Geographic Atrophy
Conditions
Brief summary
This multicenter, randomized, single-masked, sham injection-controlled study will investigate the exposure-response and safety of lampalizumab administered intravitreally every 2 weeks (Q2W) or every 4 weeks (Q4W) for 24 weeks in participants with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). A safety run-in assessment will be conducted prior to initiating enrollment in the randomized study.
Interventions
OTHERSham
Sham injection will be administered as a matching intravitreal injection of lampalizumab.
DRUGLampalizumab
10 mg dose of lampalizumab administered intravitreally
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Complement Factor I (CFI) profile biomarker-positive result * Women of child bearing potential and men should remain abstinent or use contraceptive methods
Exclusion criteria
* History of vitrectomy surgery, submacular surgery, or other surgical intervention for AMD in study eye * Previous subfoveal focal laser photocoagulation in study eye * Laser photocoagulation in the study eye * Prior treatment with external-beam radiation therapy or transpupillary thermotherapy in study eye * Previous intravitreal drug administration in study eye. A single intraoperative administration of a corticosteroid during cataract surgery at least 3 months prior to screening is permitted * Previous cell-based intraocular treatment in study eye * Intraocular surgery in study eye * Uncontrolled glaucoma and history of glaucoma-filtering surgery in study eye * History of corneal transplant in study eye * GA in either eye due to causes other than AMD * Proliferative diabetic retinopathy in either eye * Active or history of neovascular (wet) AMD in either eye * History of idiopathic or autoimmune-associated uveitis, ocular or intraocular conditions, and infectious or inflammatory ocular disease * Active uveitis and infectious conjunctivitis, keratitis, scleritis or endophthalmitis * Previous systemic treatment with complement inhibitor and with inhibitors/modulators of visual cycle * Previous expression vector mediated intraocular treatments * Uncontrolled blood pressure and atrial fibrillation * Medical conditions associated with clinically significant risk for bleeding- * Predisposition or history of increased risk for infection * Active malignancy within the previous 12 months except for appropriately treated carcinoma in situ of cervix, resolved non-melanoma skin carcinoma, and prostate cancer with a Gleason score of less than or equal to 6, and a stable prostate-specific antigen for greater than or equal to (\>/=) 12 months * History of severe allergic reaction or anaphylactic reaction to a biologic agent or known hypersensitivity to any component of lampalizumab injection * Women of child bearing potential must have a negative serum pregnancy test within 28 days prior to initiation of study treatment * Previous participation in other studies of investigational drugs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Geographic Atrophy (GA) Area, as Assessed by Fundus Autofluorescence (FAF) at Week 24 | Baseline, Week 24 | GA or the death of photoreceptors and surrounding cells in the retina, is a common condition in participants with age-related macular degeneration (AMD). The death of these photoreceptors results in lesions that cause vision loss. The change in GA lesion area was measured by FAF and analysis of FAF images was performed by the central reading center. A positive change from baseline indicates an increase in size of geographic atrophy lesion area (worsening; disease progression). BCVA=best corrected visual acuity; ETDRS=Early Treatment Diabetic Retinopathy Scale. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum Concentrations of Lampalizumab (Q2W) | Baseline (Day 1, predose and postdose), Weeks 2,4,8,16 and 24, early termination, unscheduled predose and postdose | Lower than reportable (LTR) results on pre-dose sample were set to 0, and LTR results on post-dose sample were set to half of lower limit of quantification (LLOQ) (0.5 nanograms per milliliter (ng/mL)). |
| Serum Concentrations of Lampalizumab (Q4W) | Baseline (Day 1, predose and postdose), Weeks 4,8,16 and 24, early termination | LTR results on pre-dose sample were set to 0, and LTR results on post-dose sample were set to half of LLOQ (0.5 ng/mL). |
| Percentage of Participants With Ocular Adverse Events (AEs) | Baseline up to approximately 30 weeks | An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether considered related to the medicinal product, any new disease or exacerbation of an existing disease, recurrence of an intermittent medical condition, or any deterioration in a laboratory value or other clinical test. Ocular AEs are the events which are localized in the ocular region. |
| Percentage of Participants With Systemic (Non-ocular) Adverse Events | Baseline up to approximately 30 weeks | An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether considered related to the medicinal product, any new disease or exacerbation of an existing disease, recurrence of an intermittent medical condition, or any deterioration in a laboratory value or other clinical test. Non-ocular AEs were the systemic events. |
| Percentage of Participants With Anti-Lampalizumab Antibodies | Baseline up to approximately 30 weeks | Having treatment-induced anti-drug antibodies (ADAs) was defined as being ADA-negative at baseline and ADA-positive at any post-baseline timepoint. Having treatment-enhanced ADAs was defined as being ADA-positive at baseline with titer values increased by 0.6 titer units at any post-baseline timepoint. |
Countries
United States
Participant flow
Pre-assignment details
A total of 332 participants were screened and 92 participants were randomized out of which 3 participants from one site were removed from the randomized population due to serious good clinical practice (GCP) noncompliance. Out of 89, 4 participants were excluded from the randomized population as they did not have any post-baseline measurement. .
Participants by arm
| Arm | Count |
|---|---|
| Sham Q2W Participants received sham comparator Q2W (once every 2 weeks) for 24 weeks. | 10 |
| Sham Q4W Participants received sham comparator Q4W (once every 4 weeks) for 24 weeks. | 10 |
| Lampalizumab Q2W Participants received 10 milligrams (mg) dose of lampalizumab administered by intravitreal injections Q2W for 24 weeks. | 43 |
| Lampalizumab Q4W Participants received 10 mg dose of lampalizumab administered by intravitreal injections Q4W for 24 weeks. | 22 |
| Total | 85 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 5 | 0 |
| Overall Study | Death | 0 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Overall Study | Reason Not Specified | 0 | 0 | 3 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | Total | Lampalizumab Q4W | Sham Q2W | Lampalizumab Q2W | Sham Q4W |
|---|---|---|---|---|---|
| Age, Continuous | 78.2 years STANDARD_DEVIATION 7.7 | 80.1 years STANDARD_DEVIATION 7.7 | 73.4 years STANDARD_DEVIATION 4.4 | 78.3 years STANDARD_DEVIATION 8 | 78.2 years STANDARD_DEVIATION 7.7 |
| Geographic Atrophy Area, as Assessed by Fundus Autofluorescence (FAF) | 7.923 millimeter square (mm^2) STANDARD_DEVIATION 3.894 | 7.172 millimeter square (mm^2) STANDARD_DEVIATION 4.192 | 7.034 millimeter square (mm^2) STANDARD_DEVIATION 2.747 | 8.755 millimeter square (mm^2) STANDARD_DEVIATION 4.059 | 6.891 millimeter square (mm^2) STANDARD_DEVIATION 3.05 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 84 Participants | 22 Participants | 10 Participants | 42 Participants | 10 Participants |
| Race/Ethnicity, Customized White | 82 Participants | 22 Participants | 9 Participants | 42 Participants | 9 Participants |
| Sex: Female, Male Female | 49 Participants | 9 Participants | 7 Participants | 25 Participants | 8 Participants |
| Sex: Female, Male Male | 36 Participants | 13 Participants | 3 Participants | 18 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 46 | 0 / 22 | 0 / 10 | 0 / 11 |
| other Total, other adverse events | 21 / 46 | 13 / 22 | 7 / 10 | 7 / 11 |
| serious Total, serious adverse events | 7 / 46 | 3 / 22 | 0 / 10 | 1 / 11 |
Outcome results
Primary
Change From Baseline in Geographic Atrophy (GA) Area, as Assessed by Fundus Autofluorescence (FAF) at Week 24
GA or the death of photoreceptors and surrounding cells in the retina, is a common condition in participants with age-related macular degeneration (AMD). The death of these photoreceptors results in lesions that cause vision loss. The change in GA lesion area was measured by FAF and analysis of FAF images was performed by the central reading center. A positive change from baseline indicates an increase in size of geographic atrophy lesion area (worsening; disease progression). BCVA=best corrected visual acuity; ETDRS=Early Treatment Diabetic Retinopathy Scale.
Time frame: Baseline, Week 24
Population: Modified intent-to-treat (mITT) population included participants who were randomly assigned to study treatment and had at least one post-baseline GA area measurement. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sham Q2W | Change From Baseline in Geographic Atrophy (GA) Area, as Assessed by Fundus Autofluorescence (FAF) at Week 24 | 0.614 mm^2 | Standard Error 0.188 |
| Sham Q4W | Change From Baseline in Geographic Atrophy (GA) Area, as Assessed by Fundus Autofluorescence (FAF) at Week 24 | 1.121 mm^2 | Standard Error 0.179 |
| Lampalizumab Q2W | Change From Baseline in Geographic Atrophy (GA) Area, as Assessed by Fundus Autofluorescence (FAF) at Week 24 | 1.049 mm^2 | Standard Error 0.094 |
| Lampalizumab Q4W | Change From Baseline in Geographic Atrophy (GA) Area, as Assessed by Fundus Autofluorescence (FAF) at Week 24 | 0.911 mm^2 | Standard Error 0.123 |
p-value: 0.042880% CI: [0.162, 0.707]Mixed-Effect Model Repeated Measures
p-value: 0.336180% CI: [-0.491, 0.071]MMRM
Secondary
Percentage of Participants With Anti-Lampalizumab Antibodies
Having treatment-induced anti-drug antibodies (ADAs) was defined as being ADA-negative at baseline and ADA-positive at any post-baseline timepoint. Having treatment-enhanced ADAs was defined as being ADA-positive at baseline with titer values increased by 0.6 titer units at any post-baseline timepoint.
Time frame: Baseline up to approximately 30 weeks
Population: Safety analysis population included all randomized participants who received at least one dose of study drug. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sham Q2W | Percentage of Participants With Anti-Lampalizumab Antibodies | Treatment-induced ADA | 0 percentage of participants |
| Sham Q2W | Percentage of Participants With Anti-Lampalizumab Antibodies | Treatment-enhanced ADA | 0 percentage of participants |
| Sham Q4W | Percentage of Participants With Anti-Lampalizumab Antibodies | Treatment-enhanced ADA | 0 percentage of participants |
| Sham Q4W | Percentage of Participants With Anti-Lampalizumab Antibodies | Treatment-induced ADA | 0 percentage of participants |
| Lampalizumab Q2W | Percentage of Participants With Anti-Lampalizumab Antibodies | Treatment-induced ADA | 1 percentage of participants |
| Lampalizumab Q2W | Percentage of Participants With Anti-Lampalizumab Antibodies | Treatment-enhanced ADA | 0 percentage of participants |
| Lampalizumab Q4W | Percentage of Participants With Anti-Lampalizumab Antibodies | Treatment-induced ADA | 1 percentage of participants |
| Lampalizumab Q4W | Percentage of Participants With Anti-Lampalizumab Antibodies | Treatment-enhanced ADA | 0 percentage of participants |
Secondary
Percentage of Participants With Ocular Adverse Events (AEs)
An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether considered related to the medicinal product, any new disease or exacerbation of an existing disease, recurrence of an intermittent medical condition, or any deterioration in a laboratory value or other clinical test. Ocular AEs are the events which are localized in the ocular region.
Time frame: Baseline up to approximately 30 weeks
Population: Safety analysis population included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sham Q2W | Percentage of Participants With Ocular Adverse Events (AEs) | 60.0 percentage of participants |
| Sham Q4W | Percentage of Participants With Ocular Adverse Events (AEs) | 9.1 percentage of participants |
| Lampalizumab Q2W | Percentage of Participants With Ocular Adverse Events (AEs) | 63.0 percentage of participants |
| Lampalizumab Q4W | Percentage of Participants With Ocular Adverse Events (AEs) | 63.6 percentage of participants |
Secondary
Percentage of Participants With Systemic (Non-ocular) Adverse Events
An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether considered related to the medicinal product, any new disease or exacerbation of an existing disease, recurrence of an intermittent medical condition, or any deterioration in a laboratory value or other clinical test. Non-ocular AEs were the systemic events.
Time frame: Baseline up to approximately 30 weeks
Population: Safety analysis population included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sham Q2W | Percentage of Participants With Systemic (Non-ocular) Adverse Events | 40.0 percentage of participants |
| Sham Q4W | Percentage of Participants With Systemic (Non-ocular) Adverse Events | 63.6 percentage of participants |
| Lampalizumab Q2W | Percentage of Participants With Systemic (Non-ocular) Adverse Events | 52.2 percentage of participants |
| Lampalizumab Q4W | Percentage of Participants With Systemic (Non-ocular) Adverse Events | 50.0 percentage of participants |
Secondary
Serum Concentrations of Lampalizumab (Q2W)
Lower than reportable (LTR) results on pre-dose sample were set to 0, and LTR results on post-dose sample were set to half of lower limit of quantification (LLOQ) (0.5 nanograms per milliliter (ng/mL)).
Time frame: Baseline (Day 1, predose and postdose), Weeks 2,4,8,16 and 24, early termination, unscheduled predose and postdose
Population: Pharmacokinetics (PK) population included participants randomized to lampalizumab treatment who received at least one dose of study drug and provided at least one serum sample for determination of lampalizumab. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Q2W | Serum Concentrations of Lampalizumab (Q2W) | Day 1 (Predose) | NA ng/mL | — |
| Sham Q2W | Serum Concentrations of Lampalizumab (Q2W) | Day 1 (Postdose) | 1.31 ng/mL | — |
| Sham Q2W | Serum Concentrations of Lampalizumab (Q2W) | Week 2 | 55.5 ng/mL | Geometric Coefficient of Variation 89.1 |
| Sham Q2W | Serum Concentrations of Lampalizumab (Q2W) | Week 4 | 63.6 ng/mL | Geometric Coefficient of Variation 69.4 |
| Sham Q2W | Serum Concentrations of Lampalizumab (Q2W) | Week 8 | 64.4 ng/mL | Geometric Coefficient of Variation 83.7 |
| Sham Q2W | Serum Concentrations of Lampalizumab (Q2W) | Week 16 | 78.2 ng/mL | Geometric Coefficient of Variation 68 |
| Sham Q2W | Serum Concentrations of Lampalizumab (Q2W) | Week 24 | 62.7 ng/mL | Geometric Coefficient of Variation 141.4 |
| Sham Q2W | Serum Concentrations of Lampalizumab (Q2W) | Early Termination | 4.92 ng/mL | Geometric Coefficient of Variation 1070.9 |
| Sham Q2W | Serum Concentrations of Lampalizumab (Q2W) | Unscheduled predose | 0.500 ng/mL | — |
| Sham Q2W | Serum Concentrations of Lampalizumab (Q2W) | Unscheduled postdose | 0.500 ng/mL | — |
Secondary
Serum Concentrations of Lampalizumab (Q4W)
LTR results on pre-dose sample were set to 0, and LTR results on post-dose sample were set to half of LLOQ (0.5 ng/mL).
Time frame: Baseline (Day 1, predose and postdose), Weeks 4,8,16 and 24, early termination
Population: PK population included participants randomized to lampalizumab treatment who received at least one dose of study drug and provided at least one serum sample for determination of lampalizumab. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Q2W | Serum Concentrations of Lampalizumab (Q4W) | Day 1 (Postdose) | 2.08 ng/mL | — |
| Sham Q2W | Serum Concentrations of Lampalizumab (Q4W) | Day 1 (Predose) | NA ng/mL | — |
| Sham Q2W | Serum Concentrations of Lampalizumab (Q4W) | Week 4 | 8.52 ng/mL | Geometric Coefficient of Variation 114.3 |
| Sham Q2W | Serum Concentrations of Lampalizumab (Q4W) | Week 8 | 10.3 ng/mL | Geometric Coefficient of Variation 84.1 |
| Sham Q2W | Serum Concentrations of Lampalizumab (Q4W) | Week 16 | 8.66 ng/mL | Geometric Coefficient of Variation 88 |
| Sham Q2W | Serum Concentrations of Lampalizumab (Q4W) | Week 24 | 9.92 ng/mL | Geometric Coefficient of Variation 102 |
| Sham Q2W | Serum Concentrations of Lampalizumab (Q4W) | Early Termination | 14.1 ng/mL | — |