investigators
| Study Director: | Clinical Trials | Hoffmann-La Roche |
Study Documents (Full-Text)
Documents provided by Genentech, Inc.:
Documents provided by Genentech, Inc.:
Study Protocol [PDF] February 7, 2018
Statistical Analysis Plan [PDF] June 21, 2018
| Responsible Party: | Genentech, Inc. |
| ClinicalTrials.gov Identifier: | NCT02510794 |
| Other Study ID Numbers: |
GX28228 |
| First Posted: | July 29, 2015 Key Record Dates |
| Results First Posted: | May 6, 2021 |
| Last Update Posted: | May 6, 2021 |
| Last Verified: | April 2021 |
Additional relevant MeSH terms:
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Ranibizumab Macular Degeneration Retinal Degeneration Retinal Diseases Eye Diseases Angiogenesis Inhibitors |
Angiogenesis Modulating Agents Growth Substances Physiological Effects of Drugs Growth Inhibitors Antineoplastic Agents |