A Study of the Safety and Tolerability of Intravitreal LKA651 in Patients With Diabetic Macular Edema

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the initial safety of intravitreal (IVT) LKA651 and potential for use alone or in combination with Ranibizumab ophthalmic solution (Lucentis®) for the treatment of Diabetic Macular Edema (DME) in patients with symptomatic disease.

Detailed Description
-----------------
This first-in-human study will be conducted in 2 parts. Part 1 is an ascending dose design to assess the safety, tolerability, pharmacodynamics and pharmacokinetics of various single IVT doses of LKA651 in up to 48 subjects with diabetic macular edema. Subjects will be randomized to receive active or sham injections in a 3:1 ratio. A total of 6 cohorts (8 subjects per cohort) may be enrolled in Part 1. Each subject will participate in a screening/eligibility period (up to 60 days), a treatment period (single day), and an 84 day follow up period. A total of up to 11 visits will take place, all on an out-patient basis. An independent data monitoring committee (DMC) will be chartered to review cumulative safety data and approve each dose escalation and cohort progression in this first-in-human trial. Part 2 is a double-masked design to assess the safety/tolerability, pharmacokinetics and pharmacodynamics of a single IVT dose of LKA651 when co-administered with Lucentis®. A total of up to 3 cohorts (8 subjects per cohort) may be enrolled in Part 2. Each subject will participate in a screening/eligibility period (up to 60 days), a treatment period (combination therapy, single day), and an 84 day follow up period. A total of up to 11 visits will take place, all on an out-patient basis. For the LKA651 vs sham injections, the unmasked ophthalmologist is not permitted to do any of the assessments except for the injection (and an inspection of the injection site immediately following). All other ocular assessments after randomization will be conducted by a second ophthalmologist masked to the type of injection (active or sham). The Lucentis injection (Part 2) is given open label to all patients following either the LKA651 or sham injection.

Official Title
-----------------
A Randomized, Sham Controlled, Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamic Activity of Intravitreal LKA651 in Patients With Diabetic Macular Edema

Conditions
-----------------
Diabetic Macular Edema

Intervention / Treatment
-----------------
* Biological: LKA651 ophthalmic solution
* Biological: Ranibizumab ophthalmic solution
* Biological: Sham injection


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent must be obtained. Type 1 or type 2 diabetes that is actively managed by a physician and hemoglobin A1C ≤ 12% at screening/eligibility. Negative pregnancy test results at screening/eligibility and pre-injection on treatment day. Diabetic macular edema (DME) with center involvement in at least one eye, including those with focal or diffuse DME. ETDRS letter score in the study eye of 55 letters or worse (approximate Snellen equivalent of 20/80). The non-study eye (fellow eye) should be ≥ 60 letters or better (approximate Snellen equivalent of 20/63) at Day 1 pre-dose. Safe to withhold treatment of the study eye with laser photocoagulation, intravitreal steroid injection, or intravitreal vascular endothelial growth factor (VEGF) inhibitor (Part 1) for the duration of the study. Other protocol-defined inclusion criteria may apply. Exclusion Criteria: Proliferative diabetic retinopathy in the study eye, with the exception of tufts of neovascularization less than 1 disc area with no vitreous hemorrhage. Any progressive disease of the retina (e.g. uveitis, rod-cone dystrophy) or optic nerve (e.g. glaucoma) other than diabetic retinopathy. Any active infection involving ocular adnexa including infectious conjunctivitis, keratitis, scleritis, endophthalmitis, as well as idiopathic or autoimmune-associated uveitis in either eye. Ocular disorders in the study eye that may confound interpretation of study results, including retinal vascular occlusion, retinal detachment, macular hole, or choroidal neovascularization of any cause (e.g., AMD, ocular histoplasmosis, or pathologic myopia). Cataract surgery in the study eye, Yttrium-Aluminum-Garnet (YAG) laser capsulotomy or any intraocular surgery within the past 6 months preceding Day 1. Use of systemic anticoagulant therapy during the study, e.g., warfarin, heparin, etc. The use of aspirin is not an exclusion. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, whichever is longer; or longer if required by local regulations. Pregnant or nursing (lactating) women. Women of child-bearing potential, unless using highly effective methods of contraception during dosing of study treatment. Other protocol-defined exclusion criteria may apply.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LKA651 (Part 1)<br>LKA651 ophthalmic solution in 1 of 5 concentrations, administered as a single IVT injection in the study eye | Biological: LKA651 ophthalmic solution<br> <br> |
| Placebo Comparator: Sham injection (Part 1)<br>Sham injection in the study eye | Biological: Sham injection<br>* Mock injection administered as an empty hub without needle<br>|
| Experimental: LKA651 and Lucentis (Part 2)<br>LKA651 ophthalmic solution in 1 of 3 concentrations, administered as a single IVT injection in the study eye, followed by ranibizumab ophthalmic solution, 0.5 mg injection in the same eye 30 minutes later | Biological: LKA651 ophthalmic solution<br> <br> Biological: Ranibizumab ophthalmic solution<br> <br> * Other names: Lucentis®;|
| Placebo Comparator: Sham injection and Lucentis (Part 2)<br>Sham injection in the study eye, followed by ranibizumab ophthalmic solution, 0.5 mg injection in the same eye 30 minutes later | Biological: Ranibizumab ophthalmic solution<br> <br> * Other names: Lucentis®;Biological: Sham injection<br>* Mock injection administered as an empty hub without needle<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with a serious adverse event (SAE) that, in the opinion of the investigator, is related to the study drug |  | Up to Day 85 | 
| Number of subjects experiencing a non-serious adverse event |  | Up to Day 85 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration [mass x time / volume] (AUC(0-tlast)) | Contingent upon observed serum concentration levels | Up to Day 85 | 
| The area under the serum concentration-time curve from time zero to time 't' where t is a defined time point after administration [mass x time / volume] (AUC (0-t)) | Contingent upon observed serum concentration levels | Up to Day 85 | 
| The observed maximum serum concentration following drug administration [mass / volume] (Cmax) | Contingent upon observed serum concentration levels | Up to Day 85 | 
| The time to reach the maximum serum concentration after drug administration [time] (Tmax) | Contingent upon observed serum concentration levels | Up to Day 85 | 
| The dose normalized observed maximum serum concentration following drug administration [mass*dose / volume] (Cmax/D) | Contingent upon observed serum concentration levels | Up to Day 85 | 
| The dose-normalized area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration [mass*dose x time / volume] (AUC/D) |  | Up to Day 85 | 
| Central subfield thickness | Contingent upon observed serum concentration levels | Up to Day 85 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
OCT, Diabetic Macular Edema, Intravitreal, Retina, Ophthalmology, Lucentis