Study to Evaluate Faricimab (RO6867461; RG7716) for Extended Durability in the Treatment of Neovascular Age Related Macular Degeneration

Study Overview
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Brief Summary
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This was a Phase II, multicenter, randomized, active comparator-controlled, 52-week study to investigate the efficacy, safety and pharmacokinetics of faricimab (RO6867461; RG7716) administered with extended dosing regimens in treatment-naive participants with neovascular age related macular degeneration (nAMD). Only one eye was chosen as the study eye.

Official Title
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STAIRWAY: Simultaneous Blockade of Angiopoietin-2 and VEGF-A With the Bispecific Antibody RO6867461 (RG7716) for Extended Durability in the Treatment of Neovascular Age-Related Macular Degeneration

Conditions
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Neovascularization, Choroidal, Macular Degeneration, Age-Related

Intervention / Treatment
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* Drug: Faricimab
* Drug: Ranibizumab
* Drug: Sham Procedure


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Treatment-naive CNV secondary to AMD (nAMD) Subfoveal or juxtafoveal CNV with a subfoveal component related to the CNV activity by fundus fluorescein angiography (FFA) or spectral-domain optical coherence tomography (SD-OCT; as evidenced by subretinal fluid, subretinal hyperreflective material, evidence of leakage, or hemorrhage) CNV lesion of all types with: total lesion size (including blood, atrophy, fibrosis, and neovascularization) of 6 disc areas or less by FFA; and CNV component area of at least 50% of total lesion size by FFA; and active CNV confirmed by FFA (evidence of leakage); and CNV exudation confirmed by SD-OCT (presence of fluid) BCVA letter score of 73 to 24 letters (inclusive) on ETDRS-like charts (20/40-20/320 Snellen equivalent) on day 1 Clear ocular media and adequate pupillary dilatation to allow acquisition of good-quality retinal images to confirm diagnosis Exclusion Criteria: CNV due to causes other than AMD, such as ocular histoplasmosis, trauma, pathological myopia, angioid streaks, choroidal rupture, or uveitis Central serous chorioretinopathy at screening Retinal pigment epithelial tear involving the macula On FFA: subretinal hemorrhage, fibrosis, or atrophy of more than (>)50% of the total lesion area and/or that involves the fovea Any prior or concomitant treatment for CNV including (but not restricted to) IVT treatment (steroids, anti-VEGF, tissue plasminogen activator, ocriplasmin, C3F8 gas, air), periocular pharmacological intervention, argon laser photocoagulation, verteporfin photodynamic therapy, diode laser, transpupillary thermotherapy, or surgical intervention Cataract surgery within 3 months of baseline assessments Any other intraocular surgery (pars plana vitrectomy, glaucoma surgery, corneal transplant, radiotherapy) Prior IVT treatment (including anti-VEGF medication) except for management of cataract complication with steroid IVT treatment Prior periocular pharmacological intervention for other retinal diseases Any concurrent intraocular condition in the study eye (eg, amblyopia, aphakia, retinal detachment, cataract, diabetic retinopathy or maculopathy, or epiretinal membrane with traction) that, in the opinion of the investigator, could either reduce the potential for visual improvement or require medical or surgical intervention during the course of the study Active intraocular inflammation (grade trace or above) in the study eye on day 1 (before randomization) Current vitreous hemorrhage in the study eye Uncontrolled glaucoma (eg, progressive loss of visual fields or defined as IOP ≥25 mm Hg despite treatment with antiglaucoma medication) in the study eye Spherical equivalent of refractive error demonstrating more than 8 diopters of myopia in the study eye History of idiopathic or autoimmune-associated uveitis in either eye Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye on day 1 (before randomization) Any major illness or major surgical procedure within 1 month before screening Uncontrolled blood pressure (defined as systolic >180 mm Hg and/or diastolic >100 mm Hg while participant at rest). If a participant's initial reading exceeded these values, a second reading was taken later on the same day, or on another day during the screening period. If the participant's blood pressure was controlled by antihypertensive medication, the participant was taking the same medication continuously for at least 30 days before day 1 Stroke or myocardial infarction within 3 months before day 1 History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory findings giving reasonable suspicion of a condition that contraindicated the use of the investigational drug or that might affect interpretation of the results of the study or renders the participant at high risk for treatment complications in the opinion of the investigator Pregnant or breastfeeding, or intended to become pregnant during the study Known hypersensitivity to ranibizumab, fluorescein, any ingredients of the formulation used, dilating eye drops, or any of the anesthetic and antimicrobial drops used Treatment with investigational therapy within 3 months before initiation of study treatment

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 6 mg Faricimab Q12W<br>6 mg faricimab was given by intravitreal (IVT) injection once every 4 weeks (Q4W) up to Week 12 (4 injections), followed by 6 mg faricimab IVT injection once every 12 weeks (Q12W) from Week 24 up to Week 48 (injections at Weeks 24, 36, and 48; 3 injections). | Drug: Faricimab<br>* Faricimab was administered via IVT injections as specified during the treatment period.<br>* Other names: RG7716;Drug: Sham Procedure<br>* The sham was a procedure that mimicked an IVT injection and involved the blunt end of an empty syringe (without a needle) being pressed against the anesthetized eye. It was administered to participants in the faricimab treatments arms at applicable visits to maintain masking among treatment arms.<br>|
| Experimental: 6 mg Faricimab Q16W<br>6 mg faricimab was administered by IVT injection once every 4 weeks (Q4W) up to Week 12 (4 injections), followed by no doses up to Week 24 when a protocol-defined assessment of disease activity was performed. Participants with disease activity at Week 24 initiated 6 mg faricimab IVT Q12W dosing, and participants without disease activity at Week 24 initiated 6 mg faricimab IVT once every 16 weeks (Q16W) dosing for the remainder of the study. | Drug: Faricimab<br>* Faricimab was administered via IVT injections as specified during the treatment period.<br>* Other names: RG7716;Drug: Sham Procedure<br>* The sham was a procedure that mimicked an IVT injection and involved the blunt end of an empty syringe (without a needle) being pressed against the anesthetized eye. It was administered to participants in the faricimab treatments arms at applicable visits to maintain masking among treatment arms.<br>|
| Active Comparator: 0.5 mg Ranibizumab Q4W<br>0.5 mg of ranibizumab was administered by IVT injection once every 4 weeks (Q4W) for 48 weeks (13 injections). | Drug: Ranibizumab<br>* Ranibizumab was administered via IVT injections as specified during the treatment period.<br>* Other names: Lucentis®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 40, Using the Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA Charts | Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The analysis was performed using a Mixed Model for Repeated Measurement (MMRM) model, which included an unstructured covariance and the categorical covariates of treatment group, visit, and visit by treatment group interaction and the continuous covariate of baseline BCVA. | Baseline, Week 40 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in BCVA at Specified Timepoints, Using the ETDRS BCVA Charts | Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The analysis was performed using a Mixed Model for Repeated Measurement (MMRM) model, which included an unstructured covariance and the categorical covariates of treatment group, visit, and visit by treatment group interaction and the continuous covariate of baseline BCVA. | Baseline, Day 7, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 | 
| Number and Percentage of Participants Gaining Greater Than or Equal to (≥)15, ≥10, ≥5, or ≥0 Letters From Baseline in BCVA at Specified Timepoints | Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. This analysis was performed on observed data. | Baseline, Day 7, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 | 
| Percentage of Participants Gaining ≥15 Letters From Baseline in BCVA at Specified Timepoints | Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. This analysis was performed on observed data. The 80% confidence intervals were calculated using the Wald method. | Baseline, Day 7, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 | 
| Number and Percentage of Participants Not Losing ≥15, ≥10, ≥5, or ≥0 Letters From Baseline in BCVA at Specified Timepoints | Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a loss in BCVA letter score from baseline indicates worsening in visual acuity. This analysis was performed on observed data. | Baseline, Day 7, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 | 
| Percentage of Participants Not Losing ≥15 Letters From Baseline in BCVA at Specified Timepoints | Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. This analysis was performed on observed data. The 80% confidence intervals were calculated using the Wald method. | Baseline, Day 7, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 | 
| Percentage of Participants With BCVA Snellen Equivalent of 20/40 or Better at Specified Timepoints | Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. This analysis was performed on observed data. The 80% confidence intervals were calculated using the Wald method. | Baseline, Day 7, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 | 
| Percentage of Participants With BCVA Snellen Equivalent of 20/200 or Worse at Specified Timepoints | Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. This analysis was performed on observed data. The 80% confidence intervals were calculated using the Wald method. | Baseline, Day 7, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 | 
| Mean Change From Baseline in Central Foveal Thickness (CFT) at Specified Timepoints | Central foveal thickness (CFT) was defined as the thickness from the inner limiting membrane to the retinal pigment epithelial at the horizontal slice closest to the center of the fovea, and it was measured using spectral domain optical coherence tomography (SD-OCT). The analysis was performed using a Mixed Model for Repeated Measurement (MMRM) model, which included an unstructured covariance and the categorical covariates of treatment group, visit, and visit by treatment group interaction and the continuous covariate of baseline CFT. | Baseline, Day 7, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 | 
| Mean Change From Baseline in Central Subfield Thickness (CST) at Specified Timepoints | Central subfield thickness (CST) was defined as the mean thickness from the inner limiting membrane to the retinal pigment epithelial over the 1 millimetre (mm) central subfield, and it was measured using spectral domain optical coherence tomography (SD-OCT). The analysis was performed using a Mixed Model for Repeated Measurement (MMRM) model, which included an unstructured covariance and the categorical covariates of treatment group, visit, and visit by treatment group interaction and the continuous covariate of baseline CST. | Baseline, Day 7, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 | 
| Percentage of Participants With No Intraretinal Fluid at Specified Timepoints | The absence of intraretinal fluid, subretinal fluid, cysts, or pigment epithelial detachment, as per the study's dry retina definition, were evaluated as individual dry retina outcomes. Intraretinal fluid was defined as the presence of fluid within the retina. All parameters were measured using spectral domain optical coherence tomography (SD-OCT). Anatomic outcome measures were based on results from a central reading center. This analysis was performed on observed data. The 80% confidence intervals were calculated using the Wald method. | Baseline, Day 7, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 | 
| Percentage of Participants With No Subretinal Fluid at Specified Timepoints | The absence of intraretinal fluid, subretinal fluid, cysts, or pigment epithelial detachment, as per the study's dry retina definition, were evaluated as individual dry retina outcomes. Subretinal fluid was defined as the presence of fluid between the retina and the retinal pigment epithelium. All parameters were measured using spectral domain optical coherence tomography (SD-OCT). Anatomic outcome measures were based on results from a central reading center. This analysis was performed on observed data. The 80% confidence intervals were calculated using the Wald method. | Baseline, Day 7, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 | 
| Percentage of Participants With No Cysts at Specified Timepoints | The absence of intraretinal fluid, subretinal fluid, cysts, or pigment epithelial detachment, as per the study's dry retina definition, were evaluated as individual dry retina outcomes. Cysts were defined as the presence of cystoid space (fluid) in the retina. All parameters were measured using spectral domain optical coherence tomography (SD-OCT). Anatomic outcome measures were based on results from a central reading center. This analysis was performed on observed data. The 80% confidence intervals were calculated using the Wald method. | Baseline, Day 7, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 | 
| Percentage of Participants With No Pigment Epithelial Detachment at Specified Timepoints | The absence of intraretinal fluid, subretinal fluid, cysts, or pigment epithelial detachment, as per the study's dry retina definition, were evaluated as individual dry retina outcomes. Pigment epithelial detachment was defined as the presence of a detachment of the pigment epithelium from the Bruch's membrane. All parameters were measured using spectral domain optical coherence tomography (SD-OCT). Anatomic outcome measures were based on results from a central reading center. This analysis was performed on observed data. The 80% confidence intervals were calculated using the Wald method. | Baseline, Day 7, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 | 
| Mean Baseline Value and Mean Change From Baseline of Total Area of Choroidal Neovascularization (CNV) at Week 40 and Week 52 | The total area of choroidal neovascularization (CNV) was evaluated by a central reading center using fundus fluorescein angiography (FFA). | Baseline, Week 40, Week 52 | 
| Mean Baseline Value and Mean Change From Baseline of Total Area of CNV Component at Week 40 and Week 52 | The total area of choroidal neovascularization (CNV) component (i.e., total area of CNV membrane) was evaluated by a central reading center using fundus fluorescein angiography (FFA). | Baseline, Week 40, Week 52 | 
| Mean Baseline Value and Mean Change From Baseline of Total Area of Leakage at Week 40 and Week 52 | The total area of leakage was evaluated by a central reading center using fundus fluorescein angiography (FFA). | Baseline, Week 40, Week 52 | 
| Change From Baseline in the Number of Participants With Anti-Drug Antibodies (ADA) to Faricimab at Anytime Post-Baseline | Blood samples were obtained for measurement of anti-drug antibodies (ADAs) to faricimab by a validated enzyme-linked immunosorbent assay (ELISA). | Predose at Baseline (Day 1), Weeks 16, 24, 28, 44, and 52 | 
| Safety Summary: Number and Percentage of Participants With at Least One Adverse Event | This safety summary reports the number and percentage of participants who experienced at least one adverse event (AE) during the study. The investigator independently assessed the seriousness and severity for each AE. Severity was graded according to the following grading scale: Mild = Discomfort noticed, but no disruption of normal daily activity; Moderate = Discomfort sufficient to reduce or affect normal daily activity; Severe = Incapacitating with inability to work or to perform normal daily activity. Severity and seriousness are not synonymous; regardless of severity, some AEs may have also met seriousness criteria. | From Baseline until 28 days after the last dose of study drug (up to 52 weeks) |