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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Brolucizumab 3 mg | Experimental | 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 |
|
| Brolucizumab 6 mg | Experimental | 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Brolucizumab 3 mg/50 μL | Drug | Administered as an intravitreal injection |
|
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Alcon, A Novartis Division | Alcon, A Novartis Division | Study Director |
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Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.
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This reporting group includes all subjects who signed an informed consent form and were assigned an identification number (51), minus one subject exited as a screen failure prior to treatment initiation.
Subjects were recruited from 5 study centers in Japan and 2 study centers in the United States.
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| ID | Title | Description |
|---|---|---|
| FG000 | Brolucizumab 3 mg | Brolucizumab 3 milligrams (mg)/50 microliters (μL) administered as an intravitreal injection 3 times at 4-week intervals with follow-up for 84 days from the initial injection |
| FG001 | Brolucizumab 6 mg | 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
This analysis population includes all randomized subjects
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| ID | Title | Description |
|---|---|---|
| BG000 | Brolucizumab 3 mg | 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 |
| BG001 | Brolucizumab 6 mg |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | The PK analysis set included all subjects who received an intravitreal (IVT) injection with evaluable PK data and with no major protocol deviations that could have had an impact on the PK analysis. | Posted | Mean | Standard Deviation | ng/mL | Day 0 (predose), 6 hr, 24 hr, 72 hr, 168 hr, 336 hr, 504 hr, 672 hr |
|
Adverse events (AEs) were collected from time of consent for the duration of a subject's participation in the study (up to 105 days). AEs are reported as pre-treatment and treatment-emergent.
An adverse event was defined as any untoward medical occurrence in a subject who is administered a study treatment regardless of whether or not the event has a causal relationship with the treatment. AEs were obtained through solicited and spontaneous comments from subjects and through observations by the Investigator as outlined in the study protocol. Ocular AEs are presented for both study eye and non-study eye combined.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Pre-Treatment | All subjects who signed an informed consent form and were assigned an identification number (51), minus one subject exited as a screen failure prior to treatment initiation |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cardiac failure congestive | Cardiac disorders | MedDRA 17.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Conjunctival haemorrhage | Eye disorders | MedDRA 17.0 | Systematic Assessment |
Missing AUCinf and half life values attributable to concentration values below LLOQ may result in biased estimates. Causality assessment of the ADA status is limited due to the high number of subjects with positive ADA at baseline.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Global Program Clinical Head, Ophthalmology | Alcon, A Novartis Division | 1-888-451-3937 | alcon.medinfo@alcon.com |
| ID | Term |
|---|---|
| D008268 | Macular Degeneration |
| ID | Term |
|---|---|
| D012162 | Retinal Degeneration |
| D012164 | Retinal Diseases |
| D005128 | Eye Diseases |
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| ID | Term |
|---|---|
| C000622091 | brolucizumab |
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| Brolucizumab 6 mg/50 μL | Drug | Administered as an intravitreal injection |
|
|
| 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 |
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
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Ancestry | Count of Participants | Participants |
|
| Primary Diagnosis of Neovascular Age-Related Macular Degeneration | As required by the protocol for inclusion in the study | Count of Participants | Participants |
|
| Pre-dose Anti-Drug Antibody (ADA) Status | A positive ADA titer prior to the first injection is not unexpected, as pre-existing antibodies to biotherapeutic drugs have been detected in drug-naïve subjects for a variety of antibody fragments. | Count of Participants | Participants |
|
| Brolucizumab 6 mg |
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 |
|
|
| Primary | 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. | PK analysis set | Posted | Mean | Standard Deviation | hours | Day 0 (predose), 6 hr, 24 hr, 72 hr, 168 hr, 336 hr, 504 hr, 672 hr |
|
|
|
| Primary | 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. | PK analysis set | Posted | Mean | Standard Deviation | ng*h/mL | Day 0 (predose), 6 hr, 24 hr, 72 hr, 168 hr, 336 hr, 504 hr, 672 hr |
|
|
|
| Primary | 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. | PK analysis set | Posted | Mean | Standard Deviation | ng*h/mL | Day 0 (predose), 6 hr, 24 hr, 72 hr, 168 hr, 336 hr, 504 hr, 672 hr |
|
|
|
| Primary | 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. | PK analysis set. Harmonic mean and jackknife estimate of the standard deviation are presented. | Posted | Mean | Standard Deviation | hours | Day 0 (predose), 6 hr, 24 hr, 72 hr, 168 hr, 336 hr, 504 hr, 672 hr |
|
|
|
| Primary | 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. | PK analysis set | Posted | Mean | Standard Deviation | ng/mL | Day 1 |
|
|
|
| Primary | 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. | PK analysis set | Posted | Mean | Standard Deviation | ng/mL | Day 57 |
|
|
|
| Secondary | 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. | PK analysis set | Posted | Number | percentage of participants | Day 0 (predose), Day 28, Day 84 |
|
|
|
| 0 |
| 50 |
| 0 |
| 50 |
| 2 |
| 50 |
| EG001 | Brolucizumab 3 mg | All subjects who received an IVT injection of brolucizumab 3 mg | 0 | 25 | 2 | 25 | 10 | 25 |
| EG002 | Brolucizumab 6 mg | All subjects who received an IVT injection of brolucizumab 6 mg | 0 | 25 | 1 | 25 | 11 | 25 |
| Endophthalmitis | Eye disorders | MedDRA 17.0 | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
|
| Rib fracture | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
|
| Eye pain | Eye disorders | MedDRA 17.0 | Systematic Assessment |
|
| Foreign body sensation in eyes | Eye disorders | MedDRA 17.0 | Systematic Assessment |
|
| Retinal haemorrhage | Eye disorders | MedDRA 17.0 | Systematic Assessment |
|
| Vitreal cells | Eye disorders | MedDRA 17.0 | Systematic Assessment |
|
| Vitreous floaters | Eye disorders | MedDRA 17.0 | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
Sponsor reserves the right of prior review of any publication or presentation of information related to the study.