E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Diabetic Macular Edema (DME) |
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E.1.1.1 | Medical condition in easily understood language |
Diabetic Macular Edema (DME) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Eye Diseases [C11] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10015919 |
E.1.2 | Term | Eye disorders |
E.1.2 | System Organ Class | 10015919 - Eye disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054467 |
E.1.2 | Term | Macular edema |
E.1.2 | System Organ Class | 10015919 - Eye disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10057934 |
E.1.2 | Term | Diabetic macular edema |
E.1.2 | System Organ Class | 10015919 - Eye disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10071129 |
E.1.2 | Term | Neovascular age-related macular degeneration |
E.1.2 | System Organ Class | 10015919 - Eye disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate that KSI-301 5 mg is non-inferior to aflibercept 2 mg with respect to mean change in best corrected visual acuity (BCVA) from Day 1 to Year 1 (average of Weeks 60 and 64). |
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of KSI-301 5 mg compared to aflibercept 2 mg over the study duration by assessing visual parameters.
To evaluate the efficacy of KSI-301 5 mg compared to aflibercept 2 mg over the study duration by assessing anatomical parameters.
To evaluate the durability of KSI-301 5 mg compared to aflibercept 2 mg over the study duration.
To evaluate the safety and tolerability of KSI-301 5 mg compared to aflibercept 2 mg.
To assess the systemic pharmacokinetics (exposure) and immunogenicity of KSI-301. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Treatment-naïve diabetic macular edema, with vision loss and center involvement (if present) diagnosed within 9 months of screening. 2.BCVA ETDRS letter score ≤78 and ≥ 25 (⁓20/25 to 20/320 Snellen equivalent) in the Study Eye at Screening and confirmed at Day 1. 3.CST of ≥ 320 microns on SD-OCT (Heidelberg Spectralis or equivalent on other OCT instruments) as determined by the Reading Center at the screening visit. 4.Decrease in vision in the Study Eye determined by the Investigator to be primarily the result of DME. In cases where both eyes are eligible, the eye with the worse BCVA at the Screening Visit will be selected as the Study Eye. If both eyes are eligible and have the same BCVA, the decision of which eye to select as the Study Eye will be made by the Investigator. Only one eye per participant can be included in the study. 5.Capable of giving signed informed consent 6.Male or female ≥ 18 years of age with Type 1 or Type 2 diabetes mellitus and a HbA1c of ≤12%. 7.For women of childbearing potential: agreement to remain as abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 90 days after the last dose of study intervention 8.For men: agreement to remain abstinent or use contraceptive measures and agreement to refrain from donating sperm 9.Ability and willingness to undertake all the scheduled visits and assessments |
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E.4 | Principal exclusion criteria |
1.Macular edema in the Study Eye considered to be secondary to a cause other than DME (e.g., RVO, Irvine-Gass syndrome). 2.Active iris or angle neovascularization or neovascular glaucoma in the Study Eye. 3.High-risk proliferative diabetic retinopathy characteristics in the Study Eye, using any of the following clinical criteria: a.Any vitreous or pre-retinal hemorrhage. b.Neovascularization at optic disc ≥1/3 of the disc area. c.Neovascularization elsewhere ≥1/2 of the disc area. 4.Structural damage to the center of the macula in the Study Eye that is likely to preclude improvement in BCVA following the resolution of macular edema including atrophy of the retinal pigment epithelium, subretinal fibrosis or scar, significant macular ischemia or organized hard exudates in the foveal center. 5.History of cataract surgery and/or minimally invasive glaucoma surgery (MIGS) in the Study Eye within 2 months of screening. 6.History of Yttrium-Aluminum Garnet (YAG) laser capsulotomy in the Study Eye within 2 months of screening. 7.History of Pan-retinal Photocoagulation (PRP) laser in the Study Eye within 3 months of screening. 8.Tractional retinal detachment in the Study Eye. 9.Uncontrolled glaucoma (defined as intraocular pressure ≥ 25 mmHg despite treatment with antiglaucoma medication) in the Study Eye. 10.History of glaucoma-filtering surgery (trabeculectomy or tube shunt) in the Study Eye. 11.History of retinal detachment or treatment or surgery for retinal detachment in the Study Eye. 12.History of uveitis in either eye. 13.Significant media opacities, including cataract, in the Study Eye that might interfere with visual acuity, assessment of safety, OCT or fundus photography. 14.Cataract in the Study Eye that in the judgment of the Investigator is expected to require surgical extraction within 12 months of screening. 15.Aphakia in the Study Eye. 16.Prior vitrectomy in the Study Eye. 17.Active retinal disease other than the condition under investigation in the Study Eye. 18.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). 19.Active or suspected ocular or periocular infection or inflammation in either eye at Day 1. 20.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). 21.Women who are pregnant or lactating or intending to become pregnant during the study. 22.Women of childbearing potential must have a negative urine pregnancy test result within 28 days prior to Day 1. If the urine pregnancy test is positive, it must be confirmed with a serum pregnancy test. 23.Uncontrolled blood pressure defined as a systolic value ≥ 180 mmHg or diastolic value ≥100 mmHg while at rest at Screening or on Day 1. If a participant’s initial blood pressure measurement exceeds these values, a second reading may be taken later the same day or a different day during the screening period. If the participant’s blood pressure is controlled by antihypertensive medications, the participant should be on a stable medication regimen continuously for 30 days prior to Day 1. 24.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. 25.Kidney failure requiring renal transplant, hemodialysis or peritoneal dialysis or expected to require renal transplant, hemodialysis or peritoneal dialysis during the study. 26.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. 27.History of hypersensitivity to any component of KSI-301, aflibercept, ophthalmic dye (fluorescein), dilating drops, or any of the anesthetic or antimicrobial preparations used during the study, as assessed by the Investigator. 28.Participation in an investigational study within 30 days prior to the screening visit that involved treatment with any drug (excluding vitamins and minerals) or devices.
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E.5 End points |
E.5.1 | Primary end point(s) |
Mean change in BCVA from baseline (Day 1) to the average of Weeks 60 and 64 (Year 1) in Early Treatment Diabetic Retinopathy Study (ETDRS) Letters. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint will be assessed at Week 64 |
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E.5.2 | Secondary end point(s) |
-Mean change in BCVA (ETDRS Letters) from baseline (Day 1) by visit over time. -Proportion of participants who gain ≥ 5, ≥10 and ≥15 letters from baseline by visit over time -Proportion of participants who lose ≥ 5, ≥10 and ≥15 letters from baseline by visit over time -Mean change in optical coherence tomography (OCT) central subfield thickness (CST) and other morphological parameters from baseline to the average of Weeks 60 and 64 (Year 1) and over time. -Proportion of patients with a ≥ 2-step improvement from baseline on the ETDRS DRSS at Week 52. -Mean number of intravitreal injections over the duration of the study. -Mean number of intravitreal injections from baseline to Week 60 and from Week 64 to 104 -Mean time to first re-treatment after the last monthly dose -Incidence of ocular and systemic adverse events up to Week 64 and Week 108 -Systemic pharmacokinetic profile over time. -Systemic anti-drug antibody status over time.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary endpoints for efficacy will be assessed at Weeks 64 and 104 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 34 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
United States |
Latvia |
Spain |
Germany |
Italy |
Hungary |
Slovakia |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study is defined as the last follow-up visit of the last participant enrolled (i.e., the last enrolled participant’s final visit) or a Sponsor decision to terminate the study, whichever comes first. A participant is considered to have completed the study if he/she has completed all phases of the study, including the Week 108 safety follow-up assessment.
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |