A clinical trial to evaluate the safety and the efficacy of NEXAGON ® (Lufepirsen Ophthalmic Gel) in subjects with Persistent Corneal Epithelial Defects (NEXPEDE-1)

INTERVENTION: Product Name: NEXAGON vehicle: sterile formulated, thermoreversible gel without the API (lufepirsen). It contains poloxamer 407, sodium phosphate dibasic heptahydrate, potassium dihydrogen phosphate, and sterile water for injection,Product Code: N/A,Pharmaceutical Form: N/A,Other descriptive name: N/A,Strength: N/A,Pharmaceutical form of the placebo: N/A,Product Name: NEXAGON,Product Code: PRD10857743,Pharmaceutical Form: OPHTHALMIC GEL,Other descriptive name: ,Strength: Lufepirsen 0.6mg,Current Sponsor code: N/A,Product Name: NEXAGON,Product Code: PRD11008705,Pharmaceutical Form: OPHTHALMIC GEL,Other descriptive name: ,Strength: Lufepirsen 0.06mg CONDITION: MedDRA version: 21.1Level: PTClassification code: 10075399Term: Persistent corneal epithelial defectSystem Organ Class: 100000004863 Persistent Corneal Epithelial Defects ; MedDRA version: 21.1Level: PTClassification code: 10075399Term: Persistent corneal epithelial defectSystem Organ Class: 100000004863 Therapeutic area: Diseases [C] ‐ Eye Diseases [C11] INCLUSION CRITERIA: male or female •Who are at least 2 years of age (US only) • Who are at least 18 years of age (all other countries),the presence of a corneal epithelial defect that is at least 2 weeks in duration and refractory to one or more conventional non‐surgical standard of care (SOC) treatments, as assessed by the Investigator,must have no clinical evidence of improvement in corneal epithelial defect within 2 weeks prior to randomization despite the use of non‐surgical SOC treatment, as assessed by the Investigator,an epithelial defect measuring at least 2 mm along the largest diameter at Day 1 of the Treatment Period,subjects or their legally authorized representative(s) must have the ability to provide written informed consent, and must do so, prior to participation in any study‐related procedures,female subjects with childbearing potential must be 1‐year postmenopausal, surgically sterilized, or have a negative urine pregnancy test at Visit 1 and 2; women of childbearing p PRIMARY OUTCOME: Main Objective:To evaluate the safety and efficacy of NEXAGON compared to the NEXAGON vehicle (vehicle) in corneal re‐epithelialization that is maintained for a minimum of 28 days in those subjects with persistent corneal epithelial defects as assessed by a central reading center (CRC) through the standardized assessment of digital images of fluorescein staining of the cornea/PCED Primary end point(s):The proportion of subjects achieving corneal re‐epithelialization that is maintained for a minimum of 28 days, based on assessment of corneal fluorescein staining images of the PCED by a CRC. [EOS] Secondary Objective:Safety: • Treatment‐emergent adverse events (TEAEs) • Vital signs (blood pressure, pulse) • Clinical laboratory tests o Hematology, serum chemistry, and urinalysis o Hemoglobin A1c (HbA1c) (diabetic status) • Patient‐reported outcome measures (ocular pain) • Visual acuity • Slit lamp biomicroscopy • National Eye Instituto (NEI) grading scale for corneal fluorescein staining • Dilated fundus ophthalmoscopy,Efficacy: • Corneal re‐epithelialization that is maintained for a minimum of 28 days in subjects, as assessed by the Investigator through the standardized evaluation of fluorescein staining of the PCED by slit lamp biomicroscopy. • Comparison of the number of dose administrations subjects received to achieve corneal re‐epithelialization that is maintained for a minimum of 28 days, as assessed by a CRC through the standardized evaluation of digital images of the PCED stained with fluorescein. • Comparison of the number of dose administrations subjects received to achieve corneal re‐epithelialization that is maintained for a minimum of 28 days, as assessed by the Investigator through the standardized assessment of fluorescein staining of the PCED by slit lamp biomicroscopy. • Time (in days) to achieve corneal re‐epithelialization as assessed by a CRC through the standardized evaluation of digital images of the PCED stained with fluorescein. • Time (in days) to achieve corneal re‐epithelialization as measured by the Investigator utilizing the standardized assessment of fluorescein staining of the PCED by slit lamp biomicroscopy. • Occurrence and severity of ocular pain as assessed by administration of the Ocular Pain Assessment Survey (OPAS). • Assessment of subjective visual health status indices by the administration of the NEI Visual Function Questionnaire (NEI VFQ‐25). • Change in best‐corrected distance visual acuity (BCDVA) using the Early Treatment of Diabetic Retinopathy Study (ETDRS). • Determination of the optimal effective dose concentration of NEXAGON,Exploratory: • Change(s) in corneal sensitivity. • Changes in aqueous matrix metalloproteinase 9 (MMP‐9) levels in subjects corneal tear fluid. SECONDARY OUTCOME: Secondary end point(s):Efficacy • The mean change from baseline (CFB) in ocular pain based on OPAS. [EOS] • The mean status CFB in NEI VFQ‐25. [EOS] • The mean CFB in BCDVA (ETDRS). [EOS] • The proportion of subjects who achieve a 15 letter (ETDRS) gain in BCDVA. [EOS] • The proportion of subjects requiring open‐label treatment during the Treatment Period. [EOT] Secondary end point(s):Efficacy • The proportion of subjects in the Open‐Label Treatment Period that achieve re‐epithelialization of the corneal epithelial defect that remains durable for a minimum of 28 days based on the CRC assessment on images. [Open‐Label EOS] Secondary end point(s):Efficacy: • The number of dose administrations subjects required to achieve corneal re‐epithelialization that is maintained for a minimum of 28 days after completing treatment, based on assessment of corneal fluorescein staining images of the PCED by Investigator. [EOS] Secondary end point(s):Efficacy: • The proportion of subjects achieving corneal re‐epithelialization based on assessment of corneal fluorescein staining images of the PCED by Investigator. [EOT] • The number of dose administrations subjects required to achieve corneal re‐epithelialization that is maintained for a minimum of 28 days after completing treatment, based on assessment of corneal fluorescein staining images of the PCED by a CRC. [EOS] Secondary end point(s):Efficacy: • The proportion of subjects achieving corneal re‐epithelialization that is maintained for a minimum of 28 days, based on assessment of corneal fluorescein staining of the PCED by the Investigator. [EOS] • The proportion of subjects achieving corneal re‐epithelialization, based on assessment of corneal fluorescein staining images of the PCED by a CRC. [EOT] Secondary end point(s):Efficacy: • The time (in days) to corneal re‐epithelialization, defined as the time from randomization to the time of corneal re‐epithelialization based on assessment of corneal fluorescein staining images of the PCED by a CRC. [All visits]. • The time (in days) to corneal re‐epithelialization, defined as the time from randomization to the time of corneal re‐epithelialization based on assessment of corneal fluorescein staining images of the PCED by Investigator. [All visits]. Secondary end point(s):Exploratory: • The mean percentage CFB in corneal neuronal sensitivity. [EOS] • The evaluation of the CFB in MMP‐9 levels in subjects tear fluid. [EOS] • The portion of subjects who experience loss of epithelium due to the removal of the bandage contact lens (BCL). [All visits] Secondary end point(s):Safety: • TEAEs [All visits] • Vital signs (blood pressure, pulse) [EOT, ET] • Clinical laboratory testing (hematology, serum chemistry, and urinalysis) [EOT, ET] • Ocular pain assessment (FACES) [All visits] • Visual acuity (ETDRS BCDVA) [All visits] • Slit lamp examination [All visits] • NEI grading scale for corneal fluorescein staining [All visits] • Dilated fundus ophthalmoscopy [EOS, ET]