Multiple Dose Safety and Efficacy of LKA651 in Patients With Diabetic Macular Edema

Study Overview
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Brief Summary
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The primary objectives of this study were to evaluate the safety and efficacy of LKA651 in patients with macular edema from diabetic macular edema (DME),

Detailed Description
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This study was a 3-arm, parallel group, randomized, patient- and investigator-masked trial planned in 90 patients with Diabetic macular edema (DME). The study consisted of a screening period of 60 days, main study (12 weeks), and an extension period (12 weeks). The study was stratified such that sentinel safety cohorts were first enrolled to test the safety of the combination of LKA651 and Lucentis before proceeding with further patient randomization. After determination of safety from Day 15 data from each sentinel cohort, patients were enrolled into 1 of 3 arms: LKA651 monotherapy, LKA651 plus Lucentis, and Lucentis monotherapy. Every patient was dosed 3 times in 4 week intervals in the treatment phase and was then followed up for an extension phase of an additional 12 weeks during which Lucentis was allowed to be administered as rescue at the discretion of the Investigator. No predefined rescue criteria were outlined as guidance.

Official Title
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A Randomized, Active-controlled, Patient and Investigator-masked, Multiple Dose Proof-of-concept Study of Intravitreal LKA651 in Patients With Diabetic Macular Edema

Conditions
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Diabetic Macular Edema

Intervention / Treatment
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* Drug: LKA651
* Drug: Lucentis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Written informed consent must be obtained before any assessment is performed. Male and female patients age 18 to 85 years of age inclusive at screening Presence of type I or type II diabetes mellitus The Early Treatment Diabetic Retinopathy Study (ETDRS) letter score in the study eye must be between 24 and 70 letters (approximate Snellen equivalent of 20/40-20/320). The non-study eye (fellow eye) should be ≥34 letters or better (approximate Snellen equivalent of 20/200) at screening Presence of Diabetic macular edema (DME) in the study eye, with decrease in vision due to foveal thickening of central macular thickness ≥ 320 µm in the central subfield, as assessed on Spectral domain optical coherence tomography (SD-OCT) and confirmed by the central reading center at screening Sufficiently clear ocular media and adequate pupil dilation in the study eye to permit fundus photographs of adequate clarity to measure diameters of retinal arteries and veins at screening Exclusion criteria Patient with history of intravitreal (IVT) anti-vascular endothelial growth factor (VEGF) treatment in the study eye <90 days from baseline Patient with history of intraocular corticosteroids including dexamethasone intravitreal implants during the 6 month period prior to baseline. Any prior use of fluocinolone acetonide intravitreal implant (Iluvien) is prohibited regardless of timing Laser photocoagulation (macular or panretinal) in the study eye during the 3-month period prior to baseline. High risk proliferative diabetic retinopathy Patients, with type 1 or type 2 diabetes who have a hemoglobin A1C ≥ 12% at screening. Any progressive disease of the retina in the study eye (e.g. uveitis,rod-cone dystrophy) or optic nerve Area of macular retinal ischemia (as measured by the foveal avascular zone) ≥ 1000 μm. Active intraocular inflammation (graded as trace or above) or active intraocular infection in either eye. Current diagnosis of or laboratory evidence for anemia, defined as a hemoglobin <10 g/dL for women and <11 g/dL for men.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LKA651<br>LKA651 Intravitreal injection | Drug: LKA651<br>* LKA651 5 mg Intravitreal injection, every 4 weeks for 12 weeks in the treatment phase<br>|
| Experimental: LKA651 + Lucentis<br>LKA651 + Lucentis Intravitreal injection | Drug: LKA651<br>* LKA651 5 mg Intravitreal injection, every 4 weeks for 12 weeks in the treatment phase<br>Drug: Lucentis<br>* Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for 12 weeks in the treatment phase<br>|
| Active Comparator: Lucentis<br>Lucentis Intravitreal injection | Drug: Lucentis<br>* Lucentis 0.3 mg (U.S. sites) or 0.5 mg (ex U.S. sites) Intravitreal injection, every 4 weeks for 12 weeks in the treatment phase<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation patient. The severity of the AEs (mild, moderate, severe) was based on the Common Terminology Criteria for Adverse Events (CTCAE). Number of participants in each category is reported in the table. A participant who falls multiple times in one category is counted only once. | Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days). | 
| Number of Participants With Ocular Adverse Events by Preferred Term in Study Eye | An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation patient. | Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days). | 
| Number of Participants With Non-ocular Adverse Events (>=2%) | An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation patient. | Adverse events are reported from first dose of study treatment until end of study treatment plus 12 weeks post treatment, up to a maximum timeframe of approximately 24 weeks (approximately 168 days). | 
| Intraocular Pressure (IOP) in Study Eye | Intraocular pressure was measured per the study site's regular practice. | Screening, and Day 85 | 
| Best Corrected Visual Acuity (BCVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity Charts in Study Eye | BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual function of the study eye was assessed using the ETDRS protocol. BCVA in study eye was analyzed with a mixed model for repeated measures. The model included treatment, visit, and the treatment by visit interaction as independent variables. An unstructured residual covariance structure was used. Baseline BCVA value and treatment naïve and treatment experienced variable were used as covariates. Min and max possible scores are 0-100 respectively. A higher score represents better visual functioning. | Days 2, 8, 15, 29, 43, 57, and 85 | 
| Inner Macular Thickness (Inferior) | Macular thickness was measured by spectral domain optical coherence tomography (SD-OCT). | Week 12 (Day 85) | 
| Inner Macular Thickness (Temporal) | Macular thickness was measured by spectral domain optical coherence tomography (SD-OCT). | Week 12 (Day 85) | 
| Outer Macular Thickness (Inferior) | Macular thickness was measured by spectral domain optical coherence tomography (SD-OCT). | Week 12 (Day 85) | 
| Outer Macular Thickness (Temporal) | Macular thickness was measured by spectral domain optical coherence tomography (SD-OCT). | Week 12 (Day 85) | 
| Number of Participants Without Changes in Foveal Avascular Zone as Measured by Fluorescein Angiography (FA) in Study Eye | Foveal avascular zone was assessed by fluorescein angiography (FA). | Days 29, 57, 85, End of Study (Up to Day 140) | 
| Mixed Model Repeated Measures Analysis of Ratio to Baseline in Central Subfield Retinal Thickness (CSFT) in the Study Eye | Central subfield thickness was measured by spectral domain optical coherence tomography (SD-OCT). Central subfield retinal thickness was analyzed with a mixed model for repeated measures. The model included treatment, visit, and the treatment by visit interaction as independent variables. An unstructured residual covariance structure was used. Log-transformed baseline central subfield retinal thickness and treatment naïve and treatment experienced variable were used as covariates. Results were back-transformed to show results as a ratio to baseline. | Days 8, 15, 29, 43, 57, 85 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Needed Retreatment With Anti-VEGF in Study Eye After Week 12 |  | Week 12 (Day 85) up to Day 140 | 
| Time to Retreatment in Study Eye With Anti-VEGF After Week 12 | Time to retreatment with anti VEGF (as determined by the investigator) after Week 12 during the additional 12 week extension phase (that was up to 16 weeks after the last dose) was examined with a Kaplan Meier plot. | Week 12 (Day 85) up to Day 140 | 
| Summary Statistics of Pharmacokinetics - Serum Concentrations of LKA651 | PK parameters were determined using non-compartmental methods using the most recent version of WinNonlin Phoenix (Version 8.2). Concentrations below the lower limit of quantification (LLOQ) were treated as 1/2 LLOQ in summary statistics. | Day 1 (0, 0.5 and 4 hrs post dose), Day 2, Day 8, Day 15, Day 29 (0, 0.5 and 4 hrs post dose), Day 43, Day 57 (0, 0.5 and 4 hrs post dose), Day 85 | 
| Summary Statistics of Pharmacokinetics - AUC0-28d of LKA651 (Serum) | Area under the curve over the dosing interval 0 to 28 days. | Day 1 - 4 hrs post dose, Day 2, Day 8, Day 15, Day 29 - 4 hrs post dose, Day 43, Day 57 - 4 hrs post dose, Day 85 | 
| Summary Statistics of Pharmacokinetics - Serum Concentrations of Lucentis |  | Day 1 - 4 hrs post dose, Day 2, Day 8, Day 15, Day 29 - 4 hrs post dose, Day 43, Day 57 - 4 hrs post dose, Day 85 | 
| Summary Statistics of Pharmacokinetics - AUC0-28d of Lucentis (Serum) | Area under the curve over the dosing interval 0 to 28 days. | Day 1 - 4 hrs post dose, Day 2, Day 8, Day 15, Day 29 - 4 hrs post dose, Day 43, Day 57 - 4 hrs post dose, Day 85 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LKA651, Macular degeneration, age-related macular degeneration (ARMD), vision loss, macula damage, retina damage, dry macular degeneration, wet macular degeneration, AMD, diabetic macular edema, DME, neovascular age-related macular degeneration, nAMD, retinal vein occlusion, RVO, Diabetic Macular edema (DME), macular edema, diabetic retinopathy, Lucentis