A Study Investigating the Safety, Tolerability, and Efficacy of Elamipretide Topical Ophthalmic Solution for the Treatment of Fuchs' Corneal Endothelial Dystrophy (FCED)

Study Overview
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Brief Summary
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This is a Phase 1/2 prospective, randomized, double-masked, and vehicle-controlled trial in two parts to evaluate the safety, tolerability, and efficacy of elamipretide topical ophthalmic solution in patients with Fuchs' Corneal Endothelial Dystrophy (FCED) presenting with mild to moderate corneal edema.

Detailed Description
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This is a Phase 1/2 trial in two parts. Part A is a prospective, randomized, double-masked, vehicle controlled, paired-eye study in approximately 16 subjects to evaluate safety, tolerability and efficacy of elamipretide 1.0% topical ophthalmic solution in patients with Fuchs' Corneal Endothelial Dystrophy (FCED) presenting with mild to moderate corneal edema. Part B is a prospective, randomized double-masked, vehicle controlled study in approximately 11 subjects to evaluate safety, tolerability, and efficacy of elamipretide 3.0% topical ophthalmic solution in patients with FCED presenting with mild to moderate corneal edema.

Official Title
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Part A: a Prospective, Randomized, Double-masked, Vehicle Controlled, Paired-eye Phase 1/2 Clinical Study to Evaluate the Safety, Tolerability and Efficacy of Elamipretide Topical Ophthalmic Solution in Subjects With Fuchs' Corneal Endothelial Dystrophy (FCED) Presenting With Mild to Moderate Corneal Edema Part B: a Prospective, Randomized, Double-masked, Vehicle Controlled, Phase 1/2 Clinical Study to Evaluate the Safety, Tolerability, and Efficacy of Elamipretide Topical Ophthalmic Solution in Subjects With FCED Presenting With Mild to Moderate Corneal Edema.

Conditions
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Fuchs' Corneal Endothelial Dystrophy (FCED)

Intervention / Treatment
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* Drug: Part A Elamipretide 1.0% Ophthalmic Solution
* Drug: Part B Elamipretide 3.0% Ophthalmic Solution
* Drug: Part A Placebo
* Drug: Part B Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults ≥18 years old at the time of Screening Visit Diagnosis of FCED OU (both eyes) based on clinical and ophthalmic test findings Clinical evidence of corneal edema OU diagnosed with FCED, including one or more of the following signs: corneal epithelial microcysts, corneal epithelial bullae, stromal folds, or stromal haze Central corneal thickness of 550 μm to 700 μm (inclusive) in at least one eye diagnosed with FCED, as measured by ultrasonic pachymetry at the time of Screening Visit and Baseline Visit Best-corrected distance visual acuity (BCVA) of 20/25 to 20/320 (inclusive) at the time of Screening Visit and Baseline Visit OU Women of childbearing potential must agree to use birth control as specified in the protocol from the date they sign the informed consent form (ICF) until after the last study Able to give informed consent and willing to comply with all study visits and examinations Part B only: The presence of central endothelium, as determined by the investigator, with an area of contiguous endothelial cells within 1 mm of the central cornea as measured by confocal laser scanning microscopy (CLSM) or specular microscopy at the time of Screening Visit Exclusion Criteria: Corneal findings of any type (including, but not limited to, stromal haze or stromal scarring), in either eye, that, based on investigator's assessment, limit the probability of visual improvement after corneal deturgescence Any ocular pathology requiring treatment with topical ophthalmic drops, with the exception of glaucoma or ocular hypertension Use of topical hypertonic saline drops for 3 days prior to Screening and throughout the duration of the study History of corneal disease (other than FCED) or corneal surgery in either eye Current use or likely need for the use of contact lens at any time during the study History of previous corneal or anterior segment surgery such as LASIK, photorefractive keratectomy, endothelial keratoplasty, penetrating keratoplasty cataract surgery or glaucoma surgery. Any disease or medical condition that in the opinion of the investigator would prevent the subject from participating in the study or might confound study results Participation in other investigational drug or device clinical trials within 30 days prior to enrollment, or planning to participate in any other investigational drug or device clinical trials within 30 days of study completion Women who are pregnant or lactating Part B only: Participation in Part A of SPIFD-101 Other protocol-defined inclusion/exclusion criteria may apply.

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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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: Elamipretide 1.0% Ophthalmic Solution Part A (Cohort 1)<br>Part A Each subject will receive one drop of elamipretide 1.0% ophthalmic solution BID in the randomly selected study eye (Cohort 1). | Drug: Part A Elamipretide 1.0% Ophthalmic Solution<br>* Part A Each subject will receive one drop of elamipretide 1.0% ophthalmic solution BID in the randomly selected study eye.<br>* Other names: MTP-131, Bendavia;|
| Experimental: Elamipretide 3.0% Ophthalmic Solution Part B (Cohort 2)<br>Part B Each subject will receive one drop of elamipretide 3.0% ophthalmic solution BID in both the right and left study eyes (Cohort 2). | Drug: Part B Elamipretide 3.0% Ophthalmic Solution<br>* Part B Each subject will receive one drop of elamipretide 3.0% ophthalmic solution BID in both eyes.<br>* Other names: MTP-131, Bendavia;|
| Placebo Comparator: Placebo A<br>Part A: Each subject will receive one drop of vehicle solution BID in the paired eye of the randomly selected study eye (Cohort 1). | Drug: Part A Placebo<br>* Part A Each subject will receive one drop of vehicle ophthalmic solution BID in the paired eye of the randomly selected study eye.<br>|
| Placebo Comparator: Part B Placebo<br>Part B Each subject will receive one drop of vehicle solution BID in both the right and left study eyes (Cohort 2). | Drug: Part B Placebo<br>* Part B: Each subject will receive one drop of vehicle ophthalmic solution BID in both eyes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and Severity of Ocular TEAEs. | The incidence and severity of ocular treatment emergent adverse events (TEAEs) | Screening Visit, Baseline (Day 1), Week 1, Week 4, Week 8, Week 12, and Week 16 | 
| The Incidence and Severity of Systemic Adverse Events | The incidence and severity of systemic treatment emergent adverse events (TEAEs) | Screening Visit, Baseline (Day 1), Week 1, Week 4, Week 8, Week 12, and Week 16 | 
| Change From Baseline in Findings From Slit Lamp Examinations (SLE) Part A | Number of participants who had a change from baseline from normal or abnormal not clinically significant, to abnormal clinically significant (CS) findings for slit lamp examinations (SLE) for Part A. Part B is reported as separate outcome since unit of measure is number of eyes. | Baseline, Week 1, Week 4, Week 8, Week 12, and Week 16 | 
| Change From Baseline in Findings From Slit Lamp Examinations (SLE) Part B | Number of eyes with a change from baseline from normal or abnormal not clinically significant, to abnormal clinically significant (CS) findings for slit lamp examinations (SLE) for Part B. Part A is reported as separate outcome. | Baseline, Week 1, Week 4, Week 8, Week 12, and Week 16 | 
| Change From Baseline in Intraocular Pressure (IOP) for Part A | Change from Baseline in intraocular pressure (IOP) using Goldmann applanation tonometry for Part A | Baseline, Week 1, Week 4, Week 8, Week 12 | 
| Change From Baseline in Intraocular Pressure (IOP) for Part B | Change from Baseline in intraocular pressure (IOP) using Goldmann applanation tonometry for Part B. Part A is reported separately. | Baseline, Week 1, Week 4, Week 8, Week 12 , and Week 16 or early discontinuation visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Central Corneal Thickness by Visit Part A as Measured by Pachymetry for Part A | Change from Baseline in Central Corneal Thickness by Visit as measured by Pachymetry for Part A. Part B is reported as a separate outcome measure. | Baseline, Week 1, Week 4, Week 8, Week 12, and Week 16 | 
| Central Corneal Thickness Part B | Central Corneal Thickness: by-subject data as measured by Pachymetry and Pentacam. Part A is reported as a separate outcome measure. | Baseline (Day 1), Week 1, Week 4, Week 8, Week 12, and Week 16, or Early discontinuation visit | 
| Change From Baseline Endothelial Cell Hexagonality in Percentage Over All 12 Weeks for Part A | Change From Baseline in Endothelial Cell Hexagonality in Percentage Over All 12 Weeks for Part A. Specular microscopy is a noninvasive photographic technique that allows visualization and analyzation the corneal endothelium. Using computer-assisted morphometry, specular microscopes analyzes the size, shape and population of the endothelial cells. Histologically, healthy corneal cells initially have a hexagonal shape. As endothelial cells die, neighboring cells enlarge to cover the empty space once occupied by the cell. This, in turn, causes the remaining cells to lose their hexagonal shape. Assessments were performed using the flex center and full auto methods for Part A and data from the flex center method was summarized. The flex center method was used for Part B. The percent of Part B is entered as a separate outcome measure. A decrease from baseline in % cell hexagonality means worse outcome, a increase from baseline means better outcome. | Baseline, Week 1, 4, 8, and 12 | 
| Corneal Endothelial Cell Hexagonality Part B | Corneal Endothelial Cell Hexagonality in Percentage by-subject data: Part B. Data was only listed in weeks where images were good enough quality to quantify. Specular microscopy is a noninvasive photographic technique that allows visualization and analyzation the corneal endothelium. Using computer-assisted morphometry, specular microscopes analyzes the size, shape and population of the endothelial cells. Histologically, healthy corneal cells initially have a hexagonal shape. As endothelial cells die, neighboring cells enlarge to cover the empty space once occupied by the cell. This, in turn, causes the remaining cells to lose their hexagonal shape. The flex center method was used for Part B. A decrease in percent of cell hexagonality from baseline means worse outcome, an increase from baseline means better outcome. | Baseline, Week 1, Week 4, Week 8, Week 12, and Week 16 or early discontinuation visit | 
| Change From Baseline in Best Corrected Visual Acuity (BCVA) Using the Early Treatment Diabetic Retinopathy Study (ETDRS) Scale for Part A. | Best corrected visual acuity (BCVA) using the using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale by visit. ETDRS charts present a series of five letters of equal difficulty on each row, with standardized spacing between letters and rows; there is a total of 14 lines (70 letters), with letter size increasing further geometrically and equivalently in every line by a factor of 1.2589 (or 0.1 log unit), moving up the chart. Minimum score of zero, maximum score of 100. Change from baseline: a more negative score is worse outcome, a more positive score is better outcome. A lower score means less letters were read correctly (worse outcome) and a higher score means more letters were read correctly (better outcome). Part B was listed separately. | Baseline, Weeks 1, 4, 8, 12, and 16 | 
| Best Corrected Visual Acuity (BCVA) Score Using ETDRS Scale for Part B | Best corrected visual acuity (BCVA) using the using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale by visit. ETDRS charts present a series of five letters of equal difficulty on each row, with standardized spacing between letters and rows; there is a total of 14 lines (70 letters), with letter size increasing further geometrically and equivalently in every line by a factor of 1.2589 (or 0.1 log unit), moving up the chart. Minimum score of zero, maximum score of 100. Change from baseline: a more negative score is worse outcome, a more positive score is better outcome. A lower score means less letters were read correctly (worse outcome) and a higher score means more letters were read correctly (better outcome). | Baseline, Weeks 1, 4, 8, 12, and 16 | 
| Change From Baseline in Endothelial Cell Density Over All 12 Weeks for Part A | Change From Baseline in Endothelial Cell Counts, or density (Counts/mm^2) over all 12 weeks for Part A. Part B is entered as a separate outcome measure. | Baseline, Weeks 1, 4, 8, and 12 | 
| Corneal Endothelial Cell Density Part B | Corneal Endothelial Cell Density: Part B, By-subject data for all time points where images were readable. For all time points where there were Poor Quality Images or too few cells to register, there were no data available, and these were not listed below. | Baseline, Weeks 1, 4, 8, 12, and 16. | 
| Change From Baseline in Endothelial Cell Coefficient of Variation Over All 12 Weeks for Part A | Change From Baseline in Endothelial Cell Coefficient of Variation Over All 12 Weeks. Coefficient of variation (CV) is Standard deviation (SD) of cell area divided by the mean cell area of endothelial cell analyzed. CV represents the coefficient, or degree, of variation in the sizes of the endothelial cells (polymegethism). By measuring the variation in size between endothelial cells, the system can measure how much cell loss is occurring. The more variation, the worse the outcome. Part B is is entered as a separate outcome measure. | Baseline, Week 12 | 
| Coefficient of Variation (CoV) Part B | Part B, By-subject data for all time points where images were readable. For all time points where there were Poor Quality Images or too few cells to register there were no data available. CoV represents the coefficient, or degree, of variation in the sizes of the endothelial cells. By measuring the variation in size between endothelial cells, the system can measure how much cell loss is occurring. A CoV less than 40 is normal. | Baseline, Weeks 1, 4, 8,12, and 16 | 
| Change From Baseline in Corneal Area Affected by Microcysts for Part A | Change from Baseline in corneal area affected by microcysts by visit for Part A. | Baseline, Weeks 1, 4, 8, 12, and 16 | 
| Corneal Area Affected by Microcysts: Part B | Corneal area affected by microcysts: by-subject data for Part B. No microcysts were present for any timepoints. | Baseline, Weeks 1, 4, 8, 12, and 16, or early discontinuation visit | 
| Change From Baseline in Corneal Bullae for Part A. | Count of participants in number, size and location of bullae by treatment. Part B is listed separately. | Baseline, Week 1, Week 4, Week 8, Week 12, Week 16 | 
| Corneal Bullae: Part B | Number, size and location of Corneal bullae: By-subject data: Part B. | Baseline, Week 1, Week 4, Week 8, Week 12, Week 16, or early discontinuation visit | 
| Change From Baseline in Severity of Corneal Stromal Folds for Part A | Change from baseline in severity of corneal stromal folds by visit. Descriptive assessment made by Investigator; severity is not assessed using a scale. | Baseline, Weeks 1, 4, 8, 12, and 16 | 
| Severity of Corneal Stromal Folds:Part B | Severity of corneal stromal folds by-subject data by visit. Descriptive assessment made by Investigator in the following categories: Not present, trace, mild. | Baseline, Week 1, 4, 8, 12, and 16, or early discontinuation visit | 
| Change From Baseline in Contrast Sensitivity (Log Score) for Part A | Change from Baseline in contrast sensitivity over all 12 weeks log score at 3, 6, 12, 18 cycles per degree (cpd) using Vector Vision's CSV-1000E. Standard tables for the VectorVision's CSV-1000E model were used to convert linear results to the log values. Lower log scores equals lower contrast sensitivity and worse outcome. Higher log scores mean higher contrast sensitivity and better outcome. For 3cpd, range is 0.7-2.08; 6 cpd: 0.91-2.29; 12 cpd: 0.61-1.99; 18cpd: 0.17-1.55, unless no gratings were visible. If no gratings were visible, .3 log was subtracted from the lowest score for 3, 6, and 12cpd. For 18cpd .01 log was used, or essentially 100% contrast. | Baseline, Week 1, 4, 8, 12 weeks | 
| Contrast Sensitivity for Part B; By-subject Data | Contrast Sensitivity log score at 3, 6, 12, 18 cycles per degree (cpd) using Vector Vision's CSV-1000E by-subject data, Part B. Part A is listed separately. Standard tables for the VectorVision's CSV-1000E model were used to convert linear results to the log values. Lower log scores equals lower contrast sensitivity and worse outcome. Higher log scores mean higher contrast sensitivity and better outcome. For 3cpd, range is 0.7-2.08; 6 cpd: 0.91-2.29; 12 cpd: 0.61-1.99; 18cpd: 0.17-1.55, unless no gratings were visible. If no gratings were visible, .3 log was subtracted from the lowest score for 3, 6, and 12cpd. For 18cpd .01 log was used, or essentially 100% contrast. | Baseline, Week 1, Week 4, Week 8, Week 12, Week 16, or early discontinuation visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fuchs' Corneal Endothelial Dystrophy, FCED, Ocuvia™, MTP-131