A Study Investigating the Safety, Tolerability, and Efficacy of Elamipretide Topical Ophthalmic Solution for Treatment of Leber's Hereditary Optic Neuropathy

Phase 2

Completed

Conditions: Leber's Hereditary Optic Neuropathy

Interventions: Drug: elamipretide (MTP-131) 1% topical ophthalmic solution
Drug: Vehicle topical ophthalmic solution

Registration Number: NCT02693119

Lead Sponsor: Stealth BioTherapeutics Inc.

Brief Summary: This is a Phase 2, prospective, randomized, double-masked, vehicle controlled, single-center study in approximately 12 subjects with LHON to evaluate safety, tolerability and efficacy of elamipretide (MTP-131) topical ophthalmic solution in this patient population. At the conclusion of 52 weeks of treatment, subjects will be offered the opportunity to enter an Open Label Extension for up to 48 additional weeks of treatment.

Detailed Description: This was a prospective, randomized, double-masked (DM), vehicle-controlled, single-center study plus open label extension period (OLE) in which approximately 12 subjects with LHON having the genetic mtDNA mutation m.11778G\>A were randomized in a masked manner into 1 of 3 groups in a 1:1:1 ratio: one drop of elamipretide 1.0% topical ophthalmic solution twice daily (BID) in the: left eye, right eye, or both eyes.

After completion of the 52-week treatment period or the Week 56 follow-up period, subjects were invited to participate in the OLE period for up to 108 weeks. During the OLE participants received 1% topical opthalmic elamipretide in both eyes (OU) daily. If a subject did not consent to the OLE, he/she completed the study at the Week 56 (±7 days) visit. There were 4 periods in this study: (1) screening period (up to 6 weeks); (2) double-masked treatment period (52 weeks); (3) OLE period (up to 108 weeks), and (4) follow-up period (4 weeks) after completion of End-of-Treatment (EOT) visit.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 12

Inclusion Criteria

Adults ≥18 and ≤ 50 years old at the time of loss of vision in the second eye.
Able to provide informed consent and willing to comply with all study visits and examinations
Diagnosis of LHON based on clinical and ophthalmic functional/anatomic test findings, and satisfactory documentation of the mitochondrial DNA mutation m.11778G>A
Loss of vision in both eyes of ≥1 year and ≤10 years at the time of the Screening Visit and current clinically stable visual function (as assessed by the Investigator)
Able to self-administer eye drops as demonstrated at screening or having a care provider who can do so
Documentation of having satisfactorily completed at least two previous Humphrey automated visual field tests prior to screening.
Women of childbearing potential must agree to use birth control as specified in the protocol from the date they sign the informed consent form

Exclusion Criteria

Any other ocular pathology requiring treatment with prescription topical ophthalmic drops (e.g., glaucoma, dry eye)
Cup to disc ratio of > 0.8 in either eye
Media opacity, suboptimal pupillary dilatation, or refractive error that interferes with adequate retinal imaging
Known to be immunocompromised or receiving systemic immunosuppression
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

Other protocol-defined inclusion/exclusion criteria may apply.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 1	elamipretide (MTP-131) 1% topical ophthalmic solution	One drop elamipretide (MTP-131) 1% topical ophthalmic solution BID applied to the left eye (OS) and one drop of vehicle topical ophthalmic solution BID in the fellow eye
Group 3	elamipretide (MTP-131) 1% topical ophthalmic solution	One drop elamipretide (MTP-131) 1% topical ophthalmic solution BID applied to both eyes (OU).
OLE	elamipretide (MTP-131) 1% topical ophthalmic solution	One drop elamipretide (MTP-131) 1% topical ophthalmic solution BID applied to both eyes (OU).
Group 1	Vehicle topical ophthalmic solution	One drop elamipretide (MTP-131) 1% topical ophthalmic solution BID applied to the left eye (OS) and one drop of vehicle topical ophthalmic solution BID in the fellow eye
Group 2	elamipretide (MTP-131) 1% topical ophthalmic solution	One drop elamipretide (MTP-131) 1% topical ophthalmic solution BID applied to the right eye (OD) and one drop of vehicle topical ophthalmic solution BID in the fellow eye
Group 2	Vehicle topical ophthalmic solution	One drop elamipretide (MTP-131) 1% topical ophthalmic solution BID applied to the right eye (OD) and one drop of vehicle topical ophthalmic solution BID in the fellow eye

Primary Outcome Measures

Name	Time	Method
Open Label Extension: Incidence of Ocular TEAEs	Assessed at Week 68, 84, 100, 116, 132, 148, 152, Week 160/ (End of treatment visit)	Open Label Extension: The incidence of ocular treatment emergent adverse events (TEAEs).
Double Masked Period: Incidence of Ocular TEAEs	Assessed at each visit: Baseline, Day 5 Visit, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 (End of treatment visit) and Week 56 (Follow up visit)	The incidence of ocular treatment emergent adverse events (TEAEs).
OLE: Severity of Ocular TEAEs	Assessed at Week 68, 84, 100, 116, 132, 148, 152, Week 160/ (End of treatment visit)	The severity of ocular treatment emergent adverse events (TEAEs).
Open Label Extension Period: Best Corrected Visual Acuity (BCVA) Using the Using the Early Treatment Diabetic Retinopathy Study (ETDRS) Scale	Assessed at each visit from Baseline from Week 68 to Week 160 (follow-up visit).	Open Label Extension Period: 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).
Double Masked Period: Severity of Ocular TEAEs	Assessed at each visit: Baseline, Day 5 Visit, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 (End of treatment visit) and Week 56 (Follow up visit)	The severity of ocular treatment emergent adverse events (TEAEs).
Double Masked Period: Best Corrected Visual Acuity (BCVA)	Assessed at each visit: Baseline, Day 5 Visit, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 (End of treatment visit) and Week 56 (Follow up visit)	Double Masked Period: 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).

Secondary Outcome Measures

Name	Time	Method
Double Masked: VFQ-39 Mental Health Score	Assessed at Baseline, Week 52 (end-of-treatment visit) and Week 56 (follow-up visit)	Change from baseline in Visual Function Questionnaire (VFQ-39) Mental Health score. National Eye Institute VFQ-39 score measures health-related quality of life of subjects with visual impairment, in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, and peripheral vision and 1 composite score. Each domain is converted to a 0 to 100 scale; the lowest and highest possible scores are set at 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.
Open Label Extension Period: PhNR-ERG B-wave Amplitude	Assessed at each visit from Baseline from Week 68 to Week 160	Change from baseline in photopic negative response electroretinography (PhNR-ERG) b-wave Amplitude by Visit. Photopic negative response electroretinography (PhNR -ERG) assesses retinal cell function. A decrease in the amplitude of the b-wave is associated with worse outcomes. Change from baseline in b-wave amplitude: a more negative number equals a decrease in amplitude, and therefore a worse outcome, a more positive number means a better outcome.
Double Masked Period: PhNR/B-wave Amplitude Ratio	Assessed at each visit from Baseline to Week 56 (follow-up visit), except for Day 5 visit.	Double Masked Period: Change from baseline in PhNR/b-wave amplitude ratio by Visit. Photopic negative response electroretinography (PhNR assesses retinal cell function. A decrease in PhNR amplitude means worse outcome.
Open Label Extension Period: PhNR Amplitude	Assessed at each visit from Baseline from Week 68 to Week 160	Open Label Extension Period: Change from baseline in PhNR Amplitude by Visit. Photopic negative response electroretinography (PhNR -ERG) assesses retinal cell function. A decrease in PhNR amplitude means worse outcome. Change from baseline: A more negative number means a better outcome, a more positive number means a worse outcome.
Open Label Extension Period: Change From Baseline by Visit PhNR/b Wave Amplitude Ratio	Assessed at each visit from Baseline from Week 68 to Week 160	Open Label Extension Period: Change from baseline by visit PhNR/b Wave Amplitude Ratio by visit. A reduced amplitude ratio equals worse outcome.
Open Label Extension Period: VFQ-39 Composite Score	Assessed at Baseline, Week 160 (End of OLE Period)	Change from baseline in Visual Function Questionnaire (VFQ-39) Composite score.National Eye Institute VFQ-39 measures health-related quality of life in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, peripheral vision, and composite score. For each domain: the lowest and highest possible scores are 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.
Open Label Extension Period: VFQ-39 Ocular Pain Score	Assessed at Baseline, Week 160 (End of OLE Period)	Change from baseline in VFQ-39 Ocular Pain score by visit. National Eye Institute VFQ-39 measures health-related quality of life in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, peripheral vision, and composite score. For each domain: the lowest and highest possible scores are 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.
Double Masked Period: Photopic Negative Response Electroretinography (PhNR-ERG) A-wave Amplitude	Assessed at each visit from Baseline to Week 56 (follow-up visit), except for Day 5 visit.	Change from baseline in photopic negative response electroretinography (PhNR-ERG) a-wave amplitude by Visit. Photopic negative response electroretinography (PhNR-ERG) assesses retinal cell function. A decrease in the amplitude of the a-wave is associated with worse outcomes. Change from baseline in a-wave amplitude: a more positive number equals a decrease in amplitude, and therefore a worse outcome, a more negative number mean a better outcome.
Double Masked Period: PhNR Amplitude	Assessed at each visit from Baseline to Week 56 (follow-up visit), except for Day 5 visit.	Double Masked Period: Change from baseline in PhNR Amplitude by Visit. Photopic negative response electroretinography (PhNR -ERG) assesses retinal cell function. A decrease in PhNR amplitude means worse outcome. Change from baseline: A more negative number means a better outcome, a more positive number means a worse outcome.
Open Label Extension Period: Change From Baseline by Visit PhNR Peak to Trough Adjusted for A-wave Amplitude	Assessed at each visit from Baseline from Week 68 to Week 160	Open Label Extension Period: Change from baseline by visit in PhNR Peak to Trough Adjusted for a-wave Amplitude by Visit. \[Calculated by b-wave amplitude - PhNR amplitude)/a-wave amplitude.\] Photopic negative response electroretinography (PhNR-ERG) assesses retinal cell function. A decrease in the amplitude of the a-wave is associated with worse outcomes. A reduced amplitude ratio equals worse outcome.
Double Masked Period: PhNR Peak to Trough Amplitude (Unadjusted) From Baseline	Assessed at each visit from Baseline to Week 56 (follow-up visit), except for Day 5 visit.	Double Masked Period: Change from baseline in PhNR Peak to Trough Amplitude (Unadjusted) by Visit. Calculated as b-wave amplitude - PhNR amplitude. Photopic negative response electroretinography (PhNR-ERG) assesses retinal cell function. A decrease in amplitude is associated with worse outcomes.
Open Label Extension Period: Photopic Negative Response Electroretinography (PhNR-ERG) A-wave Amplitude	Assessed at each visit from Baseline from Week 68 to Week 160	Change from baseline in photopic negative response electroretinography (PhNR-ERG) a-wave Amplitude by Visit. Photopic negative response electroretinography (PhNR-ERG) assesses retinal cell function. A decrease in the amplitude of the a-wave is associated with worse outcomes. Change from baseline in a-wave amplitude: a more positive number equals a decrease in amplitude, and therefore a worse outcome, a more negative number mean a better outcome.
Double Masked Period: Photopic Negative Response Electroretinography (PhNR-ERG) B-wave Amplitude	Assessed at each visit from Baseline to Week 56 (follow-up visit), except for Day 5 visit.	Change from baseline in photopic negative response electroretinography (PhNR-ERG) b-wave amplitude by visit. Photopic negative response electroretinography (PhNR -ERG) assesses retinal cell function. A decrease in the amplitude of the b-wave is associated with worse outcomes. Change from baseline in b-wave amplitude: a more negative number equals a decrease in amplitude, and therefore a worse outcome, a more positive number mean a better outcome.
Double Masked: VFQ-39 Composite	Assessed at Baseline, Week 52 (end-of-treatment visit) and Week 56 (follow-up visit)	Double Masked: Change from baseline in Visual Function Questionnaire (VFQ-39) Composite score by visit. National Eye Institute VFQ-39 measures health-related quality of life in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, peripheral vision, and composite score. For each domain: the lowest and highest possible scores are 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.
Double Masked Period: Change From Baseline by Visit PhNR Peak to Trough Adjusted for A-wave Amplitude	Assessed at each visit from Baseline to Week 56 (follow-up visit), except for Day 5 visit.	Double Masked Period: Change from baseline by visit in PhNR Peak to Trough Adjusted for a-wave Amplitude by Visit. Calculated as (b-wave amplitude - PhNR amplitude)/a-wave amplitude. A reduced amplitude ratio equals worse outcome.
Double Masked Period: Color Discrimination - Number of Plates	Assessed at each visit from Baseline to Week 56 (follow-up visit)	Double Masked Period: Change from Baseline in Color Discrimination - Number of Plates from Baseline by Visit by Ishihara Test. Score range: 0-38. Higher number equals better color discrimination equals better outcome. Lower number equals worse color discrimination equals worse outcome.
Double Masked Period: Change From Baseline in Contrast Sensitivity by Pelli-Robson Contrast Sensitivity Chart by Visit	Assessed at each visit from Baseline to Week 56 (follow-up visit)	Letters are arranged on a 60 x 85 cm chart in sets of triplets which contain the same contrast, decreasing in log10 contrast from top to bottom and left to right as participant progresses from one triplet to the other. Each group of three letters is decreased in contrast by a factor 0.71 (1/√2) (log contrast 0.15) of the proceeding set. Participant reads letters, starting with highest contrast, until unable to read letters in a single group. Score is based on the contrast of the last group read correctly.The size of the letters on the chart subtend 0.5 degrees at 3m, The test is scored in LogCS units, where each set of triplets advances in steps of 0.15 log units ranging from LogCS of 0.00 (approx. 100% contrast) to LogCS 2.25 (approx. 0.56% contrast). Change from baseline: the more negative the number means poor outcome, the more positive the number means better outcome.
Open Label Extension Period: Change From Baseline in Retinal Ganglion Cell Layer Thickness	Assessed at Baseline, Week 148,	Open Label Extension Period: Change from baseline in Retinal Ganglion Cell Layer Thickness by SD-OCT by SD-OCT by visit
Double Masked: VFQ-39 Distance Activities Score	Assessed at Baseline, Week 52 (end-of-treatment visit) and Week 56 (follow-up visit)	Change from baseline in Visual Function Questionnaire (VFQ-39) Distance Activities score. National Eye Institute VFQ-39 score measures health-related quality of life of subjects with visual impairment, in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, and peripheral vision and 1 composite score. Each domain is converted to a 0 to 100 scale; the lowest and highest possible scores are set at 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.
Open Label Extension Period: PhNR Peak to Trough Amplitude (Unadjusted)	Assessed at each visit from Baseline from Week 68 to Week 160	Open Label Extension Period: Change from baseline in PhNR Peak to Trough Amplitude (Unadjusted) by Visit. b-wave amplitude - PhNR amplitude. Photopic negative response electroretinography (PhNR-ERG) assesses retinal cell function. A decrease in the amplitude of the a-wave is associated with worse outcomes.
Double Masked: VFQ-39 General Vision Score	Assessed at Baseline, Week 52 (end-of-treatment visit) and Week 56 (follow-up visit)	Change from baseline in VFQ-39 General Vision Score. National Eye Institute VFQ-39 score measures health-related quality of life of subjects with visual impairment, in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, and peripheral vision and 1 composite score. Each domain is converted to a 0 to 100 scale; the lowest and highest possible scores are set at 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculate
Double Masked: VFQ-39 Ocular Pain Score	Assessed at Baseline, Week 52 (end-of-treatment visit) and Week 56 (follow-up visit)	Change from baseline in VFQ-39 Ocular Pain score. National Eye Institute VFQ-39 measures health-related quality of life in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, peripheral vision, and composite score. For each domain: the lowest and highest possible scores are 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.
Open Label Extension Period: VFQ-39 Near Activities	Assessed at Baseline, Week 160 (End of OLE Period)	Change from Baseline in Visual Function Questionnaire (VFQ-39) Near Activities score.. National Eye Institute VFQ-39 score measures health-related quality of life of subjects with visual impairment, in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, and peripheral vision and 1 composite score. Each domain is converted to a 0 to 100 scale; score ranges from 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.
Double Masked Period: Visual Field Mean Deviation as Measured by Humphrey Automated Visual Field Testing Stimulus III	Assessed at each visit from Baseline to Week 56 (follow-up visit), except for Day 5 visit.	Change from Baseline in visual field Mean Deviation(MD) as measured by Humphrey automated visual field testing stimulus III by visit. The Humphrey visual field test measures the entire area of peripheral vision that can be seen while the eye is focused on a central point. Mean deviation (MD) is the mean deviation in the patient's results compared to those expected from the age-matched normative database. Lower/More negative scores mean worse outcome, higher/more positive score means better outcome.
Open Label Extension Period: VFQ-39 General Health Score	Assessed at Baseline, Week 160 (End of OLE Period)	Change from baseline in Visual Function Questionnaire (VFQ-39) General Health score. National Eye Institute VFQ-39 score measures health-related quality of life of subjects with visual impairment, in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, and peripheral vision and 1 composite score. Each domain is converted to a 0 to 100 scale; the lowest and highest possible scores are set at 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.
Open Label Extension Period: Change From Baseline in Contrast Sensitivity by Visit	Assessed at each visit from Baseline from Week 68 to Week 160	Letters are arranged on a 60 x 85 cm chart in sets of triplets which contain the same contrast, decreasing in log10 contrast from top to bottom and left to right as participant progresses from one triplet to the other. Each group of three letters is decreased in contrast by a factor 0.71 (1/√2) (log contrast 0.15) of the proceeding set. Participant reads letters, starting with highest contrast, until unable to read letters in a single group. Score is based on the contrast of the last group read correctly. The size of the letters on the chart subtend 0.5 degrees at 3m, The test is scored in LogCS units, where each set of triplets advances in steps of 0.15 log units ranging from LogCS of 0.00 (approx. 100% contrast) to LogCS 2.25 (approx. 0.56% contrast). Change from baseline: the more negative the number means poor outcome, the more positive the number means better outcome.
Double Masked Change From Baseline in Retinal Ganglion Cell Layer Thickness	Assessed at Baseline and Week 52 (end-of-treatment visit)	Change from baseline in Retinal Ganglion Cell Layer Thickness by SD-OCT From Baseline by Visit
Open Label Extension Period: VFQ-39 General Vision Score	Assessed at Baseline, Week 160 (End of OLE Period)	Change from baseline in VFQ-39 General Vision score. National Eye Institute VFQ-39 score measures health-related quality of life of subjects with visual impairment, in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, and peripheral vision and 1 composite score. Each domain is converted to a 0 to 100 scale; the lowest and highest possible scores are set at 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculate
Double Masked Period: Mean Retinal Nerve Fiber (RNFL) Layer Thickness	Assessed at Baseline and Week 52 (end-of-treatment visit)	Change from baseline in retinal nerve fiber layer thickness by spectral domain optical coherence tomography (SD-OCT). RNFL measures the loss of retinal ganglion cell axons. RNFL thickness decreases as disease progresses. A positive number, or, absence of change from baseline reflects a good clinical outcome, a negative number reflects loss of thickness, or a bad outcome.
Open Label Extension Period: Retinal Nerve Fiber Layer Thickness	Assessed at Baseline, Week 148	Open Label Extension Period: Change from baseline in Retinal Nerve Fiber Layer Thickness by SD-OCT by visit. Change from baseline in retinal nerve fiber layer thickness by spectral domain optical coherence tomography (SD-OCT). RNFL measures the loss of retinal ganglion cell axons. RNFL thickness decreases as disease progresses. A positive number, or, absence of change from baseline reflects a good clinical outcome, a negative number reflects loss of thickness, or a bad outcome.
Open Label Extension Period: Change From Baseline in Color Discrimination - Number of Plates by Visit	Assessed at each visit from Baseline from Week 68 to Week 160	Open Label Extension Period: Change from Baseline in Color Discrimination - Number of Plates from Baseline by Visit by Ishihara Test. Score range: 0-38. Higher number equals better color discrimination equals better outcome. Lower number equals worse color discrimination equals worse outcome.
Open Label Extension Period: VFQ-39 Distance Activities Score	Assessed at Baseline, Week 160 (End of OLE Period)	Change in Visual Function Questionnaire (VFQ-39) Distance Activities Score.National Eye Institute VFQ-39 score measures health-related quality of life of subjects with visual impairment, in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, and peripheral vision and 1 composite score. Each domain is converted to a 0 to 100 scale; the lowest and highest possible scores are set at 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.
Open Label Extension Period: VFQ-39 Social Functioning Score	Assessed at Baseline, Week 160 (End of OLE Period)	Change from baseline in Visual Function Questionnaire (VFQ-39) Social Functioning Score. National Eye Institute VFQ-39 score measures health-related quality of life of subjects with visual impairment, in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, and peripheral vision and 1 composite score. Each domain is converted to a 0 to 100 scale; the lowest and highest possible scores are set at 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.
Double Masked: VFQ-39 Near Activities Score	Assessed at Baseline, Week 52 (end-of-treatment visit) and Week 56 (follow-up visit)	Change from Baseline in VFQ-39 Near Activities Score from Baseline. National Eye Institute VFQ-39 measures health-related quality of life in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, peripheral vision, and composite score. For each domain: the lowest and highest possible scores are 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.
Open Label Extension Period: Visual Field Mean Deviation (dB) Measured by Humphrey From Baseline	Assessed at each visit from Baseline from Week 68 to Week 160	Change from Baseline in visual field Mean Deviation(MD) as measured by Humphrey automated visual field testing stimulus III by visit. The Humphrey visual field test measures the entire area of peripheral vision that can be seen while the eye is focused on a central point. Mean deviation (MD) is the mean deviation in the patient's results compared to those expected from the age-matched normative database. Lower/More negative scores mean worse outcome, higher/more positive score means better outcome.
Open Label Extension Period:VFQ-39 Dependency Score	Assessed at Baseline, Week 160 (End of OLE Period)	Change from baseline in Visual Function Questionnaire (VFQ-39 ) Dependency Score. National Eye Institute VFQ-39 score measures health-related quality of life of subjects with visual impairment, in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, and peripheral vision and 1 composite score. Each domain is converted to a 0 to 100 scale; the lowest and highest possible scores are set at 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.
Open Label Extension Period: VFQ-39 Color Vision Score	Assessed at Baseline, Week 160 (End of OLE Period)	Change from baseline in Visual Function Questionnaire (VFQ-39) Color Vision score. National Eye Institute VFQ-39 score measures health-related quality of life of subjects with visual impairment, in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, and peripheral vision and 1 composite score. Each domain is converted to a 0 to 100 scale; the lowest and highest possible scores are set at 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.
Double Masked: Slit Lamp Changes From Baseline: Vehicle Eye and Elamipretide Eye	Assessed at each visit: Baseline, Day 5 Visit, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 (End of treatment visit) and Week 56 (Follow up visit)	Incidence of Change from normal or Abnormal, clinically insignificant to normal clinically significant
Double Masked: VFQ-39 Social Functioning Score.	Assessed at Baseline, Week 52 (end-of-treatment visit) and Week 56 (follow-up visit)	Change from baseline in Visual Function Questionnaire (VFQ-39) Social Functioning score. National Eye Institute VFQ-39 score measures health-related quality of life of subjects with visual impairment, in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, and peripheral vision and 1 composite score. Each domain is converted to a 0 to 100 scale; the lowest and highest possible scores are set at 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.
Open Label Extension Period: VFQ-39 Role Difficulties Score	Assessed at Baseline, Week 160 (End of OLE Period)	Change from baseline in Visual Function Questionnaire (VFQ-39) Role Difficulties Score. National Eye Institute VFQ-39 score measures health-related quality of life of subjects with visual impairment, in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, and peripheral vision and 1 composite score. Each domain is converted to a 0 to 100 scale; the lowest and highest possible scores are set at 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.
Open Label Extension Period: Intraocular Pressure (IOP)	Assessed at Baseline, Week 68, 84, 100, 116, 132, 148, 152, Week 160/ (End of treatment visit)	Change from baseline in Intraocular Pressure (IOP) in mmHg by Visit.
Open Label Extension Period: Dilated Fundus Changes From Baseline: Vehicle Eye and Elamipretide Eyes	Assessed at Baseline, Week 68, 84, 100, 116, 132, 148, 152, Week 160/ (End of treatment visit)	Incidence of Change from normal or Abnormal-clinically insignificant, to normal clinically significant
Double Masked: VFQ-39 Role Difficulties Score	Assessed at Baseline, Week 52 (end-of-treatment visit) and Week 56 (follow-up visit)	Change from baseline in Visual Function Questionnaire (VFQ-39) Role Difficulties score National Eye Institute VFQ-39 score measures health-related quality of life of subjects with visual impairment, in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, and peripheral vision and 1 composite score. Each domain is converted to a 0 to 100 scale; the lowest and highest possible scores are set at 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.
Double Masked: VFQ-39 Peripheral Score	Assessed at Baseline, Week 52 (end-of-treatment visit) and Week 56 (follow-up visit)	Change from baseline in Visual Function Questionnaire (VFQ-39) Peripheral Score . National Eye Institute VFQ-39 score measures health-related quality of life of subjects with visual impairment, in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, and peripheral vision and 1 composite score. Each domain is converted to a 0 to 100 scale; the lowest and highest possible scores are set at 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.
OLE: Slit Lamp Examination (SLE)-Vehicle Eye	Assessed at Baseline, Week 68, 84, 100, 116, 132, 148, 152, Week 160/ (End of treatment visit)	Open Label Extension: Shift in Slit Lamp Examination from Baseline by Visit: number of eyes that changed from normal or abnormal not clinically significant, to abnormal clinically significant for Vehicle Eyes
Open Label Extension Period: VFQ-39 Mental Health Score	Assessed at Baseline, Week 160 (End of OLE Period)	Change from baseline in Visual Function Questionnaire (VFQ-39) Mental Health Score . National Eye Institute VFQ-39 score measures health-related quality of life of subjects with visual impairment, in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, and peripheral vision and 1 composite score. Each domain is converted to a 0 to 100 scale; the lowest and highest possible scores are set at 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.
Double Masked: VFQ-39 Dependency Score	Assessed at Baseline, Week 52 (end-of-treatment visit) and Week 56 (follow-up visit)	Change from baseline in Visual Function Questionnaire (VFQ-39) Dependency score. National Eye Institute VFQ-39 score measures health-related quality of life of subjects with visual impairment, in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, and peripheral vision and 1 composite score. Each domain is converted to a 0 to 100 scale; the lowest and highest possible scores are set at 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.
Double Masked: VFQ-39 Color Vision Score	Assessed at Baseline, Week 52 (end-of-treatment visit) and Week 56 (follow-up visit)	Change from baseline in Visual Function Questionnaire (VFQ-39) Color Vision score. National Eye Institute VFQ-39 score measures health-related quality of life of subjects with visual impairment, in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, and peripheral vision and 1 composite score. Each domain is converted to a 0 to 100 scale; the lowest and highest possible scores are set at 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.
Double Masked Period: Change in Intraocular Pressure (IOP)	Assessed at each visit: Baseline, Day 5 Visit, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 (End of treatment visit) and Week 56 (Follow up visit)	Double Masked Period: Change in intraocular Pressure (IOP) in mmHg from Baseline by Visit
OLE: Slit Lamp Examination (SLE)-Elamipretide Eye	Assessed at Baseline, Week 68, 84, 100, 116, 132, 148, 152, Week 160/ (End of treatment visit)	Open Label Extension: Shift in Slit Lamp Examination from Baseline by Visit: number of eyes that changed from normal or abnormal not clinically significant, to abnormal clinically significant for Elamipretide Eyes
Double Masked: Dilated Fundus Changes From Baseline: Vehicle Eye and Elamipretide Eyes	Assessed at each visit: Baseline, Day 5 Visit, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 (End of treatment visit) and Week 56 (Follow up visit)	Double Masked: Dilated Fundus Changes from Baseline: Vehicle Eye and Elamipretide Eyes Incidence of Change from normal or Abnormal-clinically insignificant, to normal clinically significant
Double Masked: VFQ-39 General Health Score	Assessed at Baseline, Week 52 (end-of-treatment visit) and Week 56 (follow-up visit)	Change from baseline in Visual Function Questionnaire (VFQ-39) General Health score. National Eye Institute VFQ-39 score measures health-related quality of life of subjects with visual impairment, in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, and peripheral vision and 1 composite score. Each domain is converted to a 0 to 100 scale; the lowest and highest possible scores are set at 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.
Open Label Extension Period: Visual Function Questionnaire (VFQ-39) Peripheral Score	Assessed at Baseline, Week 160 (End of OLE Period)	Change from baseline in Visual Function Questionnaire (VFQ-39) Peripheral Score . National Eye Institute VFQ-39 score measures health-related quality of life of subjects with visual impairment, in 12 domains: general vision, ocular pain, near activities, distance activities, vision-specific social functioning, vision-specific mental health, vision-specific role difficulties, vision-specific dependency, driving, color vision, and peripheral vision and 1 composite score. Each domain is converted to a 0 to 100 scale; the lowest and highest possible scores are set at 0 and 100 points, respectively. Higher score means higher functioning. Scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score. For the composite score, the vision-targeted sub-scale scores are averaged, excluding the general health questions. Domain scores from each cohort are averaged and the change from baseline per domain is calculated.