Diabetic Macular Edema
Conditions
Keywords
DME, Kodiak, Vascular endothelial growth factor, Anti-VEGF, VEGF, Antibody biopolymer conjugate, Retinal Degeneration, Retinal Diseases, Eye Diseases, Vision Disorders, Vision, low, Aflibercept, Eylea, Diabetes mellitus, Diabetes, Diabetic retinopathy, Diabetic macular edema, Macular edema, KSI-301
Brief summary
This Phase 3 study will evaluate the efficacy, durability, and safety of KSI-301 compared to aflibercept in participants with treatment-naïve DME.
Detailed description
This is a Phase 3, prospective, randomized, double-masked, two-arm, multi-center non-inferiority study evaluating the efficacy and safety of repeated intravitreal dosing of KSI-301 5 mg in participants with treatment-naïve DME. The primary endpoint will be assessed at Year 1; additional secondary endpoints for efficacy will be assessed at Years 1 and 2.
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, Caregiver, Outcomes Assessor)
Masking description
For masking purposes, sham injections will be administered at every monthly visit if an active treatment is not administered. To preserve masking, two investigators are required for this study. The masked Investigator will be responsible for the examinations and safety assessments. The unmasked Investigator will perform the injections and post-treatment assessments.
Intervention model description
Participants will be randomized 1:1 into one of two treatment arms: KSI-301 or aflibercept.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent prior to participation in the study. 2. Treatment-naïve diabetic macular edema, with vision loss and center involvement (if present) diagnosed within 9 months of screening. 3. BCVA ETDRS letter score between 78 and 25 (-20/25 to 20/320 Snellen equivalent), inclusive, in the Study Eye. 4. CST of ≥ 320 microns on SD-OCT (Heidelberg Spectralis or equivalent on other OCT instruments) as determined by the Reading Center. 5. Decrease in vision determined by the Investigator to be primarily the result of DME. 6. Type 1 or Type 2 diabetes mellitus and a HbA1c of ≤12%. 7. Other protocol-specified inclusion criteria may apply.
Exclusion criteria
1. Macular edema in the Study Eye considered to be secondary to a cause other than DME. 2. Active iris or angle neovascularization or neovascular glaucoma in the Study Eye. 3. High-risk proliferative diabetic retinopathy characteristics in the Study Eye. 4. History of Pan-retinal Photocoagulation (PRP) laser in the Study Eye within 3 months of screening. 5. Tractional retinal detachment in the Study Eye. 6. Active retinal disease other than the condition under investigation in the Study Eye. 7. Any history or evidence of a concurrent ocular condition present, that in the opinion of the Investigator could require either medical or surgical intervention or affect macular edema or alter visual acuity during the study (e.g., vitreomacular traction, epiretinal membrane). 8. Active or suspected ocular or periocular infection or inflammation in either eye at Day 1. 9. Any prior use of an approved or investigational treatment for DME in the Study Eye (e.g., anti-VEGF, intraocular or periocular steroids, macular laser photocoagulation). 10. Women who are pregnant or lactating or intending to become pregnant during the study. 11. Uncontrolled blood pressure defined as a systolic value ≥ 180 mmHg or diastolic value ≥100 mmHg while at rest. 12. Recent history (within the 6 months prior to screening) of myocardial infarction, stroke, transient ischemic attack, acute congestive heart failure or any acute coronary event. 13. 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. 14. Other protocol-specified
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in BCVA | Day 1 to Week 64 | Mean change in best-corrected visual acuity (BCVA) from baseline to the average of Weeks 60 and 64 (using Early Treatment Diabetic Retinopathy Study (ETDRS) Letters). 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 Patients With a ≥ 2-step Worsening on the ETDRS DRSS in Studies KS301P104 and KS301P105 Combined | Day 1 to Week 52 | Percentage of patients with a ≥ 2-step worsening on the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) from baseline at Week 52 using last observation carried forward (LOCF) in Studies KS301P104 and KS301P105 combined. The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached). |
| Percentage of Patients With a ≥ 2-step Worsening on the ETDRS DRSS in Study KS301P105 | Day 1 to Week 52 | Percentage of patients with a ≥ 2-step worsening on the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) from baseline at Week 52 using last observation carried forward (LOCF) in Study KS301P105. The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached). |
| Percentage of Patients in the KSI-301 Arm on a Q8W, Q12W, Q16W, Q20W, or Q24W Treatment Interval | Week 56 | Percentage of patients in the KSI-301 arm on a Q8W, Q12W, Q16W, Q20W, or Q24W treatment interval at the primary endpoint. Analyses include KSI-301 patients who completed a treatment interval from Week 56 onwards. |
| Mean Number of Intravitreal Injections | Day 1 to Week 60 | Mean number of intravitreal injections from Day 1 to Week 60 |
| Mean Change in OCT CST | Day 1 to Week 64 | Mean change in Optical Coherence Tomography (OCT) central subfield retinal thickness (CST) baseline to the average of Weeks 60 and 64 |
Countries
Czechia, France, Hungary, Israel, Italy, Poland, Puerto Rico, United States
Participant flow
Recruitment details
Participants were recruited based on physician referral at 75 medical centers between September 2020 and January 2022. The first participant was enrolled on 30 September 2020 and the last on 31 January 2022.
Pre-assignment details
Of 689 screened participants, 459 met eligibility criteria and were randomized to treatment. Two randomized subjects in KSI-301 arm never received treatment, so do not have reason for not completing treatment. Each participant contributed only one study eye to this study.
Participants by arm
| Arm | Count |
|---|---|
| KSI-301 (Arm A) Intravitreal injection of KSI-301 (5 mg) once every 4 weeks for 3 monthly doses followed by an individualized dosing regimen (every 8 to 24 weeks) via intravitreal injection from Week 16 to Week 100.
KSI-301: Intravitreal Injection
Sham 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. | 229 |
| Aflibercept (Arm B) Intravitreal injection of aflibercept (2 mg) once every 4 weeks for 5 monthly doses followed by aflibercept (2 mg) once every 8 weeks via intravitreal injection from Week 24 to 100.
Aflibercept: Intravitreal Injection
Sham 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. | 228 |
| Total | 457 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 10 |
| Overall Study | Lost to Follow-up | 5 | 6 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Subject did not meet inclusion criteria 1 so was withdrawn from the study | 0 | 1 |
| Overall Study | Withdrawal by Subject | 7 | 6 |
Baseline characteristics
| Characteristic | KSI-301 (Arm A) | Aflibercept (Arm B) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 96 Participants | 91 Participants | 187 Participants |
| Age, Categorical Between 18 and 65 years | 133 Participants | 137 Participants | 270 Participants |
| Age, Continuous | 62.2 years STANDARD_DEVIATION 9.34 | 61.6 years STANDARD_DEVIATION 9.9 | 61.9 years STANDARD_DEVIATION 9.62 |
| BCVA in the Study Eye, Letters | 64.2 Letters STANDARD_DEVIATION 11.43 | 64.3 Letters STANDARD_DEVIATION 11.21 | 64.2 Letters STANDARD_DEVIATION 11.31 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 42 Participants | 58 Participants | 100 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 182 Participants | 161 Participants | 343 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 9 Participants | 14 Participants |
| Geographic Region North America | 149 Participants | 147 Participants | 296 Participants |
| Geographic Region Rest of World | 80 Participants | 81 Participants | 161 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 22 Participants | 12 Participants | 34 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants | 11 Participants | 19 Participants |
| Race (NIH/OMB) White | 194 Participants | 201 Participants | 395 Participants |
| Sex: Female, Male Female | 97 Participants | 79 Participants | 176 Participants |
| Sex: Female, Male Male | 132 Participants | 149 Participants | 281 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 228 | 6 / 229 |
| other Total, other adverse events | 113 / 228 | 104 / 229 |
| serious Total, serious adverse events | 53 / 228 | 57 / 229 |
Outcome results
Primary
Mean Change in BCVA
Mean change in best-corrected visual acuity (BCVA) from baseline to the average of Weeks 60 and 64 (using Early Treatment Diabetic Retinopathy Study (ETDRS) Letters). 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: Day 1 to Week 64
Population: Full analysis set defined as all randomized subjects who received any study treatment (KSI-301 or aflibercept). Subjects will be analyzed according to their randomized treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| KSI-301 (Arm A) | Mean Change in BCVA | 6.7 ETDRS Letters | Standard Error 0.8 |
| Aflibercept (Arm B) | Mean Change in BCVA | 11.5 ETDRS Letters | Standard Error 0.81 |
p-value: >0.999995.04% CI: [-6.65, -2.81]Mixed Models Analysis
Secondary
Mean Change in OCT CST
Mean change in Optical Coherence Tomography (OCT) central subfield retinal thickness (CST) baseline to the average of Weeks 60 and 64
Time frame: Day 1 to Week 64
Population: Full analysis set defined as all randomized subjects who received any study treatment (KSI-301 or aflibercept). Subjects will be analyzed according to their randomized treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| KSI-301 (Arm A) | Mean Change in OCT CST | -154.7 Microns | Standard Deviation 128.03 |
| Aflibercept (Arm B) | Mean Change in OCT CST | -194.2 Microns | Standard Deviation 154.44 |
Secondary
Mean Number of Intravitreal Injections
Mean number of intravitreal injections from Day 1 to Week 60
Time frame: Day 1 to Week 60
Population: Safety Analysis Set includes all patients who received any study treatment (KSI-301 or aflibercept).~Patients will be analyzed according to the study treatment they actually received. One patient was randomized to KSI-301, but received aflibercept.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| KSI-301 (Arm A) | Mean Number of Intravitreal Injections | 5.8 injections | Standard Deviation 1.64 |
| Aflibercept (Arm B) | Mean Number of Intravitreal Injections | 9.2 injections | Standard Deviation 1.91 |
Secondary
Percentage of Patients in the KSI-301 Arm on a Q8W, Q12W, Q16W, Q20W, or Q24W Treatment Interval
Percentage of patients in the KSI-301 arm on a Q8W, Q12W, Q16W, Q20W, or Q24W treatment interval at the primary endpoint. Analyses include KSI-301 patients who completed a treatment interval from Week 56 onwards.
Time frame: Week 56
Population: Analyses include KSI-301 patients who completed a treatment interval from Week 56 onwards.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| KSI-301 (Arm A) | Percentage of Patients in the KSI-301 Arm on a Q8W, Q12W, Q16W, Q20W, or Q24W Treatment Interval | Number of participants on the KSI-301 Q12W | 23 Participants |
| KSI-301 (Arm A) | Percentage of Patients in the KSI-301 Arm on a Q8W, Q12W, Q16W, Q20W, or Q24W Treatment Interval | Number of participants on the KSI-301 Q16W | 14 Participants |
| KSI-301 (Arm A) | Percentage of Patients in the KSI-301 Arm on a Q8W, Q12W, Q16W, Q20W, or Q24W Treatment Interval | Number of participants on the KSI-301 Q20W | 10 Participants |
| KSI-301 (Arm A) | Percentage of Patients in the KSI-301 Arm on a Q8W, Q12W, Q16W, Q20W, or Q24W Treatment Interval | Number of participants on the KSI-301 Q24W | 109 Participants |
| KSI-301 (Arm A) | Percentage of Patients in the KSI-301 Arm on a Q8W, Q12W, Q16W, Q20W, or Q24W Treatment Interval | Number of participants on the KSI-301 Q8W | 54 Participants |
Secondary
Percentage of Patients With a ≥ 2-step Worsening on the ETDRS DRSS in Studies KS301P104 and KS301P105 Combined
Percentage of patients with a ≥ 2-step worsening on the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) from baseline at Week 52 using last observation carried forward (LOCF) in Studies KS301P104 and KS301P105 combined. The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached).
Time frame: Day 1 to Week 52
Population: All randomized subjects in Studies KS301P104 and KS301P105 who received any study treatment (KSI-301 or aflibercept) with evaluable results at baseline and evaluable results on or prior to Week 52. The population for studies KS301P104 and KS301P105 are identical in terms of treatment indication and inclusion/exclusion criteria. Please refer to NCT04611152 to review demographics, other study details and adverse events for participants in KS301P104 study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KSI-301 (Arm A) | Percentage of Patients With a ≥ 2-step Worsening on the ETDRS DRSS in Studies KS301P104 and KS301P105 Combined | 6 Participants |
| Aflibercept (Arm B) | Percentage of Patients With a ≥ 2-step Worsening on the ETDRS DRSS in Studies KS301P104 and KS301P105 Combined | 3 Participants |
p-value: <0.000195.04% CI: [-0.7, 2]Cochran-Mantel-Haenszel
Secondary
Percentage of Patients With a ≥ 2-step Worsening on the ETDRS DRSS in Study KS301P105
Percentage of patients with a ≥ 2-step worsening on the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) from baseline at Week 52 using last observation carried forward (LOCF) in Study KS301P105. The Diabetic Retinopathy Disease Severity Scale (DRSS) may be used to describe overall retinopathy severity as well as the change in severity over time. Severity range from level 10 (DR absent) to level 85 (advanced proliferative DR: posterior fundus obscured, or center of macula detached).
Time frame: Day 1 to Week 52
Population: All randomized subjects who received any study treatment (KSI-301 or aflibercept) with evaluable results at baseline and evaluable results on or prior to Week 52.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| KSI-301 (Arm A) | Percentage of Patients With a ≥ 2-step Worsening on the ETDRS DRSS in Study KS301P105 | 6 Participants |
| Aflibercept (Arm B) | Percentage of Patients With a ≥ 2-step Worsening on the ETDRS DRSS in Study KS301P105 | 3 Participants |
p-value: <0.000195.04% CI: [-1.4, 3.9]Cochran-Mantel-Haenszel