Clinical trial NCT02693119
Conditions: Leber's Hereditary Optic Neuropathy
Keywords: LHON Ocuvia™ elamipretide MTP-131
Sponsor: Stealth BioTherapeutics Inc.
Start date: 2016-03-01; Completion date: 2019-12-01
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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 arm 2: 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 arm 3: One drop elamipretide (MTP-131) 1% topical ophthalmic solution BID applied to both eyes (OU). arm 4: One drop elamipretide (MTP-131) 1% topical ophthalmic solution BID applied to both eyes (OU).
Interventions: intervention 1: elamipretide (MTP-131) 1% topical ophthalmic solution intervention 2: Vehicle topical ophthalmic solution
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
SPILH-201/SPILH-201OLE Version 10.0 
Elamipretide Topical Ophthalmic Solution (MTP-131) 
 
 
 
 
 
A Prospective, Randomized, Double-Masked, Vehicle Controlled, Phase 2 Clinical Study with 
Open Label Extension to Evaluate the Safety, Tolerability and Efficacy of Elamipretide (MTP-
131) Topical Ophthalmic Solution in Subjects with Leber’s Hereditary Optic Neuropathy 
(LHON) 
 
NCT02693119 
 
11 Mar 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


SPILH-201/SPILH-201OLE Version 10.0 
Elamipretide Topical Ophthalmic Solution (MTP-131) 
 
 
A Prospective, Randomized, Double-Masked, Vehicle Controlled, Phase 2 
Clinical Study with Open Label Extension to Evaluate the Safety, Tolerability 
and Efficacy of Elamipretide (MTP-131) Topical Ophthalmic Solution in 
Subjects with Leber’s Hereditary Optic Neuropathy (LHON) 
Study Phase: 
Phase 2 
 
Product Name: 
Elamipretide Topical Ophthalmic Solution 
 
IND Number: 
114,234 
 
Formulation: 
Topical Ophthalmic 
 
Sponsor: 
 
 
 
 
Sponsor Chief Clinical 
Development Officer: 
Stealth BioTherapeutics Inc. 
275 Grove Street, Suite 3-107 
Newton, MA 02466 
+1 (617) 600-6880 
 
Jim Carr, Pharm.D. 
Chief Clinical Development Officer 
275 Grove Street 3-107, Newton, MA 02466, USA 
Jim.Carr@StealthBT.com 
+1 617-762-2503 
 
Sponsor Study No.: 
SPILH-201/SPILH-201OLE 
 
Protocol Date: 
Protocol Version: 
11 Mar 2019 
 
Version 10.0 
Confidentiality Statement 
The information contained in this document is confidential and is the property of Stealth 
BioTherapeutics Inc. No part of it may be transmitted, reproduced, published, or used by 
anyone without the written permission of Stealth BioTherapeutics Inc. 
 
 
 
 
 
 
 
 
Confidential 
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Table 1:  Emergency Contact Information 
 
Role in Study 
Name 
Address and Telephone Number 
Sponsor Medical Monitor 
Sandrin Bergheanu, 
Stealth BioTherapeutics Inc. 
MD, PhD 
275 Grove Street, Suite 3-107 
Newton, MA 02466 
+31 (0) 641 476 460 
Note: Individual site contacts will be included as part of the study file. 


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SPONSOR’S PROTOCOL SIGNATURE PAGE 
 
 
A Prospective, Randomized, Double-Masked, Vehicle Controlled, Phase 2 Clinical Study with 
Open Label Extension to Evaluate the Safety, Tolerability, and Efficacy of Elamipretide Topical 
Ophthalmic Solution in Subjects with Leber’s Hereditary Optic Neuropathy (LHON) 
Study No.: 
SPILH-201/SPILH-201OLE 
 
 
Sponsor: Stealth BioTherapeutics Inc. 
275 Grove Street, Suite 3-107 
Newton, MA 02466 
 
 
 
 
Protocol Date: 
11 Mar 2019 
Protocol Version: 
Version 10.0 
 
Signature: 
Date: 
 
 
_0_3_/_1 1_/_2_0_1 9  
 
Jim Carr, Pharm.D. 
Chief Clinical Development Officer 
Stealth BioTherapeutics Inc. 


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INVESTIGATOR’S PROTOCOL SIGNATURE PAGE 
A Prospective, Randomized, Double-Masked, Vehicle Controlled, Phase 2 Clinical Study with 
Open Label Extension to Evaluate the Safety, Tolerability and Efficacy of Elamipretide (MTP- 
131) Topical Ophthalmic Solution in Subjects with Leber’s Hereditary Optic Neuropathy 
(LHON) 
Study No.: 
SPILH-201/SPILH-201OLE 
 
 
Sponsor: 
Stealth BioTherapeutics, Inc. 
275 Grove Street, Suite 3-107 
Newton, MA  02466 
+1 (617) 600-6888 
 
 
Protocol Date/Version: 
11 Mar 2019/Version 10.0 
 
I have read all pages of this clinical study protocol for which Stealth BioTherapeutics is the 
sponsor. I agree to conduct the study outlined in the protocol and to comply with all the terms 
and conditions set out therein. I confirm that I will conduct the study in accordance with ICH 
GCP guidelines. I will also ensure that sub-Investigator(s) and other relevant members of my 
staff have access to copies of this protocol, and the ICH GCP guidelines to enable them to work 
in accordance with the provisions of these documents. 
Investigator: 
 
 
 
Printed Name: 
Signature: 
Date: 
Site Address: 


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1. 
SYNOPSIS 
 
Name of Sponsor/Company:  Stealth BioTherapeutics Inc. 
Investigational Product:  Elamipretide Topical Ophthalmic Solution 
Title of Study: A Prospective, Randomized, Double-Masked, Vehicle Controlled, Phase 2 
Clinical Study with Open Label Extension To Evaluate the Safety, Tolerability and Efficacy of 
Elamipretide (MTP-131) Topical Ophthalmic Solution in Subjects with Leber’s Hereditary 
Optic Neuropathy (LHON) 
Study Centers: This single center study will be conducted at the Doheny Eye Center, 
University of California, Los Angeles, California, United States (US). 
Study Objective: This study has two parts: a double-masked period and an open-label 
extension period.  The objectives for each part of the study are as follows: 
• 
The objective of the double-masked period is to evaluate the safety, tolerability, and 
efficacy of elamipretide 1.0% topical ophthalmic solution relative to vehicle administered two 
times per day (BID) for 52 weeks in the treatment of LHON. 
• 
The objective of the open-label extension is to evaluate the safety and tolerability up to 
an additional 108 weeks of treatment via in an open label setting for subjects who complete 
the double-masked period. 
Study Design 
This is a prospective, randomized, double-masked, vehicle controlled, single-center study plus 
open label extension (OLE) in approximately 12 subjects with LHON having the genetic 
mitochondrial DNA mutation m.11778G>A. Each subject will be randomized in a blinded 
manner into one of three treatment groups in a 1:1:1 ratio: (a) 1 drop of elamipretide 1.0% 
topical ophthalmic solution BID applied to the left eye (OS) and 1 drop of vehicle topical 
ophthalmic solution BID in the fellow eye, (b) 1 drop of elamipretide 1.0% topical ophthalmic 
solution BID applied to the right eye (OD) and 1 drop of vehicle topical ophthalmic solution 
BID in the fellow eye, or (c) 1 drop of elamipretide 1.0% topical ophthalmic solution BID to 
each eye (OU). After completing 52 weeks of masked treatment, all subjects will be invited to 
continue into an OLE of 1 drop of elamipretide 1.0% topical ophthalmic solution BID instilled 
into both eyes (Oculus Uterque [OU]) for up to an additional 108 weeks. 
There are 4 periods in this study: 
• 
Screening (up to 6 weeks) 
• 
Double-masked treatment period (52 weeks) 
• 
Open-Label Extension period (108 weeks) 
• 
Follow-up Period (4 weeks) after completion of End of Treatment (EOT) visit (for 
subjects not enrolling in an expanded access program (EAP)). 
Screening 
Written informed consent will be obtained from all subjects prior to the Screening Visit. 
Screening procedures may be completed on more than one day, as long as all procedures are 


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completed during the Screening Period. All other visits may be completed over a 1 or 2 day 
period, at the discretion of the Investigator, as long as all procedures are completed during the 
allowable window for that visit. 
The Screening examination will be performed no more than 42 days prior to the Baseline visit. 
For applicable female subjects, urine pregnancy testing will be performed prior to initiation of 
treatment. The day of randomization is defined as Study Day 1. Subjects will be considered 
enrolled in the study upon randomization. 
Once informed consent has been obtained, confirmation of LHON genetic mutation 
m.11778G>A by mitochondrial deoxyribonucleic acid (DNA) analysis will be performed, if 
not previously confirmed by written documentation using reliable test methods. Additional 
data will be collected from a complete pre-treatment examination, consisting of vital signs, 
physical exam, serum pregnancy test for women of child-bearing potential, routine blood 
chemistries and urinalysis, measurement of best corrected visual acuity (BCVA) using the 
Early Treatment Diabetic Retinopathy Study (ETDRS) scale, manifest refraction, intraocular 
pressure (IOP) measurement, slit lamp examination, dilated fundus examination, fundus 
photography, Humphrey automated visual field testing (SITA FAST 30-2 stimulus III), mean 
retinal nerve fiber layer (RNFL) and mean retinal ganglion cell layer (RGCL) thickness as 
measured by spectral domain optical coherence tomography (SD-OCT; Cirrus), photopic 
negative response electroretinography (PhNR-ERG), full field ERG and the Visual 
Functioning Questionnaire-39 (VFQ-39) to assess visual quality-of-life measures. 
Subjects will undergo Humphrey automated visual field testing at both Screening (Visit 1) and 
Baseline (Visit 2) visits (performed at least 1 day apart). In the event that a subject’s 2 visual 
field tests differ by greater than 5 dB, an additional two Humphrey automated visual field tests 
may be performed at either the Baseline Visit or within 1 week of the Baseline Visit.  If the 
test does not occur on the day of the Baseline Visit, other Baseline procedures, which have 
already been completed, should not be repeated. In order to be randomized into the study, 
subjects must have two consecutive visual field tests with results that meet the study criteria 
and that are within 5 dB of each other. Subjects will be considered enrolled in the study upon 
randomization. 
Double-masked Treatment Period 
At the time of randomization, training on the proper administration of topical ophthalmic 
solution and self-administration (by the subject or regular caregiver) will occur. Subjects will 
be read a standard script explaining the importance of applying the correct drug product to 
each eye on a twice daily basis for the 52-week Treatment Period. Efficacy, safety, and 
tolerability will be measured throughout the Treatment Period. Visits will occur at: Day 5 (±2 
days), Week 4 (± 4 days), Week 8 (± 4 days), Week 12 (± 4 days), Week 16 (± 7 days), Week 
20 (± 7 days), Week 24 (± 7 days), Week 28 (± 7 days), Week 32 (± 7 days), Week 36 (± 7 
days), Week 40 (± 7 days), Week 44 (± 7 days), Week 48 (± 7 days), and Week 52 (± 7 days). 
After completion of the 52-week Treatment Period or the Week 56 follow up period, subjects 
will be invited to participate in the OLE for up to 108 weeks. If a subject does not consent to 
the OLE, he/she will complete the study at the Week 56 (±7 days) visit. 
Open-Label Extension 
The OLE will begin after the subject completes the Week 52 or Week 56 visit. Following 
completion of all Week 52 or Week 56 procedures described in the Schedule of Events 


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(Attachment 1), subjects will receive a supply of 1.0% elamipretide topical ophthalmic drops 
to instill at home. Subjects (or trained caregivers) should administer elamipretide OU BID 
every day. Subjects will visit the trial site for the 16-Month Visit (Week 68), the 20-Month 
Visit (Week 84), the 24-Month Visit (Week 100), the 28-Month Visit (Week 116), the 32- 
Month Visit (Week 132), the 36-Month Visit (Week 148), and the 39-Month/End of OLE 
Treatment (EOT) Visit (Week 160) to complete assessments as described in the Schedule of 
Events. Monthly safety telephone calls will be completed in between site visits. The monthly 
safety telephone call script is provided in Attachment 4. Subjects will have the opportunity to 
continue receiving elamipretide through an EAP immediately following the 36 or 39-Month 
(EOT) Visit. For those subjects who consent to enroll in the EAP at either visit, there will not 
be a Follow-Up Period. That visit will be considered the End-of-Study visit.  For those 
subjects who wishes not to enroll in an EAP, the Follow-up Period will begin after completion 
of 39-Month (EOT) visit and will last for 4 weeks.  During the Follow-Up Period, subjects 
will continue to follow all study requirements. At the end of the Follow-Up Period, subjects 
will return to the trial site for the End-of-Study visit for final study assessments and to return 
used and unused bottles and all other study instruments/materials to the trial site. 
Study procedures, their timing, and additional details are found in the Schedule of Events, 
Attachment 1. 
Investigational Product, Dosage and Mode of Administration: 
Double-Masked Period: Elamipretide topical ophthalmic solution 1.0%, 1 drop administered 
topically BID to treatment eye. Vehicle solution, 1 drop administered topically BID to control 
eye. 
OLE Period: Elamipretide topical ophthalmic solution 1.0%, 1 drop administered topically 
BID into both eyes 
Number of Subjects (planned): 
Approximately 12 subjects will be enrolled in this study and open label extension. 
Inclusion Criteria 
A subject must meet the following criteria to be eligible for inclusion in the study: 
1. Adults ≥18 and ≤ 50 years old at the time of loss of vision in the second eye. Loss of 
vision in both eyes of ≥1 year and ≤10 years at the time of the Screening Visit. 
2. Able to provide informed consent and willing to comply with all study visits and 
examinations 
3. Diagnosis of LHON based on clinical and ophthalmic functional/anatomic test findings, 
and satisfactory documentation of the mitochondrial DNA mutation m.11778G>A 
4. 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) 
5. Mean Deviation (MD) between -7.5 and -30 dB on Humphrey automated visual field 
testing (SITA FAST 30-2, stimulus III) on two tests during the Screening Period. In 
addition, the MD on the two qualifying, exams must be within 5 dB of each other for the 
subject to qualify for study inclusion 
Note: As described in the Study Design, up to four Humphrey automated visual field tests 
are allowed during the Screening Period. 


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6. Adequate mean retinal nerve fiber layer (RNFL) thickness based on the investigator’s 
assessment with consideration of spectral domain optical coherence tomography (SD- 
OCT) values, such as between 50 and 90 microns (inclusive) OU. 
7. Adequate retinal ganglion cell layer (GCL) thickness based on the investigator’s 
assessment with consideration of SD-OCT values of at least 40 microns OU. 
8. Media clarity, subject able to undergo pupillary dilation and able to cooperate sufficiently 
for adequate ophthalmic visual function testing and anatomic assessment 
9. Able to self-administer eye drops as demonstrated at screening or having a care provider 
who can do so 
10. Documentation of having satisfactorily completed at least two previous Humphrey 
automated visual field tests prior to screening. 
11. If of childbearing potential or in a relationship with a partner of childbearing potential, are 
able to abstain from sex or use acceptable contraception during the study and for 28 days 
after dosing. 
a. For men: Abstinence is only acceptable if it is in line with the preferred and usual 
lifestyle of the subject. The subject also agrees to use an acceptable method of 
contraception should they become sexually active with a partner of child-bearing 
potential. Subjects must use a condom with spermicide from the date of informed 
consent until at least 28 days after the last dose of study drug. Periodic abstinence 
(e.g. calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception. 
For women: Abstinence is only acceptable when it is in line with the preferred and 
usual lifestyle of the subject. The subject agrees to use an acceptable method of 
contraception should they become sexually active. Maintenance of a monogamous 
relationship with a male partner who has been surgically sterilized by vasectomy (the 
vasectomy procedure must have been conducted at least 60 days before the Screening 
visit or confirmed via sperm analysis), barrier method (e.g., condom or occlusive cap) 
with spermicidal foam/gel/film/cream AND either hormonal contraception (oral, 
implanted, or injectable) or an intrauterine device or system are acceptable methods. 
Note: Non-childbearing potential is defined as surgical sterilization (i.e., bilateral 
oophorectomy, hysterectomy, or tubal ligation) or postmenopausal (defined as not 
having a period for at least 12 consecutive months prior to Screening). 


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Exclusion Criteria: 
A subject who meets any of the following criteria will be excluded from the study: 
Ocular conditions 
1. Any other ocular pathology requiring treatment with prescription topical ophthalmic drops 
(e.g., glaucoma, dry eye) 
2. Cup to disc ratio of > 0.8 in either eye 
3. Any active ocular or periocular infection; any history of recurrent or chronic infection or 
inflammation in the study eye 
4. History of herpetic infection in either eye 
5. History of intraocular surgery 
6. Active corneal disease 
7. Current use or likely need for the use of contact lens at any time during the study 
8. Concurrent disease in either the study eye or fellow control eye that could require medical 
or surgical intervention during the study period 
9. Media opacity, suboptimal pupillary dilatation, or severe refractive error that interferes 
with adequate retinal imaging 
Systemic conditions 
10. Known to be immunocompromised or receiving systemic immunosuppression 
11. Any systemic or non-ocular symptoms that in the opinion of the Investigator may be 
related to LHON (i.e. “LHON-plus”), per investigator’s assessment and decision. 
12. Any disease, medical condition or psychological condition that in the opinion of the 
Investigator would prevent the subject from participating in the study or might confound 
study results 
General 
13. 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 
14. History of participation in an interventional clinical trial investigating the use of gene 
therapy as a treatment for LHON 
15. History of allergic reaction to the investigational drug or any of its components 
16. History of histamine intolerance (e.g., a known deficiency of endogenous histamine 
degradation) 
17. Current use of or likely need for any excluded medication (idebenone and vitamins 
acceptable) 
18. Women who are pregnant or lactating 
Planned Study Duration: 
Up to 170 weeks, including up to 6 weeks for screening prior to Day 1/Baseline study 
randomization, a 52 week double-masked treatment period, a 108 week OLE, and a 4 week 
safety follow-up period (for subjects not enrolling in an EAP). 


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Criteria for Evaluation: 
Safety Endpoint: 
• 
The incidence and severity of systemic and ocular adverse events (AEs) 
Efficacy Endpoints: 
• 
Change from Baseline in photopic negative response electroretinography (PhNR-ERG) 
response pattern 
• 
Change from Baseline in visual field MD as measured by Humphrey automated visual 
field testing stimulus III 
• 
Change from Baseline in color discrimination / contrast sensitivity 
• 
Change from Baseline in best corrected visual acuity (BCVA) 
• 
Change from Baseline in VFQ-39 score 
• 
Change from Baseline in mean retinal nerve fiber layer thickness by SD-OCT 
• 
Change from Baseline in mean retinal ganglion cell layer thickness by SD-OCT 
Optional (per subject secondary use consent): 
Exploratory Biomarkers may be evaluated post study completion: 
• 
Serum phosphorylated axonal neurofilament analysis 
• 
Serum mitochondrial DNA copy number 
Statistical Methods: 
This study has a double-masked treatment component, in which comparisons of the 
elamipretide treated eye will be compared to the vehicle treated eye. Outcomes for the 
double-masked period will be analyzed consistent with this design characteristic. 
This study also has an open-label treatment component, in which both eyes will receive 
elamipretide treatment.  The key outcomes of interest will be the comparison of the vehicle 
eye outcomes (per the double-masked treatment period) to the continued outcomes from the 
elamipretide eye (also from the double-masked treatment period) as both eyes are treated with 
elamipretide. Open-label data will be presented using the following treatment identifier 
conventions: 
• 
Vehicle to Elamipretide (eyes originally randomized to vehicle in DB and then treated 
with elamipretide in OLE) 
• 
Elam to Elam (eyes originally randomized to elamipretide in DB and continuing 
treatment with elamipretide in OLE) 
• 
Total (pooling both eyes) 
Analysis Populations: All subjects who receive at least one dose of study drug will be 
included in the Safety Population. In general, subjects in the Safety Population are expected to 
have received active treatment in at least one eye and so will be identified as such. 
Safety Analyses: Adverse events will be summarized by system organ class (SOC) and 
preferred term (PT), presenting the number and percentage of subjects having treatment- 
emergent AEs.  SAEs and AEs resulting in discontinuation will be presented. 


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For the Double-masked period, AEs will be presented as follows: 
Adverse Events attributed to an individual eye or both eyes will be tabulated by specific 
treatment received in that eye or eyes. 
Systemic AEs will be presented overall (as all patients during the double-masked period 
receive both elamipretide AND vehicle). 
For the OLE, AEs will be presented overall for all patients (and eyes) combined. Severity and 
relationship to study drug will be listed as appropriate. 
OLE analysis will consist of all safety data being presented overall (pooled) for all subjects. 
Efficacy Analyses: Baseline, demographic and other non-eye specific characteristics will be 
presented by single eye vs. both eye (receiving active) treatment groups. Continuous variables 
will be summarized by descriptive statistics (sample size, mean, standard deviation, median, 
and minimum and maximum). Discrete variables will be summarized by frequencies and 
percentages. All study data are to be displayed in the data listings. Subject disposition 
summaries will include the number of subjects treated (i.e., in the Safety population). The 
number and percentage of subjects who complete or discontinue from the study will be 
summarized by reason. Subject’s age, sex, weight, height, BMI, and other demographic 
characteristics will be recorded and summarized.  Medical history will be listed. 
Plots and figures that demonstrate the time-course of changes in efficacy parameters over 
time, from baseline (prior to the start of double-masked treatment) through the double-masked 
treatment period and through the open-label treatment period will be presented. A mixed 
model for repeated measures (MMRM) will be used, with effects for treatment, study visit, 
and treatment*visit interaction, and a random effect for subject. The model-based adjusted 
means (LSMeans) and standard errors will be presented in these plots. 
Statistical analysis of this study will be the responsibility of the Sponsor or its designee. 
Additional details regarding analyses of efficacy measures within single eye treated subjects 
and between subjects (single eye vs. bilateral) will be included in separate statistical analysis 
plan. 
Sample Size: 
For this Phase 2 study, the sample size of 12 subjects is based on the rarity of the disease 
under investigation and is judged as reasonable for exploring clinical safety, tolerability, and 
efficacy outcomes in this first study in the target population. 


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Table of Contents 
SPONSOR’S PROTOCOL SIGNATURE PAGE .......................................................................... 3 
1. 
SYNOPSIS .............................................................................................................................. 5 
TABLE OF CONTENTS .............................................................................................................. 12 
2. 
LIST OF ABBREVIATIONS AND DEFINITIONS ............................................................ 15 
3. 
INTRODUCTION ................................................................................................................. 17 
4. 
STUDY OBJECTIVE ............................................................................................................ 20 
5. 
INVESTIGATIONAL PLAN................................................................................................ 20 
5.1. 
SUMMARY OF DESIGN ..................................................................................................... 20 
5.2. 
DISCUSSION OF DESIGN AND CONTROL ........................................................................... 22 
5.3. 
SCHEDULE OF EVENTS ..................................................................................................... 22 
6. 
STUDY POPULATION ........................................................................................................ 22 
6.1. 
NUMBER OF SUBJECTS PLANNED .................................................................................... 22 
6.2. 
STUDY POPULATION ........................................................................................................ 22 
6.2.1. INCLUSION CRITERIA ....................................................................................................... 22 
6.2.2. EXCLUSION CRITERIA ..................................................................................................... 23 
6.3. 
DISCONTINUATION .......................................................................................................... 24 
6.4. 
REPLACEMENT OF SUBJECTS ........................................................................................... 24 
7. 
STUDY TREATMENTS ...................................................................................................... 25 
7.1. 
DOSE MODIFICATION AND DISCONTINUATION OF SUBJECT DOSING ............................... 25 
7.1.1. DOSE MODIFICATION ...................................................................................................... 25 
7.1.2. DOSE JUSTIFICATION ....................................................................................................... 25 
7.2. 
TREATMENT OF SUBJECTS ............................................................................................... 25 
7.2.1. 
Randomization ........................................................................................................ 25 
7.2.2. 
Study Drug Identification ....................................................................................... 26 
7.2.3. 
Packaging, Labeling, and Storage ........................................................................... 26 
7.2.4. 
Supply and Disposition of Treatments .................................................................... 26 
7.2.5. 
Treatment Logistics and Accountability ................................................................. 27 
7.2.6. 
Treatment Compliance ............................................................................................ 27 
7.3. 
MASKING AND UNMASKING ............................................................................................ 28 
7.4. 
STUDY VISIT DESCRIPTIONS ............................................................................................ 28 
7.4.1. 
Clinical Study.......................................................................................................... 28 
7.4.2. 
Open Label Extension ............................................................................................. 32 
7.5. 
CONCOMITANT AND PROHIBITED MEDICATIONS ............................................................. 34 
8. 
EFFICACY, SAFETY EVALUATIONS, SAMPLE COLLECTION AND TESTING, AND 
APPROPRIATENESS OF MEASUREMENTS .......................................................................... 36 


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8.1. 
EFFICACY MEASURES ...................................................................................................... 36 
8.1.1. 
Appropriateness of Measures .................................................................................. 36 
8.2. 
SAFETY EVALUATIONS .................................................................................................... 37 
8.2.1. 
Adverse Events ....................................................................................................... 37 
8.3. 
PRETREATMENT EVENTS ................................................................................................. 37 
8.4. 
BASELINE MEDICAL CONDITIONS ................................................................................... 37 
8.4.1. 
Abnormal Laboratory and Other Abnormal Investigational Findings .................... 38 
8.4.2. 
Serious Adverse Events .......................................................................................... 38 
8.4.3. 
Events that Do Not Meet the Definition of a Serious Adverse Event ..................... 38 
8.4.4. 
Recording of Adverse Events ................................................................................. 38 
8.5. 
INVESTIGATOR ASSESSMENTS ......................................................................................... 39 
8.5.1. 
Severity/Intensity .................................................................................................... 39 
8.5.2. 
Relationship to the Investigational Medicinal Product ........................................... 40 
8.6. 
ADVERSE EVENT REPORTING PERIOD ............................................................................. 40 
8.7. 
SERIOUS ADVERSE EVENT EXPEDITED REPORTING ......................................................... 41 
8.8. 
PREGNANCY AND IN UTERO DRUG EXPOSURE ................................................................ 41 
8.9. 
RESPONSIBILITIES TO REGULATORY AUTHORITIES, INVESTIGATORS, ETHICS 
COMMITTEES, AND ETHICAL/INSTITUTIONAL REVIEW BOARDS ................................................. 42 
8.10. SAMPLE COLLECTION AND TESTING ................................................................................ 43 
9. 
STUDY VARIABLES AND STATISTICAL ANALYSIS .................................................. 44 
9.1. 
DETERMINATION OF SAMPLE SIZE ................................................................................... 44 
9.2. 
STATISTICAL AND ANALYTICAL PLANS ........................................................................... 44 
9.2.1. 
General Considerations ........................................................................................... 44 
9.2.2. 
Subject Disposition ................................................................................................. 45 
9.2.3. 
Subject Characteristics ............................................................................................ 45 
9.2.4. 
Treatment Compliance ............................................................................................ 45 
9.2.5. 
Endpoints and Methodology ................................................................................... 45 
9.2.6. 
Efficacy Endpoints .................................................................................................. 45 
9.2.7. 
Exploratory Biomarkers (Optional: per secondary use consent) ............................ 46 
9.2.8. 
Safety Analyses ....................................................................................................... 46 
10. 
STUDY MONITORING ................................................................................................... 48 
10.1. SOURCE DOCUMENT REQUIREMENTS .............................................................................. 48 
10.2. CASE REPORT FORM REQUIREMENTS .............................................................................. 48 
10.3. STUDY MONITORING ....................................................................................................... 48 
11. 
DATA QUALITY ASSURANCE ..................................................................................... 49 
11.1. DATA CAPTURE SYSTEM ................................................................................................. 49 
12. 
AUDITS AND INSPECTIONS ......................................................................................... 50 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................. 51 


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13.1. GOOD CLINICAL PRACTICE STATEMENT ......................................................................... 51 
13.2. INFORMED CONSENT ....................................................................................................... 51 
13.3. SUBJECT CONFIDENTIALITY AND DATA PROTECTION ..................................................... 51 
13.4. INSTITUTIONAL REVIEW BOARD ..................................................................................... 51 
13.5. REGULATORY CONSIDERATIONS ..................................................................................... 52 
13.5.1. 
Protocol Signatures ............................................................................................. 52 
13.5.2. 
Final Report Signature ........................................................................................ 52 
13.5.3. 
Study Monitoring ................................................................................................ 52 
13.5.4. 
Retention of Records ........................................................................................... 53 
13.5.5. 
Disclosure of Information ................................................................................... 53 
14. 
REFERENCES .................................................................................................................. 54 
ATTACHMENT 1. SPILH-201 SCHEDULE OF EVENTS ..................................................... 55 
ATTACHMENT 2. SPILH-201OLE SCHEDULE OF EVENTS ............................................. 59 
ATTACHMENT 3. CLINICAL LABORATORY TESTS ........................................................ 61 
ATTACHMENT 4. SAMPLE MONTHLY TELEPHONE SCRIPT ........................................ 62 


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2. 
LIST OF ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition or Explanation 
AE 
adverse event 
BCVA 
best corrected visual acuity 
BID 
two times per day 
CIOMS 
Council for International Organizations of Medical Sciences 
CRF 
case report form 
dB 
Decibel 
DFE 
dilated fundus examination 
DNA 
deoxyribonucleic acid 
EAP 
Expanded Access Program 
EC 
Ethical Committee 
eCRF 
electronic case report form 
ECG 
Electrocardiogram 
EDC 
electronic data capture 
ERB 
Ethical Review Board 
ETC 
electron transport chain 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
GCP 
Good Clinical Practice 
GCL 
ganglion cell layer 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IOP 
intraocular pressure 
IWRS 
Interactive Web Randomization System 
ISCEV 
International Society for Clinical Electrophysiology of Vision 
LHON 
Leber’s hereditary optic neuropathy 
MD 
mean deviation 
MedDRA 
Medical  Dictionary for Regulatory Activities 
mtDNA 
mitochondrial DNA 
OD 
right eye 
OLE 
Open Label Extension 
OS 
left eye 
OU 
each eye 
PhNR-ERG 
photopic negative response electroretinography 
PT 
preferred term 
RGC 
retinal ganglion cells 
RGCL 
retinal ganglion cell layer 


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Abbreviation 
Definition or Explanation 
RNFL 
Retinal nerve fiber layer 
SAE 
serious adverse event 
SD-OCT 
spectral domain optical coherence tomography 
SLE 
slit lamp examination 
SOC 
system organ class 
SUSARs 
suspected unexpected serious adverse reactions 
US 
United States 
VEGF 
vascular endothelial growth factor 
VFQ-39 
Visual Functioning Questionnaire-39 


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3. 
INTRODUCTION 
Stealth BioTherapeutics Inc. (Stealth) is a biotechnology company with a focus on treating 
mitochondrial dysfunction. Stealth’s lead candidate is elamipretide, a novel tetrapeptide, for the 
treatment of diseases in which mitochondrial dysfunction is an integral component. Stealth has 
conducted preclinical and Phase 1 and 2 clinical studies to assess elamipretide in diseases with 
unmet treatment needs including inherited mitochondrial diseases. 
Optic neuropathies are common to more than 20 inherited mitochondrial diseases (Yu-Wai-Man 
et al. 2011). Leber’s hereditary optic neuropathy (LHON) is the most common mitochondrial 
DNA (mtDNA) disorder.  It results from a single point mutation occurring in mtDNA.  Over 
95% of cases are due to one of three point mutations in the mitochondria genome: m.3460G>A, 
m.11778G>A and m.14484T>C (Schrier and Falk 2011). The disease is maternally transmitted 
and primarily affects young adults between 20 and 30 years of age. Importantly, all three primary 
LHON mitochondrial DNA mutations result in amino acid substitutions in protein subunits that 
compose Complex I of the electron transport chain (ETC). LHON differs from most other 
mitochondrial diseases in that it shows high tissue specificity. Subjects with most other 
mitochondrial diseases have defects in multiple organs, including brain, muscle, heart and other 
vital organs, whereas the clinical features of LHON are usually localized to the eye’s retinal 
ganglion cells. These cells are essential for transmission of visual information from the 
photoreceptors of the retina to the brain, which processes this information into visual images. 
Clinically, LHON is characterized by bilateral sub-acute loss of central vision as a result of 
degeneration of the retinal ganglion layer, initially within the papillomacular bundle. At onset, 
patients describe a loss of color vision in one eye followed by a painless subacute decrease in 
central vision accompanied by an enlarging centrocaecal scotoma (a horizontal oval defect in the 
field of vision situated between and embracing both the point of fixation and the blind spot). 
The presence of mtDNA point mutations is required for the development of LHON, although 
there are other factors that contribute to disease manifestation. Additional genetic and 
environmental factors such as tobacco smoke and drinking alcohol can interact with the primary 
mtDNA defect and determine whether a carrier of one of the genetic mutations ultimately 
develops optic nerve dysfunction leading to blindness. 
A characteristic pathologic finding of LHON is the selective deterioration of retinal ganglion 
cells (RGC) whose axons form the optic nerve. The mechanism(s) that directly links 
mitochondrial dysfunction to the selective vulnerability of the RGC’s is not fully understood. In 
the chronic phase of LHON, patients typically have a bilateral visual deficit that is symmetrical 
and permanent.  Most remain legally blind, unable to drive, or find employment. 
Leber’s hereditary optic neuropathy shows incomplete penetrance with only 50% of male and 
10% of female carriers developing the optic neuropathy in their lifetime. Secondary (non- 
environmental) factors modulating the mitochondrial DNA LHON mutations still remain largely 


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undefined, although the gender bias has been linked to the synergistic influence of visual-loss 
susceptibility loci on the X-chromosome. Genetic factors, however, cannot provide a complete 
explanation for the reduced penetrance. 
In summary, LHON is genetic multifactorial disease, with environmental triggers operating at 
the individual level contributing to the observed intra- and inter-familial variability in 
penetrance. 
MTP-131 reduces mitochondrial oxidative stress by enhancing mitochondrial function via 
selective interaction with cardiolipin.  It has been found effective in multiple preclinical models 
of eye disease. In cultured cells, MTP-131 has been shown to reduce glucose- and peroxide- 
induced oxidative stress, apoptosis and to improve cell survival in human retinal endothelial cells 
(Li et al. 2011), human trabecular meshwork cells (Chen et al. 2011), and human retinal 
pigmented epithelial cells (Liang et al. 2010). Pre-treatment with MTP-131 has been shown to 
protect cultured retinal pigmented epithelium from mitochondrial dysfunction caused by 
repetitive hydroquinone exposure (Cousins, 2015). When given subcutaneously to streptozocin- 
diabetic rats, MTP-131 reduced oxidative stress, prevented apoptosis, and reduced VEGF-2 
receptor expression and retinal leakage of Evans Blue dye (Huang et al. 2013). MTP-131 given 
subcutaneously to high fat and/or streptozotocin diabetic mice prevented and corrected visual 
functional loss (Alam et al. 2012). In a recent open-label, dose-escalation study, two of fifteen 
patients with diabetic macular edema treated for 28 days with topical MTP-131 solution showed 
a greater than twenty percent decrease in central subfield thickness (unpublished data, Stealth 
BioTherapeutics Protocol SPIOC-101). In this study, twenty subjects with either DME or AMD 
were enrolled into one of two dosing cohorts; 0.3% ophthalmic solution to one eye twice daily 
for 28 days or 1.0% ophthalmic solution to one eye twice daily for 28 days. A total of four AEs 
were reported in the study; none were considered related to MTP-131 by the investigator. There 
were no local tolerability issues reported, and there were no significant findings on physical 
examinations, ophthalmic examinations, vital signs or laboratory measurements. It is theorized 
that treatment with MTP-131 of subjects suffering from retinal diseases associated with 
mitochondrial dysfunction may have an effect on mitochondrial oxidative stress levels and 
retinal disease activity. 
SPIFD-101: A 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 has completed treatment of 
16 subjects. This was a Randomized, Double-Masked, Vehicle Controlled Dosing regimen which 
included MTP-131 1.0% topical ophthalmic solution relative to vehicle administered two times 
per day (BID) for 12 weeks, and 4 weeks of follow up evaluation. Two SAEs occurred in one 
subject that were unrelated to study drug; small bowel blockage and dehydration. Both SAEs 
resolved with no sequelae. The subject withdrew from the study during the SAE. No serious 
adverse reactions (SARs), or suspected unexpected SARs (SUSARs) have been reported. 


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SPIFD-101 is extending to a Part B portion and is expected to enroll an additional 11 subjects to 
be treated with 3.0% elamipretide topical ophthalmic solution or vehicle BID for 12 weeks. 


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4. 
STUDY OBJECTIVE 
This study has two parts: a double-masked period and an open-label extension period. The 
objectives for each part of the study are as follows: 
• The objective of the double-masked period is to evaluate the safety, tolerability, and 
efficacy of elamipretide 1.0% topical ophthalmic solution relative to vehicle administered 
two times per day (BID) for 52 weeks in the treatment of LHON. 
• 
The objective of the open-label extension is to evaluate the safety and tolerability over an 
additional 108 weeks of treatment in an open label setting for subjects who complete the 
double-masked period. 
 
5. 
INVESTIGATIONAL PLAN 
5.1. 
Summary of Design 
This is a prospective, randomized, double-masked, vehicle-controlled, single-center study plus 
OLE in which approximately 12 subjects with LHON having the genetic mitochondrial DNA 
mutation m.11778G>A are planned to be randomized in a blinded manner into one of three 
groups in a 1:1:1 ratio: (a) 1 drop of elamipretide 1.0% topical ophthalmic solution BID OS and 
1 drop of vehicle topical ophthalmic solution BID in the fellow eye, (b) 1 drop of elamipretide 
1.0% topical ophthalmic solution BID OD and 1 drop of vehicle topical ophthalmic solution BID 
in the fellow eye, or (c) 1 drop of elamipretide 1.0% topical ophthalmic solution BID OU. After 
completion of the 52-week Treatment Period or the Week 56 follow up period, subjects will be 
invited to participate in the OLE for up to 108 weeks. If a subject does not consent to the OLE, 
he/she will complete the study at the Week 56 (±7 days) visit. There are 4 periods in this study: 
• 
Screening (up to 6 weeks) 
• 
Double-Masked treatment period (52 weeks) 
• 
Open-Label Extension period (108 weeks) 
• 
Follow-up Period (4 weeks) after completion of End of Treatment (EOT) visit (for 
subjects not enrolling in an EAP). 
Screening 
Written informed consent will be obtained from all subjects prior to the Screening Visit. 
Screening procedures may be completed on more than one day, as long as all procedures are 
completed during the Screening Period. All other visits may be completed over a 1 or 2 day 
period, at the discretion of the Investigator, as long as all procedures are completed during the 
allowable window for that visit. 
The Screening examination will be performed no more than 42 days prior to the Baseline visit. 
For applicable female subjects, urine pregnancy testing will be performed prior to initiation of 
treatment. The day of randomization is defined as Study Day 1. 
Once informed consent has been obtained, confirmation of LHON genetic mutation 
m.11778G>A mitochondrial DNA by mitochondrial DNA analysis will be performed, if not 
previously confirmed by written documentation using reliable test methods. Additional data will 
be collected from a complete pre-treatment examination, consisting of vital signs, physical exam, 


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routine blood chemistries and urinalysis, measurement of best corrected visual acuity (BCVA) 
using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, manifest refraction, 
intraocular pressure (IOP) measurement, slit lamp examination, dilated fundus examination, 
fundus photography, Humphrey automated visual field testing (SITA FAST 30-2 stimulus III), 
mean retinal nerve fiber layer and mean retinal ganglion cell layer thickness as measured by 
spectral domain optical coherence tomography (SD-OCT; Cirrus), photopic negative response 
electroretinography (PhNR-ERG), full field ERG and the Visual Functioning Questionnaire-39 
(VFQ-39) to assess visual quality-of-life measures. 
Subjects will undergo Humphrey automated visual field testing at both the Screening (Visit 1) 
and Baseline (Visit 2) visits (performed at least one day apart). In the event that a subject’s two 
visual field tests differ by greater than 5 dB, additional Humphrey automated visual field tests 
may be repeated until a qualifying exam is produced or the investigator suspends repeat 
examination. If the test does not occur on the day of the Baseline Visit, other Baseline 
procedures, which have already been completed, should not be repeated. In order to be 
randomized into the study, subjects must have two visual field tests with results that meet the 
study criteria and that are within 5 dB of each other. 
Double-Masked Treatment Period 
At the time of randomization, training on the proper administration topical ophthalmic solution 
and self-administration (by the subject or regular caregiver) will occur. Subjects will be read a 
standard script explaining the importance of applying the correct drug product to each eye on a 
twice daily basis for the 52-week Treatment Period. Safety, tolerability and efficacy will be 
measured throughout the Treatment Period. After completion of the 52-week treatment period or 
the Week 56 follow up period, subjects will be invited to participate in the OLE for up to 
108weeks. If a subject does not consent to the OLE, depending on when the OLE was offered, 
he/she will either complete the study or continue to be monitored for safety and efficacy during a 
4-week Follow-Up Period and will complete a Week 56 (±7 days) visit. 
Open Label Extension Period 
The OLE will begin after the subject completes the Week 52 or Week 56 visit. Following 
completion of all Week 52 or Week 56 procedures described in the Schedule of Events 
(Attachment 1), subjects will receive a supply of 1.0% elamipretide topical ophthalmic drops for 
self-instillation at home.  Subjects (or trained caregivers) should administer elamipretide OU 
BID every day. Subjects will return to the site for assessments at the 16-Month Visit (Week 68), 
the 20-Month Visit (Week 84), the 24-Month Visit (Week 100), the 28-Month Visit (Week 116), 
the 32-Month Visit (Week 132), the 36-Month Visit (Week 148), and the 39-Month Visit /End of 
Treatment (EOT) Visit (Week 160) as described in the Schedule of Events. Monthly safety 
telephone calls will be conducted between site visits. The script is provided in Sample Monthly 
Telephone Script Attachment 4.  The OLE 4 week follow-up period will begin after completion 
of self-dosing and the OLE EOT visit. During the follow-up period, subjects will continue to 
follow all study requirements. At the end of the follow-up period, subjects will return to the trial 
site for the End-of-Study/Early Termination/Discontinuation visit for final safety and efficacy 
assessments and to return all used and unused bottles and any other study instruments/materials 
to the trial site. Subjects will have the opportunity to continue receiving elamipretide through an 
EAP immediately following the 36-Month Visit (Week 148) or the EOT visit (Week 160). For 
those subjects who consent to the EAP at either visit, there will not be a Follow-Up Period. That 
visit will be considered the End-of-Study visit for these subjects. 


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Note: The end of study may occur following Regulatory approval and commercial availability or 
at the termination of the clinical development of 1% topical elamipretide solution in subjects 
with LHON. 
 
5.2. 
Discussion of Design and Control 
This prospective, randomized, double-masked, vehicle-controlled, Phase 2 clinical study is 
designed to evaluate the safety, tolerability, and efficacy of elamipretide topical ophthalmic 
solution administered at a concentration of 1.0% BID for 52 weeks. The OLE is designed to 
investigate long term safety and efficacy of treatment with elamipretide 1.0% topical ophthalmic 
solution during an additional 108 weeks of treatment. 
 
5.3. 
Schedule of Events 
Study procedures, their timing, and additional details are found in the Schedule of Events, 
Attachment 1. 
 
6. 
STUDY POPULATION 
6.1. 
Number of Subjects Planned 
Approximately 12 subjects will be enrolled in this study. 
 
6.2. 
Study Population 
6.2.1. 
Inclusion Criteria 
A subject must meet the following criteria to be eligible for inclusion in the study: 
1. Adults ≥18 and ≤ 50 years old at the time of loss of vision in the second eye. Loss of vision 
in both eyes of ≥1 year and ≤10 years at the time of the Screening Visit. 
2. Able to provide informed consent and willing to comply with all study visits and 
examinations 
3. Diagnosis of LHON based on clinical and ophthalmic functional/anatomic test findings, and 
satisfactory documentation of the mitochondrial DNA mutation m.11778G>A 
4. 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) 
5. Mean Deviation (MD) between -7.5 and -30 dB on Humphrey automated visual field testing 
(SITA FAST 30-2, stimulus III) on two consecutive tests during the Screening Period. In 
addition, the MD on the two qualifying, consecutive exams must be within 5 dB of each 
other for the subject to qualify for study inclusion. 
Note: As described in the Study Design, up to four Humphrey automated visual field tests are 
allowed during the Screening Period. 
6. Adequate mean retinal nerve fiber layer (RNFL) thickness based on the investigator’s 
assessment with consideration of spectral domain optical coherence tomography (SD-OCT) 
values, such as between 50 and 90 microns (inclusive) OU. 
7. Adequate retinal ganglion cell layer (GCL) thickness based on the investigator’s assessment 
with consideration of SD-OCT values of at least 40 microns OU. 


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8. Media clarity, subject able to undergo pupillary dilation and able to cooperate sufficiently for 
adequate ophthalmic visual function testing and anatomic assessment 
9. Able to self-administer eye drops as demonstrated at screening or having a care provider who 
can do so 
10. Documentation of having satisfactorily completed at least two previous Humphrey automated 
visual field tests prior to screening 
11. If of childbearing potential or in a relationship with a partner of childbearing potential, are 
able to abstain from sex or use acceptable contraception during the study and for 28 days 
after dosing. 
a. For men: Abstinence is only acceptable if it is in line with the preferred and usual 
lifestyle of the subject. The subject also agrees to use an acceptable method of 
contraception should they become sexually active with a partner of child-bearing 
potential. Subjects must use a condom with spermicide from the date of informed 
consent until at least 28 days after the last dose of study drug. Periodic abstinence 
(e.g. calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception. 
b. For women: Abstinence is only acceptable when it is in line with the preferred and 
usual lifestyle of the subject. The subject agrees to use an acceptable method of 
contraception should they become sexually active. Maintenance of a monogamous 
relationship with a male partner who has been surgically sterilized by vasectomy (the 
vasectomy procedure must have been conducted at least 60 days before the Screening 
visit or confirmed via sperm analysis), barrier method (e.g., condom or occlusive cap) 
with spermicidal foam/gel/film/cream AND either hormonal contraception (oral, 
implanted, or injectable) or an intrauterine device or system are acceptable methods. 
 
 
Note: Non-childbearing potential is defined as surgical sterilization (i.e., bilateral 
oophorectomy, hysterectomy, or tubal ligation) or postmenopausal (defined as not having 
a period for at least 12 consecutive months prior to Screening). 
 
6.2.2. 
Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
 
Ocular conditions 
 
1. Any other ocular pathology requiring treatment with prescription topical ophthalmic drops 
(e.g., glaucoma, dry eye) 
2. Cup to disc ratio of > 0.8 in either eye 
3. Any active ocular or peri-ocular infection; any history of recurrent or chronic infection or 
inflammation in the study eye 
4. History of herpetic infection in either eye 
5. History of intra-ocular surgery 
6. Active corneal disease 
7. Current use or likely need for the use of contact lens at any time during the study 
8. Concurrent disease in either the study eye or fellow control eye that could require medical or 
surgical intervention during the study period 
9. Media opacity, suboptimal pupillary dilatation, or severe refractive error that interferes with 


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adequate retinal imaging 
 
Systemic conditions 
10. Known to be immunocompromised or receiving systemic immunosuppression 
11. Any systemic or non-ocular symptoms that in the opinion of the Investigator may be related 
to LHON (i.e. “LHON-plus”), per investigator’s assessment and decision. 
12. Any disease, medical condition or psychological condition that in the opinion of the 
Investigator would prevent the subject from participating in the study or might confound 
study results 
 
General 
13. 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 
14. History of participation in an interventional clinical trial investigating the use of gene therapy 
as a treatment for LHON 
15. History of allergic reaction to the investigational drug or any of its components 
16. History of histamine intolerance (e.g., a known deficiency of endogenous histamine 
degradation) 
17. Current use of or likely need for any excluded medication (idebenone and vitamins 
acceptable) 
18. Women who are pregnant or lactating 
 
6.3. 
Discontinuation 
A subject has the right to withdraw from the study at any time, for any reason. 
 
The Investigator and Sponsor have the right to withdraw a subject from the study in the event of 
an intercurrent illness, adverse event (AE), treatment failure, pregnancy, protocol violation, non- 
compliance with study visits, and for any other reason. An excessive rate of withdrawals would 
render the study uninterpretable; therefore, unnecessary withdrawal of subjects should be 
avoided. 
 
Should a subject decide to withdraw, all efforts will be made to complete and report observations 
as thoroughly as possible.  Appropriate early termination/study discontinuation procedures 
should be followed. 
 
6.4. 
Replacement of Subjects 
In the event that a subject is randomized into the study but is discontinued prior to receiving any 
study drug, then an additional subject may be enrolled. Any other subjects who prematurely 
discontinue from the study will not be replaced and no other additional subjects will be enrolled. 


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7. 
STUDY TREATMENTS 
7.1. 
Dose Modification and Discontinuation of Subject Dosing 
7.1.1. 
Dose Modification 
Dose modification for individual subjects is permitted as below, if the Primary Investigator and 
Sponsor agree it is in the best interest of the subject. A subject who experiences an AE related to 
local tolerability of (e.g., ocular burning/stinging, discharge, or conjunctival erythema) may be 
withdrawn, or instructed to skip a number of days of treatment and/or the subject may be 
instructed to decrease the frequency of dose administration per day for either a number of days or 
until the end of the treatment phase of the study. 
 
7.1.2. 
Dose Justification 
The dose selected for this clinical study is based on data from nonclinical pharmacology studies 
in metabolically stressed mice, where both 1% and 3% MTP-131 applied topically once daily has 
been associated with restoration of visual function in a dose dependent manner (Prusky et al 
2004). Additionally, MTP-131 given subcutaneously to high fat and/or streptozotocin diabetic 
mice prevented and corrected visual functional loss (Alam et al. 2012) and subcutaneously to 
streptozotocin-diabetic rats reduced oxidative stress, prevented apoptosis, and reduced VEGF-2 
receptor expression and retinal leakage of Evans Blue dye (Huang, Li et al. 2013). 
 
In the completed SPIOC-101 clinical trial, twice daily dosing with elamipretide topical 
ophthalmic solution administered at either 0.3% or 1.0% was well tolerated and no safety issues 
emerged at either dose during twenty-eight days of daily treatment. Four unrelated, non- 
ophthalmic adverse events were reported, and there were no reports of local tolerability issues. 
This is consistent with the 90-day toxicology studies, completed in rabbits and dogs, and in the 
39-week toxicity study in dogs, in which no treatment-related systemic toxicity or ocular 
pathology affecting the major vision critical structures of the eye was observed. 
 
Mononuclear cell infiltrates in the palpebral and bulbar conjunctivae and nictitating membranes 
were observed in the more sensitive species (dog), which regressed during a recovery phase. 
Although the aforementioned preclinical toxicological findings were reversible upon cessation of 
treatment, in any patient complaining of persistent, local ocular irritation such as stinging or 
burning upon instillation of drops, the elamipretide treatment regimen should be reduced or 
stopped. 
 
7.2. 
Treatment of Subjects 
7.2.1. 
Randomization 
On study Day 1, each subject will be randomized in a blinded manner into one of three groups in 
a 1:1:1 ratio: (a) 1 drop of elamipretide 1.0% topical ophthalmic solution BID OS and 1 drop of 
vehicle topical ophthalmic solution BID in the fellow eye, (b) 1 drop of elamipretide 1.0% 
topical ophthalmic solution BID OD and 1 drop of vehicle topical ophthalmic solution BID in 
the fellow eye, or (c) 1 drop of elamipretide1.0% topical ophthalmic solution BID OU. After 
completion of the Week 52 or Week 56 visit, all subjects consenting to the OLE will be provided 
with elamipretide topical ophthalmic 1.0% solution for use OU BID. 


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7.2.2. 
Study Drug Identification 
All study drug is intended for ophthalmic administration. Elamipretide topical ophthalmic 
solution and/or vehicle are supplied as a 1.0% solution packaged in one of three configurations: 
 
1. In white, 10 mL high density polyethylene bottles with a dropper top. Each bottle 
contains nominally 3 mL of solution as either study drug (elamipretide 1.0% topical 
ophthalmic solution) or vehicle. Each bottle also contains sodium chloride appropriate 
for isotonicity and acetic acid and/or sodium hydroxide as needed for pH adjustment. 
Each bottle should be opened and used to dose the subject’s single eye twice in one day. 
 
2. In Low Density Polyethylene (LDPE) ampoules also known as blow fill seal units. These 
are single use units that are manufactured in cards of 4 units and enclosed in a foil pouch. 
The ampoules contain nominally 0.3 mL of the same solutions of study drug or vehicle. 
Each ampoule should be used once to dose into the patient’s single eye. Each pouch of 
four units contains enough doses for two days per eye. 
 
3. Elamipretide ophthalmic sterile solution consisting of a sterile, aqueous, isotonic, clear 
elamipretide solution in a multi-use 7.5 mL polypropylene ophthalmic dropper 
dispensing bottle that dispenses approximately 40 µL in each drop. The elamipretide 
solution is formulated at 10 mg/ml (1%) mg/mL in isotonic phosphate buffer, sodium 
chloride, and benzalkonium chloride (preservative). Solution pH is adjusted with sodium 
hydroxide or hydrochloric acid. Each bottle contains a 30 day supply of BID drops for 
both eyes. 
 
7.2.3. 
Packaging, Labeling, and Storage 
Clinical study: Study drug will be supplied in kits or cartons as a supply for each eye during the 
treatment period. Kits designated for use in the right eye will be labeled with a red border and 
have a kit number starting with the letter “R” and should only be used in the subject’s right eye. 
Kits designated for use in the left eye will have no border and will be labeled with a kit number 
starting with the letter “L” and should only be used in the subjects left eye. 
 
OLE (single dose bottle-one a day): Study drug, supplied in kits of 8 10mL high density 
polyethylene bottles with a dropper top containing 3mL of 1.0% elamipretide topical ophthalmic 
solution, will be supplied as open label stock labeled for use in both eyes. 
 
OLE (multi-dose bottle - monthly): Study, drug, supplied as a one (1) x 7.5 mL polypropylene 
bottle with a dropper top nozzle and cap containing 6.5 mL of 10mg/ml (1%) elamipretide 
topical ophthalmic solution, will be supplied as open label stock labelled for use in both eyes for 
one (1) month. 
 
Study drug supplies are to be stored in a secure area refrigerated (2-8°C) while at the 
investigative site, and are to be stored in a refrigerator by the subject. 
 
7.2.4. 
Supply and Disposition of Treatments 
Double-masked period: An Interactive Web Randomization System (IWRS) will be used to 
designate patients to receive one of three treatment regimens from the following for the duration 
of the study: 


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• 
Active in right eye, placebo in left eye 
 
• 
Active in left eye, placebo in right eye 
 
• 
Active in both the left eye and right eye 
 
On the first treatment day and periodically thereafter, each subject will receive a kit with the 
appropriate quantity of doses containing a solution of the active ingredient or a placebo solution 
and labeled in a masked fashion. The patient will be instructed to administer one drop in each 
eye twice in a given day for the duration of the study. 
 
Patients will receive the investigational product either directly from the Investigator’s staff or a 
contract organization responsible for shipping supplies to each study subject in accordance with 
instructions provided by the Sponsor. Each kit of supply is intended to provide therapy for a 
single eye for a specific number of days. All remaining solution will be reconciled according to 
the Sponsor’s instructions. All supplies are to be stored refrigerated prior to use. Detailed 
instructions to the patient for use, storage, and shipping will be provided with each supply of the 
investigational drug product. 
 
OLE period: Open label treatment will be assigned by the site.  An initial supply of treatment 
will be provided to the patient at each site visit. Additional supplies may be dispensed or shipped 
to the patient via a contract organization responsible for shipping supplies to study patients. The 
patient will be instructed to administer one drop in each eye twice a day for the duration of the 
OLE. 
 
7.2.5. 
Treatment Logistics and Accountability 
All drug accountability records must be kept current, and the Investigator must be able to 
account for all used and unused study drug. These records should contain the dates, quantity, 
and study medication: 
 
• 
Received at site 
• 
Dispensed to each subject, 
• 
Returned from each subject and 
• 
Disposed of at the site or returned to the Sponsor or designee. 
Double-masked period: Subjects will be asked to return study drug supplies at the Week 4, Week 
8, Week 12, Week 16, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, and Week 
44, Week 48, and Week 52 visits. The clinical monitor responsible for the study site will provide 
written approval for the destruction or return of unused study medication following 
reconciliation of all clinical supplies. 
OLE period: Subjects will be asked to return study drug supplies at Week 68, 84, 100, 116, 132, 
148, and 160 visits. A contract organization responsible for shipping supplies to study subjects 
may be utilized to collect and return study drug supplies to the site for accountability. The 
clinical monitor responsible for the study site will provide written approval for the destruction or 
return of unused study medication following reconciliation of all clinical supplies. 
 
7.2.6. 
Treatment Compliance 


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All study drug compliance records must be kept current and must be made available for 
inspection by the Sponsor and regulatory agency inspectors. 
 
7.3. 
Masking and Unmasking 
Double-masked portion: This is a double-masked study. Treatment assignment will not be 
known to the subjects, the Sponsor, or the staff who are involved in the clinical evaluation of the 
subjects and the analysis of data. 
Unmasking the subject allocation to treatment for the purposes of treating AEs is performed 
through the IWRS, which may supplement or take the place of emergency codes generated by a 
computer drug-labeling system. This option may be used ONLY if the subject’s well-being 
(related to one or both eye(s)) requires knowledge of the subject’s treatment assignment. As all 
subjects are exposed to active drug, systemic AEs do not require unmasking. All instances of 
unmasking will be recorded and reported by the IWRS. 
If an Investigator, site personnel performing assessments, or subject is unmasked, the subject 
must be discontinued from the study. In cases where there are ethical reasons to have the subject 
remain in the study, the Investigator must obtain specific approval from the Sponsor for the 
subject to continue in the study. 
In case of an emergency, the Investigator has the sole responsibility for determining if 
unmasking of a subject’s treatment assignment is warranted. Subject safety must always be the 
first consideration in making such a determination. If the Investigator decides that unmasking is 
warranted, the Investigator should make every effort to contact the Sponsor prior to unmasking a 
subject’s treatment assignment. If a subject’s treatment assignment is unmasked, the Sponsor 
must be notified immediately. 
OLE portion: Subjects will be assigned to open label treatment, with all subjects consenting to 
participation, receiving 1.0% elamipretide topical ophthalmic solution. 
 
7.4. 
Study Visit Descriptions 
Study procedures, their timing, and additional details are found in the Schedule of Events, 
Attachment 1.  A list of all clinical laboratory tests to be performed is found in Attachment 2. 
Screening procedures may be completed on more than one day, as long as all procedures are 
completed during the Screening Period. All other visits may be completed over a 1 or 2 day 
period, at the discretion of the Investigator, as long as all procedures are completed during the 
allowable window for that visit. 
 
7.4.1. 
Clinical Study 
 
7.4.1.1. 
Screening (Day -42 to Day -2) Visit 1 
Written ICF will be obtained from all subjects prior to conducting any screening procedures. 
After the subject has provided the signed ICF, the following assessments and procedures will be 
conducted: 
Assess inclusion and exclusion criteria 
Mitochondrial DNA analysis to confirm genetic mutation m11778G>A status (if not previously 
confirmed by written documentation using reliable test methods) 


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Demographics including ethnicity, race, eye color, history of smoking, and alcohol use 
Medical/ocular history and concurrent illnesses 
Concomitant medications 
Adverse events. (Note: An AE that occurs between the time the subject signs the ICF and the 
time the subject is dosed with study drug will be summarized in the medical history electronic 
case report form [eCRF] and not recorded as an AE unless the event meets the definition of a 
serious adverse event (SAE). This applies to screen failures as well. For subjects who fail 
screening, AEs and updates [if applicable] must be recorded in the medical history eCRF until 
the date the subject was determined to have failed screening.) 
Vital signs including temperature, sitting blood pressure after sitting for 5 minutes, and pulse 
Physical examination (physical examination will include general appearance, skin, chest, heart, 
abdomen, extremities, and nervous system) 
Electrocardiogram (ECG) (all scheduled ECGs must be performed after the subject has rested 
quietly for at least 5 minutes in the supine position) 
Blood draw for hematology and chemistry 
Serum pregnancy test (women of child bearing potential only) 
Manifest refraction and BCVA testing per ETDRS protocol 
Intraocular pressure (IOP) 
Color discrimination and contrast sensitivity 
Ophthalmic examination including slit lamp examination (SLE) and dilated fundus examination 
(DFE) 
Spectral domain optical coherence tomography (SD-OCT; Cirrus) for RNFL and RGCL 
thickness 
Fundus photography 
Humphrey automated visual field examination 
Photopic negative response electroretinography (PhNR-ERG) 
Full Field ERG 
7.4.1.2. 
Baseline (Day 1) Visit 2 
The following procedures and assessments will be conducted: 
Inclusion and exclusion criteria 
Concomitant medications 
AEs (prior to study drug administration, AEs are captured as medical history, unless they qualify 
as SAEs) 
Vital signs including temperature, sitting blood pressure, and pulse 
ECG 
Blood draw for hematology and chemistry 


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Urinalysis 
BCVA testing per ETDRS protocol 
IOP 
Ophthalmic examination including SLE and DFE 
SD-OCT for RNFL and RGCL thickness 
Humphrey automated visual field examination 
PhNR-ERG 
Visual Functioning Questionnaire-39 (VFQ-39) 
Color discrimination and contrast sensitivity 
Serum for phosphorylated axonal neurofilament analysis (Optional: per subject secondary use 
consent) 
Serum for mitochondrial DNA copy number (Optional: per subject secondary use consent) 
Urine pregnancy test (for women of child-bearing potential only) 
In order to be deemed eligible for the study, the results of both the Screening and Baseline 
Humphrey automated visual field exams must meet study criteria and be within 5 dB of one 
another. If the Screening and Baseline exams are not within 5 dB of one another, the Humphrey 
automated visual field exam may be repeated, as discussed in Summary of Design (Section 5.1). 
Subjects deemed eligible for the study based on the above assessments will then undergo the 
following: 
 
• 
Randomization to the study; the day of randomization is defined as Study Day 1 
• 
Training on the proper administration of topical ophthalmic solution 
• 
Medication dispensed 
7.4.1.3. 
Day 5 (± 2 days), Week 4 (± 4 days), Week 8 (± 4 days), Week 12 (± 4 days), 
Week 16 (± 7 days), Week 20 (± 7 days), Week 24 (± 7 days), Week 28 (± 7days), 
Week 32 (± 7 days), Week 36 (± 7 days), Week 40 (± 7 days), Week 44 (± 7 
days), Week 48 (± 7 days) Visits 
The following information will be collected: 
Concomitant medications 
AEs 
The following procedures and assessments will be conducted: 
Vital signs including temperature, sitting blood pressure, and pulse 
BCVA testing per ETDRS protocol 
IOP 
SLE and DFE 
Color discrimination and contrast sensitivity 


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Humphrey automated visual field examination 
PhNR-ERG (not on Day 5) 
Blood for safety 
Medication dispensed 
Medication returned 
7.4.1.4. 
Week 52 (± 7 days)/End of Treatment Visit 
The following information will be collected: 
Vital Signs 
Physical Exam 
Blood for Safety 
Urine pregnancy test (for women of child-bearing potential) 
ECG 
ETDRS BCVA 
IOP 
Color discrimination and contrast sensitivity 
Slit lamp & fundus exam 
SD-OCT for RNFL and GCL thickness 
Fundus Photography 
Humphrey automated visual field examination (SITA FAST 30-2, stimulus III) 
PhNR-ERG 
Full field ERG 
Quality of Life Questionnaire (VFQ-39) 
Serum for phosphorylated axonal neurofilament analysis (Optional per subject secondary use 
consent) 
Serum mitochondrial DNA copy number (Optional per subject secondary use consent) 
Medication Returned 
Adverse Events 
Concomitant medications 
Invite subjects to participate in the OLE; obtain informed consent from willing subjects 
 
7.4.1.5. 
Week 56 (± 7 days)/End-of-Study Visit (Follow-up Period) 
All of the assessments listed in Section 7.4.1.4 will be conducted, as well as the following: 
Urine pregnancy test (for women of child-bearing potential only) 
Manifest refraction 


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Serum for phosphorylated axonal neurofilament analysis (Optional: per subject secondary use 
consent) 
Serum mitochondrial DNA copy number (Optional: per subject secondary use consent) 
VFQ-39 
PhNR-ERG 
Invite subjects who were not offered participation in the OLE at the prior visit (Week 52) to 
consider participation; obtain informed consent from willing subjects 
 
7.4.1.6. 
Early Discontinuation Visit 
All of the assessments listed in Section 7.4.1.4 will be conducted, as well as the following: 
ECG 
Fundus photography 
SD-OCT for RNFL and GCL thickness 
PhNR-ERG 
Full-field ERG 
VFQ-39 
Physical examination 
Blood for safety 
Serum for phosphorylated axonal neurofilament analysis (Optional: per subject secondary use 
consent) 
Serum for mitochondrial DNA copy number (Optional: per subject secondary use consent) 
Urine pregnancy test (for women of child-bearing potential only) 
Medication returned 
 
7.4.2. 
Open Label Extension 
 
7.4.2.1. 
Week 52 or Week 56 Visit 
 
When the subject agrees to participate in the OLE (whether Week 52 or Week 56), the following 
assessments/procedures will be performed. 
 
Written ICF will be obtained from all subjects prior to conducting any OLE procedures. 
Train the patient on the proper administration of the OLE topical ophthalmic solution 
Dispense OLE supplies 
Instruct the patient to self-dose with OLE medication in the evening of the beginning of the 
OLE. 
Schedule return visit; remind patient to expect a telephone contact in approximately one month. 
 
7.4.2.2. 
Week 68, 84, and 100 (± 14 days) Visit and Week 116, 132, 148 and 160 (± 7 


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days) Visit 
The following information will be collected: 
Vital signs 
Blood chemistry and hematology 
EDTRS BCVA 
Manifest Refraction 
IOP 
Color discrimination and contrast sensitivity 
Slit lamp and dilated fundus exam 
Humphry Automated Visual Field exam 
PhNR-ERG 
Full Field ERG (Week 100 and Week 148 only) 
SD-OCT for RNFL and GCL (Week 148 only) 
Fundus Photography (Week 148 only) 
Quality of Life questionnaire (Week 148 only) 
AE collection 
Concomitant Medication collection 
Medication dispensed (excluding Week 160, and week 148 if enrolling in an EAP) 
Medication returned. A contract organization responsible for shipping supplies to study subjects 
may be dispatched to collect and return study drug supplies to the site for accountability. 
Schedule next site visit 
For subjects continuing into an EAP after the Week 148 or EOT visit (Week 160), in addition to 
the assessments above, the following will also be collected: 
Physical Exam 
Urine pregnancy test (for women of child-bearing potential) 
Collect all used and unused open-label supplies. A contract organization responsible for shipping 
supplies to study subjects may be dispatched to collect and return study drug supplies to the site 
for accountability 
 
 
7.4.2.3 
Monthly Safety Telephone Calls (approximately every 4 weeks between site 
visits) 
Monthly safety telephone calls should follow the monthly telephone script provided in 
Attachment 4. 


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Document concomitant medication (including supplements and vitamins) since the last site visit 
or monthly safety telephone call 
Document AEs 
Assess and document general compliance with open label self-dosing; document any reported 
missed doses 
 
7.4.2.4 
Week 164 End of OLE/Early Termination/Discontinuation (± 7 days) Visit 
Document concomitant medication (including supplements and vitamins) since the last site visit 
or monthly safety telephone call 
Document AEs 
Physical Exam 
Vital signs 
Blood chemistry and hematology 
Urine pregnancy test (for women of child-bearing potential) 
EDTRS BCVA 
Manifest Refraction 
IOP 
Color discrimination and contrast sensitivity 
Slit lamp and dilated fundus exam 
SD-OCT for RNFL and GCL 
Fundus Photography 
Humphry Automated Visual Field exam 
PhNR-ERG 
Quality of Life questionnaire 
Collect all used and unused open-label supplies. A contract organization responsible for shipping 
supplies to study subjects may be dispatched to collect and return study drug supplies to the site 
for accountability 
 
7.4.2.5 
Unscheduled Visits 
All attempts should be made to keep subjects on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for 
any other reason, as warranted. 
 
7.5. 
Concomitant and Prohibited Medications 
 
From 30 days prior to Baseline until the Follow-up Visit, subjects may not use any of the 
following medications: 
 
• 
Medications known to be toxic to the lens, retina or optic nerve.  Examples include 


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deferoxamine, chloroquine/hydroxychloroquine (Plaquenil), tamoxifen, phenothiazines, 
ethambutol, and aminoglycosides 
• 
Systemic immunosuppressive drugs 
• 
Any topical medications (approved or investigational) for any ocular condition in either 
eye other than the study medication. Systemic medications (prescription or non- 
prescription) for the treatment of ocular conditions may be used if deemed safe and 
appropriate by both the Primary Investigator and the Sponsor 
 
All other medications must be used at a stable dose from the time of signing the ICF until the 
follow-up visit. 


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8. 
EFFICACY, SAFETY EVALUATIONS, SAMPLE COLLECTION 
AND TESTING, AND APPROPRIATENESS OF 
MEASUREMENTS 
8.1. 
Efficacy Measures 
The efficacy measures for this study are: 
• 
Change from Baseline in PhNR-ERG response pattern 
• 
Change from Baseline in visual field MD as measured by Humphrey automated visual 
field testing stimulus III 
• 
Change from Baseline in color discrimination / contrast sensitivity 
• 
Change from Baseline in BCVA 
• 
Change from Baseline in VFQ-39 score 
• 
Change from Baseline in mean retinal nerve fiber layer thickness by SD-OCT 
• 
Change from Baseline in mean retinal ganglion cell layer thickness by SD-OCT 
8.1.1. 
Appropriateness of Measures 
All measures used to assess safety and efficacy in this study are consistent with those widely 
used and generally recognized as reliable, accurate, and relevant. 
 
8.1.1.1. 
Photopic Negative Response Electroretinography 
Photopic negative response electroretinography (PhNR –ERG) is an electrophysiological 
technique for assessing ganglion cell function (Preiser, 2013); it is a component of the flash 
ERG, which follows after the “b wave.”  Data from patients suffering from glaucoma suggests 
that a decrease in the amplitude of this component of the ERG is associated with pathologic RGC 
activity (Viswanathan, 2001). It is hypothesized that patients suffering from LHON may have a 
decrease in the amplitude of the PhNR-ERG (i.e., become less negative), which may increase 
(i.e., become more negative) with interventions designed to improve retinal ganglion cell 
function. 
 
8.1.1.2. 
Contrast Sensitivity 
Contrast sensitivity will be measured using the Pelli-Robson Contrast Sensitivity Chart. 
 
8.1.1.3. 
Color Discrimination 
Color discrimination will be measured using the Ishihara Color TestBest Corrected Visual Acuity 
Best corrected visual acuity will be measured using the ETDRS scale. 
 
8.1.1.4. 
Visual Field Testing 
Visual Field Mean Deviation will be measured using Humphrey automated visual field testing 
stimulus III. 
 
8.1.1.5. 
Full field ERG 
Full field ERG will be performed in compliance with the ISCEV standard. 


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8.2. 
Safety Evaluations 
The Investigator is responsible for monitoring the safety of subjects who have entered this study 
and for alerting the Sponsor or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the subject. The Investigator is responsible for the 
appropriate medical care of subjects during the study. The Investigator remains responsible for 
following, through an appropriate health care option, AEs that are serious, considered related to 
the study treatment or the study procedures, or that caused the subject to discontinue before 
completing the study. 
The safety profile of elamipretide will be assessed through the recording, reporting, and 
analyzing of adverse events, clinical evaluations, and laboratory tests. 
Comprehensive assessment of any apparent toxicity experienced by study subjects will be 
performed throughout the course of the study, from the time of the subject’s signature of 
informed consent. Study site personnel will report any AE, whether observed by the Investigator 
or reported by the subject.  The reporting period for AEs is described in Section 8.6. 
8.2.1. 
Adverse Events 
An AE is defined as any untoward medical occurrence in the form of signs, symptoms, abnormal 
laboratory findings, or diseases that emerge or worsen relative to Baseline during administration 
of an Investigational Medicinal Product (IMP), regardless of causal relationship. 
Adverse Events may include the following: 
• 
Suspected adverse drug reactions: side effects known, or suspected, to be caused by the 
IMP 
• 
Other medical experiences, regardless of their relationship with the IMP, such as injury, 
surgery, accidents, extensions of symptoms or apparently unrelated illnesses, and 
significant abnormalities in clinical laboratory values, psychological testing, or physical 
examination findings 
• 
Events occurring as a result of protocol interventions (pre- or post-IMP administration) 
• 
Reactions from IMP overdose, abuse, withdrawal, sensitivity, or toxicity. 
8.3. 
Pretreatment Events 
Untoward events and/or incidental diagnoses that occur prior to IMP administration are by 
definition, unrelated to the study drug. Pretreatment events or incidental diagnoses will be 
recorded on the past medical history eCRF. However, if a pretreatment event is assessed by the 
Investigator as related to a study procedure and/or meets seriousness criteria (criteria for an 
SAE), it will be recorded as an AE on the AE eCRF and processed and followed accordingly. 
8.4. 
Baseline Medical Conditions 
Those medical conditions related to the disease under study whose changes during the study are 
consistent with natural disease progression, or which are attributable to a lack of clinical efficacy 
of the IMP, are NOT considered as AEs and should not be recorded as such in the eCRF. These 
conditions are handled in the efficacy assessments and should be documented on the medical 
history page of the eCRF. 


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Baseline medical conditions, not in the therapeutic area of interest/investigation, that worsen in 
severity or frequency during the study should be recorded and reported as AEs. 
8.4.1. 
Abnormal Laboratory and Other Abnormal Investigational Findings 
Abnormal laboratory findings and other objective measurements should NOT be routinely 
captured and reported as AEs. However, abnormal laboratory findings or other objective 
measurements that: 
• 
meet the criteria for a SAE 
• 
result in discontinuation of the Investigational Medicinal Product, 
• 
require medical intervention or 
• 
are judged by the Investigator to be clinically significant changes from Baseline should 
be reported on the AE pages of the eCRF. 
When reporting an abnormal laboratory finding on the AE pages of the eCRF, a clinical 
diagnosis should be recorded rather than the abnormal value itself, if this is available (for 
example, “anemia” rather than “decreased red blood cell count” or “hemoglobin = 10.5 g/dl”). 
8.4.2. 
Serious Adverse Events 
A SAE is any AE that: 
• 
Results in death. In case of a death, the cause of death is used as the AE term, and the 
fatality is considered as the OUTCOME. 
• 
Is life-threatening. The term “life-threatening” refers to a SAE in which the subject is at 
risk of death at the time of the event; it does not refer to an event that hypothetically 
might cause death if it were more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital anomaly or birth defect 
• 
Is otherwise medically important: Important medical events may be considered as SAEs 
when, based upon medical judgment, they may jeopardize the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
For the purposes of reporting, any suspected transmission of an infectious agent via an IMP is 
also considered an SAE and all such cases should be reported in an expedited manner as 
described in Section 8.7. 
8.4.3. 
Events that Do Not Meet the Definition of a Serious Adverse Event 
Elective hospitalizations to simplify study treatment or study procedures (e.g., an overnight stay 
to facilitate chemotherapy and related hydration therapy application) are not considered as SAEs. 
However, all events leading to unplanned hospitalizations (not documented prior to ICF signing) 
or unplanned prolongation of an elective hospitalization (e.g., undesirable effects of any 
administered treatment) must be documented and reported as SAEs. 
8.4.4. 
Recording of Adverse Events 
Complete, accurate, and consistent data on all AEs experienced for the duration of the reporting 
period will be recorded on an ongoing basis in the appropriate section of the eCRF. Among 


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these AEs, all SAEs must be additionally documented and reported using the study specific SAE 
eCRF, as described in Section 8.7. 
It is important that each AE report include a description of the event along with the duration 
(onset and resolution dates), severity, relationship to IMP, potential causal/confounding factors, 
treatment given or other action taken (including dose modification or discontinuation of the 
IMP), and the outcome.  Ocular AEs must include which eye(s) are involved. 
As the quality and precision of acquired AE data are critical, Investigators should use the AE 
definitions provided and should observe the following guidelines when completing the AE pages 
of the eCRF: 
• 
Whenever possible, recognized medical terms should be used to describe AEs rather than 
lay terms (for example, ‘influenza’ rather than ‘flu’), and abbreviations should be 
avoided. 
• 
Adverse events should be described using a specific clinical diagnosis, if available, rather 
than a list of signs or symptoms (for example, ‘congestive heart failure’ rather than 
‘dyspnea, rales, and cyanosis’). However, signs and symptoms that are not associated 
with an identified disease or syndrome, or for which an overall diagnosis is not yet 
available, should be reported as individual AEs. 
• 
Provisional diagnoses (eg, “suspected myocardial infarction”) are acceptable, but should 
be followed up with a definitive diagnosis if later available. Similarly, a fatal event with 
an unknown cause should be recorded as “death of unknown cause.” 
• 
In cases of surgical or diagnostic procedures, the condition or illness leading to the 
procedure is considered the AE rather than the procedure itself. 
Adverse events occurring secondary to other events (eg, sequelae or complications) should be 
identified by the primary cause. A primary AE, if clearly identifiable, generally represents the 
most accurate clinical term to record in the eCRF. 
8.5. 
Investigator Assessments 
8.5.1. 
Severity/Intensity 
Investigators must assess the severity/intensity of AEs according to the following qualitative 
toxicity scale: 
Mild: 
The subject is aware of the event or symptom, but the event or symptom is 
easily tolerated. 
Moderate: 
The subject experiences sufficient discomfort to interfere with or reduce his 
or her usual level of activity. 
Severe: 
Significant impairment of functioning: the subject is unable to carry out usual 
activities. 


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8.5.2. 
Relationship to the Investigational Medicinal Product 
Investigators must systematically assess the causal relationship of AEs to the IMP using the 
following definitions (the decisive factor being the temporal relationship between the AE and 
administration of the IMP): 
Probable: 
A causal relationship is clinically/biologically highly plausible, there is a 
plausible time sequence between onset of the AE and administration of the 
IMP, and there is a reasonable response on withdrawal. 
Possible: 
A causal relationship is clinically/biologically plausible and there is a 
plausible time sequence between onset of the AE and administration of the 
IMP. 
Unlikely: 
A causal relationship is improbable and another documented cause of the 
AE is most plausible. 
Unrelated: 
A causal relationship can be excluded and another documented cause of the 
AE is most plausible. 
8.6. 
Adverse Event Reporting Period 
The AE reporting period begins when the subject signs the informed consent and continues 
through the post-treatment Follow-Up Period defined as 30 days after last administration of 
study drug. For patients continuing treatment with elamipretide through an EAP at the week 148 
or EOT visit, the AE reporting period will end at the that visit. Within a study, all subjects who 
took at least 1 dose of IMP, whether they completed the Treatment Period or not, should enter 
the 30-day safety Follow-Up Period as defined above, unless enrolling in an EAP. 
New protocol-related AEs (caused by any intervention required by the protocol) and updates on 
all AEs ongoing or with an unknown outcome must be recorded until the last subject visit 
required by the protocol. A last batch of queries will be sent after the last study visit if remaining 
ongoing/unknown outcomes of reported AEs are pending.  However, SAEs and medically 
relevant ongoing/unknown outcome AEs will be followed until resolution or stabilization by the 
Sponsor’s Pharmacovigilance department. 
Beyond the defined reporting period, any new unsolicited SAE spontaneously reported to the 
Sponsor by the Investigator will be collected and processed. This and any additional information 
on SAEs obtained after database lock will reside solely in the Pharmacovigilance study file. 
If a subject is documented as lost-to follow-up, ongoing/unknown outcome AEs will not be 
followed. 


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For subjects who fail screening, AEs and updates must be recorded in the medical history eCRF 
until the date the subject was determined to have failed screening. Beyond that date, only SAEs 
and medically relevant AEs will be followed by the Sponsor’s Pharmacovigilance group and all 
data will be housed within the Pharmacovigilance study file. 
8.7. 
Serious Adverse Event Expedited Reporting 
In the event of an SAE occurring during the reporting period, the Investigator must immediately 
(e.g., within a maximum of 24 hours after becoming aware of the event) inform the Sponsor as 
detailed in the Clinical Study Pharmacovigilance Procedural Manual. 
For any SAE, the following minimum information is required as initial notification: 
• 
Investigator/Reporter with full contact information 
• 
Subject identification details (study number, site number, subject number) 
• 
Investigational medicinal product administration details (dose and dates) 
• 
Event verbatim, a brief description of signs/symptoms/or diagnosis and the date of onset 
• 
Seriousness criteria(ion) met 
• 
Relationship of the event to the IMP (e.g., the causality according to the Investigator) 
Reporting procedures and timelines are the same for any new information (follow-up) on a 
previously reported SAE. 
All SAE reports must be completed as described in the eCRF completion guidelines and 
submitted to the Drug Safety through the Electronic Data Capture (EDC) system of the clinical 
database. Other relevant information from the clinical database (including demographic data, 
medical history, concomitant medication, and study drug dosing information) will automatically 
be sent to the Sponsor's safety department via the EDC system when the SAE form is submitted. 
For names, addresses, and telephone and fax numbers for SAE back-up reporting, refer to the 
information included in the Clinical Study Pharmacovigilance Procedural Manual. 
The Investigator/Reporter must respond to any request for follow-up information (eg, additional 
information, outcome and final evaluation, specific records where needed) or to any question the 
Sponsor may have on the SAE within the same timelines as described for initial reports. This is 
necessary to permit a prompt assessment of the event by the Sponsor and (as applicable) to allow 
the Sponsor to meet strict regulatory timelines associated with expedited safety reporting 
obligations. 
8.8. 
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator as related to study treatment (e.g., resulting 
from an interaction between study drug and a contraceptive medication) are considered adverse 
events unto themselves. However, all pregnancies with an estimated conception date during the 
AE reporting period, as defined in Section 8.6 must be recorded in the AE section of the eCRF. 
This applies to both pregnancies in female subjects and in female partners of male subjects. 
Female partners of male subjects will be consented to collection of their personal health 
information. 


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The Investigator must notify the Sponsor in an expedited manner of any pregnancy using the 
Pregnancy Form and the back-up reporting procedure as described Clinical Study 
Pharmacovigilance Procedural Manual. Investigators must actively follow-up, document, and 
report on the outcome of all pregnancies, even if subjects are withdrawn from the study. 
The Investigator must notify the Sponsor of these outcomes using Section II of the Pregnancy 
Form and submit the information using the back-up reporting procedure. Any abnormal outcome 
must be reported in an expedited manner, while normal outcomes must be reported within 
45 days from delivery. 
In the case of an abnormal outcome, whereby the mother sustains an event, the SAE Report 
Form is required and will be submitted as described above. 
8.9. 
Responsibilities to Regulatory Authorities, Investigators, Ethics 
Committees, and Ethical/Institutional Review Boards 
The Sponsor will send appropriate safety notifications to regulatory authorities in accordance 
with applicable laws and regulations. 
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs involving his/her subjects to the Ethics Committee and/or Ethical/Institutional 
Review Board (EC/ERB/IRB) that approved the study. 
In accordance with International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines, the Sponsor will inform the Investigator of findings that could adversely affect 
the safety of subjects, impact the conduct of the study, or alter the EC’s/IRB’s 
approval/favorable opinion to continue the study. In particular, and in line with respective 
regulations, the Sponsor will inform the Investigator of AEs that are both serious and unexpected 
and are considered to be related to the administered product (suspected unexpected serious 
adverse reactions [SUSARs]). The Investigator should place copies of these safety reports in the 
Investigator site file. National regulations with regard to safety report notifications to 
Investigators will be taken into account. 
When specifically required by regulations and guidelines, the Sponsor will provide appropriate 
safety reports directly to the IRB and will maintain records of these notifications. When direct 
reporting by the Sponsor is not clearly defined by national or site-specific regulations, the 
Investigator will be responsible for promptly notifying the concerned IEC/IRB of any safety 
reports provided by the Sponsor and of filing copies of all related correspondence in the 
Investigator site file. 
For studies covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/SUSARs will be carried out in accordance with that directive 
and with the related detailed guidance’s. 


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8.10. 
Sample Collection and Testing 
Attachment 1 lists the study procedures, their timing, and additional details for the double 
masked portion of the study 
Attachment 2 lists the study procedures, their timing, and additional details for the OLE portion 
of the study. 
Attachment 3 lists the laboratory tests that may be performed for this study. 


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9. 
STUDY VARIABLES AND STATISTICAL ANALYSIS 
9.1. 
Determination of Sample Size 
For this Phase 2 study plus OLE, the sample size of 12 subjects is based on the rarity of the 
disease under investigation and is reasonably sized for demonstrating clinical safety, tolerability, 
and a preliminary signal regarding efficacy. 
 
9.2. 
Statistical and Analytical Plans 
9.2.1. 
General Considerations 
This study has a double-masked treatment component, in which comparisons of the elamipretide 
treated eye will be compared to the vehicle treated eye. Outcomes for the double-masked period 
will be analyzed consistent with this design characteristic. 
This study also has an open-label treatment component, in which both eyes will receive 
elamipretide treatment. The key outcomes of interest will be the comparison of the vehicle eye 
outcomes (per the double-masked treatment period) to the continued outcomes from the 
elamipretide eye (also from the double-masked treatment period) as both eyes are treated with 
elamipretide. Open-label data will be presented using the following treatment identifier 
conventions: 
• 
Vehicle to Elamipretide (eyes originally randomized to vehicle in DB and then treated 
with elamipretide in OLE) 
• 
Elam to Elam (eyes originally randomized to elamipretide in DB and continuing 
treatment with elamipretide in OLE) 
• 
Total (pooling both eyes) 
 
In general, categorical variables will be summarized by the count (N) and percentage of subjects 
(%). Continuous variables will be summarized by the number of non-missing observations (N), 
mean, standard deviation, median, minimum, and maximum values. 
All study data are to be displayed in the data listings. 
 
Subject disposition summaries will include the number of subjects entered and the numbers 
treated (included in the Safety population) for all subjects. The number and percentage of 
subjects who complete or discontinue from the study will be summarized by reason for 
discontinuation. 
Subject’s age, sex, weight, BMI and other demographic characteristics will be recorded and 
summarized.  Medical history will be listed. 
All study data are to be displayed in the data listings. 
 
Statistical analysis of this study will be the responsibility of the Sponsor or its designee. 


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Additional details regarding analyses of efficacy measures within single eye treated subjects and 
between subjects (single eye vs. bilateral) will be included in separate statistical analysis plan. 
 
9.2.2. 
Subject Disposition 
All subjects who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported. If known, a reason for their discontinuation will be 
given. 
 
9.2.3. 
Subject Characteristics 
Baseline characteristics will include standard demography (e.g., ethnicity, race, eye color, history 
of smoking, and alcohol use), disease characteristics including medical history, and medication 
history for each subject. 
 
9.2.4. 
Treatment Compliance 
All drug compliance records must be kept current and must be made available for inspection by 
the Sponsor and regulatory agency inspectors. 
 
9.2.5. 
Endpoints and Methodology 
 
9.2.5.1. 
Analysis Populations 
All subjects who receive at least one dose of study drug will be included in the Safety Population 
according to the treatment received. In general, subjects in the Safety Population are expected to 
have received treatment in at least one eye and will be identified as having been assigned active 
treatment to either one or both eyes. 
 
9.2.5.2. 
Safety Endpoint 
The safety endpoint for this study is: 
 
• 
The incidence and severity of systemic and ocular AEs 
9.2.6. 
Efficacy Endpoints 
For the double-masked period analysis, efficacy data (associated with a specific eye) will be 
summarized by treatment received. 
Plots and figures that demonstrate the time-course of changes in efficacy parameters over time, 
from baseline (prior to the start of double-masked treatment) through the double-masked 
treatment period. At the time of the analysis of the open-label period data, data will be added to 
include through the open-label treatment period.  A mixed model for repeated measures 
(MMRM) will be used, with effects for treatment, study visit, and treatment-visit interaction, and 
a random effect for subject.  The model-based adjusted means (LSMeans) and standard errors 
will be presented in these plots. The efficacy endpoints for this study are: 
 
• 
Change from Baseline in PhNR-ERG response pattern 
• 
Change from Baseline in visual field MD as measured by Humphrey automated visual 
field testing stimulus III 
• 
Change from Baseline in color discrimination 
• 
Change from Baseline in contrast sensitivity 
• 
Change from Baseline in BCVA 


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• 
Change from Baseline in VFQ-39 score 
• 
Change from Baseline in retinal nerve fiber layer thickness by SD-OCT 
• 
Change from Baseline in mean retinal ganglion cell layer thickness by SD-OCT 
9.2.7. 
Exploratory Biomarkers (Optional: per secondary use consent) 
A retrospective, secondary use exploratory analysis of the following may occur post study 
completion: 
• 
Serum phosphorylated axonal neurofilament analysis 
• 
Serum mitochondrial DNA copy number 
9.2.8. 
Safety Analyses 
 
9.2.8.1. 
Adverse Events 
All AEs will be coded to SOC and PT using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary (version to be specified in the clinical study report). 
 
Adverse events will be summarized by system organ class (SOC) and preferred term (PT), 
presenting the number and percentage of subjects having treatment-emergent AEs. SAEs and 
AEs resulting in discontinuation will be presented. 
 
For the Double-masked period, AEs will be presented as follows: 
 
• 
Adverse Events attributed to an individual eye or both eyes will be tabulated by specific 
treatment received in that eye or eyes. 
 
• 
Systemic AEs will be presented overall (as all patients during the double-masked period 
receive both elamipretide AND vehicle). 
 
For the OLE, AEs will be presented overall for all patients (and eyes) combined. Severity and 
relationship to study drug will be listed as appropriate. In the summary tables, subjects may be 
counted under multiple SOCs and PTs, but for each SOC and PT, subjects are only counted once. 
If a subject has the same AE on multiple occasions, the highest severity (severe > moderate > 
mild) or drug relationship (probable > possibly related > unlikely related > unrelated) recorded 
for the event will be presented. If severity is missing, subjects will be included as missing (for 
severity). If drug relationship is missing, subjects will be included in related tables (e.g., 
considered related). Summary tables will be sorted by SOC, and then by PT. 
 
9.2.8.2. 
Deaths and Other Serious Adverse Events 
Listings will be provided for the following: 
• 
Deaths 
• 
SAEs 
• 
AEs leading to discontinuation of study drug 


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9.2.8.3. 
Clinical Laboratory Evaluations 
Summary tables for laboratory parameters (including hematology, chemistry, and urinalysis) 
will include descriptive statistics by post-dosing shifts relative to Baseline where appropriate, 
and data listings of clinically significant abnormalities. 
Subjects with laboratory data outside the normal range will be listed with abnormal values 
flagged. 
Shift tables (e.g., tables that show the number of subjects who are low, normal, or high at 
baseline versus each post-baseline scheduled assessment) will be produced. 
The number and percentage of subjects with urinalysis results outside the normal range will be 
presented by endpoint and visit. Shift tables for urinalysis will show the number of subjects 
who are normal/abnormal at Baseline and normal/abnormal at appropriate visits. 
 
9.2.8.4. 
Vital Signs 
Vital signs will be summarized by changes from Baseline values using descriptive statistics. 
 
9.2.8.5. 
Other Safety Parameters 
Change from Baseline in IOP, slit lamp examination findings and fundus examination findings 
will be analyzed. Other ocular and/or systemic safety data captured on the eCRF will be listed. 


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10. 
STUDY MONITORING 
10.1. 
Source Document Requirements 
The Investigator will maintain adequate and accurate subject records (source documents). The 
Investigator will keep all source documents on file. Source documents will be available at all 
times for inspection by authorized representatives of the regulatory authorities. 
 
10.2. 
Case Report Form Requirements 
Clinical data will be recorded in an eCRF by the study Investigator or authorized designee. The 
Investigator will ensure the accuracy, completeness, and timeliness of the data reported in the 
eCRFs. Case report forms will be available at all times for inspection by authorized 
representatives of the regulatory authorities. 
 
10.3. 
Study Monitoring 
Site monitors contracted by the Sponsor will contact and visit the Investigator, and will be 
allowed to review and inspect the various records of the trial on request (eCRFs and other 
pertinent data), provided that subject confidentiality is maintained, and that the inspection is 
conducted in accordance with local regulations. 
 
It is the site monitor’s responsibility to inspect the eCRFs at regular intervals throughout the trial 
to verify adherence to the protocol, the completeness, accuracy and consistency of the data, and 
adherence to GCP guidelines. 
 
The Investigator agrees to cooperate with the site monitor to ensure that any problems detected 
during the course of these monitoring visits are resolved. 


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11. 
DATA QUALITY ASSURANCE 
To ensure accurate, complete, and reliable data, the Sponsor or its representatives will do the 
following: 
 
• 
Provide instructional material to the study sites, as appropriate 
• 
Sponsor start-up training to instruct the Investigators and study coordinators. This 
training will give instruction on the protocol, the completion of the case report forms 
(CRFs), and study procedures. 
• 
Make periodic visits to the study site 
• 
Be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax 
• 
Review and evaluate CRF data and use standard computer edits to detect errors in 
data collection 
• 
Conduct a quality review of the database 
In addition, the Sponsor or its representatives will periodically check a sample of the subject data 
recorded against source documents at the study site. The study may be audited by the Sponsor or 
its representatives, and/or regulatory agencies at any time. Investigators will be given notice 
before an audit occurs. 
 
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the Investigator will keep records of laboratory tests, clinical notes, and subject medical 
records in the subject files as original source documents for the study. If requested, the 
Investigator will provide the Sponsor, applicable regulatory agencies, and applicable IRBs with 
direct access to original source documents. 
 
11.1. 
Data Capture System 
The computerized handling of the data after receipt of the eCRFs may generate additional 
requests via electronic queries to which the Investigator is obliged to respond by confirming or 
modifying the data questioned. These requests with their responses will be appended to the 
eCRFs held by the Investigator and Sponsor. 


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12. 
AUDITS AND INSPECTIONS 
This study may be subject to a quality assurance audit or inspection by the Sponsor, their 
designee, and the regulatory authorities. Should this occur, the Investigator will be responsible 
for: 
 
• 
Informing the Sponsor of a planned inspection by the authorities as soon as notification is 
received 
• 
Providing access to all necessary facilities, study data, and documents for the inspection 
or audit 
• 
Communicating any information arising from inspection by the regulatory authorities to 
the Sponsor immediately 
• 
Taking all appropriate measures requested by the regulatory authorities to resolve any 
problems found during the audit or inspection 
Documents subject to audit or inspection include, but are not limited to all source documents, 
CRFs, medical records, correspondence, ICFs, IRB files, documentation of certification and 
quality control of supporting laboratories, and records relevant to the study maintained in any 
supporting pharmacy facilities. Conditions of study material storage are also subject to 
inspection.  In all instances, the confidentiality of the data will be respected. 


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13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
Good Clinical Practice Statement 
It is the responsibility of the Investigator(s) to ensure that this clinical study will be conducted in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki, and 
that are consistent with the ICH guidelines for GCP and applicable regulatory requirements. 
 
13.2. 
Informed Consent 
The principles of ICF are described in the ICH Guidelines for GCP. 
 
It is the responsibility of the Investigator or designee (if acceptable by local regulations) to 
obtain written informed consent from each subject prior to his/her participation in the study and 
after the aims, methods, objectives, and potential hazards of the study have been explained to the 
subject in language that he/she can understand. The ICF will be signed and dated by the subject 
and by the Investigator or authorized designee who reviewed the ICF with the subject. 
 
Subjects who can write but cannot read will have the ICF read to them before signing and dating 
the ICF. 
 
Subjects who can understand but who can neither write nor read will have the ICF read to them 
in presence of an impartial witness, who will sign and date the ICF to confirm that ICF was 
given. 
 
The original ICF will be retained by the Investigator as part of the subject's study record, and a 
copy of the signed ICF will be given to the subject. 
 
If new safety information results in significant changes in the risk/benefit assessment and/or 
changes to the protocol impact subject’s participation, resulting in a protocol amendment, the 
ICF will be reviewed and updated appropriately. All study subjects will be informed of the new 
information and provide their written consent if they wish to continue in the study. 
 
13.3. 
Subject Confidentiality and Data Protection 
The Investigator will take all appropriate measures to ensure that the anonymity of each study 
subject will be maintained. 
 
The subject's and Investigator's personal data will be treated in compliance with all applicable 
laws and regulations. 
 
13.4. 
Institutional Review Board 
An appropriately constituted IRB, as described in ICH Guidelines for GCP, will review and 
approve: 
 
• 
The protocol, ICF, and any other materials to be provided to the subjects (eg, advertising) 
before any subject may be enrolled in the study 
• 
Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the subjects, in which 
case the IRB will be informed as soon as possible 


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In addition, the IRB will be informed of any event likely to affect the safety of subjects or the 
continued conduct of the clinical study. 
 
Records of the IRB review and approval of all study documents (including approval of ongoing 
studies) will be kept on file by the Investigator. 
 
13.5. 
Regulatory Considerations 
This study will be conducted in accordance with: 
 
1. Consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
2. The ICH GCP Guideline [E6] 
3. Applicable laws and regulations 
The Investigator or designee will promptly submit the protocol to applicable IRB(s). 
Some of 
the obligations of the Sponsor may be assigned to a third party organization. 
An identification code assigned to each subject will be used in lieu of the subject’s name to 
protect the subject’s identity when reporting AEs and/or other study-related data. 
 
13.5.1. 
Protocol Signatures 
The Sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study. 
After reading the protocol, the Investigator will sign a separate protocol acknowledgement 
document confirmed that he/she has read and agrees to abide by the protocol. 
 
13.5.2. 
Final Report Signature 
The Sponsor’s responsible medical officer will approve the final clinical study report for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study. 
 
13.5.3. 
Study Monitoring 
The Investigators and institution(s) will permit trial-related monitoring of the eCRF data by 
Stealth BioTherapeutics Inc., or their assignee by providing direct access to source data and/or 
documents. The study monitor will verify the eCRFs 100% against the source documentation. 
Any change from 100% source document verification will be documented in the associated 
monitoring report. 
Deviations from the protocol with regard to subject enrollment or study 
conduct will also be noted in the source documentation, in the eCRF and a complementary 
database. A Sponsor representative will visit the site to initiate the study, prior to the first 
treatment of the first  subject, and at agreed times throughout the study, including at the end of 
the study. Medication dispensing and clinical drug supply records will be 100% verified at the 
study site by the study monitor. It is understood that all subject specific information is 
confidential and no documentation that can link study information to the specific subject will be 
collected or retained  by the Sponsor. 


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13.5.4. 
Retention of Records 
All study related material including source documents, eCRFs, and IRB correspondence and 
analyses and any other documentation required by applicable laws and regulations will be 
maintained for 15 years after completion of the study or notification from the Sponsor that the 
data can be destroyed, whichever comes first. 
 
13.5.5. 
Disclosure of Information 
Information concerning the investigational medication and patent application processes, 
scientific data or other pertinent information is confidential and remains the property of Stealth 
BioTherapeutics Inc. The Investigator may use this information for the purposes of the study 
only. It is understood by the Investigator that Stealth BioTherapeutics Inc., will use information 
developed in this clinical study in connection with the development of the investigational 
medication and, therefore, may disclose it as required to other clinical Investigators and to 
regulatory agencies.  In order to  allow the use of the information derived from this clinical 
study, the Investigator understands that he/she has an obligation to provide complete test results 
and all data developed during this  study to the Sponsor. 
The Investigator may not submit for publication or presentation the results of this study without 
first receiving written authorization from Stealth BioTherapeutics Inc. Stealth BioTherapeutics 
Inc., agrees that,  before it publishes any results of the study, it shall provide the Investigator 
with at least 30 days for review of the pre-publication manuscript prior to the submission of the 
manuscript to the  publisher. 


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14. 
REFERENCES 
Alam, N. A., A. Wong, Y. Soong, A. V. Birk, R. Douglas, H. Szeto and G. Prusky (2012). A Novel 
Peptide (MTP-131) that Improves Mitochondrial Function Reverses Visual Decline in Mouse Models of 
Metabolic Dysfunction Leading to Diabetes American Diabetes Association, 2012 Annual Meeting. 
 
Chen, M., B. Liu, Q. Gao, Y. Zhuo and J. Ge (2011). "Mitochondria-targeted peptide MTP-131 alleviates 
mitochondrial dysfunction and oxidative damage in human trabecular meshwork cells." Invest 
Ophthalmol Vis Sci 52(10): 7027-7037. 
 
Cousins WS, Mettu PS, Brahmajothi MV (2015). "The mitochondria-targeted peptide MTP-131 
prevents hydroquinone-mediated persistent injury phenotype in cultured retinal pigment epithelium cells", 
Invest Ophthal Vis Sci 56: ARVO E-Abstract 829. 
 
Huang, J., X. Li, M. Li, J. Li, W. Xiao, W. Ma, X. Chen, X. Liang, S. Tang and Y. Luo (2013). 
"Mitochondria-targeted antioxidant peptide SS31 protects the retinas of diabetic rats." Curr Mol Med 
13(6): 935-945. 
 
Li, J., X. Chen, W. Xiao, W. Ma, T. Li, J. Huang, X. Liu, X. Liang, S. Tang and Y. Luo (2011). 
"Mitochondria-targeted antioxidant peptide SS31 attenuates high glucose-induced injury on human retinal 
endothelial cells." Biochem Biophys Res Commun 404(1): 349-356. 
 
Liang, X., A. F. Chen, J. Zhou, C. Yang and G. Sun (2010). SS31 Protects Human RPE Cells From 
Oxidative Damage and Reduce Laser-Induced Choroidal Neovascularization. Annual Association for 
Vision and Ophthamology, Annual Meeting. 
 
Preiser, D., W.A. Lagreze, M. Bach, and C.M. Poloschek (2013). "Photopic Negative Response versus 
Pattern Electroretinogram in Early Glaucoma." IOVS 54(2): 1182-1191. 
 
Prusky GT, Alam NM, Beekman S, Douglas RM (2004). "Rapid quantification of adult and developing 
mouse spatial vision using a virtual optomotor system." IOVS 45(12):4611-6. 
 
Schrier, S. A. and M. J. Falk (2011). "Mitochondrial disorders and the eye." Curr Opin Ophthalmol. 
 
Viswanathan, S., L.J. Frishman, J.G. Robson, and J.W. Walters (2001). "The Photopic Negative Response 
of the Flash Electroretinogram in Primary Open Angle Glaucoma." IOVS 42(2): 514-522. 
Yu-Wai-Man, P., P. G. Griffiths and P. F. Chinnery (2011). "Mitochondrial optic neuropathies - disease 
mechanisms and therapeutic strategies." Prog Retin Eye Res 30(2): 81-114. 


SPILH-201/SPILH-201OLE Protocol Version 10.0 
Elamipretide Topical Ophthalmic Solution (MTP-131) 
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Attachment 1. SPILH-201 Schedule of Events 
 
 
 
 
Screening 
Period 
Treatment Period 
Follow-up 
Period 
Days/Weeks 
Screeninga 
(Day -42 to Day 
-2) 
Day 1/ 
Baseline 
Day 5 
(± 2 days) 
Weeks 4, 8, 
12 
(± 4 days) 
Weeks 16, 
20, 24, 28, 
32, 36, 40, 
44, 48 
(± 7 days) 
Week 52 
(± 7 days) 
End-of 
Treatment 
Visit 
Week 56 
(± 7 days) 
Follow-up 
Visit 
Early 
Termination/ 
Discontinuation 
Visit 
Visit 
1 
2 
3 
4, 5, 6 
7, 8, 9, 10, 
11, 12, 13, 
14, 15 
16 
17 
Informed consent 
X 
Eligibility 
X 
X 
mtDNA testing to confirm 
m11778A>G statusb 
X 
Randomizationc 
X 
Demographics 
X 
Medical/Ocular history 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exame 
X 
X 
X 
Blood for safetyf 
X 
Xd 
X 
X 
X 
X 
Pregnancy testg 
X 
X 
X 
X 
X 
ECGh 
X 
X 
X 
X 
ETDRS BCVA 
X 
X 
X 
X 
X 
X 
X 
X 
Manifest refraction 
X 
X 
IOP 
X 
X 
X 
X 
X 
X 
X 
X 
Color discrimination and 
contrast sensitivity 
X 
X 
X 
X 
X 
X 
X 
X 


SPILH-201/SPILH-201OLE Protocol Version 10.0 
Elamipretide Topical Ophthalmic Solution (MTP-131) 
Confidential 
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Stealth BioTherapeutics Inc. 
 
 
 
 
 
Screening 
Period 
Treatment Period 
Follow-up 
Period 
Days/Weeks 
Screeninga 
(Day -42 to Day 
-2) 
Day 1/ 
Baseline 
Day 5 
(± 2 days) 
Weeks 4, 8, 
12 
(± 4 days) 
Weeks 16, 
20, 24, 28, 
32, 36, 40, 
44, 48 
(± 7 days) 
Week 52 
(± 7 days) 
End-of 
Treatment 
Visit 
Week 56 
(± 7 days) 
Follow-up 
Visit 
Early 
Termination/ 
Discontinuation 
Visit 
Visit 
1 
2 
3 
4, 5, 6 
7, 8, 9, 10, 
11, 12, 13, 
14, 15 
16 
17 
Slit lamp & fundus exam 
X 
X 
X 
X 
X 
X 
X 
X 
SD-OCT for RNFL and 
GCL thickness 
X 
X 
X 
X 
Fundus Photography 
X 
X 
X 
Humphrey automated 
visual field examination 
(SITA FAST 30-2, 
stimulus III)i 
X 
X 
X 
X 
X 
X 
X 
PhNR-ERG 
X 
X j 
X 
X 
X 
X 
X 
Full Field ERG 
X 
X 
X 
Quality of Life 
Questionnaire (VFQ-39) 
X 
X 
X 
X 
(Optional) Serum for 
phosphorylated axonal 
neurofilament analysisk 
X 
X 
X 
X 
(Optional) Serum 
mitochondrial DNA copy 
numberl 
X 
X 
X 
X 
Medication dispensed 
X 
X 
X 
X 
Medication returned 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 


SPILH-201/SPILH-201OLE Protocol Version 10.0 
Elamipretide Topical Ophthalmic Solution (MTP-131) 
Confidential 
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Stealth BioTherapeutics Inc. 
 
 
 
 
 
 
 
Note:  All ophthalmic testing is conducted on both eyes at each time point. 
a Screening procedures may be completed on more than one day, as long as all procedures are completed during the Screening 
Period. All other visits may be completed over a 1 or 2 day period, at the discretion of the Investigator, as long as all 
procedures are completed during the allowable window for that visit. 
b If testing previously confirmed by written documentation using reliable test methods received, repeat testing not required 
c The day of randomization is defined as Study Day 1. 
d Vital signs include temperature, sitting blood pressure after sitting for 5 minutes, and pulse. 
e Physical examination will include general appearance, skin, chest, heart, abdomen, extremities, and nervous system 
f Blood for safety will consist of hematology panel and clinical chemistry.  Urinalysis will be performed at Baseline Visit only. 
g Women of childbearing potential only: serum pregnancy test to be done at screening and urine pregnancy test to be done at all 
other time points. 
h All scheduled ECGs must be performed after the subject has rested quietly for at least 5 minutes in the supine position. 
i In the event that a subject’s Screening and Baseline Visit SITA FAST 30-2 stimulus III exams are not within 5 dB of each 
other, this test may be repeated two additional times either on the day of the Baseline Visit or within 1 week of the Baseline 
Visit prior to randomization. If the test does not occur on the day of the Baseline Visit, other Baseline procedures, which have 
already been completed, should not be repeated. 
j If Screening Visit and Baseline Visit are less than 72 hours apart, this does not need to be repeated. 
k According to Protocol version 5.0, collection of serum for phosphorylated axonal neurofilament analysis is optional and subject’s consent 
will be obtained prior to sample collection and analysis. For subjects who have previously consented to sample collection and analysis 


SPILH-201/SPILH-201OLE Protocol Version 10.0 
Elamipretide Topical Ophthalmic Solution (MTP-131) 
Confidential 
Page 58 of 62 
Stealth BioTherapeutics Inc. 
 
 
 
 
 
under protocol versions 1.0, 2.0, 3.0 or 4.0, investigator will obtain subject’s consent for potential secondary use exploratory biomarker 
analysis. 
l. According to Protocol version 5.0, collection of serum mitochondrial DNA copy number is optional and subject’s consent will be 
obtained prior to sample collection and analysis. For subjects who have previously consented to sample collection and analysis under 
protocol versions 1.0, 2.0, 3.0 or 4.0, investigator will obtain subject’s consent for potential secondary use exploratory biomarker analysis. 


SPILH-201/SPILH-201OLE Protocol Version 10.0 
Elamipretide Topical Ophthalmic Solution (MTP-131) 
Confidential 
Page 59 of 62 
Stealth BioTherapeutics Inc. 
 
 
 
 
 
 
Attachment 2. SPILH-201OLE Schedule of Events 
 
 
 
 
Treatment Period 
Follow-Up 
Periodi 
Assessment 
OLE starte 
Monthly Safety 
Telephone Call 
(approximately 
every 4 weeks 
between site 
visits) 
16-Month Visit 
(Week 68 ±14 days); 
20-Month Visits 
(Week 84 ±14 days); 
24-Month Visit 
(Week 100 ±14 days); 
28-Month Visit 
(Week 116 ±7 days); 
32-Month Visit 
(Week 132 ±7 days); 
36-Month Visit 
(Week 148 ±7 days) 
39-Month Visit 
(Week 160 ±7 days) 
End of Treatment Visit 
End-of-Study 
Visit/ Early 
Discontinuation 
Visit 
(Week 164 ±7 
days) 
Visit Number 
1 
2, 3, 4, 5, 6, 7, 8 
9 
Informed Consenta 
X 
Concomitant Medication 
X 
X 
X 
Review AEs 
X 
X 
X 
Physical Examb 
Xh 
X 
Vital Signs 
X 
X 
12-Lead ECGd 
Pregnancy Test 
Xh 
X 
Blood Chemistry & Hematology 
X 
X 
Urinalysis 
EDTRS BCVA 
X 
X 
Manifest Reaction 
X 
X 
Intraocular Pressure (IOP) 
X 
X 
Color discrimination and 
contrast sensitivity 
X 
X 
Slit lamp & dilated fundus exam 
X 
X 
SD-OCT for RNFL and GCL 
Xh 
X 
Fundus Photography 
Xh 
X 
Humphrey Automated Visual 
Field exam 
X 
X 
PhNR-ERG 
X 
X 
Full Field ERG 
Xf 
Quality of Life Questionnaire 
Xh 
X 
Medication Dispensed 
X 
Xg 
Medication Returned 
X 
X 
a. 
The ICF must be signed prior to any OLE trial related procedures or dosing are performed. 
b. Physical examination will include: general appearance, skin, head, eyes, ears, nose, throat, neck (including 
thyroid), lymph nodes, chest, heart, abdomen, extremities, and nervous system. 
c. 
Vital signs will include HR, RR, and BP after sitting for 5 min, and temperature. 


SPILH-201/SPILH-201OLE Protocol Version 10.0 
Elamipretide Topical Ophthalmic Solution (MTP-131) 
Confidential 
Page 60 of 62 
Stealth BioTherapeutics Inc. 
 
 
 
 
 
d. All scheduled ECGs must be performed after the subject has rested quietly for at least 10 min in the supine 
position 
e. 
OLE begins at week 52 or week 56 visit ((± 7 days) (after all week 52 or week 56 assessments for the double 
masked treatment period are completed) and the subject consents to the OLE 
f. 
At Week 100 and Week 148 only. 
g. Excluding Week 160, and excluding Week 148 if subject enrolling in an EAP. 
h. Collected at week 148 only. 
i. 
For subjects enrolling in an EAP at the Week 148 visit or Week 160 (EOT) visit, there is no Follow-Up Period. 
All Follow-Up Assessments will be performed at the visit where subject enrolls in an EAP. 


SPILH-201/SPILH-201OLE Protocol Version 10.0 
Elamipretide Topical Ophthalmic Solution (MTP-131) 
Confidential 
Page 61 of 62 
Stealth BioTherapeutics Inc. 
 
 
 
 
 
 
Attachment 3. 
Clinical Laboratory Tests 
 
 
 
 
Clinical Laboratory Tests 
Hematology: 
Clinical Chemistry: 
Hemoglobin 
Serum Concentrations of: 
Hematocrit 
Sodium 
Erythrocyte count (RBC) 
Potassium 
Leukocytes (WBC) 
Total bilirubin 
Neutrophils, segmented 
Alkaline phosphatase 
Lymphocytes 
Alanine aminotransferase (ALT) 
Monocytes 
Aspartate aminotransferase (AST) 
Eosinophils 
Blood urea nitrogen (BUN) 
Basophils 
Creatinine 
Platelets 
Calcium 
Glucose (non-fasting) 
Urinalysis: 
Albumin 
Specific gravity 
Chloride 
pH 
Protein 
Optional Secondary Use Exploratory 
Biomarkers 
Glucose 
Serum for mitochondrial DNA copy number 
Ketones 
Serum for phosphorylated axonal neurofilament 
analysis 
Blood 
Pregnancy Test 
(Women of childbearing potential only) 


SPILH-201/SPILH-201OLE Protocol Version 10.0 
Elamipretide Topical Ophthalmic Solution (MTP-131) 
Confidential 
Page 62 of 62 
Stealth BioTherapeutics Inc. 
 
 
 
 
 
 
Attachment 4. 
Sample Monthly Telephone Script 
 
 
 
 
This page provides a sample script for the phone call that should occur approximately every 4 
weeks after the patient consents to participate in the OLE portion to ensure the safe and 
compliant use of the OLE study drug and to appropriately collect the safety events with use of 
the study drug. 
The sample script below is provided to assist clinical sites with conducting monthly safety 
telephone calls. Additional questions are permitted to ensure completeness of answers. 
During each monthly safety telephone call, the following script should be followed: 
 
 
Script 
 
Hello, my name is  
, and I'm calling from (name of facility and/or Investigator’s 
name office). I am calling since it has been a month since we last spoke about your experience 
using elamipretide, the study drug in the SPILH-201 OLE trial in which you are participating in. 
May I ask you a few questions about your experience? 
Have you or a trained caregiver been administering the study drug twice a day? 
Have you missed administering the study drops? If so, how many times? 
Do you have any questions/concerns regarding administering the study drops? 
 
Have you experienced any worsening of your health or any new problems/conditions while on 
the study drops since (our last telephone call or your last site visit)? 
Have you started taking any new medications or changed, increased, or decreased any existing 
medications since (our last telephone call or your last site visit)? 
Could we schedule the next (telephone call or site visit)? (schedule telephone call or site visit) 
Do you have any additional questions? 
Thank you for speaking with me today. If you have any additional questions, please call me at 
(phone number) 


 
LR2TELJ6TKC6RM78KIP2LS 
 
 
 
Jim Carr 
Party ID: 4AP8S4IKTKNPLL5YW7X6GC 
IP Address: 50.203.117.38 
jim.carr@stealthbt.com 
 
 
 
 
Multi-Factor 
Digital Fingerprint Checksum 
 
435be9f84d24ad6542251b9894c18af30354c0e8 
 
 
Timestamp 
Audit 
2019-03-11 13:31:24 -0700 
All parties have signed document. Signed copies sent to: Anthony Abbruscato, 
Jim Carr, and Quality Systems. 
2019-03-11 13:31:23 -0700 
Document signed by Jim Carr (jim.carr@stealthbt.com) with drawn signature. - 
50.203.117.38 
2019-03-11 13:30:56 -0700 
Document viewed by Jim Carr (jim.carr@stealthbt.com). - 50.203.117.38 
2019-03-11 13:25:51 -0700 
Document created by Quality Systems (qualitysystems@stealthbt.com). - 
96.230.125.25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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