Neovascular Age-Related Macular Degeneration
Conditions
Keywords
AMD, nAMD, wetAMD, Age-Related Macular Degeneration
Brief summary
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
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.
Interventions
DRUGBrolucizumab 3 mg/50 μL
Administered as an intravitreal injection
DRUGBrolucizumab 6 mg/50 μL
Administered as an intravitreal injection
Sponsors
Alcon Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Concentration of RTH258 Obtained 24 Hours Post Day 56 Injection [C24hr (ng/mL)] | Day 57 | 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. |
| Maximum Analyte Serum Concentration [Cmax (ng/mL)] | Day 0 (predose), 6 hr, 24 hr, 72 hr, 168 hr, 336 hr, 504 hr, 672 hr | 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. |
| Time to Reach Maximum Analyte Serum Concentration [Tmax (h)] | Day 0 (predose), 6 hr, 24 hr, 72 hr, 168 hr, 336 hr, 504 hr, 672 hr | 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. |
| Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration [AUC0-tlast (ng*h/mL)] | Day 0 (predose), 6 hr, 24 hr, 72 hr, 168 hr, 336 hr, 504 hr, 672 hr | 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. |
| Area Under the Concentration-time Curve From 0 to Infinity [AUC0-inf (ng*h/mL)] | Day 0 (predose), 6 hr, 24 hr, 72 hr, 168 hr, 336 hr, 504 hr, 672 hr | 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. |
| Elimination Half-life in Serum [t1/2 (h)] | Day 0 (predose), 6 hr, 24 hr, 72 hr, 168 hr, 336 hr, 504 hr, 672 hr | 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. |
| Concentration of RTH258 Obtained 24 Hours Post Day 0 Injection [C24hr (ng/mL)] | Day 1 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Positive Anti-drug Antibody (ADA) Status (Test) | Day 0 (predose), Day 28, Day 84 | 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. |
Participant flow
Recruitment details
Subjects were recruited from 5 study centers in Japan and 2 study centers in the United States.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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 | 25 |
| 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 | 25 |
| Total | 50 |
Baseline characteristics
| Characteristic | Brolucizumab 3 mg | Brolucizumab 6 mg | Total |
|---|---|---|---|
| Age, Continuous | 71.1 years STANDARD_DEVIATION 8.53 | 73.6 years STANDARD_DEVIATION 7.09 | 72.4 years STANDARD_DEVIATION 7.87 |
| Ancestry Japanese | 13 Participants | 13 Participants | 26 Participants |
| Ancestry Non-Japanese | 12 Participants | 12 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 24 Participants | 48 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Pre-dose Anti-Drug Antibody (ADA) Status Negative | 11 Participants | 7 Participants | 18 Participants |
| Pre-dose Anti-Drug Antibody (ADA) Status Positive | 14 Participants | 18 Participants | 32 Participants |
| Primary Diagnosis of Neovascular Age-Related Macular Degeneration | 25 Participants | 25 Participants | 50 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 13 Participants | 13 Participants | 26 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 12 Participants | 24 Participants |
| Region of Enrollment Japan | 13 Participants | 12 Participants | 25 Participants |
| Region of Enrollment United States | 12 Participants | 13 Participants | 25 Participants |
| Sex: Female, Male Female | 9 Participants | 11 Participants | 20 Participants |
| Sex: Female, Male Male | 16 Participants | 14 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 50 | 0 / 25 | 0 / 25 |
| other Total, other adverse events | 2 / 50 | 10 / 25 | 11 / 25 |
| serious Total, serious adverse events | 0 / 50 | 2 / 25 | 1 / 25 |
Outcome results
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.
Time frame: Day 0 (predose), 6 hr, 24 hr, 72 hr, 168 hr, 336 hr, 504 hr, 672 hr
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Brolucizumab 3 mg | Area Under the Concentration-time Curve From 0 to Infinity [AUC0-inf (ng*h/mL)] | 3380 ng*h/mL | Standard Deviation 6860 |
| Brolucizumab 6 mg | Area Under the Concentration-time Curve From 0 to Infinity [AUC0-inf (ng*h/mL)] | 9770 ng*h/mL | Standard Deviation 12600 |
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.
Time frame: Day 0 (predose), 6 hr, 24 hr, 72 hr, 168 hr, 336 hr, 504 hr, 672 hr
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Brolucizumab 3 mg | Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration [AUC0-tlast (ng*h/mL)] | 2480 ng*h/mL | Standard Deviation 5470 |
| Brolucizumab 6 mg | Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration [AUC0-tlast (ng*h/mL)] | 9160 ng*h/mL | Standard Deviation 12300 |
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.
Time frame: Day 1
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Brolucizumab 3 mg | Concentration of RTH258 Obtained 24 Hours Post Day 0 Injection [C24hr (ng/mL)] | 13.5 ng/mL | Standard Deviation 20 |
| Brolucizumab 6 mg | Concentration of RTH258 Obtained 24 Hours Post Day 0 Injection [C24hr (ng/mL)] | 65.7 ng/mL | Standard Deviation 107 |
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.
Time frame: Day 57
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Brolucizumab 3 mg | Concentration of RTH258 Obtained 24 Hours Post Day 56 Injection [C24hr (ng/mL)] | 12.4 ng/mL | Standard Deviation 21.8 |
| Brolucizumab 6 mg | Concentration of RTH258 Obtained 24 Hours Post Day 56 Injection [C24hr (ng/mL)] | 45.0 ng/mL | Standard Deviation 59.9 |
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.
Time frame: Day 0 (predose), 6 hr, 24 hr, 72 hr, 168 hr, 336 hr, 504 hr, 672 hr
Population: PK analysis set. Harmonic mean and jackknife estimate of the standard deviation are presented.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Brolucizumab 3 mg | Elimination Half-life in Serum [t1/2 (h)] | 108 hours | Standard Deviation 40.7 |
| Brolucizumab 6 mg | Elimination Half-life in Serum [t1/2 (h)] | 103 hours | Standard Deviation 52.5 |
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.
Time frame: Day 0 (predose), 6 hr, 24 hr, 72 hr, 168 hr, 336 hr, 504 hr, 672 hr
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Brolucizumab 3 mg | Maximum Analyte Serum Concentration [Cmax (ng/mL)] | 20.7 ng/mL | Standard Deviation 29.4 |
| Brolucizumab 6 mg | Maximum Analyte Serum Concentration [Cmax (ng/mL)] | 77.6 ng/mL | Standard Deviation 105 |
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.
Time frame: Day 0 (predose), 6 hr, 24 hr, 72 hr, 168 hr, 336 hr, 504 hr, 672 hr
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Brolucizumab 3 mg | Time to Reach Maximum Analyte Serum Concentration [Tmax (h)] | 20.3 hours | Standard Deviation 24.6 |
| Brolucizumab 6 mg | Time to Reach Maximum Analyte Serum Concentration [Tmax (h)] | 17.4 hours | Standard Deviation 14.7 |
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.
Time frame: Day 0 (predose), Day 28, Day 84
Population: PK analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brolucizumab 3 mg | Percentage of Subjects With Positive Anti-drug Antibody (ADA) Status (Test) | 16.0 percentage of participants |
| Brolucizumab 6 mg | Percentage of Subjects With Positive Anti-drug Antibody (ADA) Status (Test) | 4.0 percentage of participants |