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

• Sponsor: Genentech, Inc.
• Information provided by (Responsible Party): Genentech, Inc.

Study Description

Brief Summary:

This is a Phase II clinical study to evaluate the efficacy, safety and pharmacokinetics of three different formulations of ranibizumab delivered via RPDS implant compared with the standard of care (SOC) intravitreal (ITV) injections of ranibizumab, in participants with subfoveal neovascular AMD.

Condition or disease	Intervention/treatment	Phase
Macular Degeneration	Drug: Ranibizumab	Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	220 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
Estimated Study Completion Date :	March 27, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ranibizumab Dose 1; Participants will receive ranibizumab delivered through the implant with Dose 1 formulation in the study eye on Day 1 and if required, implant refill will be done starting from Month 1 according to protocol-defined 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 (Dose 1, 2 and 3).; Other Name: Lucentis®
Experimental: Ranibizumab Dose 2; Participants will receive ranibizumab delivered through the implant with Dose 2 formulation in the study eye on Day 1 and if required, implant refill will be done starting from Month 1 according to protocol-defined 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 (Dose 1, 2 and 3).; Other Name: Lucentis®
Experimental: Ranibizumab Dose 3; Participants will receive ranibizumab delivered through the implant with Dose 3 formulation in the study eye on Day 1 and if required, implant refill will be done starting from Month 1 according to protocol-defined 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 (Dose 1, 2 and 3).; Other Name: Lucentis®
Active Comparator: Ranibizumab 0.5 mg ITV injection; Participants will receive 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 (Dose 1, 2 and 3).; Other Name: Lucentis®

Outcome Measures

Primary Outcome Measures :

1. Time Until a Participant First Requires the RPDS Implant Refill According to Protocol-Defined Refill Criteria [ Time Frame: Baseline up to approximately 38 months ]

Secondary Outcome Measures :

1. Change From Baseline in Best Corrected Visual Acuity (BCVA) at Month 9 [ Time Frame: Baseline, Month 9 ]
2. Change From Baseline in BCVA Over Time [ Time Frame: Baseline up to Month 38 ]
3. Average Change From Baseline in BCVA Over Time [ Time Frame: Baseline up to Month 38 ]
4. 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 38 ]
5. Number of Implant Clogging at Month 9 [ Time Frame: Month 9 ]
6. Observed Maximum Serum concentration (Cmax) of Ranibizumab [ Time Frame: Predose (0 hour) on Day 1 up to approximately 38 months (detailed timeframe is provided in description field) ]
   ITV: Predose (0 hour) on Day 1 and Months 1,3,6,9, and at study completion (up to approximately 38 months); RPDS: Predose (0 hour) on Day 1, 1 hour post treatment on Day 1, Day 2, Day 7, and Day 14, Predose (0 hour) Monthly and as applicable on Day 1 and 7 post treatment starting at Month 2 (up to approximately 38 months)
7. Area Under the Concentration-Time Curve (AUC) of Ranibizumab [ Time Frame: Predose (0 hour) on Day 1 up to approximately 38 months (detailed timeframe is provided in description field) ]
   ITV: Predose (0 hour) on Day 1 and Months 1,3,6,9, and at study completion (up to approximately 38 months); RPDS: Predose (0 hour) on Day 1, 1 hour post treatment on Day 1, Day 2, Day 7, and Day 14, Predose (0 hour) Monthly and as applicable on Day 1 and 7 post treatment starting at Month 2 (up to approximately 38 months)
8. Time to Maximum Concentration (Tmax) of Ranibizumab [ Time Frame: Predose (0 hour) on Day 1 up to approximately 38 months (detailed timeframe is provided in description field) ]
   ITV: Predose (0 hour) on Day 1 and Months 1,3,6,9, and at study completion (up to approximately 38 months); RPDS: Predose (0 hour) on Day 1, 1 hour post treatment on Day 1, Day 2, Day 7, and Day 14, Predose (0 hour) Monthly and as applicable on Day 1 and 7 post treatment starting at Month 2 (up to approximately 38 months)
9. Terminal Half-Life (t1/2) of Ranibizumab [ Time Frame: Predose (0 hour) on Day 1 up to approximately 38 months (detailed timeframe is provided in description field) ]
   ITV: Predose (0 hour) on Day 1 and Months 1,3,6,9, and at study completion (up to approximately 38 months); RPDS: Predose (0 hour) on Day 1, 1 hour post treatment on Day 1, Day 2, Day 7, and Day 14, Predose (0 hour) Monthly and as applicable on Day 1 and 7 post treatment starting at Month 2 (up to approximately 38 months)
10. Observed Serum Concentration (Ct) of Ranibizumab Over Time [ Time Frame: Predose (0 hour) on Day 1 up to approximately 38 months (detailed timeframe is provided in description field) ]
    ITV: Predose (0 hour) on Day 1 and Months 1,3,6,9, and at study completion (up to approximately 38 months); RPDS: Predose (0 hour) on Day 1, 1 hour post treatment on Day 1, Day 2, Day 7, and Day 14, Predose (0 hour) Monthly and as applicable on Day 1 and 7 post treatment starting at Month 2 (up to approximately 38 months)
11. 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 approximately 38 months (detailed timeframe is provided in description field) ]
    ITV: Predose (0 hour) on Day 1 and Months 1,3,6,9, and at study completion (up to approximately 38 months); RPDS: Predose (0 hour) on Day 1, 1 hour post treatment on Day 1, Day 2, Day 7, and Day 14, Predose (0 hour) Monthly and as applicable on Day 1 and 7 post treatment starting at Month 2 (up to approximately 38 months)
12. Percentage of Participants With Ocular and Non-Ocular Adverse Events (AEs) and Serious AEs (SAEs) [ Time Frame: Baseline up to approximately Month 38 ]
13. Percentage of Participants With Positive Serum Antibodies to Ranibizumab [ Time Frame: Baseline, Predose (0 hour) on Day 14, Months 1, 3, 6, 9, and at early termination (up to approximately 38 months) ]

Eligibility Criteria

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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)

Contacts and Locations

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Sponsors and Collaborators

Genentech, Inc.

Investigators

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Study Director:	Clinical Trials	Hoffmann-La Roche

More Information

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Responsible Party:	Genentech, Inc.
ClinicalTrials.gov Identifier:	NCT02510794 History of Changes
Other Study ID Numbers:	GX28228
First Posted:	July 29, 2015
Last Update Posted:	March 8, 2019
Last Verified:	March 2019

Additional relevant MeSH terms:

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Ranibizumab; Macular Degeneration; Wet Macular Degeneration; Retinal Degeneration; Retinal Diseases; Eye Diseases	Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Antineoplastic Agents