Clinical trial NCT02848313
Conditions: Age-Related Macular Degeneration
Sponsor: Stealth BioTherapeutics Inc.
Start date: 2016-10-28; Completion date: 2018-04-10
Enrollment: 40 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, Phase 1 single-center study in approximately 40 subjects who have 1 eye with intermediate AMD, including a high-risk drusen without geographic atrophy (GA) subgroup and a noncentral GA subgroup. Eligible subjects will receive 40 mg of elamipretide administered as a once daily 1.0 mL subcutaneous injection for 12 weeks.

Detailed description:

Arms: arm 1: Participants had one 1 eye with intermediate age-related macular degeneration with high-risk drusen without geographic atrophy \[GA\]), i.e. the presence of either at least 1 large (≥125 μm) druse or multiple medium-size (63-124 μm) drusen.

Participants received 40 mg dose of elamipretide administered once daily as a 1.0mL SC injection. arm 2: Participants had 1 eye with intermediate AMD with noncentral geographic atrophy \[NCGA\]; i.e. evidence of GA with cumulative area ≥1.27 mm2 (approximately 0.5 disc area\[DA\]) by fundus autofluorescence (FAF) that spared the fovea (defined as retinal pigment epithelium (RPE) and outer retina intact by spectral-domain optical coherence tomography \[SD-OCT\]).

Participants in this arm also received 40 mg dose of elamipretide administered once daily as a 1.0mL SC injection.
Interventions: intervention 1: Elamipretide
Intervention descriptions: intervention 1: 40 mg dose of elamipretide administered once daily as a 1.0mL SC injection.

Protocol documents:
Prot_SAP_000.pdf: 
Elamipretide (MTP-131) 
SPIAM-101 Clinical Protocol Version 7.0, 20Jun17 
 
 
 
 
 
 
An Open-Label, Phase 1 Clinical Study to Evaluate the Safety and Tolerability of 
Subcutaneous Elamipretide in Subjects with Intermediate Age-Related Macular 
Degeneration 
 
 
NCT02848313 
 
 
Protocol Date: 20 June 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Elamipretide (MTP-131) 
SPIAM-101 Clinical Protocol Version 7.0, 20Jun17 
 
 
 
 
An Open-Label, Phase 1 Clinical Study to Evaluate the Safety and Tolerability of 
Subcutaneous Elamipretide in Subjects with Intermediate Age-Related Macular 
Degeneration 
 
 
 
 
Study Phase: 
Phase 1 
 
Product Name: 
Elamipretide (MTP-131) sterile solution 
 
IND Number: 
114,234 
 
Formulation: 
Subcutaneous 
 
Study No.: 
SPIAM-101 
 
Sponsor: 
Stealth BioTherapeutics, Inc. 
275 Grove Street, Suite 3-107 
Newton, MA 02466 
 
Sponsor Contact: 
W. Douglas Weaver, MD, 
Chief Medical Officer 
617-600-6888 
 
Protocol Date/Version: 
20 June 2017/v 7.0 Final 
 
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. 
 
 
 
 
 
 
 
 
 
 
 
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Table 1:  Emergency Contact Information 
 
Role in Study 
Name 
Address and Telephone Number 
Investigator 
Scott Cousins, MD 
Duke Eye Center 
2351 Erwin Road 
Durham, NC 27705 
+1 (919) 684-9010 
Sponsor Medical Monitor W Douglas Weaver, MD 
Stealth BioTherapeutics, Inc. 
275 Grove Street, Suite 3-107 
Newton, MA 02466 
+1 (617) 600-6888 


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1. 
SYNOPSIS 
 
Investigational Drug Product: 
elamipretide (MTP-131) 
Active Ingredient: 
elamipretide (MTP-131) 
Study Title: 
An Open-Label, Phase 1 Clinical Study to Evaluate the Safety and Tolerability 
of Subcutaneous Elamipretide in Subjects with Intermediate Age-Related 
Macular Degeneration 
Study Number: 
SPIAM-101 
Study Phase: 
Phase 1 
Study Objectives: 
The primary objective of this study is: 
• 
To evaluate the safety and tolerability of subcutaneous (SC) injections of 
elamipretide in subjects with intermediate age-related macular 
degeneration (AMD) 
The secondary objectives of this study are: 
• 
To evaluate the feasibility of administration of SC injections of 
elamipretide in subjects with intermediate AMD 
• 
To evaluate the changes from baseline in physical/ophthalmic 
examinations 
Study Design: 
This is an open-label, Phase 1 single-center study in approximately 40 
evaluable subjects who have 1 eye with intermediate AMD, including a high- 
risk drusen without geographic atrophy (GA) cohort and a noncentral GA 
cohort. 
Cohort 1: High-risk drusen is defined as the presence of at least 1 large 
(≥ 125 μm) druse or multiple medium-size (between 63 and 124 μm) drusen. 
Cohort 2: Noncentral GA is defined as evidence of GA with cumulative area 
≥1.27 mm2 (approximately 0.5 disc area [DA]) by fundus autofluorescence 
(FAF), which spares the fovea (defined as retinal pigment epithelium and 
outer retina intact by spectral domain-optical coherence tomography [SD- 
OCT]). 
The study eye of eligible subjects must fall into one of the two cohorts, as 
defined above, cannot have choroidal neovascular (CNV) AMD or advanced 
central GA, and may not have previously received antiangiogenic therapies (in 
addition to meeting other specified inclusion/exclusion criteria). The AMD 
disease status of the fellow eye is not restricted: the fellow eye may have 
intermediate AMD with high-risk drusen, advanced central GA, or CNV 
AMD, and the fellow eye is allowed to receive antiangiogenic therapies. 
Written informed consent will be obtained from all subjects before the 
Screening visit. 
The screening examination will be performed no more than 14 days before the 
Baseline visit. Data to be collected from the screening examination will 
include significant and/or ongoing medical and ocular history, vital sign 
measurements, physical examination, routine blood samples for hematology, 
chemistry, and urinalysis, ECG, manifest refraction, measurement of 
best-corrected visual acuity (BCVA) using the Early Treatment Diabetic 
Retinopathy Study (ETDRS) scale completed twice, intraocular pressure 
measurement, slit-lamp examination, dilated fundus examination, fundus 
photography, spectral domain optical coherence tomography (SD-OCT), FAF, 
fluorescein angiography*, best-corrected low-luminance (LL) visual acuity 
completed twice, mesopic microperimetry, dark adaptometry, and Low- 
Luminance Questionnaire.  Women of childbearing potential will have a 
serum pregnancy test.  *Fluorescein angiography assessments done as 


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standard of care and completed within 90 days prior to dosing are allowed to 
be used for screening purposes. 
After the screening examination, relevant data will be reviewed by the PI or 
designee to confirm study eligibility. Eligible subjects will return for the 
Baseline (Day 0) visit, at which time qualified subjects will be assigned to 
study treatment. Each subject will be assigned into 1 of the 2 study disease 
cohorts, after determination of the subject’s disease state in the Screening 
Period. Elamipretide will be supplied as 40 mg/1 mL of sterile solution for SC 
injection. The dose of elamipretide will be 40 mg administered as a once daily 
1.0 mL SC injection. 
At the time of initial study drug administration, training on the proper SC 
administration of the study drug solution (by the subject, regular caregiver, or 
his/her appropriate designee) will occur. Subjects will be trained using a 
standard script explaining the importance of proper administration of study 
drug on a daily basis for the 24-week Study Treatment Period. The first dose 
may be given by a qualified member of the study team, by the subject, or 
caregiver at the PIs discretion. The option of a visiting nurse to oversee the 
study drug administration will be discussed with the subject and provided, as 
needed. 
Safety and tolerability will be measured throughout the Study Treatment 
Period, while exploratory anatomical and physiologic endpoints will be 
measured at time points as specified in the Schedule of Events. Visits will 
occur at: Day 7 (± 3 days), Week 4 (± 7 days), Week 8 (± 7 days), Week 12 (± 
7 days), Week 16 (± 7 days), Week 20 (± 7 days), and Week 24 (± 7 days), 
with phone calls to collect safety information completed at Week 2 (± 4 days), 
Week 6 (± 4 days), Week 10 (± 4 days), Week 14 (± 4 days), Week 18 (± 4 
days), and Week 22 (± 4 days). 
Ocular imaging will be read by an independent reading center and findings 
uploaded to the electronic data capture (EDC) system on a regular basis 
throughout the study. 
After completion of the 24-week Study Treatment Period, subjects will 
continue to be monitored for safety during the 4-week Follow-Up Period. A 
post-study drug follow-up visit is scheduled at Week 28 (± 7 days). 
Study procedures, their timing, and additional details are found in the 
Schedule of Events (Table 3). 
Investigational Product, Dose 
and Mode of Administration: 
Elamipretide will be supplied as 40 mg/1 mL of sterile solution for SC 
injection. The dose of elamipretide will be 40 mg administered as a once daily 
1.0 mL SC injection. Study drug will be administered at approximately the 
same time each day by SC injection in the abdomen (rotating clockwise 
around the 4 abdominal quadrants), and may be administered by any of the 
following individuals: the clinical site staff, designated caregiver, or the 
subject. Refer to dosing instructions document for more details. 
Study Population: 
Subjects who have intermediate AMD confirmed clinically and by the PI or 
designee’s interpretation of standard imaging procedures will be enrolled in 1 
of 2 disease cohorts: 
1. Intermediate age-related macular degeneration - high-risk drusen without 
GA cohort 
or 
2. Intermediate age-related macular degeneration - noncentral GA cohort. 
Inclusion Criteria: 
For this study, only 1 eye of an eligible subject will be designated as the study 
eye. However, all specified ophthalmic testing will be performed on both eyes 


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at each time point. A potential subject must meet the following criteria to be 
eligible for inclusion in the study: 
Intermediate AMD – noncentral GA disease cohort: 
1. Adults ≥ 55 years of age with 1 eye with intermediate AMD – noncentral 
GA. For this study, noncentral GA is defined as well-demarcated area(s) 
of GA with a cumulative area ≥ 1.27 mm2 (approximately 0.5 DA) by 
FAF, which spares the fovea (defined as retinal pigment epithelium and 
outer retina intact by SD-OCT). 
2. Geographic atrophy may be multifocal, but the cumulative GA lesion size 
must be: 
a. 
> 1.27 mm2 (approximately > 0.5 DA) and < 10.16 mm2 
(approximately < 4 DA). 
b. Must reside completely within the FAF imaging field (field 2 to 
30-degree image centered on the fovea). 
3. Presence of measurable hyperautofluorescence adjacent to the discrete 
foci of GA. 
OR 
Intermediate AMD – high-risk drusen without GA disease cohort: 
4. ≥ 55 years of age with one eye with intermediate AMD – high-risk drusen 
without GA. 
5. High-risk drusen is defined as presence of either at least 1 large 
(≥ 125 μm) druse or multiple medium-size (between 63 and 124 μm) 
drusen. 
General (both disease cohorts): 
6. No evidence of choroidal neovascularization (CNV) (active or prior 
history) in the macula of the study eye. 
7. Able to provide informed consent and willing to comply with all study 
visits and examinations. 
8. Women of childbearing potential who are not pregnant or nursing and 
have a negative serum pregnancy test at screening. 
9. Best-corrected visual acuity assessed by Early Treatment Diabetic 
Retinopathy Study (ETDRS) letters ≥ score of 55 (Snellen equivalent ≥ 
20/70). 
10. Low-luminance visual acuity deficit (defined as difference between 
BCVA and LL visual acuity) > 5 letters. 
11. Has at least two Low-Luminance Questionnaire sub scale results, in 
which one of the abnormal subscales is either general dim light vision or 
dim light reading. 
12. The fellow eye may have intermediate AMD without noncentral GA (i.e., 
high-risk drusen), intermediate AMD with noncentral GA, CNV 
neovascular AMD, or central GA. Ongoing treatment with antiangiogenic 
therapies in the fellow eye is allowable. 
13. No evidence of visually significant cataract OR pseudophakia without 
evidence of posterior capsular opacity. 
14. Sufficiently clear ocular media, adequate pupillary dilation, fixation to 
permit quality fundus imaging, and able to cooperate sufficiently for 
adequate ophthalmic visual function testing and anatomic assessment 
15. Able to administer SC study drug solution as demonstrated at screening or 
able to have a care provider or appropriate designee who can administer 
the study drug (i.e. a capable family member or a care giver). 


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16. 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 3 months after dosing. 
a. 
For men: Abstinence is only acceptable if it is in line with the 
preferred and usual lifestyle of the subject. The subject also 
agrees to use an acceptable method of contraception should they 
become sexually active. Subjects must use a condom with 
spermicide from the date of informed consent until at least 3 
months after the last dose of study drug. Periodic abstinence (e.g. 
calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not acceptable methods of contraception. 
b. For women: abstinence is only acceptable when it is in line with 
the preferred and usual lifestyle of the subject. The subject agrees 
to use an acceptable method of contraception should they 
become sexually active. Maintenance of a monogamous 
relationship with a male partner who has been surgically 
sterilized by vasectomy (the vasectomy procedure must have 
been conducted at least 60 days before the Screening visit or 
confirmed via sperm analysis), barrier method (e.g., condom or 
occlusive cap) with spermicidal foam/gel/film/cream AND either 
hormonal contraception (oral, implanted, or injectable) or an 
intrauterine device or system are acceptable methods. 
17. Ability and willingness to undertake all scheduled visits and assessments. 
When both eyes are eligible for the study, only one eye (study eye) will be 
included. In that case, the eye with the greater LL visual acuity deficit will be 
chosen for inclusion. Data will be collected to assess potential effects of study 
drug on the fellow eye. 
Exclusion Criteria: 
A subject with study eye that meets any of the following criteria will be 
excluded from the study: 
Ocular conditions – study eye 
1. Age-related macular degeneration with any evidence of central GA (i.e. 
involving the fovea). 
2. Atrophic retinal disease due to causes other than AMD. 
3. Presence or diagnosis of exudative AMD or choroidal neovascularization 
in the study eye. 
4. History of diabetic retinopathy (a history of diabetes mellitus without 
retinopathy is not a criterion for exclusion). 
5. Presence of vitreous hemorrhage. 
6. History of retinal detachment or macular hole (stage 3 or 4) in the study 
eye. 
7. Presence of macular pucker. 
8. History of uncontrolled glaucoma, defined as advanced cup-to-disc ratio 
> 0.7 and intraocular pressure > 25, with or without topical 
antihypertensive eye drops; treatment of ocular hypertension or controlled 
glaucoma are not criteria for exclusion. 
9. History of advanced guttae indicative of Fuchs endothelial dystrophy. 
10. Presence of visually-significant cataract OR presence of significant 
posterior capsular opacity in the setting of pseudophakia. 
11. Presence of significant keratopathy that would cause scattering of light or 
alter visual function, especially in LL conditions. 
12. Ocular incisional surgery (including cataract surgery) in the study eye 
within 3 months before Day 0. 
13. Aphakia. 


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14. History of vitrectomy surgery, submacular surgery, or any vitreoretinal 
surgery. 
15. Prior treatment with Visudyne® (verteporfin), external-beam radiation 
therapy (for intraocular conditions), or transpupillary thermotherapy. 
16. History of prophylactic subthreshold laser treatment for retinal disease. 
17. Previous intravitreal drug delivery (e.g. intravitreal corticosteroid 
injection, anti-angiogenic drugs, or device implantation) in the study eye. 
Ocular conditions – either eye 
18. Active uveitis and/or vitritis (grade trace or above) in either eye. 
19. History of idiopathic or autoimmune-associated uveitis in either eye. 
20. Active, infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in 
either eye. 
Systemic conditions 
21. Known to be immunocompromised or receiving systemic 
immunosuppression therapy. 
22. 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. 
23. Estimated glomerular filtration rate < 30 mL/min, by Modification of Diet 
of Renal Disease (MDRD). 
General 
24. Participation in other investigational drug or device clinical trials during 
and/or within 30 days before enrollment, or planning to participate in any 
other investigational drug or device clinical trials within 30 days of study 
completion. 
25. History of allergy to fluorescein that is not amenable to treatment. 
26. Inability to comply with study or follow-up procedures. 
27. Inability to obtain color fundus photograph, FAF, and fluorescein 
angiography of sufficient quality to be analyzed and interpreted. 
28. History of allergic reaction to the investigational drug or any of its 
components. 
Planned Duration of 
Treatment: 
Up to 30 weeks of study participation; including up to 2 weeks for screening 
before Baseline (Day 0) study enrollment, a 24-week period on study drug, 
and a 4-week safety Follow-up Period. 
Screening Period: 2 weeks 
Study Treatment Period: 24 weeks 
Follow-up Period: 4 weeks 
Primary Safety and 
Tolerability Endpoints: 
• 
The incidence and severity of AEs 
• 
Changes from baseline in vital sign measurements 
• 
Changes from baseline in ECGs 
• 
Changes from baseline in clinical evaluations 
• 
Changes from baseline in clinical laboratory evaluations 


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Secondary Endpoints for Both 
Noncentral GA and High Risk 
Drusen Without GA: 
• 
Compliance of administration of subcutaneous elamipretide 
• 
Number of home health visits necessary for subject or caregiver to learn 
how to inject elamipretide 
• 
Change in fundus hyperautofluorescence 
• 
Change from baseline in LL visual acuity 
• 
Change from baseline in mesopic light sensitivity by microperimetry 
• 
Change in dark adaptometry 
• 
Change in drusen volume (“retinal pigment epithelium – drusen 
complex”, as measured by automated segmentation) by SD-OCT 
• 
Change in fundus photography 
• 
Change in BCVA 
• 
Change in speed reading at standard light 
• 
Change in speed reading at low light 
• 
Change in LL visual function by the Low-Luminance Questionnaire 
• 
Change in National Eye Institute VFQ-39 score 
Secondary Endpoints for High 
Risk Drusen Without GA: 
• 
Change in drusen volume (“retinal pigment epithelium – drusen 
complex”, as measured by automated segmentation) by SD-OCT. 
Sample Size and Statistical 
Methods: 
For this Phase 1 study, the sample size of 40 evaluable subjects is reasonably 
sized for demonstrating clinical safety and tolerability. An equal enrollment 
(1:1) of approximately 20 subjects per cohort (cohort 1: 20 and cohort 2:  20) 
is targeted, but subject availability may dictate the actual enrollment ratio 
between the cohorts. 
General Methods: 
Continuous variables will be summarized by descriptive statistics (sample 
size, mean, standard deviation, median, and minimum and maximum). 
Discrete variables will be summarized by frequencies and percentages. All 
study data are to be displayed in the data listings. Importantly, tabulated data 
will be presented for each Cohort as well as the Total Sample (i.e., data from 
both cohorts pooled together). 
All data are to be displayed in the data listings, sorted by subject and visit, or 
where appropriate. Each listing will have indication of which cohort each 
subject was assigned to. 
Analysis Populations: 
All subjects who receive at least 1 dose of study drug will be included in the 
safety population. In general, subjects in the safety population are expected to 
have received active study drug and so will be identified as such. 
Baseline Characteristics and Disposition 
Baseline demographic and other non-eye specific characteristics will be 
presented by disease cohort. Subject disposition summaries will include the 
number of subjects treated (i.e., in the Safety population). The number and 
percentage of subjects who complete or discontinue from the study will be 
summarized by reason. Subject’s age, sex, weight, and other demographic 
characteristics will be recorded and summarized. Medical history will be 
listed. 
Safety Analyses: 
Adverse events will be summarized by system organ class and preferred term, 
presenting the number and percentage of subjects having adverse events. 
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characterized by specific study cohort. Severity and relationship to study drug 
will be listed as appropriate. 
Efficacy Analyses: 
Changes in endpoints will be presented by time point for each cohort as well 
as pooled. For continuous data of the by-cohort outcomes, a mixed model for 
repeated measures (MMRM) will be used, with fixed effects for cohort, 
baseline covariate, study visit, the cohort-by-visit interaction, and random 
effects for subject. For continuous data for the pooled outcomes, an MMRM 
with fixed effects for baseline covariate and study visit, and random effects for 
subject will be used. Plots of the Least Square Mean (LSMean) values over 
time will be presented for each endpoint. 
Interim Analysis 
This is an open-label study, and thus monitoring of data outcomes over the 
course of the study may be performed. In addition, an interim analysis may be 
performed on partial or all data when the first 20 subjects have completed 
through 24 weeks of treatment. 
The interim analysis may be performed by the Sponsor or their 
designee. Assessments of both safety and efficacy endpoints will be 
performed utilizing similar methods as are planned for the final analysis. 
Additional details of all statistical analyses will be included in a separate 
statistical analysis plan. 


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2. 
TABLE OF CONTENTS 
1. 
SYNOPSIS .............................................................................................................. 3 
2. 
TABLE OF CONTENTS ..................................................................................... 10 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS ......................................... 14 
4. 
INTRODUCTION ................................................................................................ 16 
4.1. 
Disease Background ....................................................................................................... 16 
4.1.1. 
Age-related Macular Degeneration ..........................................................................16 
4.1.2. 
Age-Related Macular Degeneration With Mitochondrial Abnormalities ................17 
4.1.3. 
Age-Related Macular Degeneration Trigger Factors Causing Mitochondrial 
Dysfunction .............................................................................................................17 
4.1.4. 
Mitrochondrial Dysfunction and Rationale for Mitochrondria-targeted Drugs .......17 
4.1.5. 
Visual Dysfunction and Deficit in Low-Luminance Activities of Daily Living .....18 
4.1.6. 
Low-Luminance Deficit – Photoreceptor Mitochondrial Dysfunction and 
Rationale for Mitochondria-targeted Drugs ............................................................18 
4.1.7. 
Elamipretide – a Novel Mitochondria-targeted Drug ..............................................19 
4.1.8. 
Elamipretide in Preclinical Models of Dry Age-related Mitochondrial 
Degeneration ...........................................................................................................19 
4.2. 
Elamipretide Risk/Benefit Assessment .......................................................................... 20 
4.2.1. 
Potential Risks and Benefits ....................................................................................20 
4.2.2. 
Conclusions ..............................................................................................................25 
5. 
OBJECTIVES ....................................................................................................... 25 
5.1. 
Primary Objective .......................................................................................................... 25 
5.2. 
Secondary Objectives ..................................................................................................... 25 
6. 
INVESTIGATIONAL PLAN .............................................................................. 25 
6.1. 
Summary of Study Design ............................................................................................. 25 
6.2. 
Schedule of Events ......................................................................................................... 27 
6.2.1. 
Screening Period ......................................................................................................32 
6.2.2. 
Study Treatment Period ...........................................................................................32 
6.2.3. 
Follow-up Period .....................................................................................................33 
6.3. 
Study Assessments ......................................................................................................... 33 
6.3.1. 
Physical Examination...............................................................................................33 
6.3.2. 
Vital Sign Measurements .........................................................................................33 
6.3.3. 
12-lead Electrocardiogram .......................................................................................33 
6.3.4. 
Clinical Laboratory Testing .....................................................................................33 
6.3.5. 
Concomitant Medications ........................................................................................34 
6.3.6. 
Subject Diary ...........................................................................................................34 


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6.3.7. 
Adverse Events ........................................................................................................35 
6.3.8. 
Low-Luminance Questionnaire and Visual Function Questionnaire-39 .................35 
6.3.9. 
Other Study Assessments .........................................................................................35 
7. 
STUDY POPULATION ....................................................................................... 36 
7.1. 
Number of Subjects Planned .......................................................................................... 36 
7.2. 
Study Population ............................................................................................................ 36 
7.2.1. 
Inclusion Criteria .....................................................................................................37 
7.2.2. 
Exclusion Criteria ....................................................................................................38 
7.3. 
Discontinuation .............................................................................................................. 40 
7.3.1. 
Discontinuation of Subjects .....................................................................................40 
7.3.2. 
Discontinuation of Study Sites .................................................................................41 
7.3.3. 
Discontinuation of the Study ...................................................................................41 
7.4. 
Replacement of Subjects ................................................................................................ 41 
7.5. 
Other Medications and Therapies .................................................................................. 41 
7.5.1. 
Prohibited Medications ............................................................................................41 
7.5.2. 
Concomitant Medications ........................................................................................41 
8. 
STUDY DRUG ...................................................................................................... 42 
8.1. 
Study Drug Administration ............................................................................................ 42 
8.2. 
Materials and Supplies ................................................................................................... 42 
8.2.1. 
Elamipretide .............................................................................................................42 
8.3. 
Study Drug Logistics and Accountability ...................................................................... 43 
8.4. 
Study Drug Compliance ................................................................................................. 43 
8.5. 
Method of Assigning Study Drug .................................................................................. 43 
8.6. 
Rationale for Dose Selection .......................................................................................... 43 
8.7. 
Continued Access to Investigational Medicinal Product ............................................... 44 
9. 
EFFICACY, SAFETY EVALUATIONS, SAMPLE COLLECTION AND 
TESTING, AND APPROPRIATENESS OF MEASURES .................................................... 44 
9.1. 
Primary Safety Measures ................................................................................................ 44 
9.2. 
Secondary Efficacy Measures ........................................................................................ 44 
9.3. 
Safety Evaluations .......................................................................................................... 45 
9.3.1. 
Adverse Events ........................................................................................................46 
9.4. 
Pre-study Drug Events ................................................................................................... 46 
9.5. 
Baseline Medical Conditions ......................................................................................... 46 
9.6. 
Abnormal Laboratory and Other Abnormal Investigational Findings ........................... 46 
9.7. 
Serious Adverse Events .................................................................................................. 47 
9.7.1. 
Events that Do Not Meet the Definition of a Serious Adverse Event......................47 
9.8. 
Recording of Adverse Events ......................................................................................... 48 
9.8.1. 
Investigator Assessments .........................................................................................48 


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9.8.2. 
Adverse Event Reporting Period .............................................................................49 
9.8.3. 
Serious Adverse Event Expedited Reporting ...........................................................50 
9.8.4. 
Pregnancy and Contraception ..................................................................................51 
9.8.5. 
Responsibilities to Regulatory Authorities, Investigators, and Institutional 
Review Board ..........................................................................................................52 
9.9. 
Appropriateness of Measurements ................................................................................. 52 
10. 
DATA QUALITY ASSURANCE ........................................................................ 53 
10.1. Data Capture System ...................................................................................................... 53 
11. 
SAMPLE SIZE AND STATISTICAL METHODS .......................................... 54 
11.1. Determination of Sample Size ........................................................................................ 54 
11.2. Statistical and Analytical Plans ...................................................................................... 54 
11.2.1. General Considerations ............................................................................................54 
11.2.2. Subject Disposition ..................................................................................................54 
11.2.3. Subject Characteristics .............................................................................................54 
11.2.4. Concomitant Therapy ...............................................................................................54 
11.2.5. Study Drug Compliance ...........................................................................................55 
11.2.6. Endpoints and Methodology ....................................................................................55 
11.2.7. Efficacy Analyses ....................................................................................................55 
11.2.8. Interim Analysis .......................................................................................................55 
11.2.9. Safety Analyses ........................................................................................................56 
12. 
INFORMED CONSENT, INSTITUTIONAL REVIEW BOARD, AND 
REGULATORY CONSIDERATIONS .................................................................................... 57 
12.1. Informed Consent ........................................................................................................... 57 
12.2. Institutional Review Board............................................................................................. 57 
12.3. Regulatory Considerations ............................................................................................. 58 
12.3.1. Protocol Approval ....................................................................................................58 
12.3.2. Final Report Approval .............................................................................................58 
12.3.3. Study Monitoring .....................................................................................................58 
12.3.4. Retention of Records ................................................................................................59 
12.3.5. Disclosure of Information ........................................................................................59 
13. 
AUDITS AND INSPECTIONS ........................................................................... 60 
14. 
REFERENCES ..................................................................................................... 61 
15. 
APPENDICES ...................................................................................................... 66 
APPENDIX A. SPONSOR’S PROTOCOL SIGNATURE PAGE ...................................... 67 
APPENDIX B. INVESTIGATOR’S PROTOCOL SIGNATURE PAGE .......................... 68 
APPENDIX C. CLINICAL LABORATORY TESTS .......................................................... 69 


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APPENDIX D. LOW-LUMINANCE QUESTIONNAIRE .................................................. 70 
APPENDIX E. VISUAL FUNCTIONING QUESTIONNAIRE-39 .................................... 80 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS 
The following abbreviations and specialist terms are used in this study protocol: 
Abbreviation 
Definition or Explanation 
AE 
Adverse event 
ACS 
Acute coronary syndrome 
ADL 
Activity of daily living 
AKI 
Acute kidney injury 
AMD 
Age-related macular degeneration 
APOE 
Apolipoprotein E 
ATP 
Adenosine triphosphate 
AUC 
Area under the plasma concentration time-curve 
AUC0-24h 
Area under the plasma concentration time-curve from 0 to 24 hours 
BCVA 
Best-corrected visual acuity 
CHF 
Congestive heart failure 
Cmax 
CNV 
Maximum plasma concentration 
Choroidal Neovascular 
DA 
Disc area 
DDI 
Drug-Drug Interaction 
eCRF 
EDC 
Electronic Case Report Form 
Electronic Data Capture 
ERG 
Electroretinogram 
ETC 
Electron transport chain 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAF 
Fundus autofluorescence 
GA 
Geographic atrophy 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IgE 
Immunoglobulin E 
IL5 
Interleukin 5 
IMP 
Investigational Medicinal Product 
IOP 
Intraocular pressure 
IRB 
ISR 
Institutional Review Board 
Injection Site Reaction 
IV 
Intravenous 


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Abbreviation 
Definition or Explanation 
LL 
Low-luminance 
LLQ 
LS Mean 
Low-Luminance Questionnaire 
Least Square Mean 
M1, M2 
Major metabolite of elamipretide (MTP-131) 
MDRD 
MMP 
MMRM 
Modification of Diet in Renal Disease 
Matrix metalloproteinase 
Mixed Model for Repeated Measures 
MedDRA 
Medical  Dictionary for Regulatory Activities 
NEI 
National Eye Institute 
NOAEL 
No-observed-adverse-effect-level 
NV 
Neovascular 
PCI 
Percutaneous coronary intervention 
PK 
Pharmacokinetics 
PI 
Principal Investigator 
PT 
Preferred term 
PTRA 
Percutaneous transluminal renal angioplasty 
RPE 
Retinal pigment epithelium 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SD-OCT 
Spectral domain-optical coherence tomography 
SOC 
System organ class 
STEMI 
ST-segment elevation myocardial infarction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum plasma concentration 
UFH 
Unfractionated heparin 
VFQ-39 
Visual Function Questionnaire-39 


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4. 
INTRODUCTION 
This study will be conducted in strict accordance with the Council for International 
Organizations of Medical Sciences International Ethical Guidelines, International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use 
(ICH) Good Clinical Practice (GCP) guideline, and all applicable laws and regulations. For 
detailed information on the study drug and the nonclinical and clinical studies conducted to date, 
please refer to the most recent edition of the elamipretide Investigator’s Brochure1. 
Mitochondria are organelles responsible for generating adenosine triphosphate (ATP) by a series 
of redox reactions through the electron transport chain (ETC) and ATP synthase. Mitochondria 
normally produce a small amount of reactive oxygen species including superoxide anions and 
hydrogen peroxide as physiological byproducts of electron transport and ATP production. Under 
conditions of metabolic or genetic stress, mitochondria can become a major endogenous source 
of reactive oxygen species such as superoxide anions, peroxynitrite, and hydroxyl radicals. 
Increased oxidative damage to the inner membrane of the mitochondria leads to imbalances in 
the electron transport chain, resulting in further increased superoxide and hydrogen peroxide 
production, which in turn can initiate a vicious cycle of further damage to membrane and 
mitochondrial proteins and mitochondrial DNA. Excess production of oxidants can damage 
mitochondrial proteins and lipids to a point that triggers mitochondria to activate signaling 
pathways that mediate nonlethal cellular injury.2 The biology of nonlethal injury at the retinal 
pigment epithelium (RPE) includes cytosolic actin aggregate formation, cell membrane blebbing 
at the basal aspect of the RPE, vimentin upregulation, decreased matrix metalloproteinase 
(MMP)-2 activity, and other mediators of sub-RPE deposit formation that are relevant to the 
pathobiology of drusen formation, the hallmark feature of early age-related macular degeneration 
(AMD).3 Additionally, compromised mitochondrial function in the photoreceptors of the 
neurosensory retina can adversely affect photodetection and phototransduction by limiting the 
efficiency of photon capture at the photoreceptors. This can result in diminished visual acuity, 
particularly in low-luminance (LL) conditions, where efficiency of photon capture is necessary 
for optimal visual function. 
 
4.1. 
Disease Background 
4.1.1. 
Age-related Macular Degeneration 
Age-related macular degeneration (AMD) is a progressive degenerative disorder of the retina 
affecting 30% of people over age 65 and is the most common cause of blindness in the elderly in 
the developed world.4 Early and intermediate stages of dry AMD are characterized by formation 
of drusen-lipid-rich deposits under the RPE.5,6 No treatments are currently available to regress 
drusen or to prevent drusen progression into geographic atrophy (GA). Dry AMD/drusen 
pathogenesis is multifactorial, and requires aging7 plus interaction among genetic,8-11 systemic 
health,12 and environmental risk factors (dietary fats, smoking).13,14 Multiple paradigms have 
been proposed to explain how risk factors contribute to deposits, including lipid accumulation in 


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Bruch’s membrane, complement activation, and formation of toxic byproducts of the visual cycle 
function. 
 
4.1.2. 
Age-Related Macular Degeneration With Mitochondrial Abnormalities 
Emerging evidence suggests an association between mitochondrial dysfunction and dry AMD 
pathobiology. Patients with inherited mitochondrial diseases develop maculopathy similar in 
appearance to dry AMD. In histopathology specimens, mitochondria are located along the basal 
aspect of RPE, often near drusen, and specifically, mitochondria in RPE with drusen are reduced 
approximately 50% as compared to age-matched controls and exhibit pathologic morphology, 
especially vacuolization. Moreover, RPE mitochondrial DNA in AMD eyes exhibit more 
oxidative damage as compared with aged control eyes without AMD. Taken together, these 
findings raise the possibility that mitochondrial dysfunction may play a pathologic role in dry 
AMD. 
 
4.1.3. 
Age-Related Macular Degeneration Trigger Factors Causing Mitochondrial 
Dysfunction 
Cigarette smoke and hydroquinone, a potent toxicant in cigarette smoke, have been 
epidemiologically associated with dry AMD, and in preclinical models, both have been identified 
as biochemical triggers of RPE cellular injury related to dry AMD. Hydroquinone mediates RPE 
injury by disruption of the mitochondrial ETC, producing mitochondrial dysfunction.15 Emerging 
evidence suggests that mitochondrial dysfunction may also be associated with other established 
triggers of dry AMD. Abnormal lipid metabolism can alter fatty acid and cholesterol content of 
the mitochondrial inner membrane, compromising ETC function.16,17 Disruption of 
phagolysosomes (i.e., by lipofuscin or inflammasome) can promote accumulation of damaged 
mitochondria since normal phagolysosomal function is required for clearance of dysfunctional 
mitochondria (mitophagy).18,19 Even complement dysregulation has been associated with 
decreased retinal ATP production.20  Taken together, these observations suggest that various 
AMD triggers may directly or indirectly induce mitochondrial dysfunction as a shared 
pathogenic mechanism. 
 
4.1.4. 
Mitrochondrial Dysfunction and Rationale for Mitochrondria-targeted Drugs 
Although mitochondria have been suggested as a source of reactive oxidants in AMD,21-25 
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. Preclinical studies suggest that many AMD triggers induce mitochondrial 
dysfunction (decreased ATP, calcium flux dysregulation, loss of mitochondrial membrane 
potential [∆Ψm], superoxide overproduction), leading to activation of specific signaling 
molecules (ASK1→ p38 MAPK → pHSP25, or pERK and pJNK), followed by activation of 
mediators of deposit formation (cytoskeleton disruption, actin aggregates, loss of ZO-1, 
blebbing, decreased MMP-14, decreased MMP-2, increased collagen IV, increased expression of 
vimentin), all of which will precede and contribute to sub-RPE deposits (as degraded blebs 


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contributing phospholipids, cytosolic proteins and degraded organelles, collagen accumulation 
and vimentin accumulation). 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 GA. 
 
4.1.5. 
Visual Dysfunction and Deficit in Low-Luminance Activities of Daily Living 
It is often assumed, incorrectly, that patients with early AMD, characterized by the presence of 
drusen, are not visually impaired because they retain good high-contrast (best-corrected) visual 
acuity and activities of daily living (ADLs) in photopic (bright-light) conditions. However, many 
drusen patients manifest severely reduced LL vision, defined both as loss of visual function 
under LL conditions and poor scores on inventories of LL ADLs.26-29 For example, 50% of 
patients with large drusen demonstrate loss of > 10 letters of visual acuity when measured under 
LL conditions (reading black letters on dark gray background)30. Studies have also shown that 
drusen patients experience decreased foveal sensitivity to dim light and delayed dark 
adaptation.31,32 These deficits translate into impaired LL ADLs: loss of reading in imperfect 
lighting, reduced mobility in dimly lit areas, impaired night driving, increased sensitivity to 
glare, and reduced night-time socialization. Because parafoveal rods in AMD eyes with drusen 
can die,33 dark adaption defects may reflect either loss or reversible dysfunction of rods. 
However, since drusen eyes usually have normal cone density,33 LL deficits most likely 
represent physiologic cone dysfunction rather than anatomic cone loss. 
 
4.1.6. 
Low-Luminance Deficit – Photoreceptor Mitochondrial Dysfunction and 
Rationale for Mitochondria-targeted Drugs 
Photoreceptor mitochondria may become susceptible to dysfunction in the setting of RPE injury 
and subRPE deposit formation, as a result of compromised RPE metabolism. ATP is crucial for 
outer segment membrane biogenesis and for transport of structural proteins.34,35 Mitochondria 
also regulate local calcium flux. Accordingly, the ellipsoid has high mitochondria density. The 
presynaptic terminal also has high mitochondria density. This is not surprising: ATP is required 
for glutamate endocytosis and vesicle localization, which is crucially related to the graded 
glutamate release for vision.36 Also, ATP is required to maintain calcium balance by 
ATP-dependent ion pumps. Thus, photoreceptor mitochondrial dysfunction, induced by exposure 
to AMD trigger factors in the setting of RPE injury and deposit formation, may contribute to LL 
acuity deficit because of deficient ATP and abnormal calcium flux regulation required for (a) 
outer segment function and (b) presynaptic neurotransmitter vesicle dynamics. Therefore, 
mitochondria-targeted drugs that reverse mitochondrial dysfunction in retinal photoreceptors 
may improve visual function by restoring ATP production and in turn boosting efficiency of 
retinal photon capture, improving LL acuity deficit. 


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4.1.7. 
Elamipretide – a Novel Mitochondria-targeted Drug 
Elamipretide is a novel tetrapeptide drug that accumulates within mitochondria and facilitates 
restoration of normal mitochondrial function.37-39 Cardiolipin is a specialized phospholipid found 
in mitochondria that is a vital component of the inner mitochondrial membrane, maintaining the 
structural integrity of the ETC.40 In doing so, cardiolipin maintains the efficiency of the redox 
reactions essential for generating the transmembrane potential and proton-motive force for 
production of ATP. In the setting of excess oxidant generation, cardiolipin is susceptible to 
peroxidation; peroxidized cardiolipin is ineffective at maintaining the structural integrity of the 
ETC. As a result, the ETC is much less efficient, accumulation of free electrons leads to a 
vicious cycle of oxidant generation, transmembrane potential is decreased, ATP production 
diminishes, and calcium flux is perturbed. Elamipretide binds to peroxidized CL,41 optimizing its 
function, and restoring transmembrane potential, ATP production, and normal calcium flux, 
while reducing superoxide generation. Elamipretide has been found to be effective in cell culture 
systems of oxidant and toxic injury and in animal models of ischemia-reperfusion, heart failure, 
and renal disease42-45 to reverse mitochondrial dysfunction and to ameliorate mediated pathology. 
Elamipretide is bioavailable after systemic injection and readily penetrates tissues and cells. 
Thus far, in human clinical trials, 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. 
 
4.1.8. 
Elamipretide in Preclinical Models of Dry Age-related Mitochondrial 
Degeneration 
In in vitro studies of RPE cell culture, elamipretide has been found to reverse mitochondrial 
dysfunction, and prevent activation of signaling cascades that activate biochemical mediators of 
deposit formation. Elamipretide has also been recently studied in 2 relevant mouse models of dry 
AMD: an acute model of subRPE deposit formation after repetitive exposure to periocular 
hydroquinone in young C57BL6J wild-type mice and a chronic model of subRPE deposit 
formation in aged (> 16 months) apolipoprotein E (APOE) 4 transgenic mice fed a high fat plus 
cholate diet. Both models are characterized by RPE mitochondrial dysfunction, evidence of 
photoreceptor mitochondrial dysfunction, RPE cellular injury evident by cytosolic actin 
aggregate formation, loss of ZO-1 junctions, increased vimentin expression, basal cell membrane 
blebbing, and decreased MMP-2 activity, all of which mediate formation of subRPE deposits 
Presence of deposits is also associated with RPE mitochondrial dysmorphology (i.e., 
vacuolization). The APOE4 mouse model is also characterized by dysfunction of the 
neurosensory retina, which is evident by a diminished a-wave (photoreceptor activation) as well 
as diminished b-wave (photoreceptor – bipolar cell synapse) by electroretinogram (ERG). In 
both models, systemic (i.e., SC) daily treatment of mice with elamipretide reversed 
mitochondrial dysfunction, downregulated biochemical mediators, and promoted regression of 
subRPE deposits (unpublished preclinical data). Moreover, elamipretide treatment reversed 


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neurosensory retinal dysfunction, restoring normal a-wave and b-wave amplitudes on ERG. This 
striking effect on retinal and visual function represents the first observed reversal of established 
retinal dysfunction in the APOE4 transgenic mouse model. 
Taken together, the profound unmet need to identify a treatment for dry AMD, a disease without 
any known effective therapy, the strong rationale for mitochondrial-targeted drugs in dry AMD, 
the well-established mechanism of action and clinical safety profile for the novel tetrapetide drug 
elamipretide, and notably the profound beneficial effects of elamipretide treatment to reverse 
subRPE deposit formation and restore retinal function in mouse models of dry AMD, 
collectively provide compelling evidence to support the clinical development of elamipretide for 
the treatment of patients with intermediate (early dry) AMD. 
 
4.2. 
Elamipretide Risk/Benefit Assessment 
4.2.1. 
Potential Risks and Benefits 
Major metabolites of elamipretide, M1 and M2, have been qualified in toxicology studies in both 
rat and dog. M1 and M2 have been demonstrated to be pharmacologically inactive in a model of 
mitochondrial dysfunction in reperfusion injury where elamipretide demonstrates statistically 
significant reduction in damage. 
In previous clinical studies of elamipretide, the most frequent treatment emergent adverse events 
(TEAEs) reported are injection site reactions, headache, nausea, and eosinophilia, as reported in 
both placebo and elamipretide-treated groups. All TEAEs should be treated by the Principal 
Investigator (PI) per standard of care. Monthly lab collections will be used to monitor for signs 
of eosinophilia. Specifically, collection of blood for hematology, chemistry, Immunoglobulin E 
(IgE), and Interleukin 5 (IL5) testing and urine for urinalysis. 
In a preclinical fertility study, elamipretide, administered by daily SC injection before 
cohabitation, through mating and implantation at doses of 2, 6, and 20 mg/kg, had no adverse 
effects on fertility in male and female rats. In a preclinical gestational study, daily intravenous 
(IV) infusion of elamipretide to mated female rats and rabbits was associated with maternal 
toxicity characterized by reduced food consumption and body weight gain at high doses but no 
developmental toxicity. In rats, the maternal no-observed-adverse-effect-level (NOAEL) was 
3 mg/kg/day, and the developmental NOAEL was 10 mg/kg/day. In rabbits, the maternal 
NOAEL was 5 mg/kg/day, and the developmental NOAEL was 50 mg/kg/day. As a precaution 
against any potential reproductive risks, this study mandates pregnancy testing for women of 
childbearing potential and the use of effective contraception for all participants of childbearing 
potential or having partners with childbearing potential during trial participation. Subjects 
enrolled in the study will be required to follow the contraceptive restrictions described in  
Section 9.8.44. Women who are pregnant or breastfeeding are excluded from study participation. 
It is possible that this drug may cause harm to a fetus or embryo. Furthermore, the safety of 
receiving elamipretide during breastfeeding is not known. 


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Elamipretide was not associated with any end organ toxicity and all clinical findings were 
reversible. No significant toxicity was observed at 3 mg/kg/hour in rats and dogs, infused 
continuously for 12 hours with elamipretide or after 90 days dosing of elamipretide by SC 
injection (6mg/day in rat; 20 mg/day in dog). 
In animal studies, evidence of drug-induced histamine release syndrome was seen with 
cutaneous vasodilation, redness of the face, and pinna and muscle twitching noted in association 
with variable increases in plasma histamine. Mild and moderate histaminergic-like reactions 
occurred at elamipretide time to maximum plasma concentration (Tmax), where maximum plasma 
concentration (Cmax) was > 16,500 ng/mL in rat [30 mg/kg/day] and > 3500 ng/mL 
[10 mg/kg/day] in dog and resolved spontaneously after approximately 4 hours post dose. This 
phenomenon was best characterized in the cardiovascular dog study where minimal decreases in 
blood pressure and a reflex increase in heart rate and peripheral vasodilation were clearly 
associated with increases in plasma histamine at doses of elamipretide > 10 mg/kg/day. At SC 
doses > 300 mg/kg/day in the rat or > 40 mg/kg in the dog, convulsions were observed when 
Cmax plasma concentrations of elamipretide were approximately 200,000 ng/mL and 
approximately 60,000 ng/mL in the rat and dog, respectively. 
In human volunteers, 2 clinical studies have assessed the safety and pharmacokinetics (PK) of 
elamipretide. At doses of up to 80 mg/day administered as a SC injection for up to 7 days, no 
subject experienced symptoms of histamine release. Plasma concentrations reached time to Tmax 
at approximately 0.75 hours postdose and mean Cmax at 80 mg/day on Day 7 was 1643 ng/mL. 
The daily dosage level for this study (40 mg) is below the dosage range utilized in these prior 
safety studies. Nonetheless, close monitoring of study subjects receiving elamipretide for clinical 
signs related to a histaminergic response, including local injection site reactions, is warranted. 
Antihistamines should be considered if clinically significant histaminergic-like reactions occur. 
In rats, dose levels above 100 mg/kg/day were associated with metabolic acidosis, electrolyte 
loss, hypocalcaemia, and hypophosphatemia. In human subjects, early clinical data suggested a 
treatment-related lowering in serum sodium levels. Expansion of the clinical study population 
has not demonstrated hyponatremia; however, close monitoring of study subjects receiving 
elamipretide for clinical and laboratory signs of hyponatremia will be conducted. Treatment for 
the condition is fluid restriction. 
Elamipretide and its 2 metabolites, M1 and M2, are excreted primarily through the kidneys. 
Patients with renal dysfunction will have higher exposure to the drug and its metabolites. A 
clinical study conducted in subjects with varying degrees of renal function (normal renal 
function and mild, moderate, and severe renal impairment) assessed the safety and PK of 
elamipretide and metabolites after IV administration of elamipretide (0.25 mg/kg/hour for 
1 hour) for 7 days. As expected, PK variables were impacted by renal function in a proportional 
manner; exposure (as the area under the plasma concentration-time curve from 0 to 24 hours 
[AUC0-24h]) to elamipretide in the severe renal impairment group was approximately 2.3 times 
higher than in the normal renal function group, while Cmax was 1.08 times higher. Elamipretide, 


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M1, and M2 had reached steady-state by 7 days of dosing. Anticipated Cmax and AUC0-24h after 
daily exposure to elamipretide at 40 mg/day by SC injection are shown in Table 2. 
Table 2: Anticipated Mean Cmax and Mean AUC0-24 Hours of elamipretide, M1 and M2 After 
Administration of elamipretide at 40 mg/day SC 
 
Analyte 
PK Parameter 
Renal Function (GRF mL/min) 
Normal 
(>90) 
Mild 
Impairment 
(60-89) 
Moderate 
Impairment 
(30-59) 
Severe 
Impairment 
(<30) 
elamipretide 
Cmax (ng/mL) 
1320 
1337 
1426 
1426 
AUC0-24h ng.hr/mL 
3810 
5372 
6782 
8649 
M1 
Cmax (ng/mL) 
436 
577 
577 
774 
AUC0-24h ng.hr/mL 
3200 
6560 
7328 
12544 
M2 
Cmax (ng/mL) 
88.8 
189 
273 
612 
AUC0-24h ng.hr/mL 
1410 
3469 
5288 
11844 
Abbreviations: AUC0-24h = area under the plasma concentration-time curve from 0 to 24 hours; Cmax = maximum plasma 
concentration; GFR = glomerular filtration rate. 
Safety and tolerability of elamipretide was not affected by renal function. Subjects with 
glomerular filtration rates < 30 mL/minute will be excluded from the study and anticipated 
plasma PK of the active compound or inactive metabolites are expected to remain within 
mandated toxicity margins. 
Generally, injection of SC elamipretide resulted in mild or moderate injection site reactions 
(ISRs), frequently characterized by erythema, induration, bruising, pruritus, pain, and/or 
urticaria. Injection site reactions were reported intermittently across multiple studies with 
elamipretide, with most subjects experiencing ISRs beginning upon first administration of 
elamipretide and continuing throughout treatment, with resolution of the ISRs typically occurring 
the day of last elamipretide administration. The resolution of ISRs, however, has occurred as late 
as 14 days after the end of elamipretide treatment in one subject. The site may be requested to 
acquire photographs of the injection site reaction and provide them to the sponsor. The subject 
will be consented to allow these photographs to be collected and transferred to sponsor for 
analysis. 
Given the potential benefit of a first-in-any-class treatment for patients with dry AMD, the 
overall risk benefit balance is therefore considered to be acceptable. 
 
4.2.1.1. 
Safety Studies - Non-clinical Studies 
Toxicology studies in rats and dogs showed that elamipretide has an acceptable profile that 
permits clinical investigations in humans for the proposed duration of the study. 


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In non-clinical safety studies in rats and dogs, no safety issues relevant to either IV infusion or 
SC administration at therapeutic doses were identified during the non-clinical evaluation of 
elamipretide. Elamipretide did not cause end-organ toxicity at any dosage tested in either rats or 
dogs. Systemic toxicity at high doses was manifested primarily by acute and transient clinical 
signs, which may have been mediated by histaminergic-like reactions. Effects were associated 
with maximum elamipretide Cmax and were rapidly reversible as the plasma concentrations of 
elamipretide and histamine decreased. Dose administration was not associated with any adverse 
effects on cardiovascular, respiratory, or central nervous system function; off-target non-adverse 
effects were limited to a transient decrease of blood pressure and heart rate, which is thought to 
be consistent with histaminergic-like reactions. In all studies, the severity of the effects was 
proportional to Cmax for elamipretide; thus, the safety margin is estimated based on Cmax, and not 
area under the plasma concentration-time curve (AUC). The plasma elamipretide threshold 
concentration for clinically relevant adverse effects appears to be approximately 20,000 ng/mL 
in both rats and dogs, which is more than 10-fold higher than the maximum anticipated human 
exposures in this trial. 
Elamipretide was negative for genotoxicity in the full battery of tests and caused no significant 
hemolysis or inhibition of receptor binding. Elamipretide was not associated with adverse effects 
on fertility or embryo-fetal development. 
No formal immunotoxicity studies have been performed. As a tetrapeptide, the immunogenic 
potential of the drug is expected to be low. 
 
4.2.1.2. 
Human Safety 
To date, 17 clinical trials have been completed with parenteral elamipretide, including 14 clinical 
studies with the IV formulation and 3 studies with the SC formulation. In 11 clinical 
pharmacology trials completed, the primary objective was not to treat a disease state (9 trials 
with the IV formulation and 2 trials with the SC formulation). 
Eight of the 11 clinical pharmacology trials evaluated single doses of IV or SC elamipretide, and 
three trials evaluated multiple doses of IV and SC elamipretide (SPISC-101 and SPISC-102 
evaluated both single and multiple dose SC elamipretide). Parenteral administration of 
elamipretide was assessed following single and multiple IV and SC doses in approximately 200 
healthy subjects in 11 completed clinical pharmacology studies. Single IV doses ranged from 
0.005 mg/kg/hour to 0.25 mg/kg/hr, typically administered over 4 hours, while 0.25 mg/kg/hr 
administered over 1 hour daily for 7 days was the multiple-dose regimen studied. Single SC 
doses ranged from 2 mg to 80 mg administer as 0.5 or 1 mL injections, while multiple-dose 
regimen of 6 mg to 80 mg administered as 0.25, 0.5, or 1 mL injections daily for 7 days were 
studied. 
No safety concerns have been identified with administration of IV or SC elamipretide for up to 
seven days. In these studies, the only systemic adverse event reported in over 5% of subjects was 
headache (7.3%).  Nausea and hyponatraemia were each reported in 3.0% of the subjects. All 


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other events were reported with incidence of <2.0%. The majority of TEAEs were assessed by 
the investigator to be of mild severity, resolved without sequelae and did not require 
intervention. There were no significant findings for group mean clinical laboratory, vital sign, 
ECG, or physical examination parameters within or across trials. 
The SC formulation of elamipretide has been studied in both single- and multiple-dose trials in 
healthy volunteers and patient populations. Generally, injection of SC elamipretide resulted in 
mild or moderate injection site reactions, frequently characterized by erythema, induration, 
bruising, pruritus, pain, and/or urticaria. Injection site reactions were reported intermittently 
across dosing with elamipretide, with most subjects experiencing ISRs beginning upon first 
administration of elamipretide and continuing throughout treatment, with resolution of the ISRs 
typically occurring the day of last elamipretide administration. The resolution of ISRs, however, 
has occurred as late as 14 days after the end of elamipretide treatment in one subject. 
In subjects with renal impairment, exposure, as measured by AUC, to elamipretide and both of 
its metabolites (M1 and M2) increased proportionally to the degree of renal impairment. 
However, there was no evidence of increased toxicity as a consequence of impaired renal 
function. Similarly, in the Drug-Drug Interaction (DDI) studies carried out to date, co- 
administration of elamipretide with aspirin, with clopidogrel, or with unfractionated heparin 
(UFH) did not indicate a change in the nature, severity or frequency of AEs to the safety profile 
of either elamipretide or the comparator. 
Elamipretide, administered by parenteral routes, was also assessed in completed studies in 
multiple patient populations including subjects with stable congestive heart failure (CHF), acute 
coronary syndrome (ACS) subjects who were undergoing primary percutaneous coronary 
intervention (PCI) and stenting for ST-segment elevation myocardial infarction (STEMI), 
subjects with acute kidney injury (AKI) undergoing percutaneous transluminal renal angioplasty 
(PTRA), subjects with genetically confirmed mitochondrial disease with signs and symptoms of 
mitochondrial myopathy and/or exercise intolerance, and subjects over 60 years of age with 
evidence of skeletal muscle mitochondrial dysfunction. Single and multiple IV and SC doses of 
elamipretide were assessed with generally no notable differences between the elamipretide and 
placebo arms in the frequency or severity of adverse events, except for ISRs with SC 
elamipretide administration. Additionally, eosinophilia was reported as an adverse event and 
laboratory data demonstrated elevations (>0.45 cells x109/L) in eosinophils beginning at 
approximately 28 days after initiation of elamipretide treatment in numerous subjects. These 
laboratory findings have not been reported to be associated with any systemic clinical 
manifestations of eosinophilia. In general, these elevations were demonstrated to have returned 
to within normal range or to baseline levels at the follow-up visit. There were no other identified 
safety concerns in these trials with respect to other clinical laboratory results, physical 
examinations, vital signs, ECG data between the elamipretide and placebo. In general, the safety 
profile of systemic elamipretide was consistent with the pre-existing, comorbid medical 
conditions. 


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Across all studies, both IV and SC formulations, there has been no reported pregnancies. There 
have been no exposures during lactation, no overdoses, and no abuses or misuses reported. 
 
4.2.2. 
Conclusions 
In summary, based on the clinical and non-clinical study data, acceptable safety risks are 
expected for the current study. 
 
5. 
OBJECTIVES 
5.1. 
Primary Objective 
The primary objective of the study is: 
• 
To evaluate the safety and tolerability of SC injections of elamipretide in subjects with 
intermediate AMD 
 
5.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• 
To evaluate the feasibility of administration of SC injections of elamipretide in subjects 
with intermediate AMD 
• 
To evaluate the changes from baseline in physical/ophthalmic examinations 
 
6. 
INVESTIGATIONAL PLAN 
6.1. 
Summary of Study Design 
This is an open-label, Phase 1, single-center study in a total of approximately 40 evaluable 
subjects who have either: 1 eye with intermediate AMD - high-risk drusen without GA or 1 eye 
with intermediate AMD with noncentral GA. The study will thus include two predefined study 
disease cohorts: high-risk drusen cohort and noncentral GA cohort. 
The disease cohort high-risk drusen, is defined as presence of either at least 1 large (≥ 125 μm) 
druse or multiple medium-size (between 63 and 124 μm) drusen. 
The disease cohort noncentral GA, is defined as evidence of GA with cumulative area 
≥ 1.27 mm2 (approximately 0.5 disc area [DA]) by fundus autofluorescence (FAF), which spares 
the fovea (defined as retinal pigment epithelium and outer retina intact by SD-OCT). 
Eligible subjects may have intermediate AMD with either high-risk drusen or noncentral GA in 
the study eye but without CNV AMD in the study eye. The fellow eye (not the study eye) is 
allowed to receive antiangiogenic therapies and may have advanced central GA, advanced 
central GA, or CNV AMD, and the fellow eye is allowed to receive antiangiogenetic therapies. . 


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Eligible subjects identified during the screening process will return for the Baseline (Day 0) visit, 
at which time they will be enrolled into the study and will begin receiving the 40 mg dose of 
elamipretide administrated subcutaneously once daily. 
Written informed consent will be obtained from all subjects before the Screening visit. 
The screening examination will be performed no more than 14 days before the Baseline visit. 
Data to be collected from the screening examination will include significant and/or ongoing 
medical and ocular history, vital sign measurements, physical examination, routine blood 
samples for hematology, chemistry, and urinalysis, ECG, manifest refraction, measurement of 
best-corrected visual acuity (BCVA) using the Early Treatment Diabetic Retinopathy Study 
(ETDRS) scale completed twice, intraocular pressure measurement, slit-lamp examination, 
dilated fundus examination, fundus photography, SD-OCT, FAF, fluorescein angiography*, 
best-corrected low-luminance (LL) visual acuity completed twice, mesopic microperimetry, dark 
adaptometry, and Low-Luminance Questionnaire. Women of childbearing potential will have a 
serum pregnancy test. 
*Fluorescein angiography assessments done as standard of care and completed within 90 days prior to dosing are 
allowed to be used for screening purposes. 
After the screening examination, relevant data will be reviewed by the PI or designee to confirm 
study eligibility. 
Each subject will be assigned into 1 of the 2 predefined study disease cohorts. Elamipretide will 
be supplied as 40 mg/mL of sterile solution for SC injection. The dose of elamipretide will be 
40 mg administered as a once daily 1.0 mL SC injection. 
At the time of study drug administration, training on the proper administration of subcutaneous 
drug solution (by the subject, regular caregiver, or his/her appropriate designee) will occur. 
Subjects will be trained using a standard script explaining the importance of proper 
administration of the drug on a daily basis for the 24-week Study Treatment Period. The first 
dose may be given by a qualified member of the study team, by the subject, or caregiver at the 
PIs discretion. The option of a visiting nurse to oversee the study drug administration will be 
discussed with the subject and provided, as needed. 
Safety and tolerability will be measured throughout the Study Treatment Period, while 
exploratory anatomical and physiologic endpoints will be measured at time points as specified in 
the Schedule of Events (Table 3). Visits will occur at: Baseline (Day 0), Day 7 (± 3 days), Week 
4 (± 7 days), Week 8 (± 7 days), Week 12 (± 7 days), Week 16 (± 7 days), Week 20 (± 7 days), 
and Week 24 (± 7 days), with phone calls to collect safety information completed at Week 2 (± 4 
days), Week 6 (± 4 days), Week 10 (± 4 days), Week 14 (± 4 days), Week 18 (± 4 days), and 
Week 22 (± 4 days). 
Ocular imaging will be read by an independent reading center and findings uploaded to the 
electronic data capture (EDC) system on a regular basis throughout the study. 


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After completion of the 24-week Study Treatment Period, subjects will continue to be monitored 
for safety during the 4-week Follow-Up Period. A post-study drug follow-up visit is scheduled at 
Week 28 (±4 days). 
 
6.2. 
Schedule of Events 
Study procedures and their timing are summarized in the Schedule of Events (Table 3). A list of 
all clinical laboratory tests to be performed is found in Appendix C. 


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Table 3:  Schedule of Events 
 
Days/Weeks 
Screening 
Perioda 
Study Treatment Period 
Follow 
up 
visit 
Early 
Terminati 
on 
Screening 
(Day -14 
to Day - 
1) 
Day 
0b 
Baseli 
ne 
Day 7 
(± 3 
days) 
Week 
2 
(± 4 
days) 
Week 
4 
(± 7 
days) 
Week 
6 
(± 4 
days) 
Week 
8 
(± 7 
days) 
Week 
10 
(± 4 
days) 
Week 
12 
(± 7 
days) 
Week 
14 
(± 4 
days) 
Week 
16 
(± 7 
days) 
Week 
18 
(± 4 
days) 
Week 
20 
(± 7 
days) 
Week 
22 
(± 4 
days) 
Week 
24 
(± 7 
days) 
End 
of 
Study 
Week 
28 
(± 7 
days) 
FU 
Visit 
Early 
Terminati 
on/ 
Discontin 
uation 
Visit 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Informed 
consent 
X 
Eligibility 
X 
X 
Demographicsh 
X 
Medical/ 
Ocular historyj 
X 
X 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examinationd 
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 
IgE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IL5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy 
testing (serum) 
X 
X 
X 
ECGf 
X 
X 
X 
Adverse 
eventsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Days/Weeks 
Screening 
Perioda 
Study Treatment Period 
Follow 
up 
visit 
Early 
Terminati 
on 
Screening 
(Day -14 
to Day - 
1) 
Day 
0b 
Baseli 
ne 
Day 7 
(± 3 
days) 
Week 
2 
(± 4 
days) 
Week 
4 
(± 7 
days) 
Week 
6 
(± 4 
days) 
Week 
8 
(± 7 
days) 
Week 
10 
(± 4 
days) 
Week 
12 
(± 7 
days) 
Week 
14 
(± 4 
days) 
Week 
16 
(± 7 
days) 
Week 
18 
(± 4 
days) 
Week 
20 
(± 7 
days) 
Week 
22 
(± 4 
days) 
Week 
24 
(± 7 
days) 
End 
of 
Study 
Week 
28 
(± 7 
days) 
FU 
Visit 
Early 
Terminati 
on/ 
Discontin 
uation 
Visit 
Refraction 
X 
X 
X 
X 
X 
BCVA 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Best-corrected 
low-luminance 
VA 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IOP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Slit lamp exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dilated fundus 
exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fundus 
photography 
X 
X 
X 
X 
Spectral- 
domain optical 
coherence 
tomography 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fundus 
autofluorescen 
ce 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fluorescein 
angiographyi 
X 
Mesopic 
microperimetry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dark 
adaptometry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Days/Weeks 
Screening 
Perioda 
Study Treatment Period 
Follow 
up 
visit 
Early 
Terminati 
on 
Screening 
(Day -14 
to Day - 
1) 
Day 
0b 
Baseli 
ne 
Day 7 
(± 3 
days) 
Week 
2 
(± 4 
days) 
Week 
4 
(± 7 
days) 
Week 
6 
(± 4 
days) 
Week 
8 
(± 7 
days) 
Week 
10 
(± 4 
days) 
Week 
12 
(± 7 
days) 
Week 
14 
(± 4 
days) 
Week 
16 
(± 7 
days) 
Week 
18 
(± 4 
days) 
Week 
20 
(± 7 
days) 
Week 
22 
(± 4 
days) 
Week 
24 
(± 7 
days) 
End 
of 
Study 
Week 
28 
(± 7 
days) 
FU 
Visit 
Early 
Terminati 
on/ 
Discontin 
uation 
Visit 
Reading Speed 
at standard 
light 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reading Speed 
at low light 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Low- 
Luminance 
Questionnaire 
X 
X 
X 
X 
X 
X 
VF 
Questionnaire- 
39 
X 
X 
X 
X 
X 
Dispense study 
drug and 
Subject diary 
X 
X 
X 
X 
X 
X 
X 
Study drug 
accountability 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone 
screeng 
X 
X 
X 
X 
X 
X 
Abbreviations: BCVA = best-corrected visual acuity; ECG = electrocardiogram; 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. 
b. 
The day of enrollment is defined as study Day 0. 
c. 
Vital sign measurements include temperature, respiratory rate, sitting blood pressure after resting for 5 minutes, and pulse and weight. 
d. 
Physical examination will include general appearance, skin, chest, heart, abdomen, extremities, and nervous system. 
e. 
Blood for safety will consist of hematology panel and clinical chemistry. 
f. 
All scheduled ECGs must be performed after the subject has rested quietly for at least 5 minutes in the supine position. 
g. 
Telephone screens for safety events will occur at weeks intervening study visits: Week 2, Week 6, Week 10, Week 14, Week 18, and Week 22. 
h. 
Demographic will collect date of birth, subject initials, sex, race, ethnicity, eye color, and history of smoking. 


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i. 
Fluorescein Angiography completed for reasons of standard of care and within 90 days prior to first dose can be used for screening purposes. 
j. 
All ocular history will be collected. For all other body systems, only significant history and ongoing issues will be collected. 
k. 
BCVA and BCVA LL repeated twice at screening 


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6.2.1. 
Screening Period 
A signed and dated informed consent form (ICF) will be obtained from the subject as required by 
the protocol 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 Period within 14 days before 
the first study drug administration on Day 0. The following will be collected: 
• 
All ocular history 
• 
Significant medical history 
• 
Any ongoing medical history 
The subject’s medical history will be recorded on the Medical History section of the electronic 
case report form (eCRF). Any AEs reported from the time of signed ICF until the first dose of 
study drug should be recorded on the Medical History section of the eCRF. Any SAEs during 
this time will be reported on the AE eCRF and SAE paperwork completed within 24 hours of the 
PI learning of the SAE. 
The subject’s ocular history should also be recorded in the eCRF, including date of diagnosis, 
involvement in one or both eyes, and associated symptoms. 
 
6.2.2. 
Study Treatment Period 
Once the screening procedures are completed and the subject meets eligibility criteria, the 
subject will be assigned by the investigator into 1 of 2 study disease cohorts: intermediate AMD 
- high-risk drusen without GA cohort or intermediate AMD - noncentral GA cohort. 
The dose of elamipretide will be 40 mg administered as a once daily 1.0 mL SC injection. Study 
site personnel will instruct the subject and/or the subject’s caregiver or his/her appropriate 
designee on the techniques for drawing up the solution into the syringe and administering the 
study drug subcutaneously into the abdomen. The subject and/or the subject’s caregiver or 
his/her appropriate designee will be instructed on rotating the SC injection site clockwise around 
the four abdominal quadrants from previous injection sites. The first injection will be given at the 
study center by a qualified study staff member, the subject, or the subject’s caregiver under the 
supervision of the study site personnel. Study drug will be administered daily for the 24-week 
Study Treatment Period and should be administered at approximately the same time every day. 
Assessments for safety and tolerability will be measured according to the Schedule of Events 
(Table 3). Visits will occur at: Day 7 (± 3 days), Week 4 (± 7 days), Week 8 (± 7 days), Week 
12 (± 7 days), Week 16 (± 7 days), Week 20 (± 7 days), and Week 24 (± 7 days), with phone 
calls to collect safety information completed at Week 2 (± 4 days), Week 6 (± 4 days), Week 10 
(± 4 days), Week 14 (± 4 days), Week 18 (± 4 days), and Week 22 (± 4 days). Subjects will be 
instructed to return all used and unused vials of study drug at subsequent visits. 


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6.2.3. 
Follow-up Period 
A follow-up visit will occur 4 weeks after the last dose of study drug administration. 
Assessments will be collected according to the Schedule of Events (Table 3). 
Subjects withdrawing from the study will be asked to complete the Early Discontinuation visit 
assessments (Table 3). 
 
6.3. 
Study Assessments 
6.3.1. 
Physical Examination 
A physical examination should occur within 14 days before Day 0, at the end of the Study 
Treatment Period (Week 24), and at the Early Termination visit (for subjects who withdraw early 
from the study). The physical examination will include an assessment of general appearance, 
skin, chest, heart, abdomen, extremities, and the nervous system. 
 
6.3.2. 
Vital Sign Measurements 
Vital sign measurements (temperature, respiratory rate, sitting blood pressure after resting for 
5 minutes, and pulse) and weight will be collected within 14 days before Day 0, at every visit 
during the Study Treatment Period, the Follow-up Period, and Early Termination (for subjects 
who withdraw early from the study). All vital sign measurements are to be obtained with the 
patient in a position that is consistent throughout the study. 
 
6.3.3. 
12-lead Electrocardiogram 
A 12-lead ECG should be obtained within 14 days before Day 0, at the end of the Study 
Treatment Period (Week 24), and Early Termination (for subjects who withdraw early from the 
study). All scheduled ECGs must be performed after the subject has rested for at least 5 minutes 
in the supine position and before any blood draws. 
 
6.3.4. 
Clinical Laboratory Testing 
Samples for hematology, serum chemistry, and urinalysis assessments will be collected and 
measured as described in Table 3 and Appendix C. 
All laboratory results must be reviewed for clinically significant events. Any clinically 
significant event must be followed and reported as required by the protocol (see Section 9.6 for 
AEs and abnormal laboratory values). 
 
6.3.4.1. 
Hematology 
Blood samples for hematology assessments will be obtained within 14 days before Day 0, at 
Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28, and Early Termination (for 
subjects who withdraw early from the study). 


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6.3.4.2. 
Blood Chemistry 
Blood samples for chemistry assessments will be obtained within 14 days before Day 0, at 
Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28, and Early Termination (for 
subjects who withdraw early from the study). 
 
6.3.4.3. 
Urinalysis 
A urine sample for urinalysis will be obtained within 14 days before Day 0, at Week 4, Week 8, 
Week 12, Week 16, Week 20, Week 24, Week 28, and Early Termination (for subjects who 
withdraw early from the study). 
 
6.3.4.4. 
Immunoglobulin E (IgE) 
A blood sample for IgE testing will be obtained within 14 days before Day 0, at Week 4, Week 
8, Week 12, Week 16, Week 20, Week 24, Week 28, and Early Termination (for subjects who 
withdraw early from the study). 
 
6.3.4.5. 
Interleukin 5 (IL5) 
A blood sample for IL5 testing will be obtained within 14 days before Day 0, at Week 4, Week 
8, Week 12, Week 16, Week 20, Week 24, Week 28, and Early Termination (for subjects who 
withdraw early from the study). 
 
6.3.4.6. 
Pregnancy Testing 
If the subject is female and of child bearing potential, pregnancy testing by assessment of serum 
beta-human chorionic gonadotrophin (β-HCG) will be conducted within 14 days before Day 0, at 
Week 24, and at Early Termination (for subjects who withdraw early from the study). 
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. 
 
6.3.5. 
Concomitant Medications 
All concomitant medications started on or after Day 0 should be recorded in the eCRF at every 
visit. For additional details see Section 7.5.2. 
 
6.3.6. 
Subject Diary 
Subjects will be asked to complete Subject Diary documenting study drug compliance. Study site 
personnel will review the Subject Diary at each visit and retrain the subject on administration of 
study drug if necessary. 


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6.3.7. 
Adverse Events 
Subjects will be monitored for any untoward medical events (AEs or SAEs) from the time when 
the subject signs the informed consent and continuing through the 28 (± 7 days) days after last 
administration of study drug. 
New protocol-related AEs (caused by any intervention required by the protocol) and updates on 
all AEs ongoing or with an unknown outcome must be recorded until the last subject visit 
required by the protocol. Additional details can be found in Section 9.3.1. 
 
6.3.8. 
Low-Luminance Questionnaire and Visual Function Questionnaire-39 
The 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 (see Appendix D). Subjects will be asked to complete this 
questionnaire within 14 days before Day 0, Day 0, Week 12, Week 24, and Week 28 and at the 
Early Termination visit (for subjects who withdraw early from the study). 
The VFQ-39 is designed to assess 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 (see Appendix E). Subjects will 
be asked to complete questionnaire at Day 0, Week 12, Week 24, and Week 28 and at the Early 
Termination visit (for subjects who withdraw early from the study). 
 
6.3.9. 
Other Study Assessments 
Subjects will undergo a number of examinations to establish the subject’s baseline disease and 
change in disease over time. 
Best-corrected ETDRS visual acuity testing has become the gold standard for test for BCVA. 
The test should be conducted under standardized lighting conditions. The BCVA testing using 
the ETDRS chart will be conducted within 14 days before Day 0 (repeated twice) and at every 
visit. Subjects will also undergo testing for LL visual acuity testing within 14 days before Day 0 
(repeated twice) and at every visit. IOP will be measured by Goldmann tonometry and recorded 
within 14 days before Day 0 and at every visit except Day 7. Refraction testing will be 
performed within 14 days of Day 0, Week 4, Week 16, and Week 24. It will also be complete at 
Early Termination (for subjects that withdraw early from the study). 
The anterior segment of the eye by slit lamp biomicroscopy and regions of the vitreous, retina, 
choroid, optic nerve, and blood vessels will be examined by dilated ophthalmoscopy which will 
occur within 14 days before Day 0 and at every visit. The subject will have eye drops placed to 
dilate the pupils. Fundus photography of the posterior segment will be obtained within 14 days 
before Day 0, at Week 12, at Week 24, and at Early Termination (for subjects that withdraw 
early from the study). SD-OCT of the macula will be obtained within 14 days before Day 0, Day 
0, and at Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28, and at Early 


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Termination (for subjects that withdraw early from the study). Fundus autofluorescence imaging 
of the retinal pigment epithelium and neurosensory retina will be performed within 14 days of 
Day 0 and at every visit with the exception of Day 7, and at Early Termination (for subjects who 
withdraw early from the study). 
Fluorescein angiography (FA) will be used to examine the circulation of the retina and choroid 
using fluorescein dye and a specialized camera to trace the dye. Subjects will receive an IV 
injection of fluorescein dye in order to highlight the blood vessels in the back of the eye. During 
the procedure, subjects should be observed for any adverse reactions to the dye. FA will be 
obtained within 14 days before Day 0. Fluorescein angiography completed for standard of care 
within 90 days prior to first dose can be used as the screening assessment. 
Mesopic microperimetry will be used to measure retinal sensitivity, and dark adaptometry will be 
used to measure the absolute thresholds of rod sensitivity for the evaluation of night blindness. 
Both mesopic microperimetry and dark adaptometry and will be performed within 14 days 
before Day 0 and at all visits except for Day 7. 
To assess the subject’s reading difficulty and reading performance, a reading speed test will be 
administered under standard lighting conditions and under low luminance conditions at Day 0, 
Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28, and at the Early 
Termination visit (for subjects who withdraw early from the study). 
 
7. 
STUDY POPULATION 
7.1. 
Number of Subjects Planned 
A total of approximately 40 evaluable subjects will receive study drug: approximately 20 
subjects who have 1 eye with intermediate AMD – high risk drusen without GA, and 
approximately 20 subjects with noncentral GA. Subjects will receive elamipretide 40 mg 
administered as a once daily 1.0 mL SC injection. 
 
7.2. 
Study Population 
Subjects who have the following retinal diseases confirmed clinically and by standard imaging 
studies will be enrolled in 1 of 2 disease cohorts: 
• 
Intermediate AMD - high-risk drusen without GA 
or 
• 
Intermediate AMD - noncentral GA 


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7.2.1. 
Inclusion Criteria 
For this study, only 1 eye of an eligible subject will be included and designated as the study eye. 
However, all specified ophthalmic testing will be performed on both eyes at each time point. A 
potential subject must meet the following criteria to be eligible for inclusion in the study: 
Intermediate AMD – noncentral GA disease cohort: 
1. Adults ≥ 55 years of age with 1 eye with intermediate AMD – noncentral GA. For this study, 
noncentral GA is defined as well-demarcated area(s) of GA with a cumulative area 
≥ 1.27 mm2 (approximately 0.5 DA) by FAF, which spares the fovea (defined as retinal 
pigment epithelium and outer retina intact) by SD-OCT. 
2. Geographic atrophy may be multifocal, but the cumulative GA lesion size must be 
(A) ≥ 1.27 mm2 (approximately ≥ 0.5 DA) and < 10.16 mm2 (approximately < 4 DA) and 
(B) must reside completely within the FAF imaging field (field 2 to 30 degree image centered 
on the fovea). 
3. Presence of measurable hyperautofluorescence adjacent to the discrete foci of GA. 
OR 
Intermediate AMD – high-risk drusen without GA disease cohort: 
4. ≥ 55 years of age with one eye with intermediate AMD – high-risk drusen without GA. 
5. High-risk drusen is defined as presence of either at least 1 large (≥ 125 μm) druse or multiple 
medium-size (between 63 and 124 μm) drusen. 
General (both disease cohorts): 
6. No evidence of choroidal neovascularization (active or prior history) in the macula of the 
study eye. 
7. Able to provide informed consent and willing to comply with all study visits and 
examinations. 
8. Women of childbearing potential who are not pregnant or nursing and have a negative 
serum pregnancy test at screening. 
9. Best-corrected visual acuity by ETDRS letters ≥ score of 55 (Snellen equivalent ≥ 20/70). 
10. Low-luminance visual acuity deficit (defined as difference between BCVA and LL visual 
acuity) > 5 letters. 
11. Has at least two Low-Luminance Questionnaire sub scale results, in which one of the 
abnormal subscales is either general dim light vision or dim light reading. 
12. The fellow eye may have intermediate AMD without noncentral GA (i.e., high-risk drusen), 
intermediate AMD with noncentral GA, CNV neovascular AMD, or central GA. Ongoing 
treatment with antiangiogenic therapies in the fellow eye is allowable. 


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13. No evidence of visually significant cataract OR pseudophakia without evidence of posterior 
capsular opacity. 
14. Sufficiently clear ocular media, adequate pupillary dilation, fixation to permit quality fundus 
imaging, and able to cooperate sufficiently for adequate ophthalmic visual function testing 
and anatomic assessment. 
15. Able to administer SC study drug solution as demonstrated at screening or able to have a 
care provider or appropriate designee who can administer the study drug (i.e., a capable 
family member or a caregiver). 
16. 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 3 months 
after dosing. 
a. For men: abstinence is only acceptable if it is in line with the preferred and usual 
lifestyle of the subject. The subject also agrees to use an acceptable method of 
contraception should they become sexually active. Subjects must use a condom 
with spermicide from the date of informed consent until at least 3 months after the 
last dose of study drug. Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, or postovulation methods) and withdrawal are not acceptable 
methods of contraception. 
b. For women: abstinence is only acceptable when it is in line with the preferred and 
usual lifestyle of the subject. The subject agrees to use an acceptable method of 
contraception should they become sexually active. Maintenance of a monogamous 
relationship with a male partner who has been surgically sterilized by vasectomy 
(the vasectomy procedure must have been conducted at least 60 days before the 
Screening visit or confirmed via sperm analysis), barrier method (e.g., condom or 
occlusive cap) with spermicidal foam/gel/film/cream AND either hormonal 
contraception (oral, implanted, or injectable) or an intrauterine device or system 
are acceptable methods. 
17. Ability and willingness to undertake all scheduled visits and assessments. 
When both eyes are eligible for the study, only 1 eye will be included. In that case, the eye with 
the greater LL visual acuity deficit will be chosen for inclusion. Data on the fellow eye will be 
collected to assess potential effects of study drug on the fellow eye. 
 
7.2.2. 
Exclusion Criteria 
A subject with study eye who meets any of the following criteria will be excluded from the 
study: 
Ocular conditions – study eye 
1. Age-related macular degeneration with any evidence of central GA (i.e., involving the 
fovea). 
2. Atrophic retinal disease because of causes other than AMD. 
3. Presence or diagnosis of exudative AMD or choroidal neovascularization in the study 
eye. 


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4. History of diabetic retinopathy (a history of diabetes mellitus without retinopathy is not a 
criterion for exclusion). 
5. Presence of vitreous hemorrhage. 
6. History of retinal detachment or macular hole (stage 3 or 4) in the study eye. 
7. Presence of macular pucker. 
8. History of uncontrolled glaucoma, defined as advanced cup-to-disc ratio > 0.7 and 
IOP > 25, with or without topical antihypertensive eye drops; treatment of ocular 
hypertension or controlled glaucoma are not criteria for exclusion. 
9. History of advanced guttae indicative of Fuchs endothelial dystrophy. 
10. Presence of visually significant cataract OR presence of significant posterior capsular 
opacity in the setting of pseudophakia. 
11. Presence of significant keratopathy that would cause scattering of light or alter visual 
function, especially in LL conditions. 
12. Ocular incisional surgery (including cataract surgery) in the study eye within 3 months 
(i.e. 90 days) before Day 0. 
13. Aphakia. 
14. History of vitrectomy surgery, submacular surgery, or any vitreoretinal surgery. 
15. Prior treatment with Visudyne ® (verteporfin), external-beam radiation therapy (for 
intraocular conditions), or transpupillary thermotherapy. 
16. History of prophylactic subthreshold laser treatment for retinal disease. 
17. Previous intravitreal drug delivery (e.g., intravitreal corticosteroid injection, 
anti-angiogenic drugs, or device implantation) in the study eye. 
Ocular conditions – either eye 
18. Active uveitis and/or vitritis (grade trace or above) in either eye. 
19. History of idiopathic or autoimmune-associated uveitis in either eye. 
20. Active, infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye. 
Systemic conditions 
21. Known to be immunocompromised or receiving systemic immunosuppression. 
22. 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. 
23. Estimated glomerular filtration rate < 30 mL/minute, by MDRD. 
General 
24. Participation in other investigational drug or device clinical trials during and/or within 
30 days before enrollment, or planning to participate in any other investigational drug or 
device clinical trials within 30 days of study completion. 
25. History of allergy to fluorescein that is not amenable to treatment. 
26. Inability to comply with study or follow-up procedures. 


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27. Inability to obtain color fundus photograph, FAF, and fluorescein angiography of 
sufficient quality to be analyzed and interpreted. 
28. History of allergic reaction to the investigational drug or any of its components. 
 
7.3. 
Discontinuation 
7.3.1. 
Discontinuation of Subjects 
Subjects may be discontinued for the following reasons: 
• 
Investigator decision 
o The Investigator decides that the subject should be discontinued from the study for 
any reason. 
• 
Subject decision 
o The subject requests to be withdrawn from the study. 
o Subjects who withdraw should be explicitly asked about the contribution of 
possible AEs to their decision to withdraw consent, and any AE information 
elicited should be documented. 
o Preferably the subject should withdraw consent in writing and, if the subject 
refuses or is physically unavailable, the site should document and sign the 
reason for the subject’s failure to withdraw consent in writing. 
o The subject is lost to follow-up after a reasonable number of attempts to contact the 
subject (including documented phone calls and/or emails, and a certified letter) have 
been completed. 
• 
Sponsor decision 
o The Sponsor or its designee stops the study or stops the subject’s participation in the 
study for medical, safety, regulatory, or other reasons consistent with applicable laws, 
regulations, and GCP guidelines. 
• 
Adverse event 
o If the Investigator decides that the subject should be withdrawn because of an AE or 
because of a clinically significant laboratory value, the investigational product is to be 
discontinued and appropriate measures are to be taken. The Sponsor or its designee is 
to be alerted immediately. 
Any subject withdrawing from the study will be asked to complete the Early Termination visit 
assessments (see Table 3). 


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7.3.2. 
Discontinuation of Study Sites 
Study site (research center) participation may be discontinued if the Sponsor or its designee, the 
Investigator, or the Institutional Review Board (IRB) of the study site judges it necessary for 
medical, safety, regulatory, or other reasons consistent with applicable laws, regulations, and 
GCP guidelines. 
 
7.3.3. 
Discontinuation of the Study 
The study 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. 
 
7.4. 
Replacement of Subjects 
In order to ensure that a sufficient number of subjects are available for assessment of primary 
and secondary endpoints, subjects that are not able to be compliant, i.e. less than 80% 
compliance, with administration of the IP will be replaced. Replacement of subjects will be 
assessed and confirmed on a case by case basis by the sponsor. 
 
7.5. 
Other Medications and Therapies 
7.5.1. 
Prohibited Medications 
The use of any other investigational drug except elamipretide is prohibited during the conduct of 
the current trial. 
Prohibited medications include: 
• 
Medications known to be toxic to the lens, retina, or optic nerve. Examples include 
deferoxamine, chloroquine, hydroxychloroquine (Plaquenil®), tamoxifen, phenothiazines, 
ethambutol, and aminoglycosides. 
• 
Any ophthalmic topical medications will be reviewed and deemed safe and approved by 
the investigator. Topical drops for treatment of elevated intraocular pressure are allowed, 
including for ongoing / intermittent application of artificial tears / lubricating ointments 
for the treatment of mild ocular surface disease / dry eye. 
• 
Systemic medications (prescription or non-prescription) for the treatment of ocular 
conditions may be used if deemed safe and appropriate by both the Investigator and 
Sponsor. 
 
7.5.2. 
Concomitant Medications 
All medications, including over-the-counter treatments, vitamins, or supplements, must have 
been unchanged and constant for at least 1 month before the Baseline (Day 0) visit. All 
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of current therapeutic agents during the conduct of the study will be discouraged, unless 
medically necessary or required to treat an AE. 
Subjects will be instructed to maintain their normal diet, daily caffeine, and fiber intake 
throughout the Study Treatment Period. 
No diagnostic drops used for study assessments will be collected as concomitant medications. 
 
8. 
STUDY DRUG 
8.1. 
Study Drug Administration 
Approximately 40 evaluable subjects will receive study drug administered as a single daily SC 
injection containing 40 mg elamipretide for 24 weeks. Study drug will be administered daily in 
the subject’s abdomen (rotating clockwise around the four abdominal quadrants) by a caregiver 
or the subject. 
Study drug injection will occur at the study site on Day 0. Subjects will be trained on the 
procedure for administration of study drug. The first dose may be given by a qualified member 
of the study team, by the subject, or caregiver at the PIs discretion, a designated, trained 
caregiver is also able to administer the study drug. The subject will be instructed to administer 
study drug on a daily basis at approximately the same time each day. The option of a visiting 
nurse to oversee the study drug administration will be discussed with the subject and provided, as 
needed. 
 
8.2. 
Materials and Supplies 
Study drug elamipretide will be dispensed, stored, and administered according to the Manual of 
Procedures. Subjects will be provided with syringes and any other supplies necessary for 
injection. 
 
8.2.1. 
Elamipretide 
Elamipretide drug product will be provided as a sterile solution for administration by SC 
injection. Each single-use vial is filled with 1 mL of drug product containing the equivalent of 
40 mg elamipretide (added as MTP-131 acetate) in an isotonic, unpreserved, clear, colorless 
solution. 
Elamipretide should be store in the refrigerator at a temperature of 2 to 8°C or 35.6 to 46.6°F. 
A Manual of Procedures will be provided to the study center sites detailing dispensing directions, 
training materials for subjects, and Subject Diary. IP accountability will be documented in the 
study EDC system. 


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8.3. 
Study Drug Logistics and Accountability 
All drug accountability records must be kept current, and the Investigator must be able to 
account for all used and unused vials of study drug. These records should contain the dates, 
quantity, and study drug: 
• 
Received at site 
• 
Dispensed to each subject, 
• 
Returned from each subject, and 
• 
Disposed of at the site or returned to the Sponsor or designee 
The clinical monitor responsible for the study site will provide written approval for the 
destruction or return of used and unused study drug vials following reconciliation of all clinical 
supplies. 
 
8.4. 
Study Drug Compliance 
During the Study Treatment Period, study drug will be administered by the subject or caregiver. 
Subjects will be instructed to return all used and unused vials of study drug to the clinic at each 
visit. 
 
8.5. 
Method of Assigning Study Drug 
At Day 0, after eligibility criteria have been confirmed, a treatment cohort will be assigned to 
each subject. This is an open label non-comparative study and not randomized. 
Subjects will be dispensed study drug at each study site visit. Each kit will be labeled with 
information including the following: 
• 
Protocol number 
• 
Sponsor name 
• 
Storage conditions 
• 
Directions for use 
• 
Investigational caution statement 
 
8.6. 
Rationale for Dose Selection 
The dose and route of administration (i.e., 40 mg in 1.0 mL by SC injection) for the current study 
has previously been tested in a clinical trial involving healthy subjects. The dose for the current 
study was chosen based on the systemic exposure profile, as well as the safety observed in 
previous clinical trials. 
The plasma elamipretide threshold concentration for clinically relevant adverse effects appears to 
be approximately 20,000 ng/mL in both rats and dogs, which is more than 10-fold higher than 


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the maximum anticipated human exposures for the selected dosage in this study. In healthy 
human adults, systemic exposure (in terms of mean AUC0-24 on Day 7) to elamipretide after 
repeat SC injection at 40 mg in 1 mL was 3810 ng.hour/mL, while mean Cmax on Day 7 was 
1320 ng/mL. No accumulation of elamipretide was seen after repeat dosing for 7 consecutive 
days. Neither metabolite of elamipretide (M1 and M2) is active or implicated in toxicology. 
In a completed Phase 1 trial (SPISC-101), elamipretide given subcutaneously to healthy subjects 
at doses up to 40 mg in 1 mL once daily for 7 consecutive days was well tolerated, with no 
systemic safety issues. Local injection site reactions were limited to transient, local erythema, 
and occasional pruritus or swelling, which resolved quickly without sequelae and without 
intervention. 
 
8.7. 
Continued Access to Investigational Medicinal Product 
Elamipretide will not be made available to subjects at the conclusion of their participation in the 
study. 
 
9. 
EFFICACY, SAFETY EVALUATIONS, SAMPLE COLLECTION 
AND TESTING, AND APPROPRIATENESS OF MEASURES 
9.1. 
Primary Safety Measures 
The primary safety and tolerability endpoints for the study are: 
• 
The incidence and severity of AEs 
• 
Changes from baseline in vital sign measurements 
• 
Changes from baseline in ECGs 
• 
Changes from baseline in clinical evaluations 
• 
Changes from baseline in clinical laboratory evaluations 
The safety profile of elamipretide will be assessed through the recording, reporting, and 
analyzing of AEs, clinical evaluations, and laboratory tests. 
 
9.2. 
Secondary Efficacy Measures 
Secondary efficacy measures include: 
Both Noncentral GA and High risk drusen without GA: 
• Compliance of administration of SC elamipretide 
• 
Number of home health visits for subject or caregiver to learn how to inject elamipretide 
• 
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• 
Change from baseline in LL visual acuity 
• 
Change from baseline in mesopic light sensitivity by microperimetry 
• 
Change in dark adaptometry 
• 
Change in drusen volume (“RPE – drusen complex”, as measured by automated 
segmentation) by SD-OCT 
• 
• 
Change in BCVA 
• 
Change in reading speed at standard light 
• 
Change in reading speed at low light 
• 
Change in LL visual function by the LLQ 
• 
Change in NEI VFQ-39 score 
• 
Change in fundus photography 
High Risk Drusen Without GA: 
• 
Change in drusen volume (“RPE – drusen complex”, as measured by automated 
segmentation) by SD-OCT 
 
9.3. 
Safety Evaluations 
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting 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 
study, in the event of adverse event (AE). 
The Investigator remains responsible for following, through an appropriate health care option, of 
AEs that are serious, considered related to the study drug or the study, or that caused the subject 
to discontinue before completing the study. The subject should be followed until the event is 
resolved or explained. 
Comprehensive assessment of any apparent toxicity experienced by study subjects will be 
performed throughout the course of the study, from the date of the subject’s signature of 
informed consent. Study site personnel will report any AE, whether observed by the Investigator 
or reported by the subject. The reporting period for AEs is described in Section 9.8.2. 


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9.3.1. 
Adverse Events 
An AE is defined as any untoward medical occurrence in the form of signs, symptoms, abnormal 
laboratory findings, or diseases that emerge or worsen relative to baseline during administration 
of an investigational medicinal product (IMP), regardless of causal relationship. 
Adverse Events may include the following: 
• 
Suspected adverse drug reactions: side effects known or suspected to be caused by the 
study drug. 
• 
Other medical experiences, regardless of their relationship with the study drug, such as 
injury, surgery, accidents, extensions of symptoms or apparently unrelated illnesses, and 
significant abnormalities in clinical laboratory values, psychological testing, or physical 
examination findings. 
• 
Events occurring as a result of protocol interventions (pre- or post-IMP administration) 
• 
Reactions from study drug overdose, abuse, withdrawal, sensitivity, or toxicity. The 
Sponsor has standards for reporting AEs that are to be followed regardless of applicable 
regulatory requirements that may be less stringent. 
 
9.4. 
Pre-study Drug Events 
Untoward events and/or incidental diagnoses that occur prior to study drug administration are by 
definition, unrelated to the study drug. Pre-study drug events or incidental diagnoses will be 
recorded on the past medical history eCRF. However, if a pre-study drug event is assessed by the 
Investigator as related to a study procedure and/or meets seriousness criteria, it will be recorded 
as an AE on the AE eCRF and followed as per protocol guidelines noted in Section 9.7 and 9.8. 
 
9.5. 
Baseline Medical Conditions 
Those medical conditions related to the disease under study whose changes during the study are 
consistent with natural disease progression, or which are attributable to a lack of clinical efficacy 
of the study drug, are NOT considered as AEs and should not be recorded as such in the eCRF. 
These are handled in the efficacy assessments and should be documented on the medical history 
page of the eCRF. 
Baseline medical conditions, not in the therapeutic area of interest/investigation, that worsen in 
severity or frequency during the study will be recorded and reported as AEs. 
 
9.6. 
Abnormal Laboratory and Other Abnormal Investigational Findings 
Abnormal laboratory findings and other objective measurements should NOT be routinely 
captured and reported as AEs. However, abnormal laboratory findings or other objective 
measurements should be reported on the AE pages of the eCRF that: 
• 
Meet the criteria for a SAE 


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• 
Result in discontinuation of the IMP 
• 
Require medical intervention or 
• 
Are judged by the Investigator to be clinically significant changes from baseline 
When reporting an abnormal laboratory finding on the AE pages of the eCRF, a clinical 
diagnosis should be recorded rather than the abnormal value itself (for example, “anemia” rather 
than “decreased red blood cell count” or “hemoglobin = 10.5 g/dL”.) 
 
9.7. 
Serious Adverse Events 
An SAE is any AE from this study that: 
• 
Results in death. In case of a death, the cause of death is used as the AE term, and the 
fatality is considered as the OUTCOME. 
• 
Is life threatening. The term “life threatening” refers to a SAE in which the subject is at 
risk of death at the time of the event; it does not refer to an event that hypothetically 
might cause death if it were more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital anomaly or birth defect 
• 
Is otherwise considered medically important. 
Important medical events may be considered as SAEs when, based upon medical judgment, they 
may jeopardize the subject or may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
Examples of such events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
For the purposes of reporting, any suspected transmission of an infectious agent via an IMP is 
also considered a SAE and all such cases should be reported in an expedited manner as described 
in Section 9.8.3.3. 
 
9.7.1. 
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 (not documented prior to ICF signing) or unplanned prolongation of an elective 
hospitalization (e.g., undesirable effects of any administered medication) must be documented 
and reported as SAEs. 


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9.8. 
Recording of Adverse Events 
Complete, accurate, and consistent data on all AEs experienced for the duration of the reporting 
period (defined in Section 9.8.2) will be recorded on an ongoing basis in the appropriate section 
of the eCRF. Among these AEs, all SAEs must be additionally documented and reported using 
the study specific SAE Report Form. 
It is important that each AE report include a description of the event along with the duration 
(onset and resolution dates), severity, relationship to study drug, potential causal factors, 
treatment given or other action taken (including dose modification or discontinuation of the 
IMP), and the outcome. 
As the quality and precision of acquired AE data are critical, Investigators should use the AE 
definitions provided and should observe the following guidelines when completing the AE pages 
of the eCRF: 
Whenever possible, recognized medical terms should be used to describe AEs rather than lay 
terms (for example, “influenza” rather than “flu”), and abbreviations should be avoided. 
Adverse events should be described using a specific clinical diagnosis, if available, rather than a 
list of signs or symptoms (for example, “congestive heart failure” rather than “dyspnea, rales, 
and cyanosis”). However, signs and symptoms that are not associated with an identified disease 
or syndrome, or for which an overall diagnosis is not yet available, should be reported as 
individual AEs. 
Provisional diagnoses (e.g., “suspected myocardial infarction”) are acceptable, but should be 
followed up with a definitive diagnosis if later available. Similarly, a fatal event with an 
unknown cause should be recorded as “death of unknown cause.” 
In cases of surgical or diagnostic procedures, the condition or illness leading to the procedure is 
considered the AE rather than the procedure itself. 
Adverse events occurring secondary to other events (e.g., sequelae or complications) should be 
identified by the primary cause. A primary AE, if clearly identifiable, generally represents the 
most accurate clinical term to record in the eCRF. 
 
9.8.1. 
Investigator Assessments 
 
9.8.1.1. 
Severity/Intensity 
Investigators must assess the severity/intensity of AEs according to the following qualitative 
toxicity scale: 
 
Mild: 
The subject is aware of the event or symptom, but the event or symptom is easily 
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Moderate: The subject experiences sufficient discomfort to interfere with or reduce his or 
her usual level of activity. 
Severe: 
Significant impairment of functioning: the subject is unable to carry out usual 
activities. 
 
9.8.1.2. 
Relationship to the Investigational Medicinal Product (IMP) 
Investigators must systematically assess the causal relationship of AEs to the study drug using 
the following definitions (the decisive factor being the temporal relationship between the AE and 
administration of the study drug): 
Probable: 
A causal relationship is clinically/biologically highly plausible, there is a 
plausible time sequence between onset of the AE and administration of the study 
drug, 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 study drug. 
Unlikely: 
A causal relationship is improbable and another documented cause of the AE is 
most plausible. 
Unrelated: A causal relationship can be excluded and another documented cause of the AE 
is most plausible. 
 
9.8.2. 
Adverse Event Reporting Period 
The AE reporting period begins when the subject signs the ICF and continues through the 
clinical study’s post study drug follow-up period, defined as 28 (± 7 days) days after last 
administration of study drug. 
Note that AEs that occur between the time subject signs the ICF and the time the subject is dosed 
with study drug will be summarized in the medical history eCRF and not as an AE unless the 
event meets the definition of a SAE. All AEs which occur following first administration of study 
drug 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 required by the protocol. A last batch 
of queries will be sent after last study visit if remaining ongoing/unknown outcomes of reported 
AEs are pending. After the last batch of queries has been resolved, the CRFs and database will 
no longer be updated and the data considered final. However, SAEs and ongoing/unknown 
outcome AEs will be followed-up until resolution or stabilization by the Sponsors 
Pharmacovigilance department. Beyond this defined reporting period, any new SAE considered 
causally related to study drug should be immediately reported to the sponsor using the SAE 
report form provided.  Additional SAE information obtained after database lock will reside 
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Within the study, all subjects who took at least 1 dose of IMP, whether they completed the study 
drug period or not, should enter the 28-day period as defined above. 
If a subject is documented as lost-to follow-up, ongoing/unknown outcome AEs 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. 
 
9.8.3. 
Serious Adverse Event Expedited Reporting 
In the event a SAE occurs during the reporting period, the Investigator must immediately (within 
a maximum of 24 hours after becoming aware of the event) inform the Sponsor as detailed in the 
Clinical Trial Pharmacovigilance Procedural Manual. 
For any SAE, the following minimum information is required as initial notification: 
• 
Investigator/Reporter with full contact information 
• 
Subject identification details (study number, site number, subject number) 
• 
Study drug administration details (dose and dates) 
• 
Event verbatim terms, a brief description of signs/symptoms/diagnosis and the date of 
onset 
• 
Seriousness criteria(ion) met 
• 
Relationship of the event to the study drug (e.g., the causality according to the 
Investigator) 
Reporting procedures and timelines are the same for any new follow-up information on a 
previously reported SAE. 
All SAE reports must be completed as described in the eCRF completion guidelines and 
submitted through the electronic data capture system of the clinical database. Other relevant 
information from the clinical database (including demographic data, medical history, 
concomitant drug and study drug dosing information) will automatically be sent via the 
electronic data capture system when the SAE form is submitted. 
The names, addresses, telephone and fax numbers for SAE back-up reporting (paper), are 
included in the Safety Reporting Plan. 
The Investigator/Reporter must 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 may have on the AE within the same timelines as described for initial reports. This is 
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the Sponsor to meet strict regulatory timelines associated with expedited safety reporting 
obligations. 
 
9.8.4. 
Pregnancy and Contraception 
Any pregnancies occurring during the study and within the three months after the last dose of 
study drug 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 3 months after the last dose of study drug: 
• 
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 least 3 months 
(i.e. 90 days) after last dose of study drug. Highly effective methods of contraception are defined 
as the usage by the female partner of any form of hormonal contraception or intra-uterine device 
(which should be established prior to the start of the study) plus usage by one of the partners of 
an additional spermicide-containing barrier method of contraception. Male subjects with 
pregnant partners must use a condom with spermicide from the start of study drug until at least 3 
months after the last dose of study drug. Sperm or egg donation by subjects is not permitted from 
the start of study drug until 3 months after the study drug was administered. 
Only pregnancies considered by the Investigator as related to study drug (e.g., resulting from an 
interaction between study drug 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 9.8.2, must be recorded in the AE section of the eCRF. 
For this study, 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 
Pregnancy Form and the back-up reporting procedure as described in the Clinical Trial 
Pharmacovigilance Procedural Manual. Investigators must actively follow up, document, and 
report on the outcome of all pregnancies. 


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The Investigator must notify the Sponsor of these outcomes using Section II of the Pregnancy 
Form and submit the information using the back-up reporting procedure. Any abnormal outcome 
must be reported in an expedited manner as described in Section 9.8.3.3, while normal outcomes 
must be reported within 45 days from delivery. 
In the case of an abnormal outcome, whereby the mother sustains an event, the SAE Report 
Form is required and will be submitted as described above. 
 
9.8.5. 
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 any applicable site-specific requirements related to the 
reporting of SAEs involving subjects to the IRB that approved the study. 
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 study, or alter the 
IRB’s approval/favorable opinion to continue the study. In particular, and in line with respective 
regulations, the Sponsor will inform the Investigator of AEs that are both serious and unexpected 
and are considered to be related to the administered product (suspected unexpected serious 
adverse reaction [SUSARs]). The Investigator should place copies of the safety reports in the 
Investigator site file. 
When specifically required by regulations and guidelines, the Sponsor will provide appropriate 
safety reports to the CRO for distribution to the site and will maintain records of these 
notifications. The Investigator will be responsible for promptly notifying the concerned 
independent IRB of any safety reports provided by the Sponsor and or filing copies of all related 
correspondence in the site file. 
 
9.9. 
Appropriateness of Measurements 
The measures used to assess safety in this study are consistent with those widely used and 
generally recognized as reliable, accurate, and relevant. 


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10. 
DATA QUALITY ASSURANCE 
To ensure accurate, complete, and reliable data, the Sponsor or its representatives will do the 
following: 
• 
Provide instructional material to the study sites, as appropriate. 
• 
Sponsor start-up training to instruct the Investigators and study coordinators. This 
training will give instruction on the protocol, the completion of the eCRFs, and study 
procedures. 
• 
Make periodic visits to the study site. 
• 
Be available for consultation and stay in contact with the study site personnel by mail, 
email, 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 a sample of the subject data 
recorded against source documents at the study site. The study may be audited by the Sponsor or 
its representatives, and/or regulatory agencies at any time. Investigators will be given notice 
before an audit occurs. 
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the Investigator will keep records of laboratory tests, clinical notes, and subject medical 
records in the subject files as original source documents for the study. If requested, the 
Investigator will provide the Sponsor, applicable regulatory agencies, and applicable IRBs with 
direct access to original source documents. 
 
10.1. 
Data Capture System 
An electronic data capture system will be used in this study. The site will maintain a separate 
source for the data entered by the site into the Sponsor-provided electronic data capture system. 
Electronic case report form data will be encoded and stored in a clinical study database. Data 
managed by a central vendor, such as laboratory test data or ECG data, 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 site in that site’s study 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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11. 
SAMPLE SIZE AND STATISTICAL METHODS 
11.1. 
Determination of Sample Size 
For this Phase 1, open label study, a sample size of 40 evaluable subjects is considered sufficient. 
The sample size of the study is based on precedent set by prior Phase 1 studies of similar nature 
and design. It is considered sufficient to provide for preliminary assessment of safety and 
tolerability. 
 
11.2. 
Statistical and Analytical Plans 
11.2.1. 
General Considerations 
In general, categorical variables will be summarized by the count (N) and percentage of subjects 
(%). Continuous variables will be summarized by the number of non-missing observations (N), 
mean, standard deviation, median, minimum, and maximum values. 
All study data are to be displayed in the data listings. 
Statistical analysis of this study will be the responsibility of the Sponsor or its designee. Subject 
disposition summaries will include the number of subjects entered and the numbers treated 
(included in the Safety population) by disease cohort for all subjects. The number and percentage 
of subjects who complete or discontinue from the study will be summarized by reason for 
discontinuation for each disease cohort. 
Subject’s age, sex, weight, history of smoking, eye color, and other demographic characteristics 
will be recorded and summarized by disease cohort. Medical history will be listed. 
 
11.2.2. 
Subject Disposition 
All subjects who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported. If known, a reason for their discontinuation will be 
given. 
 
11.2.3. 
Subject Characteristics 
Baseline characteristics will include standard demography (e.g., ethnicity, race, eye color, and 
history of smoking), disease characteristics including medical history, and medication history for 
each subject. 
 
11.2.4. 
Concomitant Therapy 
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, and ethambutol) are prohibited from the Screening visit until completion of the 
study (completion of the Follow-Up visit). 


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All other medications, including any over-the-counter treatments, vitamins, or supplements, must 
have been unchanged and constant for at least one month prior to the Baseline visit and must 
remain stable through the completion of the study (completion of the Follow-up visit). 
 
11.2.5. 
Study Drug Compliance 
All drug compliance records must be kept current and must be made available for inspection by 
the sponsor and regulatory agency inspectors. 
 
11.2.6. 
Endpoints and Methodology 
 
11.2.6.1. 
General Considerations 
Data will be summarized using descriptive statistics (number of subjects, mean, median, standard 
deviation, minima, and maxima) for continuous variables and using frequencies and percentages 
for discrete variables. Data will be presented by disease cohort. 
 
11.2.6.2. 
Analysis Populations 
All subjects who receive at least 1 dose of study drug 40 mg (40 mg/1 mL of sterile solution for 
subcutaneous injection) will be included in the safety population. 
Efficacy data will be summarized by disease group. 
All presentations and analysis will be provided for the safety population. 
The details of all analyses will be described in the statistical analysis plan. 
11.2.7. 
Efficacy Analyses 
For primary and secondary efficacy endpoints, the change from baseline in all continuous 
endpoints will be summarized using descriptive statistics (mean, median, standard deviation, 
minimum, maximum) by disease cohort. Categorical variables will be described using 
frequencies and percentages. 
 
11.2.8. 
Interim Analysis 
This is an open-label study, and thus monitoring of data outcomes over the course of the study 
may be performed. In addition, an interim analysis may be performed when 20 subjects have 
completed through 24 weeks of treatment. All data from all subjects up to these interim analyses 
may be included in the assessments. 
These interim analysis will be performed by the Sponsor or their designee. Assessments of both 
safety and efficacy endpoints will be performed utilizing similar methods as are planned for the 
final analyses. 


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11.2.9. 
Safety Analyses 
AEs will be summarized by system organ class (SOC) and preferred term (PT), presenting the 
number and percentage of subjects having AEs and dose level. Severity and relationship to study 
drug will be listed as appropriate. 
 
11.2.9.1. Adverse Events 
The number and percentage of subjects experiencing 1 or more AEs will be summarized by 
disease group, relationship to study drug, and severity. Adverse events will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA) terminology. Adverse events will be 
summarized by SOC, PT, and disease cohort. 
All reported AEs will be listed, but only TEAEs will be summarized. 
The incidence of all TEAEs, drug relationship with TEAEs, and severity of TEAEs will be 
summarized. In the summary tables, subjects may be counted under multiple SOCs and PTs, but 
for each SOC and PT, subjects are only counted once. If a subject has the same AE on multiple 
occasions, the highest severity (severe > moderate > mild) or drug relationship 
(probable > possibly related > unlikely related > unrelated) recorded for the event will be 
presented. If severity is missing, subjects will be included as missing (for severity). If drug 
relationship is missing, subjects will be included in related tables (e.g., considered related). 
 
11.2.9.2. Deaths and Other Serious Adverse Events 
Listings will be provided for the following: 
• 
Deaths 
• 
SAEs 
• 
SUSARs 
• 
AEs leading to discontinuation of study drug 
 
11.2.9.3. Clinical Laboratory Evaluations 
Summary tables for laboratory parameters (including hematology, chemistry, and urinalysis) will 
include descriptive statistics of change relative to baseline where appropriate, and data listings of 
clinically significant abnormalities. 
Subjects with laboratory data outside the normal range will be listed with abnormal values 
flagged. 
Shift tables (e.g., tables that show the number of subjects who are low, normal, or high at 
baseline versus each post-baseline scheduled assessment) will be produced. 
The number and percentage of subjects with urinalysis results outside the normal range will be 
presented by endpoint and visit for each cohort. Shift tables for urinalysis will show the number 
of subjects who are normal/abnormal at baseline and normal/abnormal at the end of study. 


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11.2.9.4. Vital Signs 
Vital signs data will be summarized by changes from baseline values for each disease cohort 
using descriptive statistics. 
Shift tables for heart rate and blood pressure (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. 
 
11.2.9.5. Other Safety Parameters 
Any other safety data captured on the eCRF will be listed. 
 
12. 
INFORMED CONSENT, INSTITUTIONAL REVIEW BOARD, 
AND REGULATORY CONSIDERATIONS 
12.1. 
Informed Consent 
The Investigator is responsible for ensuring that the subject understands the potential risks and 
benefits of participating in the study, including answering any questions the subject may have 
throughout the study 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 study. 
The ICF will be used to explain the potential risks and benefits of study participation to the 
subject in simple terms before the subject is entered into the study, and to document that the 
subject is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study. The ICF will also request approval for ISR 
photographs to be taken and provided to the sponsor for surveillance use. 
The Investigator is responsible for ensuring that informed consent is given by each subject. This 
includes obtaining the appropriate signatures and dates on the ICF before the performance of any 
protocol procedures and before 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. 
 
12.2. 
Institutional Review Board 
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 approval of the protocol and the ICF must be provided to the Sponsor 
before the study may begin at the investigative site. The IRB will review the protocol as 
required. 
The study site’s IRB should be provided with the following: 
• 
The current Investigator’s Brochure and updates during the course of the study 


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• 
ICF 
• 
Relevant curricula vitae 
 
12.3. 
Regulatory Considerations 
This study 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 laws and regulations 
The Investigator or designee will promptly submit the protocol to applicable IRB(s). Some of the 
obligations of the Sponsor may be assigned to a third party organization. 
An identification code assigned to each subject will be used in lieu of the subject’s name to 
protect the subject’s identity when reporting AEs and/or other study-related data. 
 
12.3.1. 
Protocol Approval 
The Sponsor’s medical officer will approve the protocol, confirming that, to the best of their 
knowledge, the protocol accurately describes the planned design and conduct of the study. 
 
12.3.2. 
Final Report Approval 
The Sponsor’s medical officer will approve the final clinical study report for this study, 
confirming that, to the best of his or her knowledge, the report accurately describes the conduct 
and results of the study. 
 
12.3.3. 
Study Monitoring 
The Investigators and institution(s) will permit study-related monitoring of the CRF data by 
Stealth BioTherapeutics, Inc., or their assignee by providing direct access to source data and/or 
documents. The study monitor will verify the eCRFs against the source documentation. This 
study will utilize risk based monitoring. What and how much data is being verified against the 
source is documented in the Monitoring and Communications Plan.  Deviations from the 
protocol with regard to subject enrollment or study conduct will also be noted in the source 
documentation, and in the eCRF database. A Sponsor representative will visit the site to initiate 
the study, prior to the first administration of study drug for the first subject, and at agreed times 
throughout the study, including at the end of the study. Drug dispensing and clinical drug supply 
records will be 100% verified at the study site by the study monitor. It is understood that all 
subject specific information is confidential and no documentation that can link study information 
to the specific subject will be collected or retained by the Sponsor. 


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12.3.4. 
Retention of Records 
All study related material including source documents, eCRFs, Central Authority, and IRB 
correspondence and analyses and any other documentation required by applicable laws and 
regulations will be maintained for 15 years after completion of the study or notification from the 
Sponsor that the data can be destroyed, whichever comes first. 
 
12.3.5. 
Disclosure of Information 
Information concerning the investigational medication and patent application processes, 
scientific data or other pertinent information is confidential and remains the property of Stealth 
BioTherapeutics, Inc. The Investigator may use this information for the purposes of the study 
only. It is understood by the Investigator that Stealth BioTherapeutics, Inc., will use information 
developed in this clinical study in connection with the development of the investigational 
medication and therefore may disclose it as required to other clinical Investigators and to 
regulatory agencies. In order to allow the use of the information derived from this clinical study, 
the Investigator understands that he/she has an obligation to provide complete test results and all 
data developed during this study to the Sponsor. 
The Investigator may not submit for publication or presentation the results of this study without 
first receiving written authorization from Stealth BioTherapeutics, Inc. Stealth BioTherapeutics, 
Inc., agrees that before it publishes any results of the study, it shall provide the Investigator with 
at least 30 days for review of the pre-publication manuscript prior to the submission of the 
manuscript to the publisher. 


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13. 
AUDITS AND INSPECTIONS 
This study may be subject to a quality assurance audit or inspection by the Sponsor, their 
designee, and the regulatory authorities. Should this occur, the Investigator will be responsible 
for: 
• 
Informing the Sponsor of a planned inspection by the authorities as soon as notification is 
received 
• 
Providing access to all necessary facilities, study data, and documents for the inspection 
or audit 
• 
Communicating any information arising from inspection by the regulatory authorities to 
the Sponsor immediately 
• 
Taking all appropriate measures requested by the regulatory authorities to resolve any 
problems found during the audit or inspection 
Documents subject to audit or inspection include, but are not limited to all source documents, 
eCRFs, medical records, correspondence, ICFs, IRB files, documentation of certification and 
quality control of supporting laboratories, and records relevant to the study maintained in any 
supporting pharmacy facilities. Conditions of study material storage are also subject to 
inspection. In all instances, the confidentiality of the data will be respected. 


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mitochondrial bioenergetics. Br J Pharmacol.171(8):2029-50. Epub 2013/10/15. doi: 
10.1111/bph.12461. PubMed PMID: 24117165. 
38. Chakrabarti AK, Feeney K, Abueg C, Brown DA, et al. Rationale and design of the 
EMBRACE STEMI study: a phase 2a, randomized, double-blind, placebo-controlled trial to 
evaluate the safety, tolerability and efficacy of intravenous Bendavia on reperfusion injury in 
patients treated with standard therapy including primary percutaneous coronary intervention 
and stenting for ST-segment elevation myocardial infarction. Am Heart J.165(4):509-14 e7. 
Epub 2013/03/30. doi: S0002-8703(12)00848-4 [pii] 10.1016/j.ahj.2012.12.008. PubMed 
PMID: 23537966. 
39. Szeto HH, Birk AV. Serendipity and the discovery of novel compounds that restore 
mitochondrial plasticity. Clin Pharm Ther. 2014;96(6):672-83. Epub 2014/09/05. doi: 
10.1038/clpt.2014.174. PubMed PMID: 25188726; PMCID: 4267688. 
40. Szeto HH, Liu S, Soong Y, Birk AV. Improving mitochondrial bioenergetics under ischemic 
conditions increases warm ischemia tolerance in the kidney. Am J Phys Renal Phys. 
2015;308(1):F11-21. Epub 2014/10/24. doi: 10.1152/ajprenal.00366.2014. PubMed PMID: 
25339695. 
41. Birk AV, Liu S, Soon Y, et al. The mitochondrial-targeted compound SS-31 re-energized 
ischemic mitochondria by interacting with cardiolipin. J AM Soc Nephrol. 2013; 24(8); 
1250-61. doi:10.1681/ASN 2012121216. PubMed PMID:23813215. 
42. Liu S, Soong Y, Seshan SV, Szeto HH. Novel cardiolipin therapeutic protects endothelial 
mitochondria during renal ischemia and mitigates microvascular rarefaction, inflammation, 
and fibrosis. Am J Phys Renal Phys. 2014;306(9):F970-80. Epub 2014/02/21. doi: 
10.1152/ajprenal.00697.2013. PubMed PMID: 24553434. 
43. Brown DA, Hale SL, Baines CP, et al. Reduction of early reperfusion injury with the 
mitochondria-targeting peptide bendavia. J Cardiovas Pharm Ther. 2014;19(1):121-32. Epub 
2013/11/30. doi: 10.1177/1074248413508003. PubMed PMID: 24288396; PMCID: 
4103197. 
44. Sloan RC, Moukdar F, Frasier CR, Patel HD, et al. Mitochondrial permeability transition in 
the diabetic heart: contributions of thiol redox state and mitochondrial calcium to augmented 
reperfusion injury. J Mol Cell Card. 2012;52(5):1009-18. Epub 2012/03/13. doi: 
10.1016/j.yjmcc.2012.02.009. PubMed PMID: 22406429. 


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45. Ding JD, Johnson LV, Herrmann R, Farsiu S, et al. Anti-amyloid therapy protects against 
retinal pigmented epithelium damage and vision loss in a model of age-related macular 
degeneration. Proceedings of the National Academy of Sciences of the United States of 
America. 2011;108(28):E279-87. Epub 2011/06/22. doi: 10.1073/pnas.1100901108. PubMed 
PMID: 21690377; PMCID: 3136266. 


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15. 
APPENDICES 


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Appendix A. SPONSOR’S PROTOCOL SIGNATURE PAGE 
SPONSOR’S PROTOCOL SIGNATURE PAGE 
An Open-Label, Phase 1 Clinical Study to Evaluate the Safety and Tolerability of Subcutaneous 
Elamipretide in Subjects with Intermediate Age-Related Macular Degeneration 
 
 
 
Study No.: 
SPIAM-101 
Sponsor: 
Stealth BioTherapeutics, Inc. 
275 Grove Street, Suite 3-107 
Newton, MA 02466 
Protocol Date/Version: 
20 June 2017 / v 7.0 FINAL 
 
 
Printed name: 
_W_.  D_o_u_g l_a_s  We_a_v_e_r ,  M_D  
 
Signature: 
Date: 
_0_6_/_2_1 /_2_0_1_7  
 


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Appendix B. 
INVESTIGATOR’S PROTOCOL SIGNATURE PAGE 
INVESTIGATOR’S PROTOCOL SIGNATURE PAGE 
An Open-Label, Phase 1 Clinical Study to Evaluate the Safety and Tolerability of Subcutaneous 
Elamipretide in Subjects with Intermediate Age-Related Macular Degeneration 
 
Study No.: 
SPIAM-101 
Sponsor: 
Stealth BioTherapeutics, Inc. 
275 Grove Street, Suite 3-107 
Newton, MA 02466 
Protocol Date/Version: 
20 June 2017 / v 7.0 FINAL 
 
 
I have read all pages of this clinical study protocol for which Stealth BioTherapeutics, Inc. is the 
sponsor. I agree to conduct the study as outlined in the protocol and to comply with all the terms 
and conditions set out therein. I confirm that I will conduct the study in accordance with ICH 
GCP guidelines. I will also ensure that sub-Investigator(s) and other relevant members of my 
staff have access to copies of this protocol, and the ICH GCP guidelines to enable them to work 
in accordance with the provisions of these documents. 
 
Investigator: 
 
Printed name: 
Signature: 
Date: 
Site address: 
 


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Appendix C. CLINICAL LABORATORY TESTS 
Clinical Laboratory Tests 
Hematology: 
Clinical Chemistry: 
Hemoglobin 
Serum Concentrations of: 
Hematocrit 
Sodium 
Erythrocyte count (RBC) 
Potassium 
Leukocytes (WBC) 
Total bilirubin 
Neutrophils, segmented 
Alkaline phosphatase 
Lymphocytes 
Alanine aminotransferase 
Monocytes 
Aspartate aminotransferase 
Eosinophils 
Blood urea nitrogen 
Basophils 
Creatinine 
Platelets 
Creatinine kinase 
Urinalysis: 
Calcium 
Specific gravity 
Glucose (non-fasting) 
pH 
Albumin 
Protein 
Chloride 
Glucose 
Bicarbonate 
Ketones 
Total protein 
Blood 
Estimated glomerular filtration rate calculated with the Modification Diet in 
Renal Disease equation 
Pregnancy Test 
(Women of childbearing 
potential only) 
IgE 
IL5 


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Appendix D. LOW-LUMINANCE QUESTIONNAIRE 
Low Luminance Questionnaire 
INSTRUCTIONS 
Below you will find some statements about problems that involve your vision under different 
lighting conditions. After each question, you will find a list of possible answers. Please choose 
the response that best describes your situation at the present time using your 
eye. 
Please answer all the questions as if you were wearing your glasses or contact lenses (if any) 
with clear lenses (without yellow or other tints), except for the last two questions. Please take as 
much time as you need to answer each question. All your answers are confidential. In order for 
this survey to improve our knowledge about vision problems under different lighting conditions 
and how they affect your quality of life, your answers must be as accurate as possible. 
Remember, if you wear glasses or contact lenses for a particular activity, please answer the 
following questions as though you were wearing them. “Does not apply to me” means that you 
do not perform this activity or you do not encounter this situation. 
1. Do you have difficulty seeing in bright sunlight? (i.e. normal light without glare) 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X – Does not apply to me 
 
2. Do you have difficulty seeing in fluorescent lighting, like that found in stores and 
offices? 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X – Does not apply to me 


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3. Do you have difficulty seeing at dusk or at dawn? (i.e. sunrise/sunset) 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X – Does not apply to me 
 
4. Do you have difficulty seeing at night? 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X – Does not apply to me 
 
5. Do you have difficulty seeing in candlelight? 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X – Does not apply to me 
 
6. Do you have difficulty reading books or newspapers in bright light? (i.e. normal 
light without glare) 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty / stopped reading due to my vision 
X – Does not apply to me / stopped reading for other reasons 


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7. Do you have difficulty reading books or newspapers in dim light? 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty / stopped reading due to my vision 
X – Does not apply to me / stopped reading for other reasons 
 
8. In dimly lit restaurants, do you have difficulty reading menus? 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty / stopped going to restaurants due to my vision 
X – Does not apply to me / stopped for other reasons 
 
9. Do you have difficulty reading words printed on dark colored paper? 
 
1- No difficulty at all 
2-   A little difficulty 
3-   Some difficulty 
4-   A lot of difficulty 
X- Does not apply to me 
 
10. Do you have difficulty seeing to walk around in a darkened theater or 
darkened room? 
 
1- No difficulty at all 
2-   A little difficulty 
3-   Some difficulty 
4-   A lot of difficulty 
X- Does not apply to me 


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11. In dimly lit places or at night, do you have difficulty seeing people’s faces? 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
 
 
4 – A lot of difficulty 
X – Does not apply to me 
 
12. Because of your vision, do you have difficulty going out for night time social 
events such as friend’s homes, church, the theater or restaurants? 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty / stopped because of my vision 
X – Does not apply to me / do not socialize for other reasons 
 
13. In dimly lit places or at night, do you have difficulty seeing colors? 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X – Does not apply to me 
 
14. In dimly lit places or at night, do you have difficulty with depth perception? 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X – Does not apply to me 
 
15. In dimly lit rooms with dark floors, do you have difficulty seeing furniture? 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X – Does not apply to me 


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16. In walking around in dimly lit places or at night, have you bumped into 
furniture, stumbled, tripped or fallen because of your vision (for example, 
going to the bathroom during the night)? 
 
1- None of the time 
2- A little of the time 
3- Some of the time 
4- Most or all of the time 
X- Does not apply to me / have fallen for other reasons 
 
17. In dimly lit places or at night, do you depend on others to help you because 
of your vision? 
 
1- None of the time 
2- A little of the time 
3- Some of the time 
4- Most or all of the time 
X- Does not apply to me 
 
18. When you visit other people’s homes, do you have difficulty seeing because 
there is not enough light? 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty / I do not visit other people due to my vision 
X – Does not apply to me / I do not visit people for other reasons 
 
19. Do you have difficulty seeing under kitchen counters, in cabinets or in closets 
because there is not enough light? 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X – Does not apply to me 


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20. Do you have difficulty with your peripheral vision in bright sunlight? (i.e. 
normal light without glare) 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X – Does not apply to me 
 
21. Do you have difficulty with your peripheral vision under dim lighting 
conditions? 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X – Does not apply to me 
 
22. Do you have difficulty with your peripheral vision at night? 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X – Does not apply to me 
 
23. Do you limit your driving in the daytime due to your vision? 
1- No difficulty at all 
2-   A little difficulty 
3-   Some difficulty 
4- A lot of difficulty / stopped driving due to my vision 
X- Does not apply to me / stopped for other reasons 
 
24. Do you limit your driving at night due to your vision? 
1- No difficulty at all 
2 - A little difficulty 
3 - Some difficulty 
4 - A lot of difficulty / stopped driving at night most or all the time 


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X -Does not apply to me / stopped for other reasons 
25. While in a car at night, do you have difficulty seeing? 
 
1 - No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X - Does not apply to me 
 
26  . While in a car at night, do you have difficulty seeing dark colored cars? 
 
1- No difficulty at all 
2-   A little difficulty 
3-   Some difficulty 
4-   A lot of difficulty 
X- Does not apply to me 
 
27. While in a car at night, do you have difficulty reading street signs? 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X – Does not apply to me 
 
28. While in a car at night, do headlights from oncoming cars cause glare? 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X – Does not apply to me 
 
29. While in a car at night, do you have difficulty recovering normal vision after being 
glared out by oncoming headlights? 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 


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X – Does not apply to me 
 
30. While in a car at night in heavy rain, do you have difficulty seeing? 
 
1 - No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X - Does not apply to me 
 
31. While in a car at dawn or dusk, does glare from the sun create difficulty 
seeing? 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X – Does not apply to me 
 
32. While in a car driving through fog, do you have difficulty seeing? 
 
1 - No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X - Does not apply to me 
 
 
33. When entering a dimly lit room from the bright outdoors (or when entering a 
dark tunnel or driving on a road into shadows), does your eyesight take longer 
than normal getting adjusted to the change from bright into dim light? 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X – Does not apply to me 


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34. When leaving a dimly lit building into the bright outdoors (or leaving a dark 
tunnel or shadows into bright sunlight), does your eyesight take longer than 
normal getting adjusted to the change from dim into bright light? 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X – Does not apply to me 
 
35. 
While wearing dark sunglasses, do you have difficulty reading? 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X – Does not apply to me / I do not wear dark sunglasses 
 
36. 
While wearing dark sunglasses, do you have difficulty recognizing other people’s 
faces? 
 
1 – No difficulty at all 
2 – A little difficulty 
3 – Some difficulty 
4 – A lot of difficulty 
X – Does not apply to me / I do not wear dark sunglasses 
 
 
Table 1. Subscale Items 
 
 
Subscale 
Item Numbers 
Control questions 
1, 6, 20, 23, 30, 32 
General dim light vision 
2, 3, 4, 5, 13, 14, 15, 36 
Dim light reading 
7, 8, 9, 35 
Driving or riding in car 
24, 25, 26, 27 
Other ADLs 
11, 12, 18, 19 
Mobility 
10, 16, 17 


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Light transitions and glare 
28, 29, 31, 33, 34 
Peripheral vision 
21, 22 


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Appendix E. 
VISUAL FUNCTIONING QUESTIONNAIRE-39 


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MGRLYNIE4JLBJ3STAIULSL 
 
 
 
W. Douglas Weaver 
Party ID: J8RFJGJCHK9C3E76KVUZJA 
IP Address: 50.203.117.38 
doug.weaver@stealthbt.com 
 
 
 
 
Multi-Factor 
Digital Fingerprint Checksum 
 
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Timestamp 
Audit 
2017-06-21 06:58:29 -0700 
All parties have signed document. Signed copies sent to: Kit Oldham-Creamer, 
W. Douglas Weaver, and Virginia Viau. 
2017-06-21 06:58:29 -0700 
Document signed by W. Douglas Weaver (doug.weaver@stealthbt.com) with drawn 
signature. - 50.203.117.38 
2017-06-21 06:56:08 -0700 
Document viewed by W. Douglas Weaver (doug.weaver@stealthbt.com). - 
50.203.117.38 
2017-06-21 06:54:26 -0700 
Document created by Virginia Viau (virginia.viau@stealthpeptides.com). - 
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