Safety and Pharmacokinetics of RTH258 in Subjects With Age-Related Macular Degeneration

Study Overview
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Brief Summary
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The purpose of this study is to assess the systemic pharmacokinetics (PK) and safety of 2 different doses of brolucizumab (3 milligrams (mg)/50 microliters (μL) and 6 mg/50 μL) when administered at 4-week intervals for a total of 3 intravitreal injections in subjects with neovascular age-related macular degeneration (AMD).

Detailed Description
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This study has 2 arms with a 1:1 randomization. Randomization will be stratified by Japanese ethnicity. Half of the subjects in each arm will be of Japanese ethnicity. The other half of the subjects in each arm will be non-Japanese. Subjects in both arms will have visits at Screening, Day 0 (Baseline), Day 1 (24 hours post first injection), Day 3, Day 14, Day 21, Day 28, Day 56, Day 57 (24 hours post the injection on Day 56) and Day 84.

Official Title
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A Randomized, Double Masked, Three Dose Safety and Pharmacokinetic Study of RTH258 Following Intravitreal (IVT) Injection in Subjects With Neovascular Age-Related Macular Degeneration

Conditions
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Neovascular Age-Related Macular Degeneration

Intervention / Treatment
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* Drug: Brolucizumab 3 mg/50 μL
* Drug: Brolucizumab 6 mg/50 μL


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent; Active choroidal neovascularization (CNV) lesions secondary to AMD that affect the central subfield in the study eye; Best Corrected Visual Acuity (BCVA) > 23 letters in the study eye at Baseline; 50 years of age or older at the time of Screening. Exclusion Criteria: Any active ocular infection or inflammation; Treatment with aflibercept (EYLEA®), bevacizumab (AVASTIN®), ranibizumab (LUCENTIS®), brolucizumab, or an investigational drug for neovascular AMD prior to enrollment in the study, as specified in protocol; Ocular surgery in the study eye, as specified in protocol; Uncontrolled glaucoma in the study eye, as specified in protocol; Use of steroids in the study eye, as specified in protocol; Medical conditions that may prevent study completion; Pregnant or nursing (lactating) women; Women of child-bearing potential unless using contraception; Uncontrolled blood pressure, as specified in protocol; Other protocol-specified exclusion criteria may apply.

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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brolucizumab 3 mg<br>Brolucizumab 3 mg/50 μL administered as an intravitreal injection 3 times at 4-week intervals with follow-up for 84 days from the initial injection | Drug: Brolucizumab 3 mg/50 μL<br>* Administered as an intravitreal injection<br>* Other names: ESBA1008;|
| Experimental: Brolucizumab 6 mg<br>Brolucizumab 6 mg/50 μL administered as an intravitreal injection 3 times at 4-week intervals with follow-up for 84 days from the initial injection | Drug: Brolucizumab 6 mg/50 μL<br>* Administered as an intravitreal injection<br>* Other names: ESBA1008;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Analyte Serum Concentration [Cmax (ng/mL)] | Serum concentrations at each collection time point were quantitated, where possible, using a validated immunoassay method. These data were analyzed using a noncompartmental pharmacokinetic (PK) method. | Day 0 (predose), 6 hr, 24 hr, 72 hr, 168 hr, 336 hr, 504 hr, 672 hr | 
| Time to Reach Maximum Analyte Serum Concentration [Tmax (h)] | Serum concentrations at each collection time point were quantitated, where possible, using a validated immunoassay method. These data were analyzed using a noncompartmental pharmacokinetic (PK) method. | Day 0 (predose), 6 hr, 24 hr, 72 hr, 168 hr, 336 hr, 504 hr, 672 hr | 
| Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration [AUC0-tlast (ng*h/mL)] | Serum concentrations at each collection time point were quantitated, where possible, using a validated immunoassay method. These data were analyzed using a noncompartmental pharmacokinetic (PK) method. | Day 0 (predose), 6 hr, 24 hr, 72 hr, 168 hr, 336 hr, 504 hr, 672 hr | 
| Area Under the Concentration-time Curve From 0 to Infinity [AUC0-inf (ng*h/mL)] | Serum concentrations at each collection time point were quantitated, where possible, using a validated immunoassay method. These data were analyzed using a noncompartmental pharmacokinetic (PK) method. | Day 0 (predose), 6 hr, 24 hr, 72 hr, 168 hr, 336 hr, 504 hr, 672 hr | 
| Elimination Half-life in Serum [t1/2 (h)] | Serum concentrations at each collection time point were quantitated, where possible, using a validated immunoassay method. These data were analyzed using a noncompartmental pharmacokinetic (PK) method. | Day 0 (predose), 6 hr, 24 hr, 72 hr, 168 hr, 336 hr, 504 hr, 672 hr | 
| Concentration of RTH258 Obtained 24 Hours Post Day 0 Injection [C24hr (ng/mL)] | Serum concentration at the specified collection time point was quantitated, where possible, using a validated immunoassay method. The data were analyzed using a noncompartmental pharmacokinetic (PK) method. | Day 1 | 
| Concentration of RTH258 Obtained 24 Hours Post Day 56 Injection [C24hr (ng/mL)] | Serum concentration at the specified collection time point was quantitated, where possible, using a validated immunoassay method. The data were analyzed using a noncompartmental pharmacokinetic (PK) method. | Day 57 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With Positive Anti-drug Antibody (ADA) Status (Test) | A positive ADA status is defined as induced ADA status with ADA negative at predose and with a post-dose titer value increase of 2 or more dilutions at any time point or boosted ADA status with ADA positive at predose and a post-dose titer value increase by more than 3-fold (1 dilution) at any time point. | Day 0 (predose), Day 28, Day 84 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AMD, nAMD, wetAMD, Age-Related Macular Degeneration