Phase I Study to Assess the Safety and Efficacy of OCU200 for Center-Involved Diabetic Macular Edema (DME)

Study Overview
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Brief Summary
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A Phase 1 study to assess the safety and efficacy of OCU200 for center-involved diabetic macular edema

Detailed Description
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This is a multicenter, open-label, dose ranging study with 3 cohorts in the dose-escalation portion of the study and 1 cohort in the combination therapy portion of the study. An accelerated 3+3 design with parallel and sequential dosing will be used. A total of 9 to 22 participants will be enrolled in the dose-escalation portion of the study to receive OCU200 alone (9 to 18 participants enrolled according to the 3+3 design and up to 4 participants replaced due to parallel cohort initiation). For the combination therapy cohort, a total of 3 to 6 participants will be enrolled to receive OCU200 (MTD) + Lucentis. A total of up to 28 participants will be included in this study. The following algorithm will be followed for dose-escalation: Cohort 1 Low Dose (0.5 mg/mL): 3+3 participants will receive intravitreal injection of OCU200 low dose concentration. 1 of 3 results will occur from the first 3 Cohort 3 participants (first dose): If none of the first 3 participants on high dose concentration are determined by the DSMB to have a DLT, then the high dose concentration will be the determined MTD. If 2 or more of the first 3 participants on the high dose concentration are determined by the DSMB to have a DLT, then the medium dose concentration (1 mg/mL) will be the determined MTD. Any dosing on Cohort 4 will be paused and continuation will be re-assessed. If exactly 1 of the first 3 participants on high dose concentration is determined by the DSMB to have a DLT, then 3 additional participants will be enrolled on high dose concentration. Any dosing on Cohort 4 will be paused and continuation will be reassessed. If none of the 3 additional participants are determined by the DSMB to have a DLT, then the high dose concentration will be the determined MTD. If 1 or more of the 3 additional participants are determined by the DSMB to have a DLT, then the medium dose concentration will be the determined MTD. Upon positive DSMB recommendation following dose 1, participants will subsequently receive a 2nd dose (6 weeks later) according to their assigned cohort. The DSMB will review 2 weeks of safety data post 2nd dosing. If a DLT occurs after the 2nd dose of any subject, the dosing interval or dose concentration will be re-assessed. The following algorithm will be followed for combination therapy cohort: Cohort 4 MTD + Lucentis: 3 + 3 additional participants will be enrolled to receive OCU200 (High Dose or MTD) + Lucentis (in a sequential manner on dosing dates). The sentinel participant in Cohort 4 will only be dosed after DSMB review of safety data for the sentinel subject in Cohort 3 or the determination of OCU200 MTD. If the sentinel participant does not have a DLT as determined by DSMB, two additional participants will be dosed. The DSMB will continue to review all available safety data two weeks post dosing of participants. Cohort 2 Medium Dose (1 mg/mL): 3+3 participants will receive intravitreal injection of OCU200 medium dose concentration. Following the same algorithm as Cohort 1. Cohort 3 High Dose (2 mg/mL): 3+3 participants will receive intravitreal injection of OCU200 high dose concentration. Following the same algorithm as Cohort 2.

Official Title
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A Phase 1 Study To Assess The Safety And Efficacy Of OCU200 For Center-Involved Diabetic Macular Edema

Conditions
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Center Involved Diabetic Macular Edema, Diabetic Macular Edema

Intervention / Treatment
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* Drug: OCU200 Low Dose
* Drug: OCU200 Medium Dose
* Drug: OCU200 High Dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Diagnosis of Type 1 or Type 2 Diabetes Mellitus 2. Decreased visual acuity attributable primarily to DME 3. Central-involved DME with central retinal subfield thickness (CST) values, as assessed with spectral-domain optical coherence tomography (SD-OCT) of: ≥ 320 if male or ≥ 305 µm if female on Heidelberg Spectralis ≥ 305 if male or ≥ 290 if female on Zeiss Cirrus BCVA ≤ 78 and ≥ 24 letters on ETDRS chart (approximately 20/32 to 20/320 Snellen equivalents, respectively) in the study eye. Sufficient ocular media clarity, pupillary dilation and participant cooperation to permit acquisition of good quality retinal imaging No history of prior anti-VEGF injection for treatment of DME or history of at least 2 consecutive anti-VEGF intravitreal injection (less than 7 weeks apart) for the treatment of DME with documented incomplete resolution of central subfield thickening within 1 year prior to the screening visit. The last injection should be within 3 months prior to the screening visit. Exclusion Criteria: Presence of any condition that prevent clear visualization of retina (e.g., significant cataract, vitreous hemorrhage) Uncontrolled hypertension (systolic pressure above 180 mmHg or diastolic pressure above 110 mmHg) Uncontrolled glaucoma Concurrent disease in the study eye, other than central-involved DME, that could compromise BCVA, require medical or surgical intervention during the study period or could confound interpretation of the results Intravitreal or periocular steroid treatment within 3 months prior to the screening visit or fluocinolone acetonide implant (Iluvien®) within 36 months prior to screening visit or dexamethasone implant (Ozurdex®) within 6 months prior to the screening visit. Any ocular surgery within 3 months prior to the screening visit in the study eye (e.g., cataract surgery, corneal refractive surgery) Prior vitrectomy in the study eye Uncontrolled/poorly controlled diabetes, as defined by Glycated hemoglobin (HbA1c) ≥ 12% History of retinal detachment in the study eye History of any other retinal vascular disease in the study eye including conditions that affect macular perfusion (e.g., retinal artery occlusion, retinal vein occlusion, vasculitis) Focal or pan-retinal laser photocoagulation in the study eye within 3 months prior to the screening visit Presence of any inherited retinal disease (e.g., chorioretinal dystrophies, rod/cone dystrophies)Any proliferative diabetic retinopathy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 3+3 design with parallel and sequential dosing.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (Low Dose)<br>3+3 participants will receive intravitreal injection of OCU200 low dose concentration. | Drug: OCU200 Low Dose<br>* Intravitreal Injection<br>* Other names: OCU200 study low dose up to 0.5 mg/mL.;|
| Experimental: Cohort 2 (Medium Dose)<br>3+3 participants will receive intravitreal injection of OCU200 medium dose concentration. | Drug: OCU200 Medium Dose<br>* Intravitreal Injection<br>* Other names: OCU200 study medium dose up to 1 mg/mL.;|
| Experimental: Cohort 3 (High Dose)<br>3+3 participants will receive intravitreal injection of OCU200 high dose concentration. | Drug: OCU200 High Dose<br>* Intravitreal Injection<br>* Other names: OCU200 study high dose up to 2 mg/mL.;|
| Experimental: Cohort 4 (High Dose/MTD + Lucentis)<br>3 + 3 additional participants will be enrolled to receive OCU200 (High Dose or MTD) + Lucentis (in a sequential manner on dosing dates). | Drug: OCU200 High Dose<br>* Intravitreal Injection<br>* Other names: OCU200 study high dose up to 2 mg/mL.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Study Drug-related adverse events (SDAE) | Counts, frequencies and percentages of SDAEs. | 20 weeks | 
| treatment-emergent adverse events (TEAEs) | Counts, frequencies and percentages TEAEs. TEAEs are defined as an event that was not present prior to administration of the dose of study drug and present after the dose, or if it represents the exacerbation of an event that was present prior to the dose. | 20 weeks | 
| serious adverse events (SAEs) | Counts, frequencies and percentages of SAEs including Resulted in Death, Life-threatening, Hospitalization, Disabling/incapacitating, Congenital anomaly or birth defect and Medically significant AEs ( AE that did not meet any of the above criteria but could have jeopardized the subject and might have required medical or surgical intervention to prevent one of the outcomes listed above). | 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best-corrected visual acuity (BCVA) | Measured as the ETDRS letter score on the EVA tester or E-ETDRS charts. | 20 Weeks (Changes from baseline) | 
| Intraocular pressure (IOP) | IOP measurement by applanation or rebound tonometry. Confirmation with Goldmann tonometer if IOP reading is outside the normal range (8-21mmHg). | 20 weeks(Changes from baseline) | 
| Slit-lamp biomicroscopy | Changes in visual function. | 20 Weeks(Changes from baseline) | 
| Indirect ophthalmoscopy | If visual acuity is so poor that the participant is unable to count fingers or perceive hand motion, light perception will be tested with the indirect ophthalmoscope as the light source. | 20 Weeks (Changes from baseline) | 
| Color fundus photography | Color fundus photographs will be taken to evaluate retinal anatomy and grade diabetic retinopathy severity scale (DRSS). | 20 Weeks(Changes from baseline) | 
| Spectral Domain Optical Coherence Tomography (SD-OCT) | SD-OCT will be utilized to assess retinal thickness. OCT images and scans will be transmitted to a central reading center for independent analysis. | 20 Weeks(Changes from baseline) | 
| Spectral Domain Optical Coherence Tomography Angiography (SD-OCTA) | SD-OCTA will be utilized to assess retinal vasculature and images will be transmitted to a central reader for independent analysis. | 20 weeks (Changes from baseline) | 
| Wide-field Fluorescein Angiography (wf-FA) | wf-FA will be conducted at screening and EOS visits to assess central and peripheral vasculature. | 20 weeks (Changes from baseline) | 
| Anti-OCU200 antibody formation | Blood samples will be collected for the assessment. | 20 weeks | 
| OCU200 Pharmacokinetics parameters | Blood samples will be collected for the assessment. | 20 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anti-VEGF, Transferrin, Tumstatin, DME