A Phase 2 Randomized, Double-Masked, Placebo-Controlled Clinical Study to Evaluate the Safety, Efficacy and Pharmacokinetics of Elamipretide in Subjects With Age-Related Macular Degeneration With Non-central Geographic Atrophy
Phase: PHASE2
Conditions: Age-related Macular Degeneration
Sponsor: Stealth BioTherapeutics Inc.

 
 
 
 
A Phase 2, Randomized, Double-Masked, Placebo-Controlled Clinical Study to Evaluate the Safety, 
Efficacy, and Pharmacokinetics of Subcutaneous Injections of Elamipretide in Subjects with Age-
Related Macular Degeneration with Geographic Atrophy (ReCLAIM-2) 
 
NCT03891875 
 
06 Jan 2022 
 
 
 
 
 
 
 
  

  
 
CLINICAL TRIAL PROTOCOL  
A Phase 2, Randomized, Double-Masked, Placebo-Controlled Clinical Study to Evaluate 
the Safety, Efficacy, and Pharmacokinetics of Subcutaneous Injections of Elamipretide in  
Subjects with Age-Related Macular Degeneration with Geographic Atrophy (ReCLAIM-2)  
Clinical Phase:  
Phase 2  
 
Product Name:  
  
Elamipretide delivery system  
 
IND Number:  
  
114,234  
Formulation:  
Elamipretide (MTP-131) 80 mg/mL sterile solution for 
subcutaneous injection  
 
Protocol No.:  
  
SPIAM-202  
 
Sponsor:  
  
Stealth BioTherapeutics Inc.  
140 Kendrick St., Building C-West  
Needham, MA 02494  
  
Jim Carr, PharmD  
Chief Clinical Development Officer  
Stealth BioTherapeutics Inc   
140 Kendrick St., Building C-West  
Needham, MA 02494  
 Jim.Carr@StealthBT.com  
+1 617-762-2503  
06 Jan 2022/Version 4.0  
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.   
 
  
 
Elamipretide (MTP-131)  
Stealth BioTherapeutics Inc.  
 
SPIAM-202 Clinical Protocol Version 4.0 
06 January 2022  
  
Sponsor Chief Clinical 
Development Officer:   
Protocol Date/Version:  
 
 

  
  
  
 
SPONSOR’S PROTOCOL SIGNATURE PAGE  
A Phase 2, Randomized, Double-Masked, Placebo-Controlled Clinical Study to Evaluate 
the Safety, Efficacy, and Pharmacokinetics of Subcutaneous Injections of Elamipretide in  
Subjects with Age-Related Macular Degeneration with Geographic Atrophy (ReCLAIM-2)  
Protocol No.:  
Sponsor:  
Protocol Date/Version:  
Printed Name:  
Signature:   
Date:   
SPIAM-202  
Stealth BioTherapeutics Inc   
140 Kendrick St., Building C-West Needham, 
MA 02494  
06 January 2022/Version 4.0  
_______________________________________________ 
Jim Carr 
_______________________________________________  
_______________________________________________ 
01/06/2022 
Confidential and Proprietary  
2  
 
Elamipretide (MTP-131)  
Stealth BioTherapeutics Inc.  

  
 
 
SPIAM-202 Clinical Protocol Version 4.0 
06 January 2022  
INVESTIGATOR’S PROTOCOL SIGNATURE PAGE  
  
A Phase 2, Randomized, Double-Masked, Placebo-Controlled Clinical Study to Evaluate 
the Safety, Efficacy, and Pharmacokinetics of Subcutaneous Injections of Elamipretide in  
Subjects with Age-Related Macular Degeneration with Geographic Atrophy (ReCLAIM-2)  
Protocol No.:  
SPIAM-202  
Sponsor:  
Stealth BioTherapeutics Inc   
140 Kendrick St., Building C-West  
Needham, MA 02494  
    
Protocol Date/Version:  
06 January 2022/Version 4.0  
I have read all pages of this clinical trial protocol for which Stealth BioTherapeutics, Inc. is the 
sponsor. I agree to conduct the trial as outlined in the protocol and to comply with all the terms 
and conditions set out therein. I confirm that I will conduct the trial in accordance with all 
applicable local laws and regulations and International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical 
Practice (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. I agree to maintain 
the confidentiality of all information received or developed in connection with this protocol. 
Investigator:  
Printed Name:   
____________________________________________  
Signature:   
____________________________________________  
Date:   
____________________________________________  
Site Address:   
____________________________________________  
  
  
Confidential and Proprietary   
3  

  Elamipretide (MTP-131)  
Stealth BioTherapeutics Inc.  
  
SPIAM-202 Clinical Protocol Version 4.0  
06 January 2022  
Confidential and Proprietary   
5  
  
STATEMENT OF COMPLIANCE  
  
The trial will be conducted in accordance with ICH GCP and applicable United States (US) Code 
of Federal Regulations (CFR) and must comply with the ICH E6 Good Clinical Practice: 
Consolidated Guideline, the principles that have their origin in the Declaration of Helsinki, as 
well as all applicable local regulations and guidelines. The Principal Investigator will assure that 
no deviation from or changes to the protocol will take place without prior agreement from the 
Investigational New Drug (IND), Clinical Trial Application (CTA), or Investigational Device  
Exemption (IDE) sponsor or funding agency and documented approval from the Institutional 
Review Board (IRB)/ Independent Ethics Committee (IEC), except where necessary to eliminate 
an immediate hazard to the trial participants. All personnel involved in the conduct of this trial 
have completed Human Subjects Protection and ICH GCP Training.  
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB/IEC for review and approval. Approval of both the protocol and the 
consent form must be obtained before any participant is enrolled. Any amendment to the protocol 
will require review and approval by the IRB/IEC before the changes are implemented to the trial. 
All changes to the consent form will be IRB/IEC approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, 
using a previously approved consent form.  
 

  Elamipretide (MTP-131)  
Stealth BioTherapeutics Inc.  
  
SPIAM-202 Clinical Protocol Version 4.0  
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Confidential and Proprietary   
6  
1.  
TABLE OF CONTENTS  
1. 
TABLE OF CONTENTS ....................................................................................... 5  
2. 
SYNOPSIS .............................................................................................................. 9  
3. 
LIST OF ABBREVIATIONS .............................................................................. 20  
4.  
INTRODUCTION ................................................................................................ 22  
 4.1.  
Rationale for Mitochondrial-Targeted Therapies in Dry Age-Related Macular  
Degeneration ............................................................................................................................. 
22  
 4.2.  
Elamipretide–Mechanism of Action .............................................................................. 23  
 4.3.  
Elamipretide Risk/Benefit Assessment .......................................................................... 24  
 
4.3.1.  
Pre-clinical Studies ..................................................................................................24  
 
4.3.2.  
Clinical Studies ........................................................................................................25  
 4.4.  
Rationale for Dose Selection .......................................................................................... 25  
5.  
OBJECTIVES ....................................................................................................... 27  
 5.1.  
Primary Objective .......................................................................................................... 27  
 5.2.  
Secondary Objectives ..................................................................................................... 27  
6.  
METHODOLOGY AND PROCEDURES ......................................................... 28  
 6.1.  
Summary of Methodology ............................................................................................. 28  
 6.2.  
Visit Schedule ................................................................................................................ 29  
 
6.2.1.  
Screening Visit (Visit 1, Day -14 to Day -1) ...........................................................29  
 
6.2.2.  
Baseline Visit (Visit 2, Day 1) .................................................................................31  
 
6.2.3.  
Trial Treatment Period .............................................................................................31  
 
6.2.4.  
Follow-up Period .....................................................................................................33  
 6.3.  
Schedule of Events ......................................................................................................... 33  
 6.4.  
Trial Assessments ........................................................................................................... 33  
 
6.4.1.  
Medical/Surgical History and Concomitant Medications/Procedures .....................33  
 
6.4.2.  
Vital Sign Measurements .........................................................................................33  
 
6.4.3.  
Physical Examination...............................................................................................34  
 
6.4.4.  
Clinical Laboratory Testing .....................................................................................34  
 
6.4.5.  
Pregnancy Testing ....................................................................................................34  
 
6.4.6.  
Subject Diary ...........................................................................................................35  
 
6.4.7.  
Pharmacokinetics Sampling .....................................................................................35  
 
6.4.8.  
Other Trial Assessments ..........................................................................................35  

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7.  
SELECTION AND WITHDRAWAL OF SUBJECTS ..................................... 37  
 7.1.  
Inclusion Criteria ............................................................................................................ 37  
 7.2.  
Exclusion Criteria ........................................................................................................... 39  
 7.3.  
Discontinuation of Subjects ........................................................................................... 41  
 7.4.  
Replacement of Subjects ................................................................................................ 41 
 7.5.  
Discontinuation of Trial Sites ........................................................................................ 41  
 7.6.  
Discontinuation of the Trial ........................................................................................... 42  
 7.7.  
Discontinuation of Investigational Medicinal Product ................................................... 42  
8.  
TREATMENT AND RESTRICTIONS ............................................................. 43  
 8.1.  
Investigational Medicinal Product ................................................................................. 43  
 
8.1.1.  
Elamipretide Injection or Placebo ............................................................................43  
 
8.1.2.  
Elamipretide Pen Injector ........................................................................................43  
 
8.1.3.  
Elamipretide Delivery System .................................................................................43  
 8.2.  
Investigational Medicinal Product Administration ........................................................ 44  
 
8.2.1.  
Investigational Medicinal Product Treatment Regimen ..........................................44  
 
8.2.2.  
Dose Interruption of Individual Subjects .................................................................45  
 8.3.  
Investigational Medicinal Product and Accountability .................................................. 45  
 8.4.  
Investigational Medicinal Product Compliance ............................................................. 45  
 8.5.  
Randomization/Method of Assigning Investigational Medicinal Product ..................... 45  
 8.6.  
Masking and Unmasking Procedures ............................................................................. 45  
 8.7.  
Concomitant Medications .............................................................................................. 46  
 8.8.  
Prohibited Medications and Therapies ........................................................................... 46  
 8.9.  
Subject Management ...................................................................................................... 47  
8.10. Continued Access to Investigational Medicinal Product ............................................... 47  
9.  
EFFICACY, PHARMODYNAMICS, AND PHARMOKINETICS ASSESSMENTS 
.......................................................................................................................... 48  
 9.1.  
Efficacy Measures .......................................................................................................... 48  
 
9.1.1.  
Primary Efficacy Endpoint: .....................................................................................48  
 
9.1.2.  
Secondary Efficacy Endpoints .................................................................................48  
 
9.1.3.  
Exploratory Efficacy Endpoints ...............................................................................48  
 9.2.  
Pharmacokinetics Measures ........................................................................................... 48  
10.  
SAFETY ASSESSMENTS ................................................................................... 50  
10.1. Adverse Events/Adverse Device Effects ........................................................................ 50  
10.2. Safety Evaluations .......................................................................................................... 50  
10.3. Pre-Treatment Events ..................................................................................................... 51  
10.4. Baseline Medical History Conditions ............................................................................ 51  

  Elamipretide (MTP-131)  
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10.5. Medical and Surgical Procedures ................................................................................... 51  
10.6. Abnormal Laboratory and Other Abnormal Investigational Findings ........................... 51  
10.7. Symptomatic Overdose .................................................................................................. 52  
10.8. Serious Adverse Events/Serious Adverse Device Effects .............................................. 52  
10.8.1. Events that Do Not Meet the Definition of a Serious Adverse Event .....................53  
10.9. Recording of Adverse Events/Adverse Device Effects .................................................. 53  
10.10. Investigator Assessments ............................................................................................... 53 
10.10.1. Severity/Intensity .....................................................................................................53  
10.10.2. Relationship to the Investigational Medicinal Product/Elamipretide Delivery  
System .....................................................................................................................54  
10.10.3. Outcome of an Adverse Event/Adverse Device Effect ............................................54  
10.11. Adverse Events of Special Interest................................................................................. 55  
10.11.1. Investigator Injection Site Reaction Assessment .....................................................55  
10.11.2. Unexpected Adverse Events/Unanticipated Adverse Device Effects ......................55  
10.12. Adverse Event/Adverse Device Effect Reporting Period .............................................. 
55  
10.13. Serious Adverse Event/Serious Adverse Device Effect Expedited Reporting .............. 56  
10.14. Pregnancy and Contraception ......................................................................................... 
57 10.15. Responsibilities to Regulatory Authorities, Investigators, and Institutional Review  
Board  ........................................................................................................................................ 
59  
11.  
SAMPLE SIZE AND STATISTICAL METHODS .......................................... 60  
11.1. Determination of Sample Size ........................................................................................ 60  
11.2. Statistical and Analytical Plans ...................................................................................... 60  
11.2.1. General Considerations ............................................................................................60  
11.2.2. Analysis Populations:...............................................................................................60  
11.2.3. Baseline Characteristics and Disposition of Subjects ..............................................61  
11.2.4. Efficacy Analyses ....................................................................................................61  
11.2.5. Interim Analysis .......................................................................................................61 
11.2.6. Safety Analyses ........................................................................................................61  
11.2.7. Pharmacokinetic Analyses .......................................................................................63  
12.  
TRIAL MONITORING ....................................................................................... 64  
12.1. Source Document Requirements .................................................................................... 64 
12.2. Case Report Form Requirements ................................................................................... 64  
12.3. Trial Monitoring ............................................................................................................. 64  
13. 
DATA QUALITY ASSURANCE ........................................................................ 65  
13.1. Data Capture System ...................................................................................................... 65  

  Elamipretide (MTP-131)  
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14.  
INFORMED CONSENT, INSTITUTIONAL REVIEW BOARD, AND 
REGULATORY CONSIDERATIONS .................................................................................... 66  
14.1. Changes in Protocol ....................................................................................................... 66  
14.2. Informed Consent ........................................................................................................... 66  
14.3. Ethics Review ................................................................................................................. 67  
14.4. Regulatory Considerations ............................................................................................. 67  
14.4.1. Retention of Records ................................................................................................67  
14.4.2. Disclosure of Information ........................................................................................67  
15.  
REFERENCES ..................................................................................................... 69 
16.  
APPENDICES ...................................................................................................... 72  
Appendix 1. Schedule of Events ............................................................................................... 72  
Appendix 2. Table for Grading the Severity of Injection Site Reactions ................................. 75  
  
  
  
  
 

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SPIAM-202 Clinical Protocol Version 4.0  
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2.  
SYNOPSIS  
Sponsor/Company: Stealth BioTherapeutics Inc.  
Investigational Combination Product:  
Elamipretide delivery system   
Active Ingredient:  
Elamipretide (MTP-131)  
Title of Trial: A Phase 2, Randomized, Double-Masked, Placebo-Controlled Clinical Study to  
Evaluate the Safety, Efficacy, and Pharmacokinetics of Subcutaneous Injections of  
Elamipretide in Subjects with Age-Related Macular Degeneration with Geographic Atrophy 
(ReCLAIM-2)  
Protocol Number:  
SPIAM-202  
Clinical Phase:  
Phase 2  
Objectives:  
Primary Objective  
The primary objective of this trial is to:   
• 
Evaluate the safety and tolerability of subcutaneous (SC) injections of elamipretide 
administered with the elamipretide delivery system in subjects with age-related macular 
degeneration (AMD) with non-central geographic atrophy (GA)  
Secondary Objectives  
The secondary objectives of the trial are to:  
• 
Evaluate the efficacy of SC injections of elamipretide administered with the 
elamipretide delivery system in subjects with AMD with non-central GA.  
• 
Study the pharmacokinetic profile of elamipretide and its metabolites.  

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Criteria for Evaluation   
Primary Efficacy Endpoints:  
• 
Low-luminance best-corrected visual acuity (LL BCVA).  
• 
GA area as measured by optical coherence tomography (OCT).  
Secondary Efficacy Endpoints:  
• 
Low-luminance reading acuity (LL RA).  
• 
Best-corrected visual acuity (BCVA).  
• 
GA area as measured by fundus autofluorescence (FAF).  
Exploratory Efficacy Endpoints:  
• 
Volumetric OCT and ellipsoid zone (EZ) mapping as defined as:  
o Macular Percentage of EZ Total Attenuation o 
Macular Percentage of EZ Partial Attenuation o 
Central 1-mm mean EZ-RPE thickness o Central 
2-mm mean EZ-RPE thickness  
• 
National Eye Institute Visual Function Questionnaire-39 (VFQ-39) score.  
• 
Reading acuity at standard light.  
• 
Visual function by the Low-luminance Questionnaire (LLQ).  
• 
EQ-5D-5L score.  
• 
Conversion to choroidal neovascularization (CNV).  
• 
BCVA and LL BCVA in non-study eyes.  
• 
GA area as measured by OCT in non-study eyes with GA.  
  
For efficacy endpoints, the unit of analysis will be the study eye as defined as the following:  
  
Study Eye: Eyes are eligible for analysis if they meet all of the inclusion criteria and none of 
the exclusion criteria. In the case that both eyes are eligible for analysis, the study eye will be 
the eye with worse LL BCVA at baseline. If the eyes have equal LL BCVA, then the right eye 
will be the study eye.  
Safety Endpoints:  
• 
The incidence and severity of adverse events (AEs)/ adverse device effects (ADEs).  
• 
Vital sign measurements.  
• 
Clinical evaluations (ocular and non-ocular).  
• 
Clinical laboratory evaluations.  
• 
Slit lamp examination.  
• 
Dilated fundus examination.  

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Pharmacokinetics (PK) Variables:  
Characterization of the PK parameters of elamipretide and its metabolites in plasma, including 
apparent clearance, maximum plasma concentration (Cmax), and area under the plasma 
concentration time-curve from 0 to 24 hours (AUC0-24), will be performed via population PK 
(PopPK) modelling.   
Trial Population: Adults ≥ 55 years of age with at least 1 eye with AMD with non-central GA 
as determined by FAF. GA must be ≥ 0.05 mm2 and ≤ 10.16 mm2 -in size and reside 
completely within the FAF 30 or 35 degree image. All GA lesions must be extrafoveal (at least 
150 µm from foveal center) with preserved outer retinal structural details, as confirmed by the 
reading center.  Subjects must not have evidence of CNV (by history, OCT, or fluorescein 
angiography [FA]), have a BCVA score of ≥ 55 letters, an LL BCVA score of ≥ 10 letters, or an 
LL VA deficit (defined as the difference between BCVA and LL BCVA) of > 5 letters. Subjects 
(or a caregiver) must also be able to administer the investigational medicinal product (IMP).   
Investigational Medicinal Product, Dose and Administration:  
Elamipretide injection will be supplied as a sterile 3 mL single-patient-use, multi-dose glass 
cartridge containing sterile elamipretide solution (elamipretide HCl [80 mg/mL], phosphate 
buffer, and benzyl alcohol) for use with the elamipretide delivery system (the IMP  
[elamipretide or placebo], the elamipretide pen injector, and single-use needle). The dose of 
elamipretide is administered as a once daily fixed dose of 0.5 mL (40 mg) SC injection with the 
elamipretide delivery system.  
Trial site staff will train subjects (and caregivers if needed) and ensure understanding of proper 
SC injection technique on Day 1 with use of the elamipretide delivery system. An elamipretide 
delivery system training kit and checklist will be provided to the trial site to assist in training. 
On Day 1, site staff should witness IMP administration by subject or caregiver.  Any new 
caregiver should complete the training at a trial site visit before administering IMP to a 
subject.  On non-visit days, the subject (or trained caregiver) will administer the IMP via daily 
SC injections rotating around the four abdominal quadrants. If necessary, SC injection in the 
thigh may be utilized after Investigator consultation with the Sponsor. The time of the IMP 
administration should be approximately the same time each day. If a subject is concurrently 
receiving another SC therapy, unique locations for injections for the IMP, independent from 
the location of the concomitant therapy injections, should be used (after Investigator 
consultation with the Sponsor).  
Reference therapy, dosage and mode of administration:  
The placebo for this trial will be composed of sodium chloride, phosphate buffer, and benzyl 
alcohol similar to the excipients used to manufacture the active drug but without the active 
drug substance. The placebo will be handled and administered identically to active drug.  

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Methodology:  
This is a Phase 2, randomized, placebo-controlled, double-masked, multi-center, safety, 
efficacy, and PK trial to be conducted in the U.S. Approximately 180 subjects who have at least 
1 eye with AMD with non-central GA will be included.  
A Screening Visit (Visit 1) will be performed no more than 14 days before the Baseline Visit 
(Visit 2, Day 1). Eligible subjects will return for the Baseline visit, at which time subjects will 
be randomized in a 2:1 ratio (approximately 120 subjects in the treatment arm and 60 subjects 
in the placebo arm) to receive either 0.5 mL (40mg) elamipretide or placebo administered with 
the elamipretide delivery system as a single daily SC injection.   
Safety, tolerability, and efficacy will be evaluated throughout the Treatment Period (Visit 2 to 
Visit 8), while exploratory anatomical and physiologic endpoints will be measured at time 
points as specified in the Schedule of Events. Plasma samples for PK evaluations will be 
collected at Visit 3 (Week 4) and Visit 4 (Week 8). Ocular imaging will be read by an 
independent reading center.  
After completion of the 48-week Treatment Period (Visit 2 to Visit 8), subjects will continue to 
be monitored for safety during the 4-week Follow-Up Period. The Follow-Up Period is an IMP 
administration-free period. A Follow-Up visit is scheduled at Week 52 (Visit 9).   
SPIAM-202 Design Schematic  
  
Visit Schedule:  
Subjects will be required to participate in 9 visits at the trial site, including 1 Screening Visit  
(Visit 1), 7 Treatment Period visits (Visit 2 to Visit 8) over 48 weeks, and 1 Follow-Up Visit 
(Visit 9) 4 weeks after the last day of treatment. Subjects discontinuing IMP, but willing to 
continue participation in the trial, will remain in the trial and have all possible trial assessments 
completed.   
  
SPIAM-202 Visit Schedule  
Period  
Screening 
Visit  
Baseline Visit and Treatment Period  
Follow-Up Visit  
 
Visit Number  
1  
2 to 8  
9  
Day/Week  
Day -14 to 
Day -1  
Day 1 to Week 48  
Week 52  

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Planned Duration of Trial and Treatment Period:  
The trial duration is 54 weeks, which includes 2 weeks of screening, a 48-week Treatment  
Period, and a Follow-Up Visit scheduled at 4 weeks after the last day of IMP administration.  

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Inclusion Criteria  
  
Subjects must meet all of the following Inclusion Criteria to be eligible for the study:  
1. Adults ≥ 55 years of age with at least 1 eye with AMD with non-central GA. For this 
study, non-central GA is defined as:  
a. well-demarcated area(s) of GA; presence and area will be determined primarily 
by FAF.   
b. All GA lesions must be at least 150 µm from foveal center with preserved outer 
retinal structural details, as confirmed by the reading center.  
Ocular conditions–study eye  
2. GA in the study eye at the Screening Visit may be multi-focal, but the cumulative GA 
lesion and size (by FAF, as determined by the reading center) must:  
a. be ≥ 0.05 mm2 and ≤ 10.16 mm2 and  
b. reside completely within the FAF 30 or 35 degree image.  
3. No evidence of CNV by history, OCT or FA in the study eye.  
4. BCVA by Early Treatment Diabetic Retinopathy Study (ETDRS) score of ≥ 55 letters 
(Snellen equivalent ≥ 20/70) in the study eye at the Screening Visit and Baseline 
Visit.  
5. LL BCVA by ETDRS score of ≥ 10 letters in the study eye at the Screening Visit and 
Baseline Visit.  
6. LL VA deficit (defined as the difference between BCVA and LL BCVA) of > 5 letters 
in the study eye at Screening and Baseline Visits.  
7. The fellow eye may have any of the following: no AMD, AMD without GA, AMD 
with GA, CNV AMD, or central GA. Ongoing treatment with anti-angiogenic 
therapies in the fellow eye is allowable.  
8. Sufficiently clear ocular media, adequate pupillary dilation, fixation to permit quality 
fundus imaging, and ability to cooperate sufficiently for adequate ophthalmic visual 
function testing and anatomic assessment in the study eye.  
Systemic and general criteria  
9. Able to administer IMP or have an appropriate designee who can administer the IMP 
(i.e., a capable family member or a caregiver).   
10. Able to provide informed consent and willing to comply with all study visits, 
examinations, IMP administrations, and conditions of the study protocol.   

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11. Women of childbearing potential who are not pregnant or nursing and have a negative 
serum pregnancy test at screening.   
12. 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 1 month after last dose.   
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. Acceptable 
methods include: 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. Subjects must use 
a condom with spermicide from the date of informed consent until at least 1 
month after the last dose of study drug. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or post-ovulation methods) and withdrawal are not 
acceptable methods of contraception. Male subjects with pregnant partners must 
use a condom.  
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 for 1 month after last dose should they become 
sexually active. Acceptable methods include: 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. Alternatively, 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). Non-childbearing potential is defined as 
surgical sterilization (e.g., bilateral oophorectomy, hysterectomy, or tubal 
ligation) or post-menopausal (defined as permanent cessation of menstruation 
for at least 12 consecutive months prior to the Screening Visit).  

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Exclusion Criteria:  
Subjects with a study eye who meets any of the following criteria will be excluded from the 
study:  
Ocular conditions–study eye  
1. The absence of observable hyper-FAF at the margins of the GA in the study eye (only 
for lesions ≥ 0.25mm2).  
2. Atrophic retinal disease of causality other than AMD including myopia-related 
maculopathy and monogenetic macular dystrophies including pattern dystrophy and 
adult-onset Stargardt disease in the study eye.   
3. Presence or diagnosis of exudative AMD or CNV in the study eye.  
4. Presence of retinal vein occlusion in the study eye.  
5. Presence of diabetic retinopathy (a history of diabetes mellitus without retinopathy is 
not a criterion for exclusion) in either eye.  
6. Presence of vitreous hemorrhage in the study eye.  
7. History of retinal detachment in the study eye.   
8. History of macular hole (stages 2 to 4) in the study eye.  
9. Presence of an epiretinal membrane that causes distortion of the retinal contour in the 
study eye.  
10. Presence of vitreomacular traction in the study eye.  
11. At the Screening Visit, advanced glaucoma resulting in a cup to disc ratio of > 0.8 in 
the study eye.  
12. History of glaucoma filtration surgery or uncontrolled glaucoma defined as intraocular 
pressure (IOP) > 22 mmHg at baseline despite anti-glaucoma treatment with or without 
topical anti-hypertensive eye drops in the study eye OR currently using > 2 medications 
(note: combination medications count as 2 medications).  
13. Presence of visually significant cataract OR presence of significant posterior capsular 
opacity in the setting of pseudophakia. Significant cataract is defined as > +2 nuclear 
sclerosis based upon the scale below or any Posterior Subcapsular Cataract in the study 
eye. The Sponsor, or its designee, will supply the trial sites with a copy of the standard 
photographs.  
Grade  
Description  
+1  
Opacity is absent  

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+2  
Opacity is present, but less than Nuclear Standard Photograph #2  

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+3  
Opacity is present, and as severe as or worse than Nuclear Standard Photograph #2  
 
 
  
  Source: (Chew et al. 2010)  
14. Presence of significant keratopathy or any other media or corneal opacity that would 
cause scattering of light or alter visual function, especially in LL conditions in the study 
eye.   
15. Ocular incisional or laser surgery (including cataract surgery) in the study eye within 90 
days before Day 1.  
16. Yag laser capsulotomy in the study eye within 30 days before Day 1.  
17. Aphakia in the study eye.   
18. History of vitrectomy surgery, submacular surgery, or any vitreoretinal surgery in the 
study eye.  
19. Prior treatment with Visudyne® (verteporfin) ocular photodynamic therapy, 
externalbeam radiation therapy (for intraocular conditions), or transpupillary 
thermotherapy in the study eye.  
20. History of subthreshold laser treatment or other forms of photobiomodulation for AMD 
in the study eye.  
21. Intravitreal drug delivery in the past 60 days or 5-half-lives of the injected drug 
whichever is longer (e.g., intravitreal corticosteroid injection, anti-angiogenic drugs, or 
device implantation) in the study eye.  
22. Current use of medications known to be toxic to the lens, retina, or optic nerve (e.g., 
deferoxamine, chloroquine/hydroxychloroquine [Plaquenil®], tamoxifen, 
phenothiazines, ethambutol, digoxin, and aminoglycosides) from the Screening Visit 
through the completion of the trial.   
23. Concurrent disease in the study eye that could require medical or surgical intervention 
during the study period.  
Ocular conditions––either eye  
24. History of herpetic infection in either eye.  
25. Active uveitis and/or vitritis (grade trace or above) in either eye.  
26. History of idiopathic or autoimmune-associated uveitis in either eye.  
27. Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye.  
Systemic conditions  
28. Known to be immunocompromised or receiving systemic immunosuppression for ≥ 4 
consecutive weeks prior to screening.  

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29. Any disease or medical condition that in the opinion of the Investigator would prevent 
the subject from successfully participating in the study or might confound study results.  
General  
30. Participation in other investigational drug or device clinical studies within 30 days of 
enrollment and/or planning to participate in any other investigational drug or device 
clinical studies within 30 days of study completion.   
31. History of allergy to fluorescein that is not amenable to treatment.  
32. Creatinine clearance of ≤ 30 mL/min at the Screening Visit (using Modification of Diet 
in Renal Disease Study formula)  
33. Inability to comply with study or follow-up procedures.  
34. Inability to obtain color fundus photograph, FAF, and FA of sufficient quality to be 
analyzed and interpreted.  
35. Active malignancy or any other cancer from which the subject has been cancer-free for 
< 2 years.   
36. History of allergic reaction to the investigational drug or any of its components.  
37. Prior treatment with Elamipretide.   
Safety Variables:  
AEs, ADEs, clinical laboratory measurements (chemistry, hematology, and urinalysis), vital 
signs, and physical examinations will be assessed.  
Statistical Methods:  
Determination of Sample Size  
A sample size of 180 subjects provides ≥ 80% power to detect a 5 letter (1 line) change from 
baseline mean difference in LL BCVA between drug and placebo, assuming a standard 
deviation of 11 letters, at a two-sided alpha-level of 0.1, and provides approximately 80% 
power to detect a 30% difference in the change from baseline in square root transformed total 
GA area by OCT between drug and placebo, assuming a standard deviation of 0.2 mm/year, 
and an average change of 0.33 mm/year, at a two-sided alpha-level of 0.1.    
General Considerations  
Continuous variables will be summarized by descriptive statistics (sample size, mean, standard 
deviation, median, minimum, and maximum). Discrete variables will be summarized by 
frequencies and percentages. Tabulated data will be presented for each treatment arm.   
All data will be displayed in the data listings, sorted by subject and visit, where appropriate.  
Each listing will indicate which treatment arm each subject was assigned to.  
Analysis Populations:  

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Statistical analysis will be performed in the following populations:  
Safety Population – Includes all trial subjects who receive at least 1 dose of IMP. Subjects will 
be analyzed according to the actual treatment they received.  
Intent-to-Treat (ITT) Population – Includes all randomized subjects. Subjects will be analyzed 
in the treatment group to which they were randomized.  
Modified Intent-to-Treat (mITT) Population – Includes all ITT subjects who receive at least 1 
dose of IMP and have at least 1 post-baseline value for LL BCVA or GA area on OCT. 
Subjects will be analyzed in the treatment group to which they were randomized and 
generally included in efficacy analyses for which post-baseline data are available.   
Per-Protocol (PP) Population – Includes all ITT subjects without major protocol 
violations/deviations likely to affect the primary outcome of the trial as judged by a masked 
evaluation prior to the unmasking of the study treatment. Subjects will be analyzed according to 
the actual treatment they received.  
PK Population – Includes all trial subjects who have at least 1 evaluable PK sample taken 
during their participation.  
Baseline Characteristics and Disposition of Subjects  
The subject disposition summary will include the number of subjects in each population. The 
number and percentage of subjects who complete or discontinue from the trial will be 
summarized by reason. Each subject’s age, sex, weight, and other demographic characteristics 
will be recorded and summarized. Medical history will be listed.  
Safety Analyses  
Safety data analysis will be conducted using the Safety population.   
All AEs will be coded to system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA). All reported AEs will be listed, but only 
treatment-emergent AEs (TEAEs) will be summarized. The incidence of all TEAEs, injection 
site TEAEs (e.g., pain/tenderness, erythema, induration/swelling, and pruritus), 
treatmentemergent serious adverse events (TESAEs), drug-related TEAEs, and TEAEs by 
severity will be summarized by SOC, PT, and treatment arm.  
All ADEs will be coded to SOC and PT using the MedDRA. All reported ADEs will be listed, 
but only treatment-emergent ADEs (TEADEs) will be summarized. The incidence of all 
TEADEs, injection site TEADEs (e.g., pain/tenderness, erythema, induration/swelling, and 
pruritus), treatment-emergent serious adverse device effects (TESADEs), device-related 
TEADEs, and device-related TEADEs by severity will be summarized by SOC, PT, and 
treatment arm.  
Summary tables for laboratory parameters (i.e., clinical hematology, chemistry laboratory 
parameters, and urinalysis) will include descriptive statistics for change from 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 

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post-baseline scheduled assessment) will be produced. Vital signs will be summarized by 
changes from baseline values for each treatment arm using descriptive statistics.  
Efficacy Analyses  
For efficacy endpoints, the unit of analysis will be the study eye as defined by the following: 
Eyes are eligible for analysis if they meet all of the inclusion criteria and none of the exclusion 
criteria. In the case that both eyes are eligible for analysis, the study eye will be the eye with 
worse LL BCVA as determined at baseline. If the eyes have equal LL BCVA, then the right eye 
will be the study eye.  
Changes from baseline in efficacy endpoints will be presented by time point for each treatment 
arm. For continuous data, a mixed model for repeated measures (MMRM) will be used for 
each eye separately (study eye and fellow eye), with fixed effects for treatment arm, study 
visit, the treatment arm-by-visit interaction, baseline as a covariate, a baseline-by-visit 
interaction and a random effect for subject using an unstructured covariance structure. The 
primary time point for analysis is planned to be Week 48 (End of Treatment Visit). A decision 
may be made to conduct an interim analysis prior to completion of the trial.  
For efficacy, the primary analysis population will be the mITT on observed data.  
A family-wise alpha level of 0.1 will be maintained for the primary endpoint family, using 
Hochberg’s procedure at the primary time point of 48 weeks. If both primary endpoints are 
significantly different from placebo at the 0.1 (two-sided) level of significance (in favor of 
treatment), then both will be considered statistically significant. Otherwise, the endpoint with 
the smaller p-value of the two will be considered statistically significant, if statistically 
significant at the 0.05 (two-sided) level of significance.  
PK Analyses  
PopPK analyses will be conducted on the PK Population. The PK model will be generated and 
validated using data reported from historical, thorough PK studies. Where sufficient data allow, 
covariates will include age, gender, race, renal function (as described by eGFR), intercurrent 
conditions, and concomitant medications. Plasma samples will be analyzed for elamipretide 
using a validated liquid chromatography/tandem mass spectrometry assay.  
Pharmacokinetics modelling will be performed using NONMEM computer software.  
3.  
LIST OF ABBREVIATIONS  
Abbreviation  
Definition or Explanation  
 
ADE  
Adverse device effect  
AE  
Adverse event  
AMD  
Age-related macular degeneration  
ATP  
Adenosine triphosphate  
AUC0-24h  
Area under the plasma concentration time-curve from 0 to 24 hours 

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BCVA  
Best-corrected visual acuity  
Cmax  
Maximum plasma concentration  
CNV  
Choroidal neovascularization  
CRO  
Contract Research Organization  
eCRF  
Electronic Case Report Form  
eDC  
Electronic Data Capture  
ETC  
Electron transport chain  
ETDRS  
Early Treatment Diabetic Retinopathy Study  
FA  
Fluorescein angiography  
FAF  
Fundus autofluorescence  
FDA  
Food and Drug Administration  
GA  
Geographic atrophy  
GCP  
Good Clinical Practice  
ICF  
Informed Consent Form  
ICH  
International Conference on Harmonisation  
IEC  
Independent Ethics Committee  
IMM  
Inner mitochondrial membrane  
IMP  
Investigational Medicinal Product  
IOP  
Intraocular pressure  
IRB  
Institutional Review Board  
ISR  
Injection Site Reaction  
LL  
Low-luminance  
LLQ  
Low-Luminance Questionnaire  
M1, M2  
Major metabolite of elamipretide (MTP-131)  
MMRM  
Mixed Model for Repeated Measures  
MedDRA  
Medical Dictionary for Regulatory Activities  
mtDNA  
Mitochondrial DNA  
MTP-131   
Elamipretide, SS-31, SBT-031,   
  
Abbreviation  
Definition or Explanation  
 
NOAEL  
No-observed-adverse-effect-level  
OCT  
Optical coherence tomography  
PK  
Pharmacokinetics  
PopPK  
Population Pharmacokinetics  
PT  
Preferred term  

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RA  
Reading acuity  
RBC  
Red blood cells  
ROS  
Reactive oxygen species  
RPE  
Retinal pigment epithelium  
SADE  
Serious adverse device effect  
SAE  
Serious adverse event  
SC  
Subcutaneous  
SD-OCT  
Spectral domain-optical coherence tomography  
SMP  
Safety Management Plan  
SOC  
System organ class  
SUSAR  
Suspected Unexpected Serious Adverse Reaction  
TEAE  
Treatment-emergent adverse event  
TEADE  
Treatment-emergent adverse device effect  
TESADE  
Treatment-emergent serious adverse devise effect  
UADE  
Unanticipated Adverse Device Effect  
VFQ-39  
Visual Function Questionnaire-39  
WBC  
White blood cells  
4.  
INTRODUCTION  
This trial will be conducted in strict accordance with the Council for International Organizations 
of Medical Sciences International Ethical Guidelines, International Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP) guideline, and all applicable laws and 
regulations. For detailed information on the elamipretide delivery system and the pre-clinical and 
clinical studies conducted to date, refer to the Investigator’s Brochure.  
Stealth BT is developing elamipretide injection with the elamipretide delivery system for the 
treatment of retinal diseases involving mitochondrial dysfunction such as Leber's hereditary optic 
neuropathy, Diabetic Macular Edema, and age-related macular degeneration (AMD). 
Elamipretide (also known as MTP-131) is a first-in-class mitochondrial protective tetrapeptide 
that has been extensively studied in multiple pre-clinical and clinical studies for the 
normalization of mitochondrial dysfunction.  
4.1.  
Rationale for Mitochondrial-Targeted Therapies in Dry Age-Related  
Macular Degeneration  
The eye is the highest consumer of mitochondrial adenosine triphosphate (ATP) in the brain, due 
to the intensive bioenergetics required to support visual function. Mitochondrial-mediated 
oxidative stress is considered a likely contributing factor to the underlying pathologic processes 
of AMD, with reactive oxygen species (ROS) causing injury to the photoreceptors, the retinal 
pigment epithelium (RPE), and the choriocapillaris. Pre-clinical studies suggest that diseases of 

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the RPE, such as dry AMD, may be exacerbated by light-induced mitochondrial dysfunction, and 
that mitochondrial DNA (mtDNA) mutations appear to accumulate over time in diseased RPE as 
a consequence of chronic and ongoing oxidative stress. Mitochondrial dysmorphology observed 
in RPE cells from human dry AMD donor eyes is consistent with severe dysfunction, and 
mtDNA from these human eyes demonstrate increased oxidative damage with increases 
commensurate with disease severity. Cigarette smoking and high fat diets, both of which 
contribute to mitochondrially deleterious oxidative stress, are known to be environmental risk 
factors for dry AMD onset and progression. These findings suggest a key role for mitochondrial 
dysfunction in the pathology of the disease.  
Although mitochondria have been suggested as a source of reactive oxidants in AMD, 
mitochondrial dysfunction is not oxidant overproduction alone; it also includes loss of ATP, 
calcium flux dysregulation, and other changes, which have been overlooked as pathogenic 
mechanisms in AMD (Feher et al. 2006, Decanini et al. 2007, Ethen et al. 2007, Owsley et al. 
2007, Nordgaard et al. 2008). Pre-clinical studies suggest that many AMD triggers induce 
mitochondrial dysfunction, leading to activation of specific signaling molecules, followed by 
activation of mediators of deposit formation, all of which will precede and contribute to sub-RPE 
deposits. It is hypothesized that prevention or reversal of mitochondrial dysfunction by specific 
mitochondria-targeting molecules may prevent and perhaps reverse pre-existing deposit 
biochemistry at the RPE, restoring physiologic function of the RPE and promoting clearance of 
drusen deposits in dry AMD. In turn, mitochondria-targeted therapies may facilitate improved 
visual function in affected eyes and may prevent progression to vision-threatening AMD disease, 
neovascular AMD, and geographic atrophy (GA).  
4.2.  
Elamipretide–Mechanism of Action  
Elamipretide is a small peptide that targets the mitochondria and normalizes and protects 
dysfunctional mitochondria, without affecting healthy mitochondria and cells, via a novel 
mechanism that ameliorates electron transport chain (ETC) deficiencies in disease. Extensive 
investigation has shown that elamipretide effectively maintains mitochondrial bioenergetics, 
including membrane potential and respiration, under pathological conditions. Elamipretide has 
been shown to improve cellular ATP levels in dysfunctional mitochondria, prevent pathological 
ROS formation and opening of the mitochondrial permeability transition pore, and, as a 
consequence, reduce the extent of both apoptosis and necrosis. Elamipretide has minimal or no 
effect in normal mitochondria, cells, or organs (Min et al. 2011, Siegel et al. 2013).  
Elamipretide binds reversibly to cardiolipin, which plays a key role in multiple mitochondrial 
functions, including establishing the structure of the inner mitochondrial membrane (IMM) and 
keeping the complexes of the ETC in optimal close proximity to one another, optimizing their 
function (Houtkooper and Vaz 2008, Wallace et al. 2010, Claypool and Koehler 2012). 
Cardiolipin is particularly susceptible to peroxidation by ROS, leading to dysfunctional ETC 
structure, impaired oxidative phosphorylation, and electron leakage.   

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Stealth BT has demonstrated that treatment of cells or isolated organs undergoing oxidative stress 
with elamipretide can maintain the normal morphology of the IMM and the association of the 
ETC complexes within the IMM, protecting them from degradation in the presence of increased 
ROS (Figure 1). Numerous studies have shown an improvement in various downstream 
consequences of mitochondrial dysfunction following treatment with elamipretide, including 
reduced fibrosis, inflammation, and cell death.  
Elamipretide has been extensively studied in multiple pre-clinical studies and in clinical trials for 
diseases involving mitochondrial dysfunction. Multiple peer-reviewed publications from more 
than 20 independent laboratories demonstrate elamipretide consistently improves mitochondrial, 
cellular, and organ function in both in vitro and in vivo disease models for which mitochondrial 
dysfunction is understood to be an important component, including cardiovascular, renal, 
metabolic, skeletal muscle, neurodegenerative, and genetic mitochondrial disease (Manczak et al.  
2010, Birk et al. 2013, Dai et al. 2013, Eirin et al. 2013, Siegel et al. 2013). Conversely, 
elamipretide is expected to have minimal or no effect in disease models in which mitochondrial 
dysfunction is not critical to pathogenesis or disease etiology.  
  
Figure 1  
Beneficial Effects of Elamipretide on Mitochondrial Function  
Elamipretide Mechanism of Action: ATP=adenosine triphosphate; CoQ=coenzyme Q10; Cyt C=cytochrome C;  
ELAM=elamipretide; ROS=reactive oxygen species Source: 
(Brown et al. 2013)  
As in models of stress induced ROS, Elamipretide stabilizes ETC structure and function in 
disease states, ultimately reducing cellular apoptosis and necrosis and improving function in 
highly energy dependent organ systems including the eye.  
Notably, elamipretide is efficacious in pre-clinical models of eye disease. For example, in 
cultured cells, elamipretide has been shown to reduce glucose- and peroxide-induced oxidative 
stress and apoptosis and to improve cell survival in human retinal endothelial cells, human 

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trabecular meshwork cells, and human retinal pigmented epithelial cells (Liang et al. 2010, Chen 
et al. 2011, Li et al. 2011, Dai et al. 2013). Also, when given subcutaneously to diabetic rats, 
elamipretide reduced oxidative stress, prevented apoptosis, and reduced VEGF-2 receptor 
expression and retinal leakage of Evans Blue dye (Huang et al. 2013). Finally, elamipretide given 
to diabetic mice not only prevented but also corrected visual functional loss (Alam et al. 2012).   
4.3.  
Elamipretide Risk/Benefit Assessment  
For additional information regarding elamipretide safety and efficacy, and risk/benefit 
assessment, please refer to the elamipretide Investigator’s Brochure.  
4.3.1.  
Pre-clinical Studies  
Several pre-clinical studies have demonstrated the potential effect of elamipretide treatment for  
AMD. In RPE cells cultured from dry AMD donor eyes, elamipretide treatment improved 
mitochondrial function at baseline, particularly on maximal respiration and spare respiratory 
capacity, both important indicators of mitochondrial health. Elamipretide also improved cell 
viability for AMD donor cells at baseline, protected cells from low level oxidative stress (150 
μM), and reduced reactive oxygen species (Kapphahn et al. 2017).   
In pre-clinical models of dry AMD, researchers at Duke Eye Center observed that elamipretide 
prevented disease progression and reversed symptoms of disease in mice. Elamipretide protected 
mice against dry AMD-like symptoms induced by hydroquinone, a toxic chemical in tobacco tar, 
as evidenced by a reduction of the drusen-like deposit formation, maintenance of normal 
membrane thickness, mitochondrial morphology, and ultrastructure of the retinal pigment 
endothelium cells in treated mice (Cousins 2015).  
Elamipretide was also tested in a murine model of AMD (Cousins 2017). Treatment with 
elamipretide improved photoreceptor function and improved apparent visual acuity. After 
treatment with elamipretide, it was also observed that the sub-retinal pigment endothelium layer 
deposits in the diseased retinas were reduced or eliminated, and the mitochondrial morphology 
within and the ultrastructure of the retinal pigment endothelium cells was improved.  
4.3.2.  
Clinical Studies  
Thus far, in human clinical trials, systemic elamipretide has been studied for the treatment of 
acute coronary syndrome, chronic heart failure, ischemic kidney disease, and mitochondrial 
myopathy, and has been found to have an acceptable safety profile; sufficient data has been 
accumulated to support subcutaneous (SC) administration of up to 40 mg dosage of elamipretide.  
For AMD subjects, the safety and efficacy of topically and parenterally administered 
elamipretide was evaluated in 2 studies: SPIOC-101 and SPIAM-101. This study will use the 
elamipretide delivery system for SC administration of the IMP.  See the current Investigator's 
Brochure for more information.  

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4.4.  
Rationale for Dose Selection  
During clinical development, multiple clinical pharmacology studies have been conducted to 
assess the safety, tolerability, and pharmacokinetics (PK) of elamipretide and its metabolites.   
The dose and route of administration (40 mg by SC injection) for the current trial has previously 
been tested in clinical studies involving healthy and dry-AMD subjects. The 0.5 mL (40 mg) 
dose for the current trial with the elamipretide delivery system was chosen based on the systemic 
exposure profile, as well as the safety observed in previous clinical studies.   
The exposure to elamipretide and its major metabolites (M1, and M2) at the systemic 
noobserved-adverse-effect-level (NOAELs) reported in the chronic rat and dog studies are 
comparable to those reported at steady-state in the clinical pharmacology studies. Safety margins 
for a clinical dose of 40 mg/day SC elamipretide are demonstrated to be > 5-fold for 
elamipretide. A 24-weeks safety and efficacy study in AMD subjects (SPIAM-101) demonstrated 
that a dosing at 40 mg/day SC was associated with a favorable benefit-risk profile. Thus the 0.5 
mL/day (40 mg) SC dose with the elamipretide delivery system is proposed for testing in this 
population.   
  
  
 

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5.  
OBJECTIVES  
5.1.  
Primary Objective  
The primary objective of the trial is to:   
• Evaluate the safety and tolerability of SC injections of elamipretide administered with the 
elamipretide delivery system in subjects with AMD with non-central GA.  
5.2.  
Secondary Objectives  
The secondary objectives of the trial are to:  
• 
Evaluate the efficacy of SC injections of elamipretide administered with the elamipretide 
delivery system in subjects with AMD with non-central GA.  
• 
Study the PK profile of elamipretide and its metabolites.  
  
  
 

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6.  
METHODOLOGY AND PROCEDURES  
6.1.  
Summary of Methodology  
This is a Phase 2, randomized, placebo-controlled, double-masked, multi-center, safety, efficacy, 
and PK trial to be conducted in the U.S. Approximately 180 subjects who have at least 1 eye with 
AMD with non-central GA will be included.  
A Screening Visit (Visit 1) will be performed no more than 14 days before the Baseline Visit 
(Visit 2, Day 1). Eligible subjects will return for the Baseline Visit, at which time subjects will be 
randomized in a 2:1 ratio (approximately 120 subjects in the treatment arm and 60 subjects in the 
placebo arm) to receive either 0.5 mL (40 mg) elamipretide or placebo administered with the 
elamipretide delivery system as a single daily SC injection.   
Investigational medicinal product (IMP) will be administered with the elamipretide delivery 
system at approximately the same time each day by SC injection (rotating clockwise around the 4 
abdominal quadrants). If necessary, SC injection in the thigh may be utilized after Investigator 
consultation with the Sponsor. At the Baseline Visit (Visit 2), site staff should witness subject or 
caregiver administering the IMP with the elamipretide delivery system. At the time of initial IMP 
administration, the subject, regular caregiver, or subject’s appropriate designee (as applicable) 
will receive training on the proper SC administration of the IMP with the elamipretide delivery 
system.  
Safety, tolerability, and efficacy will be evaluated throughout the Treatment Period (Visit 2 to 
Visit 8), while exploratory anatomical and physiologic endpoints will be measured at time points 
as specified in the Appendix 1. Schedule of Events. Plasma samples for PK evaluations will be 
collected at Visit 3 (Week 4) and Visit 4 (Week 8).  Ocular imaging will be read by an 
independent reading center.   
After completion of the 48-week Treatment Period (Visit 2 to Visit 8), subjects will continue to 
be monitored for safety during the 4-week Follow-Up Period. The Follow-Up Period is an IMP 
administration-free period. A Follow-Up Visit is scheduled at Week 52 (Visit 9).   
 
Figure 2  
SPIAM-202 Design Schematic  

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6.2.  
Visit Schedule  
Subjects will be required to participate in 9 visits at the trial site, including 1 Screening Visit  
(Visit 1), 7 Treatment Period visits (Visit 2 to Visit 8) over 48 weeks, and 1 Follow-Up Visit 
(Visit 9) 4 weeks after the last day of study treatment. Subjects discontinuing IMP, but willing to 
continue participation in the trial, will remain in the trial and have all possible trial assessments 
completed per the schedule of assessments (with the exception of PK sampling), according to the 
visit schedule as described below and in Appendix 1. Schedule of Events. The trial assessments 
are outlined in Section 6.4 as well as in the Study Procedure Manual.   
The assessments to be performed at each visit are detailed below and ordered based on 
recommended priority.  
Table 1  
SPIAM-202 Visit Schedule  
Period  
Screening Visit  
Baseline Visit and Treatment Period  
Follow-Up Visit  
Visit Number  
1  
2 to 8  
9  
Day/Week  
Day -14 to Day -1  
Day 1 to Week 48  
Week 52  
6.2.1.  
Screening Visit (Visit 1, Day -14 to Day -1)  
A signed and dated informed consent form (ICF) will be obtained from the subject before any 
screening procedures are conducted. A signed copy of the ICF will be given to the subject.  
A complete medical history will be obtained during the Screening Visit (Visit 1) within 14 days 
before the first dosing of IMP with the elamipretide delivery system at the Baseline Visit (Visit 
2). The subject’s medical history will be recorded on the Medical History section of the 
electronic case report form (eCRF). Any pre-treatment events reported from the time of consent 
until first dose of the IMP will be recorded as medical history or an adverse event (AE) (as 
described in Section 10.3).   
The subject’s ocular history should also be recorded in the eCRF, including date of diagnosis, 
involvement in 1 or both eyes, and associated symptoms.  
Subjects will undergo the following screening procedures ordered based on recommended 
priority, which may be completed on more than 1 day, as long as all procedures are completed 
during the Screening Period.    
• 
Informed consent  
• 
Demographics  
• 
Medical/ocular history   
• 
Concomitant medications  
• 
Vital signs   

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• 
Physical examination   
• 
Blood for safety, consisting of hematology panel and clinical chemistry   
• 
Urinalysis   
• 
Exploratory plasma and urine samples, withdrawn and stored for future analysis; 
analysis may include genetic and/or metabolomic testing (optional)  
• 
Pregnancy testing (serum)   
• 
Refraction   
• 
Best-corrected visual acuity (BCVA)  
• 
Low-luminance BCVA (LL BCVA)  
• 
Reading acuity (RA) at standard and low-luminance (LL RA)  
• 
Slit lamp examination   
• 
Intraocular pressure (IOP)  
• 
Dilated fundus examination   
• 
Spectral-domain optical coherence tomography (SD-OCT)  
• 
Optical coherence tomography (OCT) angiography (optional); recommended for trial 
sites that have OCT angiography  
• 
Fundus photography examination for safety assessment of the RPE, choroid, 
neuroretinal structure, retinal vessels, optic nerve, and vitreous  
• 
Fundus autofluorescence (FAF)  
• 
Fluorescein angiography (FA) (FA completed for reasons of standard of care and 
within 30 days prior to first dose can be used for screening purposes if official 
documentation is provided)  
• 
Eligibility   
• 
AEs/adverse device effects (ADEs), as described in Section 10.1)  
  
Re-screening of subjects may be allowed, depending on the reason for screen-failure, after 
consultation with the Sponsor.  
6.2.2.  
Baseline Visit (Visit 2, Day 1)  
• 
Medical/ocular history and   
• 
Concomitant medications  
• 
Low Luminance Questionnaire (LLQ)  
• 
Visual Function Questionnaire-39 (VFQ-39)  
• 
EQ-5D-5L Questionnaire   
• 
Vital signs  
• 
Physical examination  
• 
Blood for safety, consisting of hematology panel and clinical chemistry  
• 
Urinalysis  
• 
Pregnancy testing (urine)  
• 
Refraction  
• 
BCVA  

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• 
LL BCVA   
• 
RA and LL RA  
• 
Slit lamp examination  
• 
IOP  
• 
Dilated fundus examination   
• 
SD-OCT  
• 
OCT angiography (optional; recommended for trial sites that have OCT angiography) 
• Fundus photography examination  
• 
FAF  
• 
Eligibility  
• 
Randomization  
• 
Dispense IMP and subject diary  
• 
IMP training and subject administration during visit  
• 
AEs/ADEs  
6.2.3.  
Trial Treatment Period  
6.2.3.1. Week 4 (± 3 days), 8 (± 3 days), 12 (± 3 days), 24 (± 3 days), and 36 (± 3 days) 
Visits (Visits 3-7)  
• 
Concomitant medications  
• 
LLQ (Weeks 12, 24, and 36 only)  
• 
VFQ-39 (Weeks 12, 24, and 36 only)  
• 
Vital signs  
• 
Physical examination (Week 24 only)  
• 
Blood for safety  
• 
Urinalysis  
• 
Exploratory plasma and urine samples (optional, Week 24 only)  
• 
Pregnancy testing (urine)  
• 
Refraction  
• 
BCVA  
• 
LL BCVA  
• 
RA and LL RA (Weeks 4, 12, and 36 only)  
• 
Slit lamp exam  
• 
IOP (Weeks 24 and 36 only)  
• 
Dilated fundus exam  
• 
SD-OCT and OCT angiography (optional) (Weeks 12, 24, and 36 only)  
• 
Fundus photography (Weeks 12, 24, and 36 only)  
• 
FAF (weeks 12, 24, and 36 only)  
• 
Dispense IMP and subject diary  
• 
IMP accountability  

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• 
PK sampling (Weeks 4 and 8); see Section 6.4.7 for sampling time points  
• 
AEs/ADEs  
6.2.3.2. Week 48 (± 3 days) Visit (End of Treatment) / Early Termination Visit  
• 
Concomitant medications  
• 
LLQ  
• 
VFQ-39  
• 
EQ-5D-5L  
• 
Vital signs  
• 
Physical examination  
• 
Blood for safety  
• 
Urinalysis  
• 
Exploratory plasma and urine samples (optional) (End of Treatment Visit only)  
• 
Pregnancy testing (urine) (Week 48 only)  
• 
Pregnancy testing (serum) (Early Termination Visit only)  
• 
Refraction  
• 
BCVA  
• 
LL BCVA  
• 
RA and LL RA  
• 
Slit lamp exam  
• 
IOP  
• 
Dilated fundus exam  
• 
SD-OCT  
• 
OCT angiography (optional)  
• 
Fundus photography  
• 
FAF  
• 
IMP accountability  
• 
Random PK sample (Early Termination Visit only); see Section 6.4.7 for sampling 
time points  
• 
AEs/ADEs  
6.2.4.  
Follow-up Period  
A Follow-Up Visit will occur 4 weeks after the last dose of IMP administration. Assessments will 
be collected according to Appendix 1. Schedule of Events. Subjects withdrawing from the trial 
will be asked to complete the Early Termination Visit assessments.   
6.2.4.1. Week 52 (± 3 days) Follow-up Visit (End of Trial)  
•  Concomitant medications  
•  Physical examination  

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•  Pregnancy testing (serum)  
•  AEs/ADEs  
6.3.  
Schedule of Events  
Trial procedures and their recommended order of priority are summarized in the Schedule of 
Events (Appendix 1. Schedule of Events). A list of all clinical laboratory tests to be performed is 
found in Section 6.4.   
6.4.  
Trial Assessments  
6.4.1.  
Medical/Surgical History and Concomitant Medications/Procedures  
  
Medical history and any concomitant medications will be recorded during the Screening Visit. At 
the Baseline Visit, a review of any additional medical history and/or new concomitant 
medication/procedures that occurred during the Screening Period will be completed.  
Concomitant medications/procedures should be updated and recorded at each trial site visit.  
  
6.4.2.  
Vital Sign Measurements  
Vital sign measurements (temperature, respiratory rate, sitting blood pressure after resting for 5 
minutes, and pulse) and weight will be collected. All vital sign measurements are to be obtained 
with the subject in a position that is consistent throughout the trial. The equipment should be 
properly calibrated/ certified. If possible, the same equipment and evaluator should be used 
throughout the trial period.  
6.4.3.  
Physical Examination  
The physical examination will include assessment of head, eyes, ears, nose, and throat, general 
appearance, skin, chest, heart, abdomen, extremities, and the nervous system. Height will be 
measured at the Screening Visit only. Measurement of weight should be performed with the 
subject dressed in indoor clothing, shoes removed, and bladder empty.  
6.4.4.  
Clinical Laboratory Testing  
All standard blood and urine tests will be analyzed by a central laboratory designated by the 
Sponsor. All laboratory results must be reviewed by the Investigator to note for clinically 
significant events. Any clinically significant event must be followed and reported (see Section 
10.6 for AEs and abnormal laboratory values). Exploratory plasma and urine samples may be 
withdrawn and stored for future analysis (analysis may include genetic and/or metabolomic 
testing, this assessment is optional). Detailed instructions for blood sample collection will be 
provided to sites in the Laboratory Manual.  

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Clinical laboratory assessments performed:  
Chemistry  
Alkaline phosphatase, alanine aminotransferase, aspartate 
aminotransferase, total bilirubin, blood urea nitrogen, creatinine, creatine 
phosphokinase, glucose (non-fasting), lactate dehydrogenase, sodium, 
potassium, albumin, total protein, calcium, chloride, and bicarbonate  
Hematology  
Hemoglobin, hematocrit, erythrocyte (red blood cell [RBC]) count, 
leukocytes (white blood cells [WBC]) count, and differential (neutrophils, 
segmented; lymphocytes; monocytes; eosinophils; basophils), platelets, 
mean corpuscular volume, mean corpuscular hemoglobin, and mean 
corpuscular hemoglobin concentration  
Urinalysis  
pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrite, 
urobilinogen, and leukocyte esterase; if the dipstick is abnormal for 
protein, blood, nitrite, or leukocyte esterase, include RBCs, WBCs, 
bacteria, and casts  
6.4.5.  
Pregnancy Testing  
For female subjects of child bearing potential, pregnancy testing by assessment of serum 
betahuman chorionic gonadotrophin will be performed at the time of the Screening Visit and at 
trial conclusion. Female subjects of child bearing potential will have a urine pregnancy test at the 
Baseline Visit and all visits during the Treatment Period, and the results of the Baseline Visit pre-
dose pregnancy test must be evaluated before randomization to ensure eligibility. Female 
subjects who are considered not to be of child bearing potential must have a history of being 
post-menopausal (no menses for 12 months without an alternative medical cause), tubal ligation, 
or other surgical sterilization such as hysterectomy or bilateral oophorectomy that is clearly 
documented in the subject’s source documents.  
6.4.6.  
Subject Diary  
Subjects will be asked to complete paper diaries documenting IMP compliance.  Trial site 
personnel will review the subject diary at each visit and retrain the subject on administration of 
IMP if necessary.  
6.4.7.  
Pharmacokinetics Sampling  
To characterize the PK of elamipretide and its metabolites, PK sampling will be conducted at the 
defined time points below:   
• 
Week 4 Visit o Pre-dose (-30 minutes) o 
0.5 hours post-dose (± 5 minutes) o 1 
hour post-dose (± 15 minutes) o 2 hours 
post-dose (± 15 minutes)  

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• 
Week 8 Visit o 4 hours post-dose (± 1 
hour) o 8 hours post-dose (± 2 hours)  
• 
Early Termination Visit o Random PK 
sample (one sample at any time during 
visit)  
For the Week 4 Visit, the subject will administer IMP at the trial site within 30 minutes after the 
pre-dose PK sample is collected.  For the Week 8 Visit, the subject will administer IMP at home, 
approximately 4 hours before arriving at the trial site. Samples should be collected as close to 
nominal as possible.  
6.4.8.  
Other Trial Assessments  
Subjects will undergo a number of examinations to establish the subject’s baseline disease and 
change in disease over time. The following assessments will be performed during Screening 
and/or at Baseline, and at various times throughout the trial.   
• 
LLQ is a vision-related quality of life scale assessing mainly mesopic and scotopic 
functioning. Subjects will be asked 36 questions about problems that involve his/her 
vision under different lighting conditions.  This assessment will be administered by the 
site staff.  
• 
VFQ-39 is designed to assess the health-related quality of life of subjects with visual 
impairment and includes: general vision, ocular pain, near activities, distance activities, 
vision-specific social functioning, vision-specific mental health, vision-specific role 
difficulties, vision-specific dependency, driving, color vision, and peripheral vision. This 
assessment will be administered by the site staff.  
• 
EQ-5D-5L is a general quality of life Questionnaire assessing mobility, self-care, usual 
activities, pain/discomfort, anxiety/depression, and overall assessment of health.  This 
assessment will be completed by the subjects.  
• 
BCVA, LL BCVA, RA, and refraction will be assessed as detailed in their respective 
study procedure manuals. Sites and site staff will be trained and certified on these 
procedures.  
• 
IOP will be measured by Goldmann tonometry or Tonopen. The same method for each 
individual subject should be used throughout the study, if possible. IOP measurement 
must be performed prior to dilation. If IOP is > 35 mmHg as measured with a tonopen, 
IOP should be measured again by Goldmann tonometry.  
• 
The anterior segment of the eye will be analyzed by slit lamp biomicroscopy.  
Magnification, slit beam, and examination procedure will be consistent with  
Investigator’s standard practice. Findings which are deemed clinically significant by the 
Investigator will be documented on each subject’s source document and corresponding 
eCRF.  

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• 
Dilated indirect ophthalmoscopy will be performed to examine the vitreous, retina, 
macula, choroid, optic nerve, and blood vessels. Findings that are deemed clinically 
significant by the Investigator will be documented on each subject’s source document and 
corresponding eCRF.  
• 
Fundus photography of the posterior segment, SD-OCT of the macula, FAF imaging of 
the RPE and neurosensory retina, and FA to examine the circulation of the retina and 
choroid and to rule out choroidal neovascularization (CNV) will be performed as outlined 
in the imaging manual. FA completed for standard of care within 30 days prior to first 
dose can be used as the screening assessment if the official medical record is provided.  
7.  
SELECTION AND WITHDRAWAL OF SUBJECTS  
Subjects meeting the following criteria will be eligible to participate in the trial. The Investigator 
will review all inclusion/exclusion criteria and make a recommendation to the Reading Center 
for subject eligibility. The Reading Center will review all retinal imaging for inclusion/exclusion 
criteria as well as the Investigator’s recommendation and make the final determination for 
subject eligibility and selection of study eye.  
7.1.  
Inclusion Criteria  
1. Adults ≥ 55 years of age with at least 1 eye with AMD with non-central GA. For this 
study, non-central GA is defined as:  
a. well-demarcated area(s) of GA; presence and area will be determined primarily 
by FAF.   
b. All GA lesions must be at least 150 µm from foveal center with preserved outer 
retinal structural details, as confirmed by the reading center.  
Ocular conditions–study eye  
2. GA in the study eye at the Screening Visit may be multi-focal, but the cumulative GA 
lesion and size (by FAF, as determined by the reading center) must:  
a. be ≥ 0.05 mm2 and ≤ 10.16 mm2 and  
b. reside completely within the FAF 30 or 35 degree image.  
3. No evidence of CNV by history, OCT or FA in the study eye.  
4. BCVA by Early Treatment Diabetic Retinopathy Study (ETDRS) score of ≥ 55 letters 
(Snellen equivalent ≥ 20/70) in the study eye at the Screening Visit and Baseline Visit.  
5. LL BCVA by ETDRS score of ≥ 10 letters in the study eye at the Screening Visit and 
Baseline Visit.  
6. LL VA deficit (defined as the difference between BCVA and LL BCVA) of > 5 letters in 
the study eye at Screening and Baseline Visits.  

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7. The fellow eye may have any of the following: no AMD, AMD without GA, AMD with 
GA, CNV AMD, or central GA. Ongoing treatment with anti-angiogenic therapies in 
the fellow eye is allowable.  
8. Sufficiently clear ocular media, adequate pupillary dilation, fixation to permit quality 
fundus imaging, and ability to cooperate sufficiently for adequate ophthalmic visual 
function testing and anatomic assessment in the study eye.  
Systemic and general criteria  
9. Able to administer IMP or have an appropriate designee who can administer the IMP 
(i.e., a capable family member or a caregiver).   
10. Able to provide informed consent and willing to comply with all study visits, 
examinations, IMP administrations, and conditions of the study protocol.   
11. Women of childbearing potential who are not pregnant or nursing and have a negative 
serum pregnancy test at screening.   
12. 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 1 
month after last dose.   
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. Acceptable methods include: 
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. Subjects must use a condom with 
spermicide from the date of informed consent until at least 1 month after the last 
dose of study drug. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
or post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. Male subjects with pregnant partners must use a condom.  
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 for 1 month after last dose should they become sexually active. 
Acceptable methods include: 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. Alternatively, 
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). Non-childbearing potential is defined as surgical sterilization  
(e.g., bilateral oophorectomy, hysterectomy, or tubal ligation) or post-menopausal 
(defined as permanent cessation of menstruation for at least 12 consecutive 
months prior to the Screening Visit).  

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7.2.  
Exclusion Criteria  
Subjects with a study eye who meets any of the following criteria will be excluded from the 
study:  
Ocular conditions–study eye  
1. The absence of observable hyper-FAF at the margins of the GA in the study eye (only for 
lesions ≥ 0.25mm2).  
2. Atrophic retinal disease of causality other than AMD including myopia-related 
maculopathy and monogenetic macular dystrophies including pattern dystrophy and 
adult-onset Stargardt disease in the study eye.   
3. Presence or diagnosis of exudative AMD or CNV in the study eye.  
4. Presence of retinal vein occlusion in the study eye.  
5. Presence of diabetic retinopathy (a history of diabetes mellitus without retinopathy is not 
a criterion for exclusion) in either eye.  
6. Presence of vitreous hemorrhage in the study eye.  
7. History of retinal detachment in the study eye.   
8. History of macular hole (stages 2 to 4) in the study eye.  
9. Presence of an epiretinal membrane that causes distortion of the retinal contour in the 
study eye.  
10. Presence of vitreomacular traction in the study eye.  
11. At the Screening Visit, advanced glaucoma resulting in a cup to disc ratio of > 0.8 in the 
study eye.  
12. History of glaucoma filtration surgery or uncontrolled glaucoma defined as IOP > 22 
mmHg at baseline despite anti-glaucoma treatment with or without topical 
antihypertensive eye drops in the study eye OR currently using > 2 medications (note: 
combination medications count as 2 medications).  
13. Presence of visually significant cataract OR presence of significant posterior capsular 
opacity in the setting of pseudophakia. Significant cataract is defined as > +2 nuclear 
sclerosis based upon the scale below or any Posterior Subcapsular Cataract in the study 
eye. The Sponsor, or its designee, will supply the trial sites with a copy of the standard 
photographs.  
Grade  
Description  
+1  
Opacity is absent  
+2  
Opacity is present, but less than Nuclear Standard Photograph #2  

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  Source: (Chew et al. 2010)  
14. Presence of significant keratopathy or any other media or corneal opacity that would 
cause scattering of light or alter visual function, especially in LL conditions in the study 
eye.   
15. Ocular incisional or laser surgery (including cataract surgery) in the study eye within 90 
days before Day 1.  
16. Yag laser capsulotomy in the study eye within 30 days before Day 1.  
17. Aphakia in the study eye.   
18. History of vitrectomy surgery, submacular surgery, or any vitreoretinal surgery in the 
study eye.  
19. Prior treatment with Visudyne® (verteporfin) ocular photodynamic therapy, externalbeam 
radiation therapy (for intraocular conditions), or transpupillary thermotherapy in the 
study eye.  
20. History of subthreshold laser treatment or other forms of photobiomodulation for AMD in 
the study eye.  
21. Intravitreal drug delivery in the past 60 days or 5-half-lives of the injected drug 
whichever is longer (e.g., intravitreal corticosteroid injection, anti-angiogenic drugs, or 
device implantation) in the study eye.  
22. Current use of medications known to be toxic to the lens, retina, or optic nerve (e.g., 
deferoxamine, chloroquine/hydroxychloroquine [Plaquenil®], tamoxifen, phenothiazines, 
ethambutol, digoxin, and aminoglycosides) from the Screening Visit through the 
completion of the trial.   
23. Concurrent disease in the study eye that could require medical or surgical intervention 
during the study period.  
Ocular conditions––either eye  
24. History of herpetic infection in either eye.  
25. Active uveitis and/or vitritis (grade trace or above) in either eye.  
26. History of idiopathic or autoimmune-associated uveitis in either eye.  
27. Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye.  
Systemic conditions  
28. Known to be immunocompromised or receiving systemic immunosuppression for ≥ 4 
consecutive weeks prior to screening.  
+3 
Opacity is present, and as severe as or worse than Nuclear Standard Photograph #2  

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29. Any disease or medical condition that in the opinion of the Investigator would prevent 
the subject from successfully participating in the study or might confound study 
results.  
  
General  
30. Participation in other investigational drug or device clinical studies within 30 days of 
enrollment and/or planning to participate in any other investigational drug or device 
clinical studies within 30 days of study completion.   
31. History of allergy to fluorescein that is not amenable to treatment.  
32. Creatinine clearance of ≤ 30 mL/min at the Screening Visit (using Modification of Diet in 
Renal Disease Study formula)  
33. Inability to comply with study or follow-up procedures.  
34. Inability to obtain color fundus photograph, FAF, and FA of sufficient quality to be 
analyzed and interpreted.  
35. Active malignancy or any other cancer from which the subject has been cancer-free for < 2 years.   
36. History of allergic reaction to the investigational drug or any of its components.  
37. Prior treatment with Elamipretide.   
7.3.  
Discontinuation of Subjects  
Subjects may be discontinued for the following reasons:  
• 
Investigator decision  
• 
Subject decision   
• 
Sponsor decision  
• 
AE/ ADE  
Any subject withdrawing from the trial will be asked to complete the Early Termination Visit 
assessments (see Section 6.2.3.2).  
7.4.  
Replacement of Subjects  
Replacement of subjects will not occur in this study.    
7.5.  
Discontinuation of Trial Sites  
Trial site participation may be discontinued if the Sponsor or its designee, the Investigator, or the 
Institutional Review Board (IRB) of the trial site judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP guidelines.  

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7.6.  
Discontinuation of the Trial  
The trial will be discontinued if the Sponsor or its designee judges it necessary for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and GCP 
guidelines.  
7.7.  
Discontinuation of Investigational Medicinal Product  
Subjects who discontinue from IMP may be asked if they wish to continue participation in the 
study.  In these cases, after agreement between the Investigator and Sponsor, subjects will return 
to the clinic for all remaining study visits and assessments (except for PK sampling) per the visit 
schedule outlined in Section 6.2.  If subjects discontinue from IMP and do not remain in the 
study, they should complete assessments for an Early Termination Visit, as outlined in Section  
6.2.   
 

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8.  
TREATMENT AND RESTRICTIONS  
8.1.  
Investigational Medicinal Product  
8.1.1.  
Elamipretide Injection or Placebo   
Elamipretide injection and placebo will be supplied separately from the elamipretide pen injector 
and single-use needle as labeled sterile 3 mL single-patient-use, multi-dose glass cartridges for 
use with the assembled elamipretide delivery system. Each cartridge contains elamipretide 
solution for up to five 0.5 mL doses.  Elamipretide solution for injection is an aqueous sterile 
solution of 80 mg/mL elamipretide HCl formulated in sodium phosphate buffer and benzyl 
alcohol. The placebo solution is composed of sodium chloride, sodium phosphate buffer, and 
benzyl alcohol.  
Elamipretide injection and the placebo single-patient-use, multi-dose glass cartridges are to be 
stored at 2 to 8°C (36 to 46°F) in a secure area and dispensed according to the Pharmacy Manual. 
Temperature records must be maintained, and temperature excursions must be reported as soon 
as they are discovered. The sponsor should be notified in the case of an excursion.  
8.1.2.  
Elamipretide Pen Injector   
The labeled elamipretide pen injector and Instructions for Use (IFU), developed by Stealth BT 
exclusively for use with the elamipretide injection or placebo 3 mL cartridges, will be supplied 
separately from the pen injector and needle.   
The elamipretide pen injector must be stored at room temperature and not refrigerated. The 
ancillary supplies (e.g., single-use needle) are to be stored at room temperature as well.  
8.1.3.  
Elamipretide Delivery System  
The elamipretide pen injector along with IMP cartridge and the single-use needle constitutes the 
elamipretide delivery system for use in this trial. The elamipretide delivery system is for personal 
use (single subject) for SC administration of a fixed dose (0.5 mL) of elamipretide injection or 
placebo. The needle provided must be used. The elamipretide delivery system is operated 
mechanically and contains no electronics. The elamipretide delivery system is depicted in Figure 
3. The user will assemble and use the elamipretide delivery system per the IFU that will be 
provided to each subject. Once assembled with the single-patient-use, multi-dose cartridge, the 
elamipretide delivery system is to be stored at room temperature for up to 5 doses and must not 
be refrigerated.   

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Figure 3:  
Elamipretide Delivery System  
  
Each subject or caregiver will be trained in the use of the elamipretide delivery system per the 
IFU prior to administration of the first dose. An elamipretide delivery system training kit and 
checklist will be provided to the trial site to assist in training.  Any new caregiver should 
complete training at a trial site visit before administering IMP to a subject.  
  
8.2.  
Investigational Medicinal Product Administration  
8.2.1.  
Investigational Medicinal Product Treatment Regimen  
A fixed dose (0.5 mL) of elamipretide injection is administered with the elamipretide delivery 
system by SC administration. Subjects will receive IMP administered as a single daily SC 
injection of elamipretide injection or placebo. The first IMP injection with the elamipretide 
delivery system will occur at the trial site on Day 1 by the subject (or designated caregiver) and 
witnessed by site staff. Each subject (or caregiver) will be trained on the use of the elamipretide 
delivery system on Day 1. A diary will be used to document administration.  Any new caregiver 
should complete training at a trial site visit before administering IMP to a subject.  
Administration should occur at approximately the same time each day (e.g., early morning, noon, 
or early afternoon) by subject or caregiver. If necessary, SC injection in the thigh may be utilized 
after Investigator consultation with the Sponsor. If a subject is concurrently receiving another SC 
therapy, unique locations for injections for the IMP, independent from the location of the 
concomitant therapy injections, should be used (after Investigator consultation with the Sponsor).  

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The Week 8 Visit requires subjects to administer the IMP with the elamipretide delivery system 4 
hours prior to a PK blood draw (± 1 hour).   
8.2.2.  
Dose Interruption of Individual Subjects  
Elamipretide administration for an individual subject may be stopped for safety reasons by the 
Investigator or following the Sponsor's recommendation. The determination of the length of the 
discontinuation, temporary or permanent, depends on the clinical situation. With the exception of 
emergency situations, the Investigator is responsible for contacting the Sponsor or designee prior 
to interrupting the subject’s daily study drug dosing regimen.   
8.3.  
Investigational Medicinal Product and Accountability  
All drug accountability records must be kept current, and the Investigator must be able to account 
for all used and unused elamipretide delivery system supplies (with the exception of needles). 
The clinical monitor responsible for the trial site will provide written approval for the destruction 
or return of used and unused IMP following reconciliation of all clinical supplies.  
The elamipretide delivery system supplies are to be available to the principal Investigator, his/her 
named sub-Investigator(s), or the study staff and are to only be used in accordance with this 
protocol. The elamipretide delivery system supplies must only be distributed to subjects properly 
qualified under this protocol to receive them.   
8.4.  
Investigational Medicinal Product Compliance  
All drug compliance records must be kept current and must be made available for inspection by 
the Sponsor and regulatory agency inspectors.  
8.5.  
Randomization/Method of Assigning Investigational Medicinal 
Product  
Each subject who signs an ICF will be assigned a screening number. Screening numbers will be 
assigned in sequential order at each site beginning with 001 and will follow the two-digit site 
number (for example, Subject 077 at Site 99 will have Screening Number 99077). Inclusion and 
exclusion criteria will be reviewed, and qualifying subjects will be enrolled into the study. Each 
subject who qualifies for entry will be assigned a subject number and corresponding treatment 
according to the randomization code. Study drug will be randomly assigned using a 2:1 
assignment ratio, via an interactive response system.  
8.6.  
Masking and Unmasking Procedures  
Trial personnel, subjects, and the Sponsor study team will be masked to treatment until the 
database is locked. The Investigator will contact the Sponsor prior to unmasking any subject’s 
treatment unless in the instance of a medical emergency.  

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In case of an immediate medical emergency or if directed by the Sponsor, and only if the 
information is required by the Investigator to manage a subject’s AE, is a subject’s treatment 
assignment to be unmasked prematurely. In cases of medical emergency, the Investigator may 
unmask a subject’s treatment assignment using the computerized system according to the 
instructions received. The Sponsor must be notified as soon as possible regarding the reason for 
unmasking.  
Whenever the treatment assignment of an individual subject is unmasked, the individual who 
performed the unmasking, the date, time, and reason for the unmasking must be logged in the 
computerized unmasking system and also included in source documentation. The name of the 
individual who broke the masking must be included in the clinic’s source documentation.  
The Sponsor designated contract research organization (CRO) will control and document, 
according to the appropriate Standard Operating Procedures, the disclosure of treatment 
assignments, and treatment identity. These procedures ensure that no masked staff (CRO, trial 
site staff, Sponsor) will have premature access to the subjects’ treatment assignments.  
8.7.  
Concomitant Medications  
Current use of or likely need for systemic medications known to be toxic to the lens, retina, or 
optic nerve (e.g., deferoxamine, chloroquine/hydroxychloroquine [Plaquenil®], tamoxifen, 
phenothiazines, ethambutol, digoxin, and aminoglycosides) are prohibited from the Screening 
Visit until completion of the trial (completion of the Follow-Up Visit).  
All chronic medications, including over-the-counter treatments, vitamins, or supplements, must 
be unchanged and constant for at least 1 month before the Baseline Visit (Day 1) or for what is 
equivalent to 5 half-lives, whichever is longer. All concomitant medications will be recorded in 
the source data and the eCRF. Changes in dosages of current therapeutic agents during the 
conduct of the trial will be discouraged, unless medically necessary or required to treat an 
AE/ADE.   
Any treatment administered from the time of informed consent to the final study visit will be 
considered concomitant medication. This includes medications that were started before the study 
and are ongoing during the study.  
Subjects will be instructed to maintain their normal diet, daily caffeine, and regular fiber intake 
throughout the Treatment Period.   
No diagnostic drops used for trial assessments will be collected as concomitant medications.   
8.8.  
Prohibited Medications and Therapies  
The use of any other investigational drug except elamipretide is prohibited from the Screening 
Visit until completion of the trial (completion of the Follow-Up Visit). Prohibited medications 
include:  

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• 
Medications known to be toxic to the lens, retina, or optic nerve, or have a potential to 
interact with the investigational product. Examples include deferoxamine, chloroquine, 
hydroxychloroquine (Plaquenil®), tamoxifen, phenothiazines, ethambutol, sacubitril – 
valsartan (Entresto®), digoxin, and aminoglycosides.  
• 
Any periocular and ocular intravitreal injected/implanted medications used in the study 
eye.  
Any ophthalmic topical medications used in the study eye will be reviewed and deemed safe and 
approved by the investigator. Topical drops for treatment of elevated IOP are allowed, including 
for ongoing/intermittent application of artificial tears/ lubricating ointments for the treatment of 
mild ocular surface disease/dry eye.  
Chronic systemic medications (prescription or non-prescription) for the treatment of ocular 
conditions may be used if deemed safe and appropriate by the Investigator and must have been 
unchanged and constant for at least 1 month before the Baseline Visit (Day 1) or for what is 
equivalent to 5 half-lives, whichever is longer.   
8.9.  
Subject Management  
There are no specific restrictions for the subject.   
8.10.  
Continued Access to Investigational Medicinal Product  
The elamipretide delivery system will not be made available to subjects at the conclusion of their 
participation in the trial.   
  
  
9.  
EFFICACY, PHARMODYNAMICS, AND PHARMOKINETICS  
ASSESSMENTS  
9.1.  
Efficacy Measures  
For efficacy endpoints, the unit of analysis will be the study eye as defined by the following:  
• 
Study Eye: Eyes are eligible for analysis if they meet all of the inclusion criteria and none 
of the exclusion criteria. In the case that both eyes are eligible for analysis, the study eye 
will be the eye with worse LL BCVA at baseline. If the eyes have equal LL BCVA, then 
the right eye will be the study eye.  
9.1.1.  
Primary Efficacy Endpoints:   
• 
LL BCVA  
• 
GA area as measured by OCT  

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9.1.2.  
Secondary Efficacy Endpoints   
• 
LL RA  
• 
BCVA   
• 
GA area as measured by FAF   
9.1.3.  
Exploratory Efficacy Endpoints   
• 
Volumetric OCT and ellipsoid zone (EZ) mapping as defined as:  
o Macular Percentage of EZ Total Attenuation o 
Macular Percentage of EZ Partial Attenuation o 
Central 1-mm mean EZ-RPE thickness o Central 
2-mm mean EZ-RPE thickness  
• 
National Eye Institute VFQ-39 score   
• 
RA at standard light  
• 
Visual function by the LLQ  
• 
EQ-5D-5L score  
• 
Conversion to CNV  
• 
BCVA and LL BCVA in non-study eyes  
• 
GA area as measured by OCT in non-study eyes with GA.  
9.2.  
Pharmacokinetics Measures  
Characterization of the PK parameters of elamipretide and its metabolites in plasma, including 
apparent clearance, maximum plasma concentration (Cmax), and area under the plasma 
concentration time-curve from 0 to 24 hours (AUC0-24), will be performed via population PK 
(PopPK) modelling.   
 

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10.  
SAFETY ASSESSMENTS  
For safety assessments, the unit of analysis will be the study eye for ophthalmological 
assessments and the subject for systemic assessments. The primary safety and tolerability 
endpoints for the trial are:  
• 
The incidence and severity of AEs/ADEs.  
• 
Vital sign measurements.  
• 
Clinical evaluations (ocular and non-ocular).  
• 
Clinical laboratory evaluations.  
• 
Slit lamp examination  
• 
Dilated fundus examination  
10.1.  
Adverse Events/Adverse Device Effects  
An AE is any untoward medical occurrence or clinical investigation in a subject administered a 
pharmaceutical product and it does not necessarily have to have a causal relationship with the 
treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not the event is considered related to the IMP.  
An ADE is an AE related to the use of an investigational medical device. This includes any event 
resulting from insufficient or inadequate instructions for use, deployment, installation, or 
operation; any malfunction of the investigational medical device; or any event resulting from 
user error or from intentional misuse of the investigational medical device.  
10.2.  
Safety Evaluations  
Subjects must be seen by a physician or designee (an appropriately trained healthcare 
professional) at every trial visit and the evaluation must be documented. Subjects should be 
asked about the status of any previously reported events or effects. Trial site personnel will report 
any AEs/ADEs, whether observed by the Investigator (or designee) or reported by the subject.  
Should the IMP be discontinued due to an AE/ADE (per Section 10.10.2), reinitiating  
(rechallenge) of the IMP may be possible, after consultation with the Sponsor (per Section 8.2.2).  
The Investigator is responsible for promptly documenting and reporting all AEs/ADEs observed 
during the trial in the subject’s eCRF and applicable forms. Investigators are responsible for 
monitoring the safety of subjects who have entered this trial 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 facilitating the appropriate medical care 
of subjects during the trial and for an AE/ADE, should one occur.  
The Investigator remains responsible for following, through an appropriate health care option, 
AEs/ADEs that are serious, considered related to the elamipretide delivery system or the trial, or 

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that caused the subject to discontinue before completing the trial. The subject should be followed 
until the event is resolved or explained.   
The Sponsor will periodically review trial safety data as outlined in the Medical Monitoring Plan.  
10.3.  
Pre-Treatment Events  
Untoward events that occur prior to the first IMP administration (pre-treatment event) and 
assessed by the Investigator as related to a trial procedure and/or meeting seriousness criteria will 
be recorded as an AE/SAE on the subject’s eCRF and applicable forms, processed, and followed 
accordingly. AEs/SAEs that occur prior to IMP administration are by definition, unrelated to the 
IMP and will be reported as such in the data listings.  
10.4.  
Baseline Medical History Conditions  
Pre-treatment events or diagnoses not related to a trial procedure and/or meeting seriousness 
criteria will be recorded as medical history on the subject’s eCRF. Medical history conditions 
related or not related to the therapeutic area of interest/investigation that worsen in severity or 
frequency during the trial in a way that is not consistent with natural disease progression, in the 
opinion of the Investigator, should be recorded and reported as AEs/ADEs.  
10.5.  
Medical and Surgical Procedures   
Medical or surgical procedures (including hospitalizations) scheduled prior to signing the 
informed consent but occurring during the trial should not be captured as AEs. The condition 
leading to the procedure should be listed in the medical history and the procedure should be 
captured on the concurrent procedures page. Medical or surgical procedures not scheduled prior 
to signing the informed consent should not be recorded as AEs; the condition that led to the need 
to perform the medical or surgical procedure will be the AE or SAE, and the procedure should be 
captured on the concurrent procedures page.  
10.6.  
Abnormal Laboratory and Other Abnormal Investigational Findings  
Abnormal laboratory findings or other objective measurements deemed clinically significant by 
the Investigator should be reported as an AE/ADE.  
When reporting an abnormal laboratory finding as an AE/ADE or SAE/SADE, the description of 
the abnormality, rather than the abnormal value itself, should be recorded. A clinical diagnosis 
should be reported if the Investigator believes the finding is consistent with a disease process.  
10.7.  
Symptomatic Overdose  
In the event of an overdose of trial medication, the Investigator should use clinical judgment in 
evaluating the presence of and treating the signs and symptoms of the overdose. The signs and 
symptoms should be reported as AEs/ADEs. Overdoses must be reported immediately to the trial 
Medical Monitor (or designee).  

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10.8.  
Serious Adverse Events/Serious Adverse Device Effects  
A serious adverse event (SAE) or SADE is any AE/ADE that:  
• 
Leads to death. (In the case of a death, the cause of death is used as the AE term, and 
the fatality is considered as the outcome)  
• 
Leads to serious deterioration in the health of the subject, that either results in o A 
life-threatening illness or injury (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), or  
o A permanent impairment of a body structure or a body function (which may 
manifest as a persistent or significant disability or incapacity), or  
o Inpatient or prolonged hospitalization, or  
o Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function,  
• 
Lead to fetal distress, fetal death, or a congenital abnormality or birth defect  
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect  
• 
Is otherwise considered medically important  
A SADE is an SAE that is related to the use of the elamipretide delivery system including the pen 
injector and needle.   
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should 
also usually be considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias, or convulsions that do 
not result in hospitalization; or development of drug dependency or drug abuse.  
Any non-serious AE/ADE that worsens and meets the criteria for a SAE/SADE should be 
reported as a SAE/SADE. The start date of the SAE/SADE should be the date the AE/ADE 
worsened to meet the criteria for a SAE/SADE.  
The Investigator is expected to take all therapeutic measures necessary for resolution of the 
SAE/SADE. Any medications or procedures necessary for treatment of the SAE/SADE must be 
recorded on the subject’s eCRF.  
As part of the routine medical monitoring, the Medical Monitor (or designee) will review all 
SAEs/SADEs reported in this trial, looking for any safety data trends or IMP-related or 
elamipretide delivery system-related issues.  

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10.8.1.  
Events that Do Not Meet the Definition of a Serious Adverse Event  
Elective hospitalizations are not considered SAEs. However, all events leading to unplanned 
hospitalizations or unplanned prolongation of an elective hospitalization (e.g., undesirable effects 
of any administered medication) must be documented and reported as SAEs/SADEs.  
10.9.  
Recording of Adverse Events/Adverse Device Effects  
Complete and accurate data on all AEs/ADEs experienced for the duration of the reporting period 
(defined below) will be recorded on an ongoing basis on the subject’s eCRF. All SAEs/SADEs 
must be reported using the trial specific SAE/SADE Report Form, in addition to the subject’s 
eCRF.  
It is important that each AE/ADE entry include a verbatim term along with, onset and resolution 
dates, severity, seriousness, relationship to the elamipretide delivery system, action taken with 
respect to the IMP, and its outcome.   
Investigators should use the AE/ADE definitions provided in the above sections and should 
observe the following guidelines when completing the subject’s eCRF:  
• 
Whenever possible, recognized medical terms should be used to describe AEs/ADEs 
rather than colloquialisms (e.g., ‘influenza’ rather than ‘flu’), and abbreviations should 
be avoided.  
• 
AEs/ ADEs should be described using a specific clinical diagnosis, if this is available, 
rather than a list of signs or symptoms (e.g., ‘congestive heart failure’ rather than 
‘dyspnea, rales, and cyanosis’). However, signs/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/ADEs.   
• 
Provisional diagnosis (e.g., “suspected Myocardial Infarction”) is acceptable but should 
be followed with a definite diagnosis (if available). Similarly, a fatal event with an 
unknown cause should be recorded as “Unknown”  
• 
In cases of surgical or diagnostic procedures, the condition/illness leading to such a 
procedure is considered as the AE/ADE rather than the procedure itself.  
10.10.  
Investigator Assessments  
10.10.1.  Severity/Intensity  
The following assessment scale applies to all AEs/ADEs with the exception of the injection site 
reaction (ISR) severity assessment.  
Severity, which is a description of the intensity of manifestation of the AE, is distinct from the 
regulatory definition of seriousness. The Investigator is required to grade the severity of each 
AE/ADE according to the following guidelines.  

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Investigators must assess the severity/intensity of AEs/ADEs according to the following 
qualitative toxicity scale:  
• 
Mild: Associated with no limitation of usual activities or only slight discomfort; 
generally not requiring alteration or cessation of IMP administration; and/or not 
needing therapeutic intervention.  
• 
Moderate: Associated with limitation of usual activities or significant discomfort; 
generally requiring alteration or cessation of IMP administration; and/or requiring 
therapeutic intervention.  
• 
Severe: Associated with inability of the subject to carry out usual activities or very 
marked discomfort; considered to be life-threatening; resulting in significant 
disability or incapacity; and requiring therapeutic intervention.  
10.10.2.  Relationship to the Investigational Medicinal Product/Elamipretide Delivery  
System  
Investigators must systematically assess the causal relationship of AEs/ADEs to the IMP or 
elamipretide delivery system according to the following guidelines:   
• 
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/use of 
the elamipretide delivery system, the event is unlikely to be attributed to 
underlying/concurrent disease, other drugs, or other factors, 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/use of the 
elamipretide delivery system.  
• 
Unlikely: A causal relationship is improbable and/or another documented cause of the 
AE is most plausible.  
• 
Unrelated: A causal relationship is clinically/biologically improbable, there is not a 
plausible time sequence between onset of the AE and administration of the IMP/use of 
the elamipretide delivery system, the event is likely to be attributed to  
underlying/concurrent disease, other drugs, or other factors, and there is no reasonable 
response on withdrawal.  
10.10.3.  Outcome of an Adverse Event/Adverse Device Effect  
Investigators must follow all AEs/ADEs and SAEs/SADEs through the clinical trial’s post 
treatment Follow-Up Period until resolution, stabilization, or withdrawal of consent. Resolution 
is defined as:  
• 
recovered/resolved,  
• 
recovering/resolving,  

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not recovered/not resolved,  
• 
recovered/resolved with sequelae,  
• 
fatal, or • unknown.  
10.11.  
Adverse Events of Special Interest  
10.11.1.  Investigator Injection Site Reaction Assessment   
Any ISR following SC administration should be reported as an AE/ADE. To standardize the 
reporting of ISRs, the following guidance should be followed when reporting an ISR as an 
AE/ADE:  
• 
The ISR should be assessed for severity using Appendix 2. Table for Grading the 
Severity of Injection Site Reactions.  
• 
Any ISR that meets any of the criteria of a SAE/SADE (Section 10.8) should be 
reported within 24 hours of the trial site first becoming aware of the event (as outlined 
in Section 10.13).  
• 
The ISR should be reported as the characteristic of the ISR, rather than the general term 
of “Injection Site Reaction”. For instance, erythema associated with an ISR should be 
reported as “injection site erythema” or “redness at injection site” rather than the broad 
term “injection site reaction”.  
• 
For ISRs that reoccur following a subsequent SC injection, only 1 event should be 
recorded on the eCRF, with the overall duration to include the start date of the first 
reported event and the end date of the last recurrent event. The severity grade should be 
the most severe of the recurrent event during this period.   
The AEs/ADEs reported as a result of an ISR should be recorded on the subject’s ISR AE eCRF. 
The Investigator is expected to use their clinical judgment regarding treatments for ISRs. Any 
medications or procedures necessary for treatment of the ISR signs and/or symptoms must be 
recorded on the subject’s eCRF.  
Additionally, trial site staff involved with the assessment of ISRs should not be involved in the 
administration of visual and reading acuity assessments, where possible.    
10.11.2.  
Unexpected Adverse Events/Unanticipated Adverse Device Effects  
The final determination of expectedness of an SAE and anticipatedness of an ADE/SADE is the 
responsibility of the Sponsor as defined and outlined in the safety management plan (SMP).  
10.12.  
 Adverse Event/Adverse Device Effect Reporting Period  
The AE/ADE reporting period begins when the subject signs the ICF and continues through the 
clinical trial’s post IMP Follow-Up Period, defined as 28 (± 7) days after the last administration 
of IMP.   

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Note that AEs that occur between the time subject signs the ICF and the time the subject is dosed 
with IMP will be summarized in the medical history eCRF and not as an AE unless the event 
meets the definition of an SAE or is related to a trial procedure. All AEs/ADEs that occur 
following first administration of IMP, either new events or events that were pre-existing but 
changed in frequency or severity, will be recorded on the AE CRF page until the last subject 
visit. Updates to all ongoing AEs/ADEs or AE/ADES with an unknown outcome must be 
recorded until the last subject visit. A last batch of queries will be sent after last subject visit if 
there are ongoing/unknown outcomes for the reported AEs/ADEs that are pending. After the last 
batch of queries has been resolved, the CRFs and database will no longer be updated and the data 
will be considered final. However, SAEs/SADEs and ongoing AEs/ADEs with unknown, 
recovering/resolving, or not recovered/not resolved outcomes will be followed-up until 
resolution or stabilization by the Sponsor's Pharmacovigilance department. Beyond this defined 
reporting period, any new SAE considered causally related to IMP should be immediately 
reported to the sponsor using the SAE/SADE report form. Additional SAE/SADE information 
obtained after database lock will reside solely in the safety database.  
Within the trial, all subjects who took at least 1 dose of IMP, whether they completed the IMP 
period or not, should enter the 28-day period as defined above. If a subject is documented as 
lostto-follow-up, ongoing/unknown outcome AEs/ADEs will not be followed-up.  
For screening failure subjects, new AEs and updates must be recorded in the CRFs until the date 
the subject was determined to be a screen failure. Beyond that date, only SAEs and medically 
relevant AEs will be followed-up by the Sponsor’s Pharmacovigilance group and all data will be 
housed within the safety database.  
10.13.  
Serious Adverse Event/Serious Adverse Device Effect Expedited 
Reporting  
If an SAE/SADE occurs during the reporting period, the Investigator must immediately (within  
24 hours after becoming aware of the SAE/SADE) inform the Medical Monitor, Sponsor, and 
Ora by telephone, fax, or e-mail as detailed in the SMP. Reporting responsibilities for 
SAEs/SADEs are detailed in the SMP.   
For any SAE/SADE, the following minimum information is required as initial notification:  
• 
Investigator/Reporter with full contact information.  
• 
Subject identification details (trial number, center number, subject number).  
• 
IMP administration details (dose, lot number, serial number of device, and dates of 
doses).  
• 
Event Verbatim, a brief description of signs/symptoms/or diagnosis and the date of 
onset.  
• 
Seriousness criteria(ion) met.  
Within 24 hours, the relationship of the event to the IMP (e.g., the causality according to the  

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Investigator) and/or to the elamipretide delivery system (serial number) and needle (e.g., the 
causality according to the Investigator) should be provided. “Unlikely” and “unrelated” events 
will be considered unrelated to IMP/use of the elamipretide delivery system and “possible” and 
“probable” events will be considered related to IMP/use of the elamipretide delivery system.  
A final determination of expectedness/anticipatedness of the event will be made by the Sponsor.  
All SAE/SADE reports must be completed as described in the eCRF completion guidelines and 
submitted through the electronic data capture (eDC) system of the clinical database. Other 
relevant information from the clinical database (including demographic data, medical history, 
concomitant drugs and IMP dosing information) will automatically be sent via the eDC system 
when the SAE/SADE form is submitted.  
The names, addresses, telephone, and fax numbers for SAE/SADE back-up reporting (paper), are 
included in the SMP.   
The Investigator/Reporter must provide follow-up information as it becomes available, respond 
to any request for follow-up information (e.g., additional information, outcome and final 
evaluation, specific records where needed), or to any question the Sponsor or Ora may have on 
the SAE/SADE within the same timelines as described for initial reports.   
All SAE/SADE reports should be transmitted according to the SMP.  
10.14.  
Pregnancy and Contraception  
Any pregnancies occurring during the trial and within the 28 days after the last dose of IMP must 
be reported to the Investigator. In addition, women of childbearing potential must agree to use 1 
of the following methods of birth control from the date they sign the ICF until 1 month after the 
last dose of IMP:  
• 
Abstinence, when it is in line with the preferred and usual lifestyle of the subject. 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.  
Non-childbearing potential is defined as surgical sterilization (e.g., bilateral oophorectomy, 
hysterectomy, or tubal ligation) or postmenopausal (defined as permanent cessation of 
menstruation for at least 12 consecutive months prior to the Screening Visit).  
For male subjects with female partners of child-bearing potential, highly effective methods of 
contraception must be adhered to from the date of informed consent and for at 1 month after last 
dose of IMP. Highly effective methods of contraception are defined as the usage by the female 

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partner of any form of hormonal contraception or intra-uterine device (which should be 
established prior to the start of the trial) plus usage by one of the partners of an additional 
spermicide-containing barrier method of contraception. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. Male subjects with pregnant partners must use a condom from the start 
of IMP until 1 month after the last dose of IMP. Sperm or egg donation by subjects is not 
permitted from the start of IMP until 1 month after the IMP was administered.  
Any pregnancy in a female subject or female partner of a male subject during the course of the 
trial and until the last follow-up visit must be reported (within 24 hours after becoming aware of 
the pregnancy) even if no AE has occurred, as detailed in the SMP. If the Investigator suspects 
the pregnancy has resulted from an interaction of the trial medication with contraceptives, then 
the pregnancy is considered as an AE.  
Only pregnancies considered by the Investigator as related to IMP (e.g., resulting from an 
interaction between IMP and a contraceptive drug) are considered AEs unto themselves. 
However, all pregnancies with an estimated conception date that occurred during the AE 
reporting period, as defined in Section 10.12, must be recorded in the AE section of the eCRF. 
For this trial, this applies to pregnancies in female subjects and in female partners of male 
subjects.  
The Investigator must notify the Sponsor in an expedited manner of any pregnancy using the 
forms and reporting procedures as described in the SMP. Investigators must actively follow up, 
document, and report on the outcome of every pregnancy, even if the subject is withdrawn from 
the trial. Any abnormal outcome must be reported in an expedited manner as described in Section 
10.13, 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/SADE 
report form described in the SMP is required and will be submitted as described above. If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE (i.e. 
postpartum complications, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly 
[including that of an aborted fetus]) the Investigator should follow the procedures for reporting 
an SAE. Additional information about pregnancy outcomes that are classified as SAEs follows.  
• 
“Spontaneous abortion” includes miscarriage and missed abortion.  
• 
All neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as SAEs. In addition, any infant death after 1 month that the 
Investigator assesses as possibly related to the in utero exposure to the investigational 
product should also be reported.  
• 
In the case of a live birth, the “normality” of the newborn can be assessed at time of 
birth. The “normality” of an aborted fetus can be assessed by gross visual inspection 
unless there are pre-abortion laboratory findings suggestive of a congenital anomaly.  

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If the pregnancy is to be terminated, the anticipated date of termination should be provided. If the 
pregnancy ends for any reason before the anticipated date of birth, the Investigator should notify 
the Sponsor.  
10.15.  
Responsibilities to Regulatory Authorities, Investigators, and 
Institutional Review Board  
The Sponsor will send appropriate safety notifications to regulatory authorities in accordance 
with applicable laws and regulations.  
The Investigator must comply with (and inform the Sponsor of) any applicable center-specific 
requirements related to the reporting of SAEs/SADEs involving his/her subjects to the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) that approved the trial.  
In accordance with ICH GCP guidelines, the Sponsor will inform the Investigator of findings that 
could adversely affect the safety of subjects, impact the conduct of the trial, or alter the 
IRB’s/IEC approval/favorable opinion to continue the trial. In particular, and in line with 
respective regulations, the Sponsor will inform the Investigator of AEs/ADEs that are both 
serious and unexpected and are considered to be related to the administered IMP/elamipretide 
delivery system (“suspected unexpected serious adverse reactions” [SUSARs] or “unanticipated 
adverse device effects” [UADEs]). 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 concerned lead IEC/central IRB and will maintain records of these 
notifications. When direct reporting by the Sponsor is not clearly defined by national or 
centerspecific 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.  
11.  
SAMPLE SIZE AND STATISTICAL METHODS  
11.1.  
Determination of Sample Size  
A sample size of 180 subjects provides ≥ 80% power to detect a 5 letter (1 line) change from 
baseline mean difference in LL BCVA between drug and placebo, assuming a standard deviation 
of 11 letters, at a two-sided alpha-level of 0.1, and provides approximately 80% power to detect a 
30% difference in the change from baseline in square root transformed total GA area by OCT 
between drug and placebo, assuming a standard deviation of 0.2 mm/year, and an average change 
of 0.33 mm/year, at a two-sided alpha-level of 0.1.    

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11.2.  
Statistical and Analytical Plans  
11.2.1.  
General Considerations  
Continuous variables will be summarized by descriptive statistics (sample size, mean, standard 
deviation, median, minimum, and maximum). Discrete variables will be summarized by 
frequencies and percentages. Tabulated data will be presented for each treatment arm.   
All data will be displayed in the data listings, sorted by subject and visit, where appropriate.  
Each listing will indicate which treatment arm each subject was assigned to.  
11.2.2.  
Analysis Populations:  
Statistical analysis will be performed in the following populations:  
Safety Population – Includes all trial subjects who receive at least 1 dose of IMP. Subjects will be 
analyzed according to the actual treatment they received.   
Intent-to-Treat (ITT) Population – Includes all randomized subjects. Subjects will be analyzed in 
the treatment group to which they were randomized.   
Modified Intent-to-Treat (mITT) Population – Includes all ITT subjects who receive at least 1 
dose of IMP and have at least 1 post-baseline value for LL BCVA or GA area on OCT. Subjects 
will be analyzed in the treatment group to which they were randomized and generally included in 
efficacy analyses for which post-baseline data are available.   
Per-Protocol (PP) Population – Includes all ITT subjects without major protocol 
violations/deviations likely to affect the primary outcome of the study as judged by a masked 
evaluation prior to the unmasking of the study treatment. Subjects will be analyzed according to 
the actual treatment they received.   
Pharmacokinetic (PK) Population – Includes all trial subjects who have at least one evaluable PK 
sample taken during their participation.   
11.2.3.  
Baseline Characteristics and Disposition of Subjects  
The subject disposition summary will include the number of subjects in each population. The 
number and percentage of subjects who complete or discontinue from the trial will be 
summarized by reason. Each subject’s age, sex, weight, and other demographic characteristics 
will be recorded and summarized. Medical history will be listed.  
11.2.4.  
Efficacy Analyses  
Changes from baseline in efficacy endpoints will be presented by time point for each treatment 
arm. For continuous data, a mixed model for repeated measures (MMRM) will be used for each 
eye separately (study eye and fellow eye), with fixed effects for treatment arm, study visit, the 

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treatment arm-by-visit interaction, baseline as a covariate, a baseline-by-visit interaction and a 
random effect for subject and using an unstructured covariance structure. The primary time point 
for analysis is planned to be Week 48 (End of Treatment Visit).    
For efficacy, the primary analysis population will be the mITT on observed data.   
A family-wise alpha level of 0.1 will be maintained for the primary endpoint family, using 
Hochberg’s procedure at the primary time point of 48 weeks. If both primary endpoints are 
significantly different from placebo at the 0.1 (two-sided) level of significance (in favor of 
treatment), then both will be considered statistically significant. Otherwise, the endpoint with the 
smaller p-value of the two will be considered statistically significant, if statistically significant at 
the 0.05 (two-sided) level of significance. Additional details of all statistical analyses will be 
presented in a separate SAP.  
11.2.5.  
Interim Analysis  
A decision may be made to conduct an interim analysis prior to completion of the trial. If so, the 
SAP, as well as details regarding the methodology for control of alpha and plans for 
dissemination of results will be finalized prior to unmasking data.  
11.2.6.  
Safety Analyses  
Safety data analysis will be conducted using the Safety population.   
11.2.6.1. Adverse Events  
All AEs will be coded to system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA). All reported AEs will be listed, but only 
treatment-emergent AEs (TEAEs) will be summarized. The number and percentage of subjects 
experiencing 1 or more AEs/ADEs will be summarized by SOC, PT, and treatment arm for each 
of the following categories: the incidence of all TEAEs, injection site TEAEs (e.g., 
pain/tenderness, erythema, induration/swelling, and pruritus), treatment-emergent serious 
adverse events (TESAEs), drug-related TEAEs, and TEAEs by severity.  
All ADEs will be coded to SOC and PT using the MedDRA. All reported ADEs will be listed, 
but only treatment-emergent ADEs (TEADEs) will be summarized. The number and percentage 
of subjects experiencing 1 or more ADEs will be summarized by SOC, PT, and treatment arm for 
each of the following categories: the incidence of all TEADEs, injection site TEADEs (e.g., 
pain/tenderness, erythema, induration/swelling, and pruritus), treatment-emergent serious 
adverse device effects (TESADEs), device-related TEADEs, and device-related TEADEs by 
severity.  

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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/ADE 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 severe (for severity). If drug 
relationship is missing, subjects will be included in related tables (i.e., considered related).  
All AEs/ADEs collected will be listed. In addition, separate listings will be provided for the 
following:  
• 
Deaths  
• 
SAEs/SADEs  
• 
AEs/ADEs leading to discontinuation of IMP.  
11.2.6.2. Clinical Laboratory Evaluations  
Summary tables for laboratory parameters (including hematology, chemistry, and urinalysis) will 
include descriptive statistics for change from 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 for each treatment arm. Shift tables for urinalysis will show the number of 
subjects who are normal/abnormal at baseline and normal/abnormal at the end of trial.  
11.2.6.3. Vital Signs  
Vital signs data will be summarized by changes from baseline values for each treatment arm 
using descriptive statistics.   
11.2.6.4. Other Safety Parameters  
The additional safety variables of slit lamp examination and dilated fundus examination will be 
summarized descriptively using quantitative and qualitative summary statistics as appropriate.   
Any other safety data captured on the eCRF will be listed.  
11.2.7.  
Pharmacokinetic Analyses  
PopPK analyses will be conducted on the PK Population. The PK model will be generated and 
validated using data reported from historical, thorough PK studies. Where sufficient data allow, 
covariates will include age, gender, race, renal function (as described by estimated Glomerular 
Filtration Rate), intercurrent conditions, and concomitant medications.  Plasma samples will be 
analyzed for elamipretide using a validated liquid chromatography/tandem mass spectrometry 

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assay. PK modelling will be performed using NONMEM computer software.  All model 
assumptions, validation, and data analysis will be detailed in a separate PK Analysis Plan.  
  
  
 

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12. 
TRIAL MONITORING  
12.1.  
Source Document Requirements  
The Investigator will prepare and 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.  
12.2.  
Case Report Form Requirements  
Clinical data will be recorded in an eCRF by the 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.  
The eCRFs should be completed by the Investigator or a qualified designee from the site as soon 
as the data is available. The Investigator is responsible for the accuracy and authenticity of all 
clinical and laboratory data entered onto the eCRFs. Prior to submission, each completed eCRF 
must be reviewed for accuracy by the Investigator or designee, corrected as necessary, and 
approved.  
12.3.  
Trial 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. The Investigator agrees to cooperate with the site 
monitor to ensure that any problems detected during the course of these monitoring visits are 
resolved.  
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.  
Deviations from the protocol with regard to subject enrollment or trial conduct will also be noted 
in the source documentation, and in the eCRF database. A Sponsor representative will visit the 
trial site to initiate the trial prior to the first administration of IMP for the first subject and at 
agreed times throughout the trial, including at the end of the trial. Drug dispensing and clinical 
drug supply records will be 100% verified at the trial site by the trial monitor. It is understood 
that all subject-specific information is confidential and no documentation that can link trial 
information to the specific subject will be collected or retained by the Sponsor.  
  
  

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13. 
DATA QUALITY ASSURANCE  
To ensure accurate, complete, and reliable data, the Sponsor or its representatives will do the 
following:  
• 
Provide instructional material to the trial sites, as appropriate.  
• 
Sponsor start-up training to instruct the investigators and trial coordinators. This 
training will give instruction on the protocol, the completion of the eCRFs, and trial 
procedures.  
• 
Make periodic visits to the trial site.  
• 
Be available for consultation and stay in contact with the trial site personnel by mail, 
telephone, and/or fax.  
• 
Review and evaluate eCRF 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 subject data recorded 
against source documents at the trial site. The trial 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 trial, and to ensure accurate, complete, and reliable 
data, the Investigator will keep records of laboratory tests, clinical notes, and medical records in 
the subject files as original source documents for the trial. If requested, the Investigator will 
provide the Sponsor, applicable regulatory agencies, and applicable IRBs/IECs with direct access 
to original source documents.  
13.1.  
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.  
An eDC will be used in this trial. The trial site will maintain a separate source for the data 
entered by the trial site into the Sponsor-provided eDC system.   
Case report form data will be encoded and stored in a clinical trial database. Data managed by a 
central vendor, such as laboratory test data or ECG data, or any data for which electronic 
documentation is provided by the subject, will be stored electronically in the central vendor’s 
database system.   
Any data for which paper documentation provided by the subject will serve as a source document 
will be identified and documented by each trial site in that center’s trial file. Paper 
documentation provided by the subject may include, for example, a paper diary to collect subject 
reported outcome measures (e.g., a rating scale), a daily dosing schedule, or an event diary.   

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14. 
INFORMED CONSENT, INSTITUTIONAL REVIEW BOARD,  
AND REGULATORY CONSIDERATIONS  
14.1.  
Changes in Protocol  
Once the protocol has been formally approved by the Sponsor and by the IRB/IEC, any change 
that might subsequently affect the approval of the IRB/IEC must be documented in the form of 
an amendment. Protocol amendments, if any, will be reviewed and implemented following 
IRB/IEC approval. The Sponsor or designee is responsible for submitting protocol amendments 
to the regulatory authorities, such as the Food and Drug Administration (FDA).   
Approval or acceptance is unnecessary for corrections of typographical errors, revisions simply 
to improve clarity, notifications of changes in monitoring personnel, or for other changes that do 
not materially affect the conduct of the trial. However, these minor changes will be documented.   
If it becomes necessary to alter the protocol to eliminate an immediate hazard to subjects, an 
amendment may be implemented by the Sponsor without prior approval by the IRB (or 
equivalent). In this circumstance, however, the Investigator must then notify the IRB in writing 
within 5 working days after implementation.  
All protocol deviations and the reasons for such deviations are to be documented in the source 
documents and reported to the Sponsor or its designee.  
14.2.  
Informed Consent  
The Investigator is responsible for ensuring that the subject understands the potential risks and 
benefits of participating in the trial, including answering any questions the subject may have 
throughout the trial and sharing in a timely manner any new information that may be relevant to 
the subject willingness to continue his or her participation in the trial.  
The ICF will be used to explain the potential risks and benefits of trial participation to the subject 
in simple terms before the subject is entered into the trial, and to document that the subject is 
satisfied with his or her understanding of the risks and benefits of participating in the trial and 
desires to participate in the trial.    
The Investigator is responsible for ensuring that informed consent is given by each subject or 
legal representative. This includes obtaining the appropriate signatures and dates on the ICF prior 
to the performance of any protocol procedures and prior to the administration of investigational 
product.  
As used in this protocol, the term “informed consent” includes all consent and assent given by 
subject or their legal representatives.  

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14.3.  
Ethics Review  
The Sponsor or its representatives must approve all ICFs before they are used at investigative 
sites. All ICFs must be compliant with the ICH guideline on GCP. Documentation of IRB/IEC 
approval of the protocol and the ICF must be provided to the Sponsor before the trial may begin 
at the investigative site.   
14.4.  
Regulatory Considerations  
This trial will be conducted in accordance with:  
• 
Consensus ethics principles derived from international ethics guidelines, including the  
Council for International Organizations of Medical Sciences International Ethical 
Guidelines  
• 
The ICH GCP Guideline [E6]  
• 
Applicable local laws and regulations  
The Investigator, Sponsor, or designee will promptly submit the protocol to applicable 
IRB(s)/IEC(s), and regulatory authorities as required. Some of the obligations of the Sponsor 
may be assigned to a third-party organization. Trial sites will not commence enrollment until 
Regulatory Authority submission/approval and site IRB/IEC favorable opinion/approval are 
granted.  
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 trial-related data.   
14.4.1.  
Retention of Records  
All trial-related material including source documents, eCRFs, Central Authority and IRB/IEC 
correspondence, analyses, and any other documentation required by applicable laws and 
regulations will be maintained for 2 years after completion of the trial or notification from the 
Sponsor that the data can be destroyed, whichever comes first.  
The Investigator must obtain the Sponsor’s written permission before disposing of any records. If 
the Investigator retires, relocates, or for any reason withdraws from the trial, then the trial 
records may be transferred to an acceptable person or institution with the written approval of the 
Sponsor.  
14.4.2.  
Disclosure of Information  
Information concerning the IMP/pen injector and delivery system 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 
trial only. It is understood by the Investigator that Stealth BioTherapeutics, Inc. will use 
information developed in this clinical trial in connection with the development of the IMP and, 

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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 trial, the Investigator 
understands that he/she has an obligation to provide complete test results and all data developed 
during this trial to the Sponsor.  
The Investigator may not submit for publication or presentation the results of this trial without 
first receiving written authorization from Stealth BioTherapeutics, Inc. Authorship and 
manuscript composition will reflect joint cooperation among all parties involved in the study.  
Authorship will be established prior to the writing of the manuscript.  
 

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15.  
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rats." Curr Mol Med 13(6): 935-945.  
16. Kapphahn, R., T. MR, E. MC, P. MJ, M. K, G. H, M. SR, L. Y, S. T, S. T and F. DA  
(2017). "Elamipretide Protects RPE and Improves Mitochondrial Function in Models of 
AMD" Poster. American Society of Cataract and Refractive Surgery.  
17. 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): 
349356.  
18. Liang, X. L., F. Chen, H. J. Zhou, C. Yang and G. Sun (2010). SS31 Protects human RPE 
cells from oxidative damage and reduces laser-induced choroidal neovascularization. 
Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting. Fort 
Lauderdale, FL.  
19. Manczak, M., P. Mao, M. J. Calkins, A. Cornea, A. P. Reddy, M. P. Murphy, H. H. Szeto, 
B. Park and P. H. Reddy (2010). "Mitochondria-targeted antioxidants protect against 
amyloid-beta toxicity in Alzheimer's disease neurons." J Alzheimers Dis 20 Suppl 2: 
S609-631.  
20. Min, K., A. J. Smuder, O. S. Kwon, A. N. Kavazis, H. H. Szeto and S. K. Powers (2011). 
"Mitochondrial-targeted antioxidants protect skeletal muscle against 
immobilizationinduced muscle atrophy." J Appl Physiol (1985) 111(5): 1459-1466.  
21. Nordgaard, C. L., P. P. Karunadharma, X. Feng, T. W. Olsen and D. A. Ferrington  

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(2008). "Mitochondrial Proteomics of the Retinal Pigment Epithelium at Progressive 
Stages of Age-Related Macular Degeneration." Investigative Ophthalmology & Visual 
Science 49(7): 2848-2855.  
22. Owsley, C., G. McGwin, Jr., G. R. Jackson, K. Kallies and M. Clark (2007). "Cone- and 
rod-mediated dark adaptation impairment in age-related maculopathy." Ophthalmology 
114(9): 1728-1735.  
23. Siegel, M. P., S. E. Kruse, J. M. Percival, J. Goh, C. C. White, H. C. Hopkins, T. J. 
Kavanagh, H. H. Szeto, P. S. Rabinovitch and D. J. Marcinek (2013). 
"Mitochondrialtargeted peptide rapidly improves mitochondrial energetics and skeletal 
muscle performance in aged mice." Aging Cell 12(5): 763-771.  
24. Wallace, D. C., W. Fan and V. Procaccio (2010). "Mitochondrial energetics and 
therapeutics." Annu Rev Pathol 5: 297-348.  
  
  

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16.  
APPENDICES  
Appendix 1. Schedule of Events  
Trial procedures and their recommended order of priority are summarized below.  
Days/Weeks  
Screening  
Perioda  
Treatment Period  
 
 
Follow Up  
Early Termination  
Screening  
(Day -14 to  
Day -1)  
Day 
1b BL  
Wk 4  
±3d  
Wk 8  
±3d  
Wk  
12  
±3d  
Wk  
24  
±3d  
Wk  
36  
±3d  
Wk 48  
±3d  
EOT  
Week 52  
(±3d) Follow Up   
EOS  
Early Termination 
Visit  
Visit  
1  
2  
3  
4  
5  
6  
7  
8  
9  
  
Informed consent  
X  
  
  
  
  
  
  
  
  
  
Demographics  
X  
  
  
  
  
  
  
  
  
  
Medical/ ocular history  
X  
X  
  
  
  
  
  
  
  
  
Concomitant medications  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Low-Luminance Questionnaire  
  
X  
  
  
X  
X  
X  
X  
  
X  
Visual Function Questionnaire-39  
  
X  
  
  
X  
X  
X  
X  
  
X  
EQ-5D-5L Questionnaire  
  
X  
  
  
  
  
  
X  
  
X  
Vital signsc  
X  
X  
X  
X  
X  
X  
X  
X  
  
X  
Physical examinationd  
X  
X  
  
  
  
X  
  
X  
X  
X  
Blood for safetye  
X  
X  
X  
X  
X  
X  
X  
X  
  
X  
Urinalysis  
X  
X  
X  
X  
X  
X  
X  
X  
  
X  
Exploratory plasma and urine 
samplesf  
X  
  
  
  
  
X  
  
X  
  
  

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Pregnancy testing (serum)  
X  
  
  
  
  
  
  
  
X  
X  
Pregnancy testing (urine)  
  
X  
X  
X  
X  
X  
X  
X  
  
  
Refraction  
X  
X  
X  
X  
X  
X  
X  
X  
  
X  
BCVA   
X  
X  
X  
X  
X  
X  
X  
X  
  
X  
Low-luminance BCVA  
X  
X  
X  
X  
X  
X  
X  
X  
  
X  
Days/Weeks  
Screening  
Perioda  
Treatment Period  
Follow Up  
Early Termination  
Screening  
(Day -14 to  
Day -1)  
Day 
1b BL  
Wk 4  
±3d  
Wk 8  
±3d  
Wk  
12  
±3d  
Wk  
24  
±3d  
Wk  
36  
±3d  
Wk 48  
±3d  
EOT  
Week 52  
(±3d) Follow Up   
EOS  
Early Termination 
Visit  
Visit  
1  
2  
3  
4  
5  
6  
7  
8  
9  
  
Reading acuity at standard and low 
luminance  
X  
X  
X  
  
X  
  
X  
X  
  
X  
Slit lamp exam   
X  
X  
X  
X  
X  
X  
X  
X  
  
X  
IOP   
X  
X  
  
  
  
X  
X  
X  
  
X  
Dilated fundus exam  
X  
X  
X  
X  
X  
X  
X  
X  
  
X  
SD-OCT  
X  
X  
  
  
X  
X  
X  
X  
  
X  
OCT angiographyg (optional)  
X  
X  
  
  
X   
X  
X   
X  
  
X  
Fundus photographyh  
X  
X  
  
  
X  
X  
X  
X  
  
X  
Fundus autofluorescence  
X  
X  
  
  
X  
X  
X  
X  
  
X  
Fluorescein angiographyi  
X  
  
  
  
  
  
  
  
  
  
Eligibility  
X  
X  
  
  
  
  
  
  
  
  

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Randomization  
  
X  
  
  
  
  
  
  
  
  
Dispense IMP and subject diary   
  
X  
X  
X  
X  
X  
X  
  
  
  
IMP accountability  
  
  
X  
X  
X  
X  
X  
X  
  
X  
IMP trainingj  
  
X  
  
  
  
  
  
  
  
  
PK samplingk  
  
  
X  
X  
  
  
  
  
  
X  
AEs/ ADEs  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Abbreviations: BCVA = best-corrected visual acuity; BL = baseline; ECG = electrocardiogram; EOS = end of study; EOT = end of treatment;  OCT = optical 
coherence tomography; PK = pharmacokinetics; RPE = Retinal pigment epithelium; SD-OCT = Spectral domain-optical coherence tomography; VA = visual 
acuity.   
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.  Re-screening of 
subjects may be allowed, depending on the reason for screen-failure, after consultation with the Sponsor. b. The first day of treatment is defined as study 
Day 1.  
c. 
Vital sign measurements include temperature, respiratory rate, sitting blood pressure after resting for 5 minutes, pulse and weight.  
d. Physical examination will include assessment of head, eyes, ears, nose, and throat, general appearance, skin, chest, heart, abdomen, extremities, and 
nervous system. Height will only be recorded at the Screening Visit.  
e. 
Blood for safety will consist of hematology panel and clinical chemistry.  
f. 
Exploratory plasma and urine samples will be withdrawn and stored for future analysis. Analysis may include genetic and/or metabolomic testing 
(optional).   
g. OCT angiography is optional. It is recommended for trial sites that has the OCT angiography capabilities.   
h. Fundus examination will be utilized for safety assessment of the RPE, choroid, neuro-retina structure, retinal vessels, optic nerve, and vitreous  
i. 
FA completed for reasons of standard of care and within 30 days prior to first dose can be used for screening purposes if official documentation is 
provided.  
j. 
The IMP training checklist will be completed for the subject or caregiver at Day 1, prior to the first dose of IMP.  Any new caregiver should complete 
IMP training at any trial site visit before administering IMP to a subject.  
k. For the Week 8 visit, the subject will administer IMP at home, approximately 4 hours ± 1 hour before arriving at the trial site. Random PK sample to be 
taken at Early Termination Visit (one sample at any time during visit).  
  
  

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SPIAM-202 Clinical Protocol Version 4.0  
 
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Appendix 2. Table for Grading the Severity of Injection Site 
Reactions  
PARAMETER  
GRADE 1 
MILD  
GRADE 2  
MODERATE  
GRADE 3 
SEVERE  
GRADE 4  
POTENTIALLY  
LIFE-THREATENING  
Injection Site  
Pain or  
Tenderness  
Report only one  
Pain or tenderness 
causing no or 
minimal limitation 
of use of limb  
Pain or tenderness 
causing greater than 
minimal limitation of 
use of limb   
Pain or tenderness 
causing inability to 
perform usual social 
& functional activities  
Pain or tenderness 
causing inability to 
perform basic self-care 
function OR  
Hospitalization indicated  
Injection Site  
Erythema or 
Redness  
Report only one  
> 15 years of age  
2.5 to < 5 cm in 
diameter OR 6.25  
to < 25 cm2 surface 
area AND  
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities  
≥ 5 to < 10 cm in 
diameter OR ≥ 25 to < 
100 cm2 surface area 
OR Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
≥ 10 cm in diameter  
OR 
  surface  
area OR Ulceration OR  
Secondary infection  
OR Phlebitis OR  
Sterile abscess OR  
Drainage OR  
Symptoms causing 
inability to perform 
usual social & 
functional activities  
Potentially life- 
threatening 
consequences (eg, 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue)  
≤ 15 years of age  
≤ 2.5 cm in 
diameter  
> 2.5 cm in diameter 
with < 50% surface 
area of the extremity 
segment involved (e.g., 
upper arm of thigh)  
≥ 50% surface area of  
the extremity segment 
involved (e.g., upper arm 
of thigh) OR Ulceration 
OR  
Secondary infection  
OR Phlebitis OR  
Sterile abscess OR  
Drainage  
Potentially life- 
threatening 
consequences (eg, 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue)  
Injection Site  
Induration or 
Swelling  
Report only one  
> 15 years of age  
Same as for  
Injection Site 
Erythema or 
Redness, > 15 
years of age  
Same as for  
Injection Site  
Erythema or 
Redness, > 15 years 
of age  
Same as for Injection  
Site Erythema or 
Redness, > 15 years of 
age  
Same as for Injection  
Site Erythema or 
Redness, > 15 years of 
age  
≤ 15 years of age  
Same as for  
Injection Site  
Erythema or 
Redness, ≤ 15 years 
of age  
Same as for  
Injection Site  
Erythema or 
Redness, ≤ 15 years 
of age  
Same as for Injection  
Site 
Erythema 
or 
Redness, ≤ 15 years of 
age  
Same as for Injection  
Site 
Erythema 
or 
Redness, ≤ 15 years of 
age  

  Elamipretide (MTP-131)  
  
SPIAM-202 Clinical Protocol Version 4.0  
 
Injection Site 
Pruritus  
Itching localized to 
the injection site 
that 
is 
relieved 
spontaneously or in 
< 48 hours of 
treatment  
Itching beyond the 
injection site that is 
not generalized OR 
Itching localized to 
the injection site 
requiring 
≥ 
48 
hours treatment  
Generalized itching 
causing inability to 
perform usual social 
& functional activities  
NA  
  
Adapted from Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Version 2.1, July 2017.  
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