Wet Macular Degeneration
Conditions
Keywords
AMD, Wet AMD, choroidal neovascularization secondary to age-related macular degeneration, KSI-301, Aflibercept, Vascular endothelial growth factor, VEGF, Anti-VEGF, Antibody biopolymer conjugate, Macular Degeneration, Wet Macular Degeneration, Retinal Degeneration, Retinal Diseases, Eye Diseases, Vision Disorders, Vision, low, Kodiak
Brief summary
This study will evaluate the efficacy, safety, durability, and pharmacokinetics of KSI-301 administered at 12, 16 and 20 weeks intervals as specified in the protocol, compared with aflibercept once every 8 weeks (Q8W), in participants with treatment-naïve neovascular (wet) age-related macular degeneration (nAMD).
Detailed description
This study is divided into a 3-week screening period, a 92-week treatment period, and a final 4-week follow-up period. At baseline patients will be randomized 1:1 into two treatment arms: KSI-301 5 mg and aflibercept 2 mg.
Interventions
DRUGKSI-301
Intravitreal Injection
DRUGAflibercept
Intravitreal Injection
OTHERSham Procedure
The sham is a procedure that mimics an intravitreal injection. It involves pressing the blunt end of an empty syringe (without a needle) against the anesthetized eye. It will be administered to participants in both treatments arms at applicable visits to maintain masking.
Sponsors
Kodiak Sciences Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
A masked evaluating investigator will be responsible for subject care except the injections and the safety assessment following the injections. An unmasked treating investigator will perform the injections and assess patient safety following the injections.
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed informed consent prior to participation in the study. * Active, treatment-naïve choroidal neovascularization (CNV) secondary to AMD. * BCVA ETDRS score between 80 and 25 letters (Snellen equivalent of 20/25 to 20/320), inclusive. * Other protocol-specified inclusion criteria may apply
Exclusion criteria
* CNV secondary to other causes in the Study Eye. * Any history of macular pathology unrelated to AMD but affecting vision or contributing to subretinal or intraretinal fluid. * Any history or evidence of a concurrent intraocular condition in the Study Eye that, in the judgment of the Investigator, could require either medical or surgical intervention during the study to prevent or treat visual loss. * Active ocular or periocular infection or inflammation. * Prior administration of any approved or investigational treatment for neovascular AMD in the Study Eye. * Uncontrolled glaucoma in the Study Eye. * Women who are pregnant or lactating or intending to become pregnant during the study. * Stroke or myocardial infarction in the 6-month period prior to Day 1. * Uncontrolled blood pressure defined as a systolic value \> 180 mmHg or diastolic value ≥100 mmHg while at rest. * History of a medical condition that, in the judgment of the Investigator, would preclude scheduled study visits, completion of the study, or a safe administration of investigational product. * Other protocol-specified
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in BCVA in the Study Eye Averaged Over Weeks 48 and 52, Full Analysis Set Year 1 | Year 1 | Best Corrected Visual Acuity (BCVA) was measured on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at a starting distance of 4 meters. The BCVA letter score ranges from 0 to 100 (best score), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects on KSI-301 Arm With a Once Every 12-Weeks, 16-Weeks or 20-Weeks Treatment Interval | Year 1 | Percentage of subjects on KSI-301 arm achieving a Once Every 12-Weeks, 16-Weeks or 20-Weeks Treatment Interval based on individualized treatment response |
| Percentage of Subjects Gaining ≥ 5, ≥10 and ≥15 Letters in BCVA From Baseline in the Study Eye, Full Analysis Set Year 1 | Year 1 | Categorical improvements in Best Corrected Visual Acuity (BCVA) of clinically relevant BCVA measurements corresponding to 1, 2 and 3 lines of the ETDRS vision testing chart |
| Percentage of Subjects Who Achieving BCVA Snellen Equivalent of 20/40 or Better in the Study Eye at Year 1 | Year 1 | Best Corrected Visual Acuity (BCVA) was measured on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at a starting distance of 4 meters. The BCVA letter score ranges from 0 to 100 (best score), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. BCVA Snellen equivalent of 20/40 was defined as ≥69 ETDRS letters |
| Percentage of Subjects With BCVA Snellen Equivalent of 20/200 or Worse in the Study Eye at Year 1 | Year 1 | Best Corrected Visual Acuity (BCVA) was measured on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at a starting distance of 4 meters. The BCVA letter score ranges from 0 to 100 (best score), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. BCVA Snellen equivalent of 20/200 or Worse was defined as BCVA ≤ 38 ETDRS Letters. |
| Mean Change in OCT Central Subfield Retinal Thickness (CST) From Day 1 | Year 1 | Central subfield thickness (CST) was defined as the distance between the internal limiting membrane (ILM) and the retinal pigment epithelium (RPE) as assessed by a central reading center. |
Countries
Czechia, Germany, Latvia, Poland, Slovakia, Spain, United States
Participant flow
Recruitment details
Participants were recruited based on physician referral at 72 medical centers between September 2019 and November 2020. The first participant was enrolled on 08 October 2019 and the last on 24 November 2020.
Pre-assignment details
Of 785 participants screened, 559 were randomized to treatment. Two randomized subjects (one subject in KSI-301 arm and one subject in aflibercept arm) never received treatment, so do not have reason for not completing treatment.
Participants by arm
| Arm | Count |
|---|---|
| KSI-301 5 mg Q12W-Q20W Participants randomized to this arm received 5 milligrams (mg) KSI-301 intravitreal (IVT) injections once every 4 weeks (Q4W) to Week 8, followed by 5 mg KSI-301 IVT injections based on disease activity assessments and may vary from Q12W to Q20W until Week 52. | 277 |
| Aflibercept 2 mg Q8W Participants randomized to this arm received 2 milligrams (mg) aflibercept intravitreal (IVT) injections Q4W to Week 8, followed by 2 mg aflibercept IVT injections Q8W to Week 52. | 280 |
| Total | 557 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 16 | 9 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Non-compliance with study drug | 0 | 3 |
| Overall Study | Patient moved out of state | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Progressive disease | 11 | 2 |
| Overall Study | Withdrawal by Subject | 6 | 10 |
Baseline characteristics
| Characteristic | KSI-301 5 mg Q12W-Q20W | Aflibercept 2 mg Q8W | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 259 Participants | 257 Participants | 516 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 23 Participants | 41 Participants |
| Age, Continuous | 76.6 years STANDARD_DEVIATION 7.35 | 76.2 years STANDARD_DEVIATION 8.27 | 76.4 years STANDARD_DEVIATION 7.82 |
| BCVA in the Study Eye, Letters | 63.6 Letters STANDARD_DEVIATION 12.23 | 63.6 Letters STANDARD_DEVIATION 12.34 | 63.6 Letters STANDARD_DEVIATION 12.27 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 9 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 260 Participants | 271 Participants | 531 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 5 Participants | 9 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 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 | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 271 Participants | 272 Participants | 543 Participants |
| Region of Enrollment Europe | 48 participants | 45 participants | 93 participants |
| Region of Enrollment North America | 229 participants | 235 participants | 464 participants |
| Sex: Female, Male Female | 178 Participants | 168 Participants | 346 Participants |
| Sex: Female, Male Male | 99 Participants | 112 Participants | 211 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 277 | 8 / 280 |
| other Total, other adverse events | 82 / 277 | 84 / 280 |
| serious Total, serious adverse events | 35 / 277 | 33 / 280 |
Outcome results
Primary
Change From Baseline in BCVA in the Study Eye Averaged Over Weeks 48 and 52, Full Analysis Set Year 1
Best Corrected Visual Acuity (BCVA) was measured on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at a starting distance of 4 meters. The BCVA letter score ranges from 0 to 100 (best score), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity.
Time frame: Year 1
Population: Full analysis set defined as all randomized subjects who received at least one treatment injection in Year 1. Subjects will be analyzed according to their randomized treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| KSI-301 5 mg Q12W-Q20W | Change From Baseline in BCVA in the Study Eye Averaged Over Weeks 48 and 52, Full Analysis Set Year 1 | 1 ETDRS Letters | Standard Error 0.78 |
| Aflibercept 2 mg Q8W | Change From Baseline in BCVA in the Study Eye Averaged Over Weeks 48 and 52, Full Analysis Set Year 1 | 7 ETDRS Letters | Standard Error 0.77 |
p-value: >0.999995.03% CI: [-8, -4]Mixed Models Analysis
Secondary
Mean Change in OCT Central Subfield Retinal Thickness (CST) From Day 1
Central subfield thickness (CST) was defined as the distance between the internal limiting membrane (ILM) and the retinal pigment epithelium (RPE) as assessed by a central reading center.
Time frame: Year 1
Population: Full analysis set defined as all randomized subjects who received at least one treatment injection in Year 1. Subjects will be analyzed according to their randomized treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| KSI-301 5 mg Q12W-Q20W | Mean Change in OCT Central Subfield Retinal Thickness (CST) From Day 1 | -96.1 Microns | Standard Deviation 123.39 |
| Aflibercept 2 mg Q8W | Mean Change in OCT Central Subfield Retinal Thickness (CST) From Day 1 | -134.1 Microns | Standard Deviation 111.17 |
Secondary
Percentage of Subjects Gaining ≥ 5, ≥10 and ≥15 Letters in BCVA From Baseline in the Study Eye, Full Analysis Set Year 1
Categorical improvements in Best Corrected Visual Acuity (BCVA) of clinically relevant BCVA measurements corresponding to 1, 2 and 3 lines of the ETDRS vision testing chart
Time frame: Year 1
Population: All randomized subjects who received at least one treatment injection in Year 1 with available data at Year 1 for analysis. Number of participants in each Row Title is not mutually exclusive as number of participants who gained \>=15 ETDRS letters includes participants who gained \>=10 ETDRS letters and participants who gained \>=5 ETDRS letters.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| KSI-301 5 mg Q12W-Q20W | Percentage of Subjects Gaining ≥ 5, ≥10 and ≥15 Letters in BCVA From Baseline in the Study Eye, Full Analysis Set Year 1 | Gain >=5 ETDRS Letters at Year 1 | 103 Participants |
| KSI-301 5 mg Q12W-Q20W | Percentage of Subjects Gaining ≥ 5, ≥10 and ≥15 Letters in BCVA From Baseline in the Study Eye, Full Analysis Set Year 1 | Gain >=10 ETDRS Letters at Year 1 | 66 Participants |
| KSI-301 5 mg Q12W-Q20W | Percentage of Subjects Gaining ≥ 5, ≥10 and ≥15 Letters in BCVA From Baseline in the Study Eye, Full Analysis Set Year 1 | Gain >=15 ETDRS Letters at Year 1 | 31 Participants |
| Aflibercept 2 mg Q8W | Percentage of Subjects Gaining ≥ 5, ≥10 and ≥15 Letters in BCVA From Baseline in the Study Eye, Full Analysis Set Year 1 | Gain >=5 ETDRS Letters at Year 1 | 148 Participants |
| Aflibercept 2 mg Q8W | Percentage of Subjects Gaining ≥ 5, ≥10 and ≥15 Letters in BCVA From Baseline in the Study Eye, Full Analysis Set Year 1 | Gain >=10 ETDRS Letters at Year 1 | 87 Participants |
| Aflibercept 2 mg Q8W | Percentage of Subjects Gaining ≥ 5, ≥10 and ≥15 Letters in BCVA From Baseline in the Study Eye, Full Analysis Set Year 1 | Gain >=15 ETDRS Letters at Year 1 | 46 Participants |
Secondary
Percentage of Subjects on KSI-301 Arm With a Once Every 12-Weeks, 16-Weeks or 20-Weeks Treatment Interval
Percentage of subjects on KSI-301 arm achieving a Once Every 12-Weeks, 16-Weeks or 20-Weeks Treatment Interval based on individualized treatment response
Time frame: Year 1
Population: Subjects with Available Data at the Planned Durability Assessment at Year 1
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| KSI-301 5 mg Q12W-Q20W | Percentage of Subjects on KSI-301 Arm With a Once Every 12-Weeks, 16-Weeks or 20-Weeks Treatment Interval | Number of participants on the KSI-301 Q12W | 71 Participants |
| KSI-301 5 mg Q12W-Q20W | Percentage of Subjects on KSI-301 Arm With a Once Every 12-Weeks, 16-Weeks or 20-Weeks Treatment Interval | Number of participants on the KSI-301 Q16W | 24 Participants |
| KSI-301 5 mg Q12W-Q20W | Percentage of Subjects on KSI-301 Arm With a Once Every 12-Weeks, 16-Weeks or 20-Weeks Treatment Interval | Number of participants on the KSI-301 Q20W | 139 Participants |
Secondary
Percentage of Subjects Who Achieving BCVA Snellen Equivalent of 20/40 or Better in the Study Eye at Year 1
Best Corrected Visual Acuity (BCVA) was measured on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at a starting distance of 4 meters. The BCVA letter score ranges from 0 to 100 (best score), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. BCVA Snellen equivalent of 20/40 was defined as ≥69 ETDRS letters
Time frame: Year 1
Population: All randomized subjects who received at least one treatment injection in Year 1 with available data at Year 1 for analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KSI-301 5 mg Q12W-Q20W | Percentage of Subjects Who Achieving BCVA Snellen Equivalent of 20/40 or Better in the Study Eye at Year 1 | 119 Participants |
| Aflibercept 2 mg Q8W | Percentage of Subjects Who Achieving BCVA Snellen Equivalent of 20/40 or Better in the Study Eye at Year 1 | 165 Participants |
Secondary
Percentage of Subjects With BCVA Snellen Equivalent of 20/200 or Worse in the Study Eye at Year 1
Best Corrected Visual Acuity (BCVA) was measured on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at a starting distance of 4 meters. The BCVA letter score ranges from 0 to 100 (best score), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. BCVA Snellen equivalent of 20/200 or Worse was defined as BCVA ≤ 38 ETDRS Letters.
Time frame: Year 1
Population: All randomized subjects who received at least one treatment injection in Year 1 with available data at Year 1 for analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KSI-301 5 mg Q12W-Q20W | Percentage of Subjects With BCVA Snellen Equivalent of 20/200 or Worse in the Study Eye at Year 1 | 13 Participants |
| Aflibercept 2 mg Q8W | Percentage of Subjects With BCVA Snellen Equivalent of 20/200 or Worse in the Study Eye at Year 1 | 8 Participants |