A Phase 3 Randomized, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Daily Subcutaneous Injections of Elamipretide in Subjects With Primary Mitochondrial Myopathy Followed by an Open-Label Treatment Extension
Phase: PHASE3
Conditions: Primary Mitochondrial Myopathy
Sponsor: Stealth BioTherapeutics Inc.

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Title: A Phase 3 Randomized, Double-Blind, Parallel-Group, Placebo-Controlled 
Trial to Evaluate the Efficacy and Safety of Daily Subcutaneous Injections of 
Elamipretide in Subjects with Primary Mitochondrial Myopathy Followed by an 
Open-Label Treatment Extension 
 
NCT: NCT03323749 
 
Final Approval Date: 15 June 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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CLINICAL TRIAL PROTOCOL 
A Phase 3 Randomized, Double-Blind, Parallel-Group, Placebo- 
Controlled Trial to Evaluate the Efficacy and Safety of Daily 
Subcutaneous Injections of Elamipretide in Subjects with 
Primary Mitochondrial Myopathy Followed by an Open-Label 
Treatment Extension 
 
Trial Phase: 
Phase 3 
Trial Number: 
SPIMM-301 
Document Version: 
Version 4.0 
Final Approval Date: 
15 June 2018 
IND Number: 
123,553 
EudraCT Number: 
2017-002447-15 
Sponsor: 
Stealth BioTherapeutics Inc. 
275 Grove Street, Suite 3-107 
Newton, MA 02466 
United States of America (USA) 
 
Sponsor Chief Clinical 
Development Officer: 
Jim Carr, Pharm.D. 
Chief Clinical Development Officer 
275 Grove Street 3-107, Newton, MA 02466, USA 
Jim.Carr@StealthBT.com 
+1 617-762-2503 
 
Sponsor Medical Monitor: 
Sandrin Bergheanu, M.D., Ph.D 
Medical Monitor 
275 Grove Street 3-107, Newton, MA 02466, USA 
Sandrin.Bergheanu@StealthBT.com 
+1 617-762-2595 
+31 (0) 641 476 460 
 
 
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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PROTOCOL APPROVAL 
 
 
Protocol Title: 
A Phase 3 Randomized, Double-Blind, Parallel-Group, 
Placebo-Controlled Trial to Evaluate the Efficacy and 
Safety of Daily Subcutaneous Injections of Elamipretide 
in Subjects with Primary Mitochondrial Myopathy 
Followed by an Open-Label Treatment Extension 
 
Protocol Number: 
SPIMM-301 
 
Protocol Date: 
15 June 2018, Version 4.0 
 
 
 
 
 
 
Jim Carr, Pharm.D. 
Chief Clinical Development Officer 
Stealth BioTherapeutics Inc. 
06/15/2018 
 
 
Date 

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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for elamipretide (MTP-131). I have read the 
SPIMM-301 protocol and agree to conduct the trial as outlined. I confirm that I will conduct the 
trial 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. I agree to maintain 
the confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
Signature of Investigator 
 
 
 
Date (DD/MMM/YYYY) 

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1. 
SYNOPSIS 
 
Name of Sponsor/Company: Stealth BioTherapeutics Inc. 
Name of Investigational Combination Product: Elamipretide delivery system 
Name of Active Ingredient: Elamipretide (MTP-131) 
Title of Trial: A Phase 3 Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Trial to 
Evaluate the Efficacy and Safety of Daily Subcutaneous Injections of Elamipretide in Subjects with 
Primary Mitochondrial Myopathy Followed by an Open-Label Treatment Extension 
Trial site(s): Multicenter (North America and Europe); approximately 27 sites 
Phase of development: 3 
Objectives: This trial is designed with 2 parts, SPIMM-301 (PART 1) and SPIMM-301 OLE (PART 
2). The objectives of each part are consistent with the trial design. 
• 
PART 1 is a 24-week, randomized, double-blind, parallel-group, placebo-controlled 
assessment of the efficacy and safety of single daily subcutaneous (SC) doses of 40 mg 
elamipretide (vs placebo) administered with the elamipretide delivery system as a 
treatment for subjects with primary mitochondrial myopathy (PMM). 
• 
PART 2 is an up to 144-week, open-label assessment of the long-term safety and 
tolerability of single daily SC doses of 40 mg elamipretide administered with the 
elamipretide delivery system in subjects with PMM. 
PART 1 objectives are: 
Primary 
• 
To evaluate the effect of single daily SC doses of 40 mg elamipretide administered with 
the elamipretide delivery system for 24 weeks on the: 
– 
Distance Walked on the 6-Minute Walk Test (6MWT) 
– 
Total Fatigue on the Primary Mitochondrial Myopathy Symptom Assessment© 
(PMMSA) 
Secondary 
• 
To evaluate the effect of single daily SC doses of 40 mg elamipretide administered with 
the elamipretide delivery system for 24 weeks as measured by changes in the: 
– 
Fatigue During Activities on the PMMSA 
– 
Neuro-QoL Short Form Fatigue 
– 
Most bothersome symptom on the PMMSA 
– 
Neuro-QoL Fatigue activities of daily living (specific items from the Neuro-QoL 
Item Bank). 
• 
To evaluate the safety and tolerability of single daily SC doses of 40 mg elamipretide 
administered with the elamipretide delivery system for 24 weeks 

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Exploratory 
• 
To evaluate the effect of single daily SC doses of 40 mg elamipretide administered with 
the elamipretide delivery system for 24 weeks as measured by changes in the: 
– 
Individual symptoms on the PMMSA 
– 
Alternate version of the PMMSA Total Fatigue Score 
– 
Individual items of the Neuro-QoL Fatigue 
– 
EQ-5D-5L 
– 
Patient Global Impression (PGI) Scales 
– 
Clinician Global Impression (CGI) Scales 
Pharmacokinetic (PK) 
• 
To evaluate the PK of elamipretide 
PART 2 objectives are: 
• 
To assess the long-term safety and tolerability of single daily SC doses of 40 mg 
elamipretide administered with the elamipretide delivery system for up to 144 weeks 
Methodology: 
This randomized, double-blind, parallel-group, placebo-controlled trial will enroll approximately 202 
subjects who have PMM. There are 2 parts to this trial. 
• 
PART 1 is a 24-week, randomized, double-blind, parallel-group, placebo-controlled 
assessment of the efficacy and safety of single daily SC doses of 40 mg elamipretide (vs 
placebo) administered with the elamipretide delivery system as a treatment for subjects 
with PMM. Subjects will be randomized (in a ratio of 1:1) to one of two groups: 
– 
24 weeks of single daily SC doses of 40 mg elamipretide or 
– 
24 weeks of single daily SC doses of placebo. 
• 
PART 2 is an up to 144-week, open-label assessment of the long-term safety and 
tolerability of single daily SC doses of 40 mg elamipretide administered with the 
elamipretide delivery system in subjects with PMM. Subjects who continue into PART 2 
will receive treatment with 40 mg SC elamipretide administered with the elamipretide 
delivery system for up to 144 weeks. Thus, treatment during PART 2 will be as follows: 
– 
Subjects who are originally randomized to elamipretide during PART 1 (double-blind 
treatment) will continue receiving elamipretide during PART 2. 
– 
Subjects who are originally randomized to placebo during PART 1 (double-blind 
treatment) will switch to treatment with elamipretide during PART 2. 
Note that the duration of PART 2 treatment for each subject will be the shortest of the following: 
• 
144 weeks 
• 
Regulatory approval and commercial availability of the elamipretide delivery system in 
the subject’s respective country 

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• 
Termination of the clinical development for elamipretide in subjects with PMM. 
PART 1 
Screening Period: Screening will begin with the subject’s signature of the informed consent form 
(ICF) and will last a minimum of 7 days to a maximum of 28 days. Subjects not previously enrolled 
in SPIMM-300, however, may have a longer screening period for review by the Adjudication 
Committee to determine their eligibility for study enrollment. Subjects will undergo Screening 
procedures as described in the PART 1 Schedule of Assessments (Appendix 1) and will be trained 
and instructed to complete the PMMSA daily during the Screening Period, in an electronic or paper 
diary, in order to characterize their baseline disease status and to assess compliance. Subjects who 
complete Screening and continue to meet all trial requirements, including all Inclusion Criteria and 
none of the Exclusion Criteria, may be randomized (stratified by the subclassification of the genetic 
abnormality determined to be the primary cause of the subject’s PMM [DiMauro 2003] as determined 
by the Adjudication Committee) and enter the Treatment Period. 
Treatment Period: The Treatment Period will begin on the day of the Baseline Visit, which is defined 
as Day 1, and lasts for 24 weeks. Subjects (and caregivers if needed) will be trained on the procedure 
for administration of the elamipretide delivery system (the investigational medicinal product [IMP] 
[elamipretide or placebo], the elamipretide pen injector, and needle) and recording of the location 
(injection in the abdomen, rotating around the four abdominal quadrants, or other appropriate location 
[after Investigator consultation with the Sponsor]) and time (at approximately the same time each day 
[e.g., early morning, noon, or early afternoon]) of the IMP administration daily in the electronic or 
paper diary. An elamipretide delivery system training kit and checklist will be provided to the clinical 
site to assist in training. At the Baseline Visit, following completion of all Baseline procedures 
described in the PART 1 Schedule of Assessments, subjects or trained caregivers will administer IMP 
at the clinical site. On non-visit days, subjects (or trained caregivers) will administer the IMP daily 
during the Treatment Period. The subject will return to the clinical site for the Week 4, Week 12, and 
Week 24 Visits for assessments, to administer the IMP (subject or trained caregiver), and to return all 
used IMP supplies. During the Treatment Period, subjects will continue to follow all trial 
requirements, including recording the location and time of the IMP administration daily and 
completing the PMMSA daily. The Treatment Period will conclude with a visit to the clinical site at 
the Week 24 Visit when subjects will return all trial-related supplies. 
At the Week 24 Visit, if the subject confirms they are willing and able to continue to adhere to trial 
requirements and the Investigator determines the subject meets the Continuation Criteria the subject 
may continue into Part 2. If the subject continues into PART 2, the subject will continue (or start, for 
subjects treated with placebo in PART 1) elamipretide therapy the day of the Week 24 Visit (using 
the PART 2 supply of IMP) and continue trial activities as described in the PART 2 Schedule of 
Assessments (Appendix 2). Subjects who will not continue into PART 2 will not be administered 
IMP and will enter the PART 1 Follow-Up Period. 
For all subjects, it is the intent that subjects who discontinue IMP (at any time) for any reason will 
continue to be followed for all protocol-planned trial visits through the completion of the PART 1 
Treatment Period, and will have all endpoints (including efficacy) collected accordingly. In the 
interest of the subject, subjects who withdraw consent or are withdrawn from the trial by the 
investigator should be encouraged to complete an Early Discontinuation Visit as soon as possible and 
an effort should be made to complete and report the observations as thoroughly as possible up to the 
date of withdrawal. 
PART 1 Follow-Up Period (for subjects not continuing into PART 2): The PART 1 Follow-Up Period 
will begin after completion of the Week 24 Visit and will last for 4 weeks. Subjects will return to the 

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clinical site for the PART 1 End-of-Trial Visit for final safety assessments, as described in the PART 
1 Schedule of Assessments, and return all remaining trial-related supplies not previously returned. 
PART 2 
While there is no screening period for PART 2, subjects continuing into PART 2 must meet the 
PART 2 Continuation Criteria. Subjects who decide not to continue in the PART 2 at the PART 1 
Week 24 Visit are not eligible to participate in PART 2. 
Treatment Period: The Treatment Period will begin on the day of the PART 1 Week 24 Visit (at the 
administration of IMP) using the PART 2 supply of IMP. Subjects (or trained caregivers) will 
administer the IMP daily during the Treatment Period. The subject will return to the clinical site for 
the Week 28, Week 36, and Week 48 Visits for assessments, to administer the IMP (subject or trained 
caregiver), and to return all used IMP supplies. Additional visits will occur every 24 weeks for the 
remainder of the Treatment Period, with phone calls to the subject every 12 weeks between clinical 
site visits. During the Treatment Period, subjects will continue to follow all trial requirements. 
In the interest of the subject, subjects who withdraw consent or are withdrawn from the trial by the 
investigator should be encouraged to complete an Early Discontinuation Visit as soon as possible and 
an effort should be made to complete and report the observations as thoroughly as possible up to the 
date of withdrawal. 
PART 2 Follow-Up Period: The PART 2 Follow-Up Period will begin after completion of the Week 
168 Visit and will last for 4 weeks. Subjects will continue to follow all trial requirements. Subjects 
will return to the clinical site for the PART 2 End-of-Trial Visit for final safety assessments, as 
described in the PART 2 Schedule of Assessments, and return all remaining trial-related supplies not 
previously returned. 
Number of subjects (planned): Approximately 202 subjects will be randomized. 
SPIMM-301 Eligibility Criteria 
A subject must meet all of the following Inclusion Criteria at the Baseline Visit to be eligible for 
inclusion in the SPIMM-301 trial: 
1. Willing and able to provide a signed informed consent form (ICF) prior to participation in 
any trial-related procedures. 
2. Agrees and is able to adhere to the trial requirements for the length of the trial, including the 
use of the elamipretide delivery system. 
3. Subject is ≥16 and ≤80 years of age. In Germany, subjects must be ≥18 years of age. 
4. Enrolled (signed ICF) in SPIMM-300 or have prior approval from the Sponsor to enroll 
without SPIMM-300 participation. 
5. Diagnosed with PMM in the opinion of the Investigator, consisting of: 
a. Molecular genetic abnormality of the mitochondrial respiratory chain, and 
b. Subject reported symptoms (i.e., exercise intolerance, fatigue, muscle weakness) or 
physical examination findings of myopathy that are the predominant symptoms of the 
subject’s mitochondrial respiratory chain disorder. 
6. The subject’s molecular genetic abnormality is consistent with PMM as confirmed by the 
Adjudication Committee. 
7. Women of childbearing potential must agree to use 1 of the following methods of birth 
control from the date they sign the ICF until 28 days after the last dose of IMP: 

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a. Abstinence, when it is in line with the preferred and usual lifestyle of the subject. Subject 
agrees to use a highly effective method of contraception should they become sexually 
active. 
b. Relationships with male partners who have been surgically sterilized by vasectomy (the 
vasectomy procedure must have been conducted at least 60 days prior to the Screening 
Visit). 
c. 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. 
Note: 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). 
8. Male subjects with female partners of child-bearing potential must be willing to use a highly 
effective method of contraception from the date they sign the ICF until 28 days after the last 
dose of IMP. 
A subject CANNOT meet any of the following Exclusion Criteria at the SPIMM-301 Baseline Visit 
to be eligible for inclusion in the trial: 
1. Subject has myopathic signs and/or symptoms due to a neuropathic process (i.e. cerebellar 
dysfunctions and peripheral neuropathies) or a gait problem that would interfere with the 
6MWT, in the opinion of the Investigator. 
2. Female subjects who are pregnant, planning to become pregnant, or breastfeeding/lactating. 
3. Walks < 100 meters or > 450 meters during the 6MWT at either the Screening Visit OR 
Baseline Visit. 
4. At the Baseline Visit, the estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, 
using the Screening Visit value with the Modification of Diet in Renal Disease (MDRD) 
Study equation. 
5. Subject has undergone an in-patient hospitalization within the 30 days prior to the Baseline 
Visit or has a planned hospitalization or a surgical procedure during the trial. 
6. Subject has clinically significant respiratory disease and/or cardiac disease (medical history 
or current clinical findings), in the opinion of the Investigator, or prior interventional cardiac 
procedure (e.g., cardiac catheterization, angioplasty/percutaneous coronary intervention, 
balloon valvuloplasty, etc.) within 3 months of the Baseline Visit. 
7. Subject has a pacemaker, implantable cardioverter-defibrillator, or cardiac resynchronization 
therapy device OR QTc elongation (using the correction factor utilized at the clinical 
site) defined as a QTc >450 msec in male subjects and >480 msec in female subjects. 
Note: At the initial electrocardiogram (ECG), if QTc exceeds these parameters, the ECG may 
be repeated 2 more times (during the same visit), and the average of the 3 QTc values used to 
determine the subject’s eligibility. 
8. ECG evidence of acute ischemia, atrial fibrillation, or active conduction system abnormalities 
with the exception of any of the following: 
a. First degree AV-block 

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b. Second degree AV-block Type 1 (Mobitz Type 1 / Wenckebach type) 
c. Right bundle branch block 
9. Subject has severe vision impairment that, in the opinion of the Investigator, may interfere 
with their ability to complete all trial requirements 
10. Subject has a seizure disorder that, in the opinion of the Investigator, may interfere with their 
ability to complete all trial requirements. 
11. Active malignancy or any other cancer from which the subject has been disease-free for < 2 
years. 
12. Subject has a solid organ transplant and/or is currently receiving treatment with therapy for 
immunosuppression, in the opinion of the Investigator. 
13. Subject has been previously diagnosed with human immunodeficiency virus (HIV), hepatitis 
B, or hepatitis C infection. 
14. Subject has a history of a systemic eosinophilic illness and/or an eosinophil count >1,000 
cells x106/L at the Screening Visit. 
15. Subject is currently participating or has participated in an interventional clinical trial (i.e., 
investigational product or device, stem cell therapy, gene therapy) within 30 days of the 
Baseline Visit; or is currently enrolled in a non-interventional clinical trial (except for 
SPIMM-300) at the Baseline Visit which, in the opinion of the Investigator, may be 
potentially confounding to the results of the current trial (e.g. exercise therapy trial). 
16. Subject has previously received elamipretide (MTP-131), for any reason. 
17. Subject has a history of active substance abuse during the year before the Baseline Visit, in 
the opinion of the Investigator. 
18. Subject has any prior or current medical condition that, in the judgment of the Investigator, 
would prevent the subject from safely participating in and/or completing all trial 
requirements. 
PART 2 Continuation Criteria 
A subject must meet all of the following PART 2 Continuation Criteria at the Week 24 Visit in PART 
1 to be eligible for PART 2: 
1. Subjects must continue to be able and willing to adhere to the trial requirements. 
2. Subject is appropriate to continue in PART 2 (i.e. subject was compliant in PART 1), in the 
opinion of the Investigator. 
3. Subject has not had a serious adverse event (SAE)/serious adverse device effect (SADE) 
attributed to the elamipretide delivery system. 
4. Subject has not permanently discontinued the elamipretide delivery system. 
Investigational product, dosage and mode of administration: 
Elamipretide injection will be supplied as a sterile 3.0 mL multidose glass cartridge containing 2.5 
mL of elamipretide solution (elamipretide HCl [80 mg/mL], phosphate buffer, and benzyl alcohol) for 
use with the elamipretide delivery system (the investigational medicinal product [IMP] [elamipretide 

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or placebo], the elamipretide pen injector, and needle) as described in the Pharmacy Manual and 
Instructions for Use (IFU) pamphlet. The dose of elamipretide will be 40 mg administered as a once 
daily 0.5 mL SC injection with the elamipretide delivery system. 
Clinical site staff will train subjects (and caregivers if needed) and ensure understanding of proper SC 
injection technique on Day 1 and use of the elamipretide delivery system. An elamipretide delivery 
system training kit and checklist will be provided to the clinical site to assist in training. On Day 1 
(and subsequent clinical site visits), IMP will be administered at the clinical site by the subject or 
trained caregiver. On non-visit days, the subject (or trained caregiver) will administer the IMP via 
daily SC injections in the abdomen, rotating around the four abdominal quadrants, or other 
appropriate location (after Investigator consultation with the Sponsor). The time of the IMP 
administration should be approximately the same time each day (e.g., early morning, noon, or early 
afternoon). If a subject is concurrently receiving another SC therapy, unique locations for injections 
for the IMP, independent from the location of the concomitant therapy injections, should be used. 
Reference therapy, dosage and mode of administration: 
The placebo for this trial will be composed of sodium chloride, phosphate buffer, and benzyl alcohol 
similar to excipients used to manufacture the investigational drug but without the active drug 
substance. The placebo will be handled and administered identically to active drug. 
Duration of Trial: Up to 176 weeks 
This trial is designed with 2 parts, PART 1 and PART 2. 
PART 1: Up to 32 weeks 
• 
Screening Period: 7 to 28 days 
• 
Treatment Period: 24 weeks 
• 
PART 1 Follow-Up Period: 4 weeks (for subjects not continuing into PART 2). Subjects 
continuing into PART 2 will not participate in the PART 1 Follow-Up Period. 
PART 2: Up to 148 weeks 
• 
Treatment Period: Up to 144 weeks 
• 
PART 2 Follow-Up Period: 4 weeks 
Criteria for evaluation: 
Efficacy: 
Efficacy will only be assessed for PART 1. 
Primary Endpoints 
• 
Distance walked (meters) during the 6MWT 
• 
Total Fatigue score on the PMMSA 
Secondary Endpoints 
• 
Fatigue During Activities score on the PMMSA 
• 
Neuro-QoL Fatigue Short Form score 
• 
Most bothersome symptom score on the PMMSA 
• 
Neuro-QoL Fatigue activities of daily living (specific items from the Neuro-QoL Item 
Bank) 

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Exploratory Endpoints 
• 
Individual symptom scores on the PMMSA 
• 
Alternate version of the PMMSA Total Fatigue Score 
• 
Individual item scores on the Neuro-QoL Fatigue 
• 
EQ-5D-5L scores 
• 
Patient Global Impression (PGI) Scales 
– 
PGI of Symptom scores 
– 
PGI of Change scores 
• 
Clinician Global Impression (CGI) Scales 
– 
CGI of Symptom scores 
– 
CGI of Change scores 
Pharmacokinetic (PK) Endpoints 
• 
PK parameters 
Safety 
For both PART 1 and PART 2, safety will be assessed through collection of the following data: 
• 
Adverse Events (AEs)/Adverse Device Effects (ADEs) 
• 
Vital Signs 
• 
Electrocardiograms (ECGs) 
• 
Clinical laboratory evaluations 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Statistical methods: 
Sample Size: 
A sample size of 202 subjects (101 per treatment arm) provides 90% power to detect a 30-meter 
difference between treatment groups in the 6MWT and also 90% power to detect a one unit difference 
in the PMMSA Total Fatigue Score, assuming standard deviations of 60 meters for 6MWT and 2 
units for the PMMSA Total Fatigue Score, at an alpha-level of 0.025. The two-sided alpha-level of 
0.025 is to account for a possible multiplicity adjustment for the primary endpoint family. 
General Considerations 
Data will be tabulated (by treatment group) using descriptive statistics (number of subjects, mean, 
median, standard deviation, minima, and maxima) for continuous variables and using frequencies and 
percentages for discrete variables. Inferential statistics will be presented where specified. A 
comprehensive statistical analysis plan (SAP) will be written and approved prior to database lock. 
This SAP will detail how missing values are to be handled, windows for trial visits, and how other 
analysis considerations will be addressed. 

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Statistical tests (where performed) will be 2-sided at the alpha=0.05 level of significance, except as 
noted to adjust for multiplicity. 
Analysis Populations 
Statistical analysis will be performed in the following populations: 
• 
Safety Population – Includes all trial subjects who receive at least 1 dose of IMP. 
Subjects will be analyzed according to the actual treatment they receive. 
• 
Intent-to-Treat (ITT) Population – Includes all trial subjects who receive at least one dose 
of IMP. Subjects will be analyzed according to the treatment group they were randomized 
to and generally included in efficacy analyses for which post-baseline data are available. 
• 
Per-Protocol (PP) Population – Includes all ITT subjects without major protocol 
violations/deviations. The list of major protocol violations/deviations will be identified 
and specified in the SAP prior to final database lock for the trial that would lead to 
exclusion for the PP analysis. 
• 
Pharmacokinetic (PK) Population – Includes all trial subjects who have at least one PK 
sample taken during their participation. 
Disposition of Subjects 
Subject disposition (including the number and percent of subjects who are randomized, who receive 
randomized treatment, who are included in each analysis population, who prematurely discontinue 
and reasons for discontinuation, and who complete the trial) will be tabulated by treatment group. The 
number and percentage of subjects by exposure duration will be tabulated. 
Subject’s age, sex, weight, height, body mass index (BMI), and other demographic characteristics will 
be recorded and summarized. Medical history will be listed. 
Efficacy 
The distance walked (meters) during the 6MWT and Total Fatigue score on the PMMSA constitute 
the family of primary endpoints. Efficacy analyses will be conducted on the ITT population. 
Analyses of continuous endpoints will be conducted utilizing a mixed model repeated measures 
(MMRM) approach, with fixed effects for treatment, visit, the treatment-by-visit interaction, and 
subject as a random effect. The outcome is the change from baseline to each on-treatment time point. 
The baseline value and a baseline by visit interaction for the endpoint will be included as covariates. 
The primary time point is at Week 24; however, all protocol-scheduled time points will be included in 
the model. The exact details of the model, including variance-covariance structure and denominator 
degrees of freedom will be specified in the SAP. 
The secondary endpoints are: 
• 
Fatigue During Activities score on the PMMSA 
• 
Neuro-QoL Fatigue Short Form score 
• 
Most bothersome symptom score on the PMMSA 
• 
Neuro-QoL Fatigue activities of daily living (specific items from the Neuro-QoL Item 
Bank) 

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These endpoints will be assessed in a similar manner as the primary efficacy endpoints. 
There will be a number of exploratory endpoints investigated; these will be assessed in a similar 
manner as the primary efficacy endpoints. 
A family-wise alpha level of 0.05 will be maintained for the primary endpoint family, using 
Hochberg’s procedure at the primary time point of 24 weeks. If both primary endpoints are 
significantly different from placebo at the 0.05 (two-sided) level of significance (in favor of 
treatment), then both will be considered statistically significant. Otherwise the endpoint with the 
smaller p-value of the two will be considered statistically significant, if statistically significant at the 
0.025 (two-sided) level of significance. 
Select secondary and exploratory endpoints will be alpha-level protected in a hierarchical fashion, 
conditional upon the statistical significance of both endpoints in the primary endpoint family. 
Additional details will be specified in the SAP. 
Safety Analyses 
Safety data analysis will be conducted for the Safety Population. 
All AEs/ADEs will be coded to system organ class (SOC) and preferred term (PT) using the latest 
Medical Dictionary for Regulatory Activities coding dictionary. All reported AEs/ADEs will be 
listed, but only treatment-emergent AEs (TEAEs)/Treatment-Emergent ADEs (TEADEs) will be 
summarized. 
The incidence of all TEAEs/TEADEs, drug relationship with TEAEs/TEADEs, and severity of 
TEAEs/TEADEs will be summarized by treatment group. In the summary tables, subjects may be 
counted under multiple SOCs and PTs, but for each SOC and PT, subjects are only counted once for 
each treatment group. If a subject has the same AE/ADE on multiple occasions, the highest severity 
(severe > moderate > mild) or drug relationship (probable > possibly related > unlikely related > 
unrelated) recorded for the event will be presented. If severity is missing, subjects will be included as 
missing (for severity). If drug relationship is missing, subjects will be included in related tables (i.e., 
considered related). Summary tables will be organized by SOC, then PT. 
Local tolerability (pain/tenderness, erythema, induration/swelling, and pruritus) of the injection site 
will be evaluated as an AE and summarized. 
Summary tables for laboratory parameters (including clinical hematology and chemistry laboratory 
parameters, 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 parameter and visit for each treatment group. Shift tables for urinalysis will show the 
number of subjects who are normal/abnormal at baseline and normal/abnormal at the end of trial. 
Vital signs and ECG data will be summarized similarly as clinical laboratory outcomes. 

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2. 
TABLE OF CONTENTS AND LISTS OF TABLES AND FIGURES 
TABLE OF CONTENTS 
PROTOCOL APPROVAL ..............................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
TABLE OF CONTENTS AND LISTS OF TABLES AND FIGURES ..................... 14 
3. 
ABBREVIATIONS AND DEFINITIONS ................................................................. 21 
4. 
INTRODUCTION ......................................................................................................23 
4.1. 
Primary Mitochondrial Myopathy (PMM) .................................................................23 
4.1.1. 
Background .................................................................................................................23 
4.1.2. 
Etiology .......................................................................................................................23 
4.1.3. 
Pathophysiology .........................................................................................................24 
4.1.4. 
Clinical Presentation ...................................................................................................25 
4.1.5. 
Prevalence ...................................................................................................................25 
4.1.6. 
Burden of Disease .......................................................................................................26 
4.1.7. 
Treatment ....................................................................................................................26 
4.2. 
Pharmacologic Basis for Elamipretide as a Potential Treatment for Primary 
Mitochondrial Myopathy (PMM) ...............................................................................26 
4.3. 
Elamipretide Risk/Benefit Assessment .......................................................................27 
4.3.1. 
Clinical Efficacy in Studies in Primary Mitochondrial Myopathy (PMM) ................27 
4.3.1.1. 
SPIMM-201 ................................................................................................................27 
4.3.1.2. 
SPIMM-202 ................................................................................................................28 
4.3.2. 
Summary of Safety .....................................................................................................31 
4.3.2.1. 
Nonclinical Study Safety Findings .............................................................................31 
4.3.2.2. 
Clinical Trial Safety Findings .....................................................................................32 
4.4. 
Discussion of Trial Design and Control .....................................................................35 
4.5. 
Rationale for Selection of Doses in the Trial ..............................................................35 
5. 
TRIAL OBJECTIVES ................................................................................................38 
5.1. 
PART 1 Objectives .....................................................................................................38 
5.1.1. 
Primary Objective .......................................................................................................38 
5.1.2. 
Secondary Objectives .................................................................................................38 
5.1.3. 
Exploratory Objectives ...............................................................................................38 
5.1.4. 
Pharmacokinetics (PK) ...............................................................................................39 

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5.2. 
PART 2 Objective .......................................................................................................39 
6. 
INVESTIGATIONAL PLAN .....................................................................................40 
6.1. 
SPIMM-301 Overall Trial Design ..............................................................................40 
6.1.1. 
PART 1 .......................................................................................................................40 
6.1.1.1. 
PART 1 Screening Period ...........................................................................................40 
6.1.1.2. 
PART 1 Treatment Period ..........................................................................................41 
6.1.1.3. 
PART 1 Follow-Up Period (for subjects not continuing into PART 2) .....................41 
6.1.2. 
PART 2 .......................................................................................................................42 
6.1.2.1. 
PART 2 Treatment Period ..........................................................................................42 
6.1.2.2. 
PART 2 Follow-Up Period .........................................................................................42 
6.2. 
Schedule of Visit Assessments ...................................................................................42 
6.2.1. 
PART 1 .......................................................................................................................42 
6.2.1.1. 
Screening Visit/Period: Day -28 to Day -1 (minimum of 7 days) ..............................42 
6.2.1.2. 
Baseline Visit (Day 1) ................................................................................................43 
6.2.1.3. 
Double-Blind Treatment Period .................................................................................45 
6.2.1.4. 
Week 4 (Day 29 ±2), Week 12 (Day 85 ±4), and Week 24 (Day 169 +14 
days) Visits .................................................................................................................45 
6.2.1.5. 
PART 1 Post-Treatment Follow-Up Period (4 weeks [+7 days]) ...............................46 
6.2.2. 
PART 2 .......................................................................................................................47 
6.2.2.1. 
PART 2 Treatment Period ..........................................................................................48 
6.2.2.2. 
PART 2 Post-Treatment Follow-Up Period (4 weeks [+7 days]) ...............................48 
6.3. 
Description of Trial Procedures ..................................................................................49 
6.3.1. 
Medical/Surgical History and Concomitant Medications/Procedures ........................49 
6.3.2. 
Physical Examination .................................................................................................49 
6.3.3. 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................50 
6.3.4. 
Vital Signs ..................................................................................................................50 
6.3.5. 
Electrocardiograms (ECGs) ........................................................................................50 
6.3.6. 
Clinical Laboratory Testing ........................................................................................50 
6.3.7. 
Pregnancy Tests ..........................................................................................................50 
6.3.8. 
Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) ........................50 
6.3.9. 
The Neuro-QoL Fatigue .............................................................................................51 
6.3.10. 
EQ-5D-5L ...................................................................................................................51 
6.3.11. 
Patient Global Impression (PGI) Scales .....................................................................51 

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6.3.12. 
Clinician Global Impression (CGI) Scales .................................................................51 
6.3.13. 
6-Minute Walk Test (6MWT) ....................................................................................51 
6.3.14. 
Pharmacokinetic (PK) Sampling ................................................................................52 
6.3.15. 
Injection Site Reaction (ISR) Assessment ..................................................................52 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................53 
7.1. 
SPIMM-301 Eligibility ...............................................................................................53 
7.1.1. 
Subject Inclusion Criteria ...........................................................................................53 
7.1.2. 
SPIMM-301 Exclusion Criteria ..................................................................................54 
7.2. 
PART 2 Eligibility ......................................................................................................55 
7.2.1. 
PART 2 Subject Continuation Criteria .......................................................................55 
7.3. 
Prohibited Medications ...............................................................................................56 
7.4. 
Criteria for Subject or Trial Discontinuation ..............................................................56 
7.4.1. 
Discontinuation of Subjects ........................................................................................56 
7.4.2. 
Discontinuation of Clinical Site Participation ............................................................57 
7.4.3. 
Discontinuation of the Trial ........................................................................................57 
8. 
INVESTIGATIONAL MEDICINAL PRODUCT MATERIALS AND 
MANAGEMENT .......................................................................................................58 
8.1. 
Treatments Administered ............................................................................................58 
8.1.1. 
Elamipretide Pen Injector ...........................................................................................58 
8.1.2. 
Elamipretide Delivery System ....................................................................................59 
8.2. 
Materials and Supplies ................................................................................................60 
8.3. 
Investigational Medicinal Product Accountability .....................................................60 
8.4. 
Treatment Compliance ................................................................................................61 
8.5. 
Randomization ............................................................................................................61 
8.6. 
Blinding and Unblinding Procedures ..........................................................................61 
9. 
EFFICACY AND SAFETY EVALUATIONS AND APPROPRIATENESS 
OF MEASUREMENTS ..............................................................................................63 
9.1. 
Efficacy Endpoints ......................................................................................................63 
9.1.1. 
Primary Endpoints ......................................................................................................63 
9.1.2. 
Secondary Endpoints ..................................................................................................63 
9.1.3. 
Exploratory Endpoints ................................................................................................63 
9.1.4. 
Pharmacokinetic (PK) Endpoints ...............................................................................63 
9.2. 
Safety Endpoints .........................................................................................................64 

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9.2.1. 
Adverse Events (AEs)/Adverse Device Effects (ADEs) ............................................64 
9.3. 
Pre-Treatment Adverse Events ...................................................................................65 
9.4. 
Medical History Conditions ........................................................................................65 
9.5. 
Medical and Surgical Procedures ...............................................................................65 
9.6. 
Abnormal Laboratory and Other Abnormal Investigational Findings .......................65 
9.7. 
Symptomatic Overdose ...............................................................................................66 
9.8. 
Serious Adverse Events (SAEs)/Serious Adverse Device Effect (SADEs) ...............66 
9.9. 
Recording of Adverse Events (AEs)/Adverse Device Effects (ADEs) ......................66 
9.9.1. 
Investigator Assessments ............................................................................................67 
9.9.1.1. 
Severity .......................................................................................................................67 
9.9.1.2. 
Relationship to the Investigational Medicinal Product (IMP)/Elamipretide 
Delivery System ..........................................................................................................68 
9.9.1.3. 
Outcome of an Adverse Event (AE)/Adverse Device Effect (ADE)..........................68 
9.9.1.4. 
Investigator Injection Site Reaction (ISR) Assessment ..............................................68 
9.9.2. 
Adverse Event (AE)/Adverse Device Effect (ADE) Reporting Period ......................69 
9.10. 
Serious Adverse Event (SAE)/Serious Adverse Device Effect (SADE) 
Expedited Reporting ...................................................................................................69 
9.10.1. 
Pregnancy and Contraception .....................................................................................70 
9.10.2. 
Responsibilities to Regulatory Authorities, Investigators and Ethics 
Committees .................................................................................................................70 
10. 
DATA QUALITY ASSURANCE ..............................................................................72 
10.1. 
Data Capture System ..................................................................................................72 
11. 
SAMPLE SIZE AND STATISTICAL METHODS ...................................................73 
11.1. 
Determination of Sample Size ....................................................................................73 
11.2. 
Statistical and Analytical Plans ..................................................................................73 
11.2.1. 
General Considerations ...............................................................................................73 
11.2.2. 
Analysis Populations ..................................................................................................73 
11.2.3. 
Subject Disposition .....................................................................................................73 
11.2.4. 
Subject Characteristics ................................................................................................74 
11.2.5. 
Efficacy Analyses .......................................................................................................74 
11.2.5.1. 
Primary Efficacy Endpoints ........................................................................................74 
11.2.5.2. 
Secondary Efficacy Endpoints ....................................................................................74 
11.2.5.3. 
Exploratory Endpoints ................................................................................................75 
11.2.5.4. 
Pharmacokinetic (PK) Endpoints ...............................................................................75 

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11.2.5.5. 
Adjustments for Multiplicity ......................................................................................75 
11.2.5.6. 
Handling of Missing Data ...........................................................................................75 
11.2.6. 
Pharmacokinetics (PK) ...............................................................................................76 
11.2.7. 
Safety Analyses ..........................................................................................................76 
11.2.7.1. 
Adverse Events (AEs)/Adverse Device Effects (ADEs) ............................................76 
11.2.7.2. 
Deaths and Other Serious Adverse Events (SAEs)/Serious Adverse Device 
Effects (SADEs) .........................................................................................................76 
11.2.7.3. 
Clinical Laboratory Evaluations .................................................................................77 
11.2.7.4. 
Vital Signs ..................................................................................................................77 
11.2.7.5. 
Electrocardiogram .......................................................................................................77 
11.2.7.6. 
Other Safety Parameters .............................................................................................77 
12. 
INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS ..................................................................................................78 
12.1. 
Informed Consent .......................................................................................................78 
12.2. 
Ethical Review ............................................................................................................78 
12.3. 
Regulatory Considerations ..........................................................................................78 
12.3.1. 
Protocol Approval .......................................................................................................79 
12.3.2. 
Final Report Approval ................................................................................................79 
12.3.3. 
Trial Monitoring .........................................................................................................79 
12.3.4. 
Retention of Records ..................................................................................................79 
12.3.5. 
Disclosure of Information ...........................................................................................79 
13. 
REFERENCES ...........................................................................................................81 
APPENDIX 1. PART 1 SCHEDULE OF ASSESSMENTS ...................................................... 82 
APPENDIX 2. PART 2 SCHEDULE OF ASSESSMENTS ...................................................... 84 
APPENDIX 3. TRIAL DESIGN SCHEMATIC ........................................................................85 
APPENDIX 4. LIST OF CLINICAL LABORATORY TESTS TO BE PERFORMED ...........86 
APPENDIX 5. COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
“BASELINE/SCREENING” ...................................................................................... 87 
APPENDIX 6. COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
“SINCE LAST VISIT” ...............................................................................................91 
APPENDIX 7. SAMPLE SAFETY TELEPHONE CALL SCRIPT .......................................... 95 
APPENDIX 8. PRIMARY MITOCHONDRIAL MYOPATHY SYMPTOM 
ASSESSMENT (PMMSA) ......................................................................................... 96 
APPENDIX 9. NEURO-QOL FATIGUE ................................................................................... 99 

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APPENDIX 10. EQ-5D-5L .......................................................................................................102 
APPENDIX 11. PATIENT GLOBAL IMPRESSION (PGI) SCALES ................................... 106 
APPENDIX 12. CLINICIAN GLOBAL IMPRESSION (CGI) SCALES ............................... 114 
APPENDIX 13. 6-MINUTE WALK TEST (6MWT) .............................................................. 117 
APPENDIX 14. TABLE FOR GRADING THE SEVERITY OF INJECTION SITE 
REACTIONS ............................................................................................................ 118 
APPENDIX 15. COUNTRY-SPECIFIC APPENDIX--GERMANY .......................................119 
 
LIST OF TABLES 
Table 1: 
Summary of Change from Baseline on Days 5 and 7 in Distance Walked 
(meters) on 6MWT (Trial SPIMM-201) .....................................................................28 
Table 2: 
Summary of Change from Baseline to Day 28 in Distance Walked (meters) 
on 6MWT (Trial SPIMM-202) ...................................................................................29 
Table 3: 
Summary of Change from Baseline by Week in PMMSA Fatigue Scores 
(Trial SPIMM-202) .....................................................................................................30 
Table 4: 
Summary of Systemic TEAEs Reported in Greater Frequency (≥ 2% 
difference)  in  Elamipretide-treated  Subjects  Compared  to  Placebo-Treated 
Subjects .......................................................................................................................32 
Table 5: 
Mean Steady-State PK Parameters* on Day 5 (Males and Females 
Combined) Following Repeat Administration of Elamipretide (MTP-131) at 
0.01, 0.1 and 0.25 mg/kg/hr as a 2-hour IV infusion, Once Daily, for 5 Days 
(Trial SPIMM-201) .....................................................................................................35 
Table 6: 
Estimated Bioavailability of SC Administration (40 mg as a 1 mL injection) 
Versus Two Hour IV Infusion Following Repeat Administration of 
Elamipretide (MTP-131) (Trial SPIMM-201) ............................................................36 
Table 7: 
Key Summary Steady-State PK Parameters Days 182 (Rat) and 273 (Dog) at 
the NOAEL/MFD with Safety Margins Versus. Human Exposure (SPISC- 
101, 40 mg/day) (Study SPI-CIT-15-03 and Study SPI-CIT-15-02) ..........................37 
 
LIST OF FIGURES 
Figure 1: Oxidative Phosphorylation .............................................................................................24 
Figure 2: Creation of Reactive Oxygen Species (ROS) .................................................................25 
Figure 3: 
SPIMM-202 Summary of Treatment Effect (Analysis Population – 
Intention-to-Treat [ITT] ..............................................................................................31 
Figure 4: 
Elamipretide Delivery System (expanded view of major components) .....................59 

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3. 
ABBREVIATIONS AND DEFINITIONS 
 
Term 
Definition 
6MWT 
6-Minute Walk Test 
ADE 
Adverse device effect 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
AUC 
Area under the plasma concentration versus time curve 
AUC0-τ 
Area under the plasma concentration vs time curve from time 0 to end of the 
dosing interval 
AUC0-inf 
Area under the plasma concentration curve from baseline to infinity 
AUC0-24 
Area under the plasma concentration curve from baseline to 24 hours postdose 
BMI 
Body mass index 
CIOMS 
Council for International Organizations of Medical Sciences 
CGI 
Clinician Global Impression Scales 
Cmax 
Maximum plasma concentration 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
ETC 
Electron Transport Chain 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration  of Pharmaceuticals for Human Use 
IFU 
Instructions for Use 
IMM 
Inner mitochondrial membrane 
IMP 
Investigational medicinal product 
ISR 
Injection site reaction 
IV 
Intravenous 
ITT 
Intention-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFD 
Maximum feasible dose 
mL 
Milliliter 
MTP-131 
Elamipretide, SS-31, SBT-031, or Bendavia™ 
mtDNA 
Mitochondrial DNA 
nDNA 
Nuclear DNA 
PK 
Pharmacokinetic(s) 
PGI 
Patient Global Impression Scales 
PMMSA 
Primary Mitochondrial Myopathy Symptom Assessment 
PT 
Preferred term 

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Term 
Definition 
RA 
Risk assessment 
ROS 
Reactive oxygen species 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SMP 
Safety Management Plan 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEADE 
Treatment-emergent adverse device effect 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 

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4. 
INTRODUCTION 
This pivotal trial will be conducted in strict accordance with the current versions of the Council 
for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, 
ICH GCP guidelines, the Declaration of Helsinki, and all applicable laws and regulations. For 
detailed information on the elamipretide delivery system and the nonclinical and clinical studies 
conducted to date, please refer to the most recent edition of the elamipretide Investigator’s 
Brochure (IB). 
 
4.1. 
Primary Mitochondrial Myopathy (PMM) 
4.1.1. 
Background 
The National Organization for Rare Disorders (NORD) Physician Guide to Mitochondrial 
Myopathies describes PMM as genetic disorders of the mitochondrial respiratory chain affecting 
predominantly, but not exclusively, skeletal muscle (Mancuso 2016). In PMM, there is an 
exaggerated response to physical exercise due to skeletal muscle respiratory chain dysfunction. 
The increased oxygen available during physical activity in the arterial bloodstream cannot be 
effectively utilized in PMM subjects by the skeletal muscle cells and as a result leads to 
debilitating muscle weakness, muscle atrophy, limited exercise capacity, and symptoms of 
fatigue. The severity of PMM is variable but the progressive reduction in muscle strength and 
exercise capacity eventually significantly compromises the ability to perform activities of daily 
living (DiMauro 2004; Pfeffer 2013; Tarnopolsky 2004). 
 
4.1.2. 
Etiology 
Mitochondria are cellular organelles with an inner and an outer membrane and a matrix 
containing mitochondrial DNA (mtDNA). Mitochondria host multiple metabolic pathways 
required for normal cellular function. Mitochondrial function is under the dual control of genes 
within mtDNA as well as within nuclear DNA (nDNA). PMM is caused by mutations in nDNA 
and/or mtDNA which result in electron transport chain (ETC) dysfunction and a corresponding 
reduction in oxidative phosphorylation and production of ATP (Chinnery 2014; DiMauro 2003). 
Mutations causing PMM are subclassified as follows (DiMauro 2003): 
• 
Disorders involving mtDNA mutations that impair mitochondrial protein synthesis in 
toto 
• 
Disorders involving mtDNA mutations that affect the subunits of the respiratory 
chain 
• 
Disorders involving nDNA mutations in genes encoding subunits or ancillary proteins 
of the respiratory chain 
• 
Disorders involving nDNA mutations causing defects of intergenomic signaling 
• 
Disorders involving nDNA mutations causing defects of mitochondrial protein 
importation 
• 
Disorders involving nDNA mutations causing alterations of the lipid milieu of the 
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• 
Disorders involving nDNA mutations causing alterations of mitochondrial motility or 
fission 
 
4.1.3. 
Pathophysiology 
As noted above, PMM entails genetic disorders of the mitochondrial respiratory chain. The 
mitochondrial respiratory chain is located within the curves, or cristae, of the inner mitochondrial 
membrane (IMM), which are also the site for the highly-specialized proteins that form the 
complexes of the ETC. The curved architecture of the cristae helps keep the ETC complexes in 
close association with one another, increasing the efficiency of ATP production and minimizing 
electron leak. This curvature is attributed to cardiolipin, a conically-shaped phospholipid found 
only in the IMM. Cardiolipin also facilitates the tight association of individual ETC complexes 
into super-complexes which enhance respiratory chain efficiency. 
Mitochondrial respiration, or oxidative phosphorylation, occurs via the complexes of the ETC, 
which is composed of four multi-subunit protein aggregates (Complexes I-IV) embedded in the 
IMM (Figure 1). These complexes, along with Complex V, are involved in the energetic 
processes of mitochondria. Energy extracted from dietary intake is converted into reducing 
equivalents (e.g., nicotinamide adenine dinucleotide [NADH]) that donate electrons to 
Complex I (NADH dehydrogenase). The energy released by the shuttling of these high-energy 
electrons along the ETC allows protons to be pumped from the matrix compartment of the 
mitochondrion into the intermembrane space. Two additional carriers comprise the ETC, 
Coenzyme Q10 (Co Q10) and cytochrome c (Cyt c), each play critical roles in the efficient transfer 
of electrons through these successive oxidation-reduction reactions. The protons pumped into the 
mitochondrial intermembrane space are then used by Complex V (ATP synthase) to catalyze the 
conversion of adenosine diphosphate (ADP) and inorganic phosphate to ATP. 
Figure 1: Oxidative Phosphorylation 
ATP=adenosine triphosphate; CoQ=coenzyme Q10; Cyt C=cytochrome C; 
Reference: Adapted with permission from: Brown DA, Sabbah HN, Shaikh SR. Mitochondrial inner membrane 
lipids and proteins as targets for decreasing cardiac ischemia/reperfusion injury. Pharmacol Ther.2013 
Dec;140(3):258-266. 
Under normal metabolic conditions, most electrons flow down the ETC, ultimately reacting with 
oxygen at Complex IV to form water. However, in PMM, mtDNA and/or nDNA mutations result 
in respiratory chain dysfunction. This dysfunction results in the “leak” or escape of electrons 
prematurely from the ETC, creating reactive oxygen species (ROS) such as superoxide radical 

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(O2-), and hydrogen peroxide (H2O2) (Figure 2). As the name suggests, ROS are highly reactive, 
and attack mitochondrial components, especially membrane lipids such as cardiolipin. This 
causes altered cardiolipin structure which in turn disrupts IMM structure, leading to a relaxation 
of cristae curvature and a drifting apart of ETC complexes. This further reduces ETC efficiency 
and increases electron leakage, perpetuating a ‘vicious cycle’ entailing increased ROS 
production, increased oxidative stress, and further reductions in ATP generation. This “vicious 
cycle” leads to mitochondrial, cellular, and organ dysfunction typical of that seen in subjects 
with mitochondrial disease. 
Figure 2: Creation of Reactive Oxygen Species (ROS) 
ATP=adenosine triphosphate; CoQ=coenzyme Q10; Cyt C=cytochrome C; ROS=reactive oxygen species 
Reference: Adapted with permission from: Brown DA, Sabbah HN, Shaikh SR. Mitochondrial inner membrane 
lipids and proteins as targets for decreasing cardiac ischemia/reperfusion injury. Pharmacol Ther.2013 
Dec;140(3):258-266. 
 
4.1.4. 
Clinical Presentation 
Exercise-induced symptoms are common in PMM, in which mitochondrial dysfunction in 
skeletal muscle mitochondria leads to reduced energy production, increased lactate production 
and phosphocreatine (PCr) depletion (Mancuso 2016). Other skeletal muscle related 
manifestations of PMM are myalgia, muscle wasting, muscle cramps, recurrent rhabdomyolysis, 
progressive external ophthalmoplegia, and ptosis. Some subjects with PMM present with only 
skeletal muscle myopathy, while others present with other organ dysfunction, but in both 
conditions, the skeletal muscle myopathy is the predominant clinical manifestation of the 
disease. 
 
4.1.5. 
Prevalence 
PMM is a phenotype of Primary Mitochondrial Disease (PMD), a larger heterogeneous group of 
mitochondrial disorders with variable phenotypic expression. There has been no formal 
characterization of the prevalence in the United States of either PMM or PMD. However, PMD 
has been estimated to affect approximately 1 in 4,300-8,000 persons with varying degrees of 
disability (Gorman 2015; Ng 2016; Chinnery 2014). The most specific estimates of clinically 
affected and genetically confirmed adults (>16 years old) with PMD were reported by Newcastle 
University as recently as May 2015 based on a cohort of adult PMD subjects in North East 

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England from 1990 to 2011 (Gorman 2015). This study concluded that PMD affects at least 1 in 
5,000 of the general population, with mtDNA mutations accounting for about three quarters 
(76.8%), and nDNA mutations accounting for about one quarter (23.2%) of the clinically 
affected adults with PMD. Since subjects diagnosed with PMM are a subset of PMD subjects, 
their prevalence can be estimated to be less than that of the larger PMD subject population. 
 
4.1.6. 
Burden of Disease 
PMM can result in significant deterioration of subject quality of life as routine activities of daily 
living (such as climbing stairs, grocery shopping, vacuuming, walking, or carrying out normal 
job functions) are limited by skeletal muscle weakness, poor endurance and easy fatigability. 
Loss of muscle mass and fixed weakness may also cause additional functional limitations 
(Taivassalo 2003; Taivassalo 2004). Patients with PMM face an inescapable range of daily 
challenges related to their disease including not being able to sustain muscle contraction, 
inability to take things from a high shelf, inability to go up and down stairs, feeling fatigued 
immediately upon waking in the morning, being bedbound, etc. This chronic disability can lead 
to depression and the inability to gain meaningful employment. On the more severe end, PMM 
can impact muscles that support breathing, cause weakness and wasting in muscles of the face 
and neck leading to difficulty with swallowing and slurred speech, vision loss and severe 
gastrointestinal dysfunction. 
PMM is a life-long debilitating disease in which subjects suffer a myriad of incapacitating 
symptoms which directly affect quality of life, with no available therapies to significantly 
improve the most prominent symptoms of muscle weakness, exercise intolerance and fatigue. 
 
4.1.7. 
Treatment 
There are currently no approved treatments for PMM. 
 
4.2. 
Pharmacologic Basis for Elamipretide as a Potential Treatment for 
Primary Mitochondrial Myopathy (PMM) 
PMM is caused by genetic mutations in nDNA and/or mtDNA causing oxidative 
phosphorylation abnormalities which result in clinical signs and symptoms. This dysfunction 
results in a reduction in ATP and an increase in ROS production. This increase in ROS may 
reach a threshold and, due to cardiolipin peroxidation and ensuing degradation of IMM structure, 
trigger additional increased ROS generation by the ETC, an effect termed “ROS-induced ROS 
release (RIRR)” (Zorov 2000; Zorov 2006). These effects constitute a positive feedback 
mechanism for enhanced ROS production leading to additional significant mitochondrial 
structural abnormalities, dysfunction and cellular injury. At a certain level of mitochondrial 
dysfunction (decreased ATP and increased ROS production), subjects experience signs and 
symptoms of their disease. 
As noted above, ROS attack and denature a number of components within the mitochondria, 
including the protein components of the ETC, membrane lipids (particularly cardiolipin), and 
mtDNA. In particular, the peroxidation or denaturing of cardiolipin has been associated with 
abnormal morphology of the inner mitochondrial membrane (IMM), reduced association of the 
ETC complexes within the IMM, a decline in ETC activity (ATP production), and the release of 
cytochrome c which initiates apoptotic signaling (Fry 1981; Chicco 2007). 

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Elamipretide improves mitochondrial function by restoring the physical and biochemical 
properties of the IMM through its association with cardiolipin. Stealth BT has demonstrated that 
treatment of cells or isolated organs undergoing oxidative stress with elamipretide can maintain 
the normal morphology of the IMM and the association of the ETC complexes within the IMM. 
Elamipretide normalizes IMM structure, which is important to keep the ETC complexes in 
optimal proximity to one another, and enhances interaction and association of the ETC 
complexes (“super-complex association”) to increase respiratory function, increase ATP 
production, and decrease ROS generation. Various studies have shown an ensuing improvement 
in various downstream consequences of mitochondrial dysfunction following treatment with 
elamipretide, including reduced fibrosis, inflammation, and cell death. 
 
4.3. 
Elamipretide Risk/Benefit Assessment 
The Investigator’s Brochure describes in detail the risks and potential benefits of treatment with 
elamipretide and should be referenced by the Investigator. A brief overview of risks and benefits 
is provided in the following sections. 
 
4.3.1. 
Clinical Efficacy in Studies in Primary Mitochondrial Myopathy (PMM) 
 
4.3.1.1. 
SPIMM-201 
The SPIMM-201 trial was a phase 1/2 multi-center, randomized, double-blind, placebo- 
controlled, multiple ascending IV dose trial that enrolled subjects ≥16 and ≤65 years with PMM. 
Three escalating doses (0.01, 0.10, and 0.25 mg/kg/hour infused for 2 hours) were studied (one 
dose per cohort) and infused daily for 5 days. The primary efficacy endpoint was distance 
walked during the 6-Minute Walk Test (6MWT) after 5 days of treatment. 
Five days of daily IV elamipretide was well tolerated with no increase in adverse events (AEs) or 
laboratory abnormalities compared to placebo. The most common TEAE overall was headache 
in 6 (16.7%) subjects, followed by dizziness in 3 (8.3%) subjects. There were no treatment- 
related TEAEs that were severe in intensity. Adverse event severity and/or frequency did not 
increase with dose. 
The primary efficacy measure of interest was the change from Baseline in distance walked 
(meters) on the 6MWT. In addition to the 6MWT, the efficacy of elamipretide was explored 
using Cardiopulmonary Exercise Testing (CPET) parameters, subject reported outcomes 
(Newcastle Mitochondrial Disease Adult Scale [NMDAS] and a Daily Symptom Questionnaire 
[DSQ]), and plasma and urinary biomarkers. 
The highest dose of elamipretide, 0.25 mg/kg/hr, was associated with a 44.1-meter improvement 
in distance walked on the 6MWT over placebo (p=0.0528) at Day 5 (Table 1). Further, there was 
a significant linear dose response for the 6MWT at Day 5, showing increasing benefit as the dose 
of elamipretide increases (p=0.014). There were no meaningful changes observed for other 
exploratory efficacy measures. 

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Table 1: 
Summary of Change from Baseline on Days 5 and 7 in Distance Walked 
(meters) on 6MWT (Trial SPIMM-201) 
 
Elamipretide 
Placebo 
(N = 9) 
0.01 mg/kg/hr 
(N = 9) 
0.10 mg/kg/hr 
(N = 9) 
0.25 mg/kg/hr 
(N = 9) 
Baseline 
Mean (SD)2 
363.9 (143.15) 
421.9 (66.85) 
360.2 (100.99) 
369.8 (96.82) 
Change on Day 51 
Mean (SD) 
14.2 (49.40) 
34.3 (43.46) 
65.4 (45.71) 
20.9 (45.18) 
LS Mean 
13.5 
36.5 
64.5 
20.4 
LSM Diff2 (90% CI)3 
-7.0 (-44.1, 30.1) 
16.1 (-21.6, 53.8) 
44.1 (7.0, 81.2) 
p-value3 
0.7523 
0.4746 
0.0528 
Change on Day 71 
Mean (SD) 
LS Mean 
LSM Diff2 (90% CI)3 
p-value3 
31.8 (41.10) 
30.3 
-8.3 (-53.0, 36.5) 
0.7561 
35.1 (56.56) 
39.5 
1.0 (-44.5, 46.4) 
0.9718 
63.6 (63.30) 
61.7 
23.1 (-21.6, 67.9) 
0.3872 
39.4 (60.74) 
38.5 
Abbreviations: 6MWT = 6-Minute Walk Test; CI = Confidence interval; LS = Least squares; LSM Diff = Least 
Squares Mean Difference; SD = Standard deviation. 
1. 
Change from Baseline = value at Visit – value at Baseline Visit. 
2. 
LSM Difference is elamipretide dose (0.01, 0.10, or 0.25 mg/kg/hr) minus placebo. 
3. 
P-value and 90% CI of the difference are based on the ANCOVA model which included treatment as a factor 
and Baseline measure as a covariate. 
 
4.3.1.2. 
SPIMM-202 
SPIMM-202 was a phase 2, randomized, double-blind, placebo-controlled, multi-center two- 
period crossover trial which enrolled 30 of the 36 subjects who completed participation in the 
SPIMM-201 trial. Subjects were randomized (1:1) to one of two treatment sequences: 
• 
Sequence 1: Period 1, 4 weeks of treatment with 40 mg subcutaneous (SC) 
elamipretide administered once daily, followed by a 4-week washout, and then, in 
Period 2, 4 weeks of treatment with SC placebo administered once daily. 
• 
Sequence 2: Period 1, 4 weeks of treatment with SC placebo administered once daily, 
followed by a 4-week washout, and then, in Period 2, 4 weeks of treatment with 40 
mg SC elamipretide administered once daily. 
The primary objective of the trial was to evaluate the effect of 4 weeks of SC elamipretide 
administered once daily on the distance walked during the 6MWT. Secondary objectives were to 
evaluate the safety and tolerability (AEs, vital signs, ECGs, clinical laboratory evaluations) as 
well as additional efficacy assessments (described below) of 4 weeks of elamipretide 
administration. 
Table 2 demonstrates that treatment with elamipretide 40 mg resulted in a 19.8-meter 
improvement in the 6MWT distance over treatment with placebo (p=0.0833). 

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Table 2: 
Summary of Change from Baseline to Day 28 in Distance Walked (meters) on 
6MWT (Trial SPIMM-202) 
 
Visit 
Elamipretide 40 mg 
(n=29) 
Placebo 
(n=30) 
End of Treatment 
Mean (SD) 
394.1 (134.16) 
378.2 (125.10) 
LS Mean 
398.3 (LSM) 
378.5 (LSM) 
LSM Diff1  (95% CI) 
19.8 (-2.8, 42.5) 
p-value2 
0.0833 
Abbreviations: 6MWT = 6-Minute Walk Test; CI = Confidence interval; LS = Least squares; LSM Diff = Least 
Squares Mean Difference; SD = Standard deviation. 
1. 
LSM Difference is elamipretide minus placebo. 
2. 
p-value and 95% CI of the difference are based on the mixed model which includes treatment, sequence and 
period as mixed effects and subjects nested within sequence as a random effect. 
A pre-specified subgroup analysis revealed that subjects walking less than 450 meters (n=22) 
(more impaired) at baseline improved more on elamipretide (24.3 meters compared to placebo) 
than subjects walking more than 450 meters (n=8) (less impaired) at baseline (8.6 meters 
compared to placebo), a finding consistent with results from a post-hoc analysis of the SPIMM- 
201 trial. 
The Primary Mitochondrial Myopathy Disease Symptom Assessment (the PMMSA, formerly the 
Mitochondrial Disease Symptom Assessment), a novel, daily patient-reported outcome (PRO) 
measure developed and validated by Stealth BT in accordance with FDA standards to assess key 
symptoms of PMM, was utilized to better understand the patients’ perspective and disease 
experience during the trial. The PMMSA assesses 10 symptoms experienced by patients with 
PMM on a 4-point scale. Stealth BT analyzed the results using pre-specified fatigue subscales 
focusing on the myopathic symptoms most commonly associated with PMM, namely, tiredness 
at rest, tiredness during activities, muscle weakness at rest, and muscle weakness during 
activities (Total Fatigue Score) as well as tiredness during activities and muscle weakness during 
activities (Total Fatigue During Activities Score). The PMMSA Total Fatigue Score has been 
shown to be reliable and valid based on the meaningful correlations with the patient global 
assessment and physician global assessment as well as performance measures in both cross- 
sectional and longitudinal analyses. The score is also strongly associated with the Neuro-QoL 
Fatigue Short Form (r=0.79, p<0.001), which provides compelling evidence that it is measuring 
similar domains. Based on the anchor- and distribution-based responder definition analyses for 
the PMMSA Total Fatigue Score, an approximate 1.6-point change from baseline (approximately 
14% on the scale) signifies a potentially clinically meaningful improvement. 
While on elamipretide, subjects reported less Total Fatigue every week, culminating in a 
clinically meaningful 1.7-point reduction in symptom severity at the end of the treatment period 
compared to placebo (2.2 point [19%] reduction from baseline) (p=0.0006). Conversely, while 
on placebo, subject-reported Total Fatigue did not change by more than 0.1 points during the 
treatment period. Similarly, while on elamipretide, subjects reported less Total Fatigue During 
Activities every week, culminating in a 0.8-point reduction in symptom severity at the end of the 
treatment period (p=0.0018). Conversely, while on placebo, subject-reported Total Fatigue 
During Activities score did not change by more than 0.2 points during the treatment period. 
Table 3 provides a summary of the change by trial week in the PMMSA fatigue scores. 

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Table 3: 
Summary of Change from Baseline by Week in PMMSA Fatigue Scores 
(Trial SPIMM-202) 
 
Endpoint 
Visit1 
LSMean 
Elamipretide 
(n=30) 
LSMean 
Placebo 
(n=30) 
LSMean Difference 
(ELAM – Placebo) 
(95% CI) 
p- 
value2 
Total Fatigue 
Pre-dose 
11.3 
11.2 
0.1 (-0.9, 1.0) 
0.8491 
Week 1 
10.0 
10.8 
-0.8 (-1.4, -0.3) 
0.0062 
Week 2 
9.9 
10.7 
-0.9 (-1.6, -0.1) 
0.0283 
Week 3 
9.3 
10.8 
-1.4 (-2.3, -0.6) 
0.0023 
Week 4 
9.1 
10.8 
-1.7 (-2.6, -0.8) 
0.0006 
Two Weeks 
Post-Treatment 
10.4 
10.9 
-0.4 (-1.1, 0.3) 
0.2247 
Total Fatigue 
During Activities 
Pre-dose 
5.9 
6.0 
-0.1 (-0.6, 0.4) 
0.6790 
Week 1 
5.2 
5.7 
-0.4 (-0.7, -0.1) 
0.0085 
Week 2 
5.2 
5.5 
-0.4 (-0.8, 0.0) 
0.0557 
Week 3 
4.9 
5.6 
-0.7 (-1.2, -0.3) 
0.0028 
Week 4 
4.8 
5.8 
-0.8 (-1.2, -0.3) 
0.0018 
Two Weeks 
Post-Treatment 
5.4 
5.7 
-0.2 (-0.5, 0.1) 
0.1013 
Abbreviations: 6MWT = 6-Minute Walk Test; CI = Confidence interval; LS = Least squares; LSM Diff = Least 
Squares Mean Difference; SD = Standard deviation. 
1. Predose, Weeks 1, 2, 3, 4, and End of Treatment Period: for Period 1 and Period 2 based on the weekly 
average of the last 7 days of visit. 
2. p-value and 95% CI of the difference are based on the mixed model which includes treatment, period, and 
sequence as fixed effects and subjects nested within sequence as a random effect. Weekly score calculated 
as the average of the daily scores over a week. If 4 or more daily scores are missing, the weekly score is set 
to missing. 
Subjects also completed the Neuro-QoL Fatigue Short Form at baseline and at the end of each 
treatment period. The results suggested a reduction in reported fatigue and quality-of-life items 
during elamipretide treatment, with a 4-point T-score reduction relative to placebo (p=0.0115). 
In addition, the first time subjects completed the PMMSA, they were asked to identify which of 
the 10 items on the PMMSA was the “most bothersome” symptom of their disease. This 
individualized secondary endpoint compared the change in severity of the selected symptom 
when the subject was treated with elamipretide vs. placebo. In this individualized approach, all 
subjects had a “symptom change” endpoint, but the individual symptoms were different across 
subjects. By focusing on the most severe symptoms for each subject, there is inherent clinical 
relevance in the individualized symptom endpoint. The results demonstrated an improvement in 
the subjects' “most bothersome” symptom culminating in a 0.3-point difference between 
treatment intervals (p=0.0111). 
Figure 3 below depicts the several efficacy variables in SPIMM-202. 

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Figure 3: 
SPIMM-202 Summary of Treatment Effect (Analysis Population – Intention- 
to-Treat [ITT] 
4.3.2. 
Summary of Safety 
 
4.3.2.1. 
Nonclinical Study Safety Findings 
The nonclinical testing of elamipretide encompasses a program of studies in pharmacology, 
metabolism, pharmacokinetics (PK), and toxicology. 
Elamipretide was effective in multiple models of cardio-renal disease and skeletal muscle 
dysfunction and has been active across all species tested to date, including mouse, rat, guinea 
pig, rabbit, dog, sheep, and pig. The effective dose range was 0.05 to 0.5 mg/kg/day. Based on 
results from a battery of secondary and safety pharmacology studies, elamipretide is not expected 
to cause any adverse off-target pharmacodynamic effects at therapeutic concentrations. 
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 are mediated by histaminergic-like reactions. Effects were associated with maximum 
elamipretide plasma concentration (Cmax) and were rapidly reversible as 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 transient decrease of blood pressure and heart rate, 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 ~20,000 ng/mL in both rats and dogs, which is 
more than 10-fold higher than the maximum observed human exposures at clinical doses. 
Intravenous administration of elamipretide to rats and dogs was well tolerated at the 
administration site. Local injection site reactions evident upon SC administration varied with 
species, dose and dose concentration. 
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 

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on fertility or embryo-fetal development. Similarly, elamipretide did not have any adverse 
effects on post-natal development. 
Elamipretide is metabolized via sequential C-terminal degradation to the tripeptide M1 and the 
dipeptide M2. The apparent t½ of M1 was comparable to that of elamipretide, whereas t½ of M2 
was longer than that of elamipretide. No sex difference was evident for either metabolite. The 
two metabolites were evaluated for systemic toxicity and in vivo genotoxicity. In addition, in 
silico analysis for genotoxic structural alerts was conducted on new impurities introduced in the 
modified manufacturing process for elamipretide HCl. This analysis confirmed the absence of 
structural alerts for genotoxicity. When tested directly, both M1 and M2 were negative for gene 
mutation, for receptor binding, and rat mast cell degranulation. Systemic exposure to the 
metabolites in rats and dogs was not related to any toxicity in acute, subchronic, or chronic 
studies. Neither M1 nor M2 metabolites showed biological activity when evaluated in an ex vivo 
guinea pig heart model. At a concentration of 1 µM, neither metabolite provided myocardial 
protection against ischemic reperfusion injury. 
 
4.3.2.2. 
Clinical Trial Safety Findings 
Parenteral administration of elamipretide was assessed following single and multiple IV and SC 
administrations. Dose levels studied ranged from approximately 0.7 mg/day to 300 mg/day. 
There were no apparent differences between the safety profiles of IV or SC elamipretide dosing 
routes except for injection site reactions which were widely reported in subjects receiving SC 
elamipretide. 
Differences (≥ 2% difference) in systemic treatment-emergent adverse events (TEAEs) reported 
in elamipretide- and placebo-treated subjects, summarized by dosing duration is displayed in 
Table 4. 
Table 4: 
Summary of Systemic TEAEs Reported in Greater Frequency (≥ 2% 
difference) in Elamipretide-treated Subjects Compared to Placebo-Treated 
Subjects 
 
Elamipretide 
Placebo 
Single Dose 
Headache 
4.5% 
2.3% 
Repeat dose ≤ 8 days 
Dizziness 
2.2% 
0.0% 
Repeat dose > 8 days (TEAEs > 5%) 
Increased eosinophils/eosinophilia 
48.6% 
0.0% 
Upper respiratory tract infection 
15.7% 
0.0% 
Increased blood immunoglobulin E 
10.0% 
0.0% 
Dizziness 
8.6% 
1.4% 
Headache 
8.6% 
2.9% 
Urinary tract infection 
7.1% 
0.0% 
Viral gastroenteritis 
5.7% 
0.0% 
Analysis of eosinophils in longer-term dosing regimens was characterized by eosinophil counts 
above the upper limit of normal (nominally 0.4 x109/L), up to a maximum count of 
approximately 2.0 x109/L. There have been no clinical signs and symptoms associated with 
elevated eosinophils. Further, the increase in eosinophils was not related to changes in other 
white cells and total white cell counts have not significantly increased.  No subject has been 

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withdrawn from treatment due to increased eosinophil counts. In general, the eosinophil counts 
appear to decrease to within normal limits with longer duration of elamipretide administration 
and return to pre-treatment levels after the end of elamipretide treatment. While TEAEs of 
respiratory tract and other infections have been reported at greater frequency than in placebo 
subjects, there is no evidence that these TEAEs are related to the increase in eosinophil counts. 
To further explore and characterize these findings of increased eosinophil counts, several studies 
have incorporated collection of Immunoglobulin E (IgE) values. Adverse events of blood 
Immunoglobulin E increased have been recorded, but no clear temporal relationship with an 
elevation in eosinophil counts has been established. Similar to the increase in eosinophils, there 
have been no clinical signs and symptoms associated with elevated IgE values. 
In SPICP-103, high dose IV infusions (56 – 140 mg/day) of elamipretide were administered 
daily for five days in healthy subjects. Four subjects reported events of paraesthesia or oral 
paraesthesia. These events generally occurred immediately after the end of the drug infusion, at 
the Tmax of elamipretide. Three of these AEs occurred in the 140-mg cohort, and 1 occurred in 
the 112-mg cohort and where Cmax was approximately 4-fold higher than that expected with the 
40-mg dose level selected for the Phase 3 clinical studies. All were reported to be mild in 
severity, resolved within 2 hours of symptom onset, and were not associated with 
hypersensitivity reactions. 
Injection site reactions were reported in the majority of subjects (>90%) receiving elamipretide 
by SC injection in any study.  Detailed characterization of the injection site reactions occurring 
in single dose SC clinical trials demonstrates that mild erythema, swelling and pruritus are the 
most commonly reported signs and symptoms and that pain and bruising may also be 
experienced. Generally, the injection site reactions resolved within 4 hours of elamipretide 
administration. In the longer-term studies reporting of injection site reaction commonly included 
the signs and symptoms previously mentioned as well as injection site induration, urticaria, 
haemorrhage and mass. In most subjects, the tolerability of the injection site reactions was not 
problematic and did not require treatment however, some subjects have been treated with topical 
and systemic antihistamines and/or topical corticosteroids in order to manage the impact of the 
signs and symptoms. In clinical trials > 8 days in duration, 4 subjects (5.7%) have discontinued 
study drug treatment due to injection site reactions and 2 additional subjects (2.9%) have had 
study drug interrupted due to injection site reaction. 
All additional assessments of safety (including vital signs and laboratory, ECG and physical 
examination findings) across all clinical studies have been unremarkable. 
In subjects with renal impairment who received elamipretide, 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 DDI studies carried out to date, co-administration of 
elamipretide with aspirin, with clopidogrel, or with UFH did not indicate a change in the nature, 
severity or frequency of AEs to the safety profile of either elamipretide or the comparator. 
Across all studies, with either IV and SC formulation, there have been no reports of pregnancy, 
exposure during lactation, overdoses, or abuse or misuse. 

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4.3.2.2.1. Clinical Safety in Primary Mitochondrial Myopathy (PMM) 
 
4.3.2.2.1.1. SPIMM-201 
The SPIMM-201 trial was a phase 1/2 multi-center, randomized, double-blind, placebo- 
controlled, multiple ascending IV dose trial that enrolled subjects ≥16 and ≤65 years with PMM. 
Three escalating doses (0.01, 0.10, and 0.25 mg/kg/hour infused for 2 hours) were studied (one 
dose per cohort) and infused daily for 5 days. The trial enrolled three cohorts of 12 subjects. 
Within each cohort, 9 subjects were randomized to active drug and 3 subjects were randomized 
to placebo. Prior to each dose escalation, the safety and tolerability data from the previous cohort 
was reviewed. No dose-limiting safety concerns were identified and 36 subjects were enrolled. 
Five days of daily IV elamipretide was well tolerated. Overall, at least one TEAE was reported 
by two-thirds of subjects. There were no deaths, serious AEs (SAEs), or TEAEs resulting in 
withdrawal in this trial. System Organ Classes (SOCs) with the most TEAEs were nervous 
system disorders (27.8%) and gastrointestinal disorders (16.7%). The most common TEAE 
overall was headache in 6 (16.7%) subjects, followed by dizziness in 3 subjects. There were no 
treatment-related TEAEs that were severe in intensity. 
 
4.3.2.2.1.2. SPIMM-202 
The SPIMM-202 trial was a randomized, double-blind, placebo-controlled, multi-center two 
period crossover trial which enrolled 30 of the 36 subjects who completed participation in the 
SPIMM-201 trial (all subjects residing in North America [35] were given the opportunity to 
participate). Subjects were randomized (1:1) to one of two sequence groups: 4 weeks of 
treatment with 40 mg SC elamipretide or placebo administered once daily in Treatment Period 1, 
followed by 4 weeks of treatment with the opposite treatment assignment once daily in 
Treatment Period 2, separated by 4-week washout period. 
Twenty-eight days of daily SC elamipretide was generally well tolerated. Overall, at least one 
TEAE was reported by all (100%) subjects during elamipretide treatment and half (50%) of 
subjects while on placebo. Injection site reactions were experienced by 80.0% subjects during 
the elamipretide treatment period, frequently characterized by erythema (57%), pruritus (47%), 
pain (20%), urticaria (20%), and irritation (10%). There were no deaths or SAEs. One subject 
withdrew from the trial due to moderate injection site pain while on elamipretide treatment. 
The only common systemic TEAE (>10%) reported during elamipretide treatment was dizziness 
(10%). Besides dizziness, all other TEAEs were reported with similar frequency and severity in 
subjects receiving elamipretide when compared to placebo. 
Laboratory data demonstrated elevations (>0.45 cells x109/L) in eosinophils beginning at 
approximately 28 days after initiation of elamipretide treatment in numerous subjects (20.0%). 
These laboratory findings were neither reported to be associated with any clinical manifestations 
nor resulted in any reported TEAEs. In general, these elevations were demonstrated to have 
returned to within normal range or to baseline levels at the follow-up visit two weeks after the 
end of elamipretide treatment. There were no other identified safety concerns in this trial with 
respect to other clinical laboratory results, physical examinations, vital signs, ECG data or 
suicide assessments between the elamipretide and placebo treated periods. 

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4.4. 
Discussion of Trial Design and Control 
SPIMM-301 is a randomized, double-blind, parallel-group, placebo-controlled assessment of 
efficacy and safety in subjects with PMM. Subjects will be randomized (1:1) to one of two 
groups: 24 weeks of single daily SC doses of 40 mg elamipretide administered with the 
elamipretide delivery system or 24 weeks of single daily SC doses of placebo. Blinded treatment 
will be used to reduce potential bias during data collection and evaluation of endpoints. 
PART 2 is an open-label, non-controlled treatment in which all subjects will receive elamipretide 
treatment for up to 144 weeks. This treatment period will allow for assessment of longer-term 
safety and tolerability in the target population, as well as allow for detection of less-frequent 
AEs/Adverse Device Effects (ADEs). 
The Trial Schematics are presented in Appendix 3. 
 
4.5. 
Rationale for Selection of Doses in the Trial 
During the course of clinical development, multiple clinical pharmacology studies have been 
conducted to assess the safety, tolerability and PK of elamipretide and its metabolites. The 
clinical development objective of these studies was to determine the most appropriate dose and 
regimen for SPIMM-301. Using safety and efficacy outcomes from SPIMM-201 and SPIMM- 
202 to determine dose-response and chronic nonclinical exposure data to determine exposure 
margins, a dose of 40 mg of SC elamipretide administered daily was deduced to be the most 
appropriate dose to maximize desirable effects and minimize undesirable effects. 
The SPIMM-201 trial (all subjects GFR > 60 mL/min) provided supporting information 
regarding safety and plasma exposure in the PMM population following repeat-dose 
administration of elamipretide at 0.01, 0.1, and 0.25 mg/kg/hr as a 2-hour IV infusion (Total 
Daily Dose [TDD] 0.02, 0.2, and 0.5 mg/kg) for 5 days. Elamipretide demonstrated an 
acceptable safety and tolerability profile. The highest dose of elamipretide, 0.25 mg/kg/hr. a 
TDD of 0.5 mg/kg/day, was associated with a 44.1-meter improvement in distance walked on the 
6MWT over placebo (p=0.0528) at Day 5. Further, there was a significant linear dose response 
for the 6MWT at Day 5, showing increasing benefit as the dose of elamipretide increases 
(p=0.014). PK data from the SPIMM-201 trial in PMM subjects is presented in Table 5. 
 
Table 5: Mean Steady-State PK Parameters* on Day 5 (Males and Females Combined) 
Following Repeat Administration of Elamipretide (MTP-131) at 0.01, 0.1 and 
0.25 mg/kg/hr as a 2-hour IV infusion, Once Daily, for 5 Days (Trial SPIMM- 
201) 
Dose 
Mean Body 
Weight of 
Dose Group 
(kg) 
Mean Total 
Daily Dose 
(TDD) (mg) 
Analyte 
Cmax (ng/mL) 
[n] 
AUC0-last 
(ng.h/mL) 
[n] 
0.01 mg/kg/hr given as 
a 2hr IV infusion 
70.6 
1.412 
MTP-131 
35.8 [n=7] 
140 [n=6] 
M1 
15 [n=7] 
111 [n=7] 
M2 
2.6 [n=7] 
44 [n=6] 
0.1 mg/kg/hr given as a 
2hr IV infusion 
63.7 
12.74 
MTP-131 
498 [n=9] 
1992 [n=5] 
M1 
183 [n=9] 
1672 [n=5] 
M2 
39.6 [n=9] 
661 [n=8] 

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Dose 
Mean Body 
Weight of 
Dose Group 
(kg) 
Mean Total 
Daily Dose 
(TDD) (mg) 
Analyte 
Cmax (ng/mL) 
[n] 
AUC0-last 
(ng.h/mL) 
[n] 
0.25 mg/kg/hr given as 
a 2hr IV infusion 
59.2 
29.6 
MTP-131 
1050 [n=9] 
4050 [n=7] 
M1 
285 [n=9] 
2190 [n=7] 
M2 
68.8 [n=9] 
1169 [n=8] 
*Calculations based on nominal time points. 
In normal renal function (GFR > 90 mL/min), the systemic exposure (in terms of mean AUC0-τ 
on Day 7) to elamipretide following repeat SC injection at 40 mg in 1 mL was 3,810 ng∙h/mL, 
while mean Cmax on Day 7 was 1,320 ng/mL. No accumulation of elamipretide was seen 
following repeat dosing for seven consecutive days. Neither metabolite of elamipretide (M1 and 
M2) is active or implicated in toxicology. 
Bioavailability for Cmax and AUC0-last following administration of a TDD of 40 mg elamipretide 
as a two hour, IV infusion and as a single SC injection can be estimated by applying a correction 
factor to the IV parameters to normalize TDD to 40 mg (assumes proportionality of relationship 
between dose levels and exposure parameters for elamipretide, M1 and M2, as previously 
described) and deriving percentage exposures (Table 6). 
 
Table 6: Estimated Bioavailability of SC Administration (40 mg as a 1 mL injection) 
Versus Two Hour IV Infusion Following Repeat Administration of Elamipretide 
(MTP-131) (Trial SPIMM-201) 
PK Parameters 
following 40mg SC 
Estimated 
Bioavailability 
Dose 
Mean 
TDD 
(mg) 
Correctio 
n factor 
for 40 mg 
TDD 
Analyte 
Cmax 
(ng/mL 
) 
AUC0-last 
(ng.h/mL 
) 
Cmax 
(ng/mL) 
AUC0-last 
(ng.h/mL 
) 
Cmax 
AUC0- 
last 
0.25 
mg/kg/hr 
given as 
a 2hr IV 
infusion 
29.6 
1.35 
MTP-131 
1418 
5468 
1,300 
3,720 
92% 
68% 
M1 
385 
2957 
436 
3,100 
113% 
105% 
M2 
92.9 
1578 
88.0 
1,950 
95% 
124% 
*Calculations based on nominal time points. 
With a bioavailability of 68% (by AUC0-last), when comparing the SC injection to the two-hour 
IV infusion, exposure to elamipretide by 40 mg SC injection will be similar to exposure 
demonstrated in the 0.25 mg/kg/hr given as a 2hr IV infusion dose group in the SPIMM-201 trial 
in subjects weighing <80 kg therefore, it was hypothesized that treatment effect would not be 
altered by the change in dose route. This hypothesis was demonstrated in a further efficacy and 
safety trial in patients with PMM receiving 40 mg SC elamipretide (or placebo) once daily for 28 
days (SPIMM-202). 
In SPIMM-202, the primary efficacy results demonstrated that treatment with elamipretide 40 
mg resulted in a 19.8-meter improvement in the 6MWT distance over treatment with placebo 
(p=0.0833). Additionally, besides injections site reactions (ISRs), the safety profile was 
comparable to placebo. 

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Chronic (26-weeks in rat, Study SPI-CIT-15-03; 39-weeks in dog, Study SPI-CIT-15-02) repeat- 
dose toxicology studies have been conducted to evaluate the systemic toxicity and local 
tolerability of elamipretide administered as SC injections, once daily. No systemic toxicity was 
apparent at any elamipretide dose tested (up to the maximum feasible dose due to local 
tolerability) and the predominant trial findings were related to local ISRs and tolerability. Safety 
margin calculations for both nonclinical species, compared to the 40 mg/day (1 mL) SC dose in 
man are provided in Table 7. 
 
Table 7: Key Summary Steady-State PK Parameters Days 182 (Rat) and 273 (Dog) at the 
NOAEL/MFD with Safety Margins Versus. Human Exposure (SPISC-101, 40 
mg/day) (Study SPI-CIT-15-03 and Study SPI-CIT-15-02) 
PK in Man Following 
40mg SC 
Safety Margin 
Trial / NOAEL 
Species 
Analyte 
Cmax 
(ng/mL) 
AUC0-last 
(ng.h/mL) 
Cmax 
(ng/mL) 
AUC0-last 
(ng.h/mL) 
By 
Cmax 
By 
AUC 
SPI-CIT-15-03 
15 mg/kg/day 
Rat 
MTP-131 
6875 
23,850 
1,300 
3,720 
x5 
x6 
M1 
7385 
43,000 
436 
3,100 
x17 
x14 
M2 
260 
2470 
88.0 
1,950 
x3 
x1.8 
SPI-CIT-15-02 
10 mg/kg/day 
Dog 
MTP-131 
13050 
21135 
1,300 
3,720 
x10 
x6 
M1 
1709 
5507 
436 
3,100 
x4 
x1.8 
M2 
312 
5093 
88.0 
1,950 
x4 
x3 
The data displayed demonstrate that exposure to elamipretide, M1 and M2 in the chronic toxicity 
studies are supportive of chronic dosing at 40 mg/day by SC injection, in human, assuming an 
average body weight of approximately 75 kg and normal renal function (GFR > 90 mL/min). 
To ensure inclusion of subjects representative of the PMM patient population, the impact of renal 
impairment on elamipretide, M1, and M2 was evaluated. Parent and metabolite exposure data 
from the chronic SC toxicity studies of elamipretide in rat and dog, extrapolated to predict 
exposure (AUC0-24) in subjects with varying degrees of renal impairment following a SC dose of 
elamipretide at 40 mg/day, demonstrate that nonclinical exposure to M2 is adequate to support 
the chronic SC administration of elamipretide at 40 mg/day in subjects with GFR ≥ 30 mL/min. 
This assessment in based on metabolite exposure in one nonclinical species which is equal to, or 
greater than, the predicted exposure in subjects with reduced renal function. 
The efficacy and safety data presented from subjects with PMM (SPIMM-201 and SPIMM-202) 
support 40 mg SC elamipretide as the appropriate dose to maximize the desirable effects without 
additional undesirable effects. The nonclinical exposure to metabolite M2 limits the study of 
higher doses of SC elamipretide, if we intend to be most inclusive of subjects (GFR ≥30 
mL/min) with PMM. 

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5. 
TRIAL OBJECTIVES 
This trial is designed with 2 parts, SPIMM-301 (PART 1) and SPIMM-301 OLE (PART 2). The 
objectives of each part are consistent with the trial design. 
• 
PART 1 is a 24-week, randomized, double-blind, parallel-group, placebo-controlled 
assessment of the efficacy and safety of single daily SC doses of 40 mg elamipretide 
(vs placebo) administered with the elamipretide delivery system as a treatment for 
subjects with PMM. 
• 
PART 2 is an up to 144-week, open-label assessment of the long-term safety and 
tolerability of single daily SC doses of 40 mg elamipretide administered with the 
elamipretide delivery system in subjects with PMM. 
 
5.1. 
PART 1 Objectives 
5.1.1. 
Primary Objective 
The primary objective of PART 1 is to evaluate the effect of single daily SC doses of 40 mg 
elamipretide administered with the elamipretide delivery system for 24 weeks on the: 
• 
Distance Walked on the 6MWT 
• 
Total Fatigue on the Primary Mitochondrial Myopathy Symptom Assessment© 
(PMMSA) 
 
5.1.2. 
Secondary Objectives 
Secondary objectives of PART 1 are: 
• 
To evaluate the effect of single daily SC doses of 40 mg elamipretide administered 
with the elamipretide delivery system for 24 weeks as measured by changes in the: 
– Fatigue During Activities on the PMMSA 
– Neuro-QoL Short Form Fatigue 
– Most bothersome symptom on the PMMSA 
– Neuro-QoL Fatigue activities of daily living (specific items from the Neuro-QoL 
Item Bank) 
• 
To evaluate the safety and tolerability of single daily SC doses of 40 mg elamipretide 
administered with the elamipretide delivery system for 24 weeks. 
 
5.1.3. 
Exploratory Objectives 
Exploratory objectives of PART 1 are to evaluate the effect of single daily SC doses of 40 mg 
elamipretide administered with the elamipretide delivery system for 24 weeks as measured by 
changes in the: 
• 
Individual symptoms on the PMMSA 
• 
Alternate version of the PMMSA Total Fatigue Score 

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• 
Individual items on the Neuro-QoL Fatigue 
• 
EQ-5D-5L 
• 
Patient Global Impression (PGI) Scales 
• 
Clinician Global Impression (CGI) Scales 
5.1.4. 
Pharmacokinetics (PK) 
• 
The PK of elamipretide 
5.2. 
PART 2 Objective 
The PART 2 objective is to assess the long-term safety and tolerability of single daily SC doses 
of 40 mg elamipretide administered with the elamipretide delivery system for up to 144 weeks. 

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6. 
INVESTIGATIONAL PLAN 
6.1. 
SPIMM-301 Overall Trial Design 
This randomized, double-blind, parallel-group, placebo-controlled trial will enroll approximately 
202 subjects who have PMM. There are 2 parts to this trial. 
• 
PART 1 is a 24-week, randomized, double-blind, parallel-group, placebo-controlled 
assessment of the efficacy and safety of single daily SC doses of 40 mg elamipretide (vs 
placebo) administered with the elamipretide delivery system as a treatment for 
subjects with PMM. Subjects will be randomized (in a ratio of 1:1) to one of two 
groups: 
– 24 weeks of single daily SC doses of 40 mg elamipretide or 
– 24 weeks of single daily SC doses of placebo. 
• 
PART 2 is an up to 144-week, open-label assessment of the long-term safety and 
tolerability of single daily SC doses of 40 mg elamipretide administered with the 
elamipretide delivery system in subjects with PMM. Subjects who continue into 
PART 2 will receive treatment with 40 mg SC elamipretide administered with the 
elamipretide delivery system for up to 144 weeks. Thus, treatment during PART 2 
will be as follows: 
– Subjects who are originally randomized to elamipretide during PART 1 (double- 
blind treatment) will continue receiving elamipretide during PART 2. 
– Subjects who are originally randomized to placebo during PART 1 (double-blind 
treatment) will switch to treatment with elamipretide during PART 2. 
Note that the duration of PART 2 treatment for each subject will be the shortest of the following: 
• 
144 weeks 
• 
Regulatory approval and commercial availability of the elamipretide delivery system 
in the subject’s respective country 
• 
Termination of the clinical development for elamipretide in subjects with PMM. 
6.1.1. 
PART 1 
 
6.1.1.1. 
PART 1 Screening Period 
Screening will begin with the subject’s signature of the informed consent form (ICF) and will 
last a minimum of 7 days to a maximum of 28 days. Subjects not previously enrolled in SPIMM- 
300, however, may have a longer screening period for review by the Adjudication Committee to 
determine their eligibility for study enrollment. Subjects will undergo Screening procedures as 
described in the PART 1 Schedule of Assessments (Appendix 1) and will be trained and 
instructed to complete the PMMSA daily during the Screening Period, in an electronic or paper 
diary, in order to characterize their baseline disease status and to assess compliance. Subjects 
who complete Screening and continue to meet all trial requirements, including all Inclusion 
Criteria and none of the Exclusion Criteria, may be randomized (stratified by the 

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subclassification of the genetic abnormality determined to be the primary cause of the subject’s 
PMM [DiMauro 2003] as determined by the Adjudication Committee) and enter the Treatment 
Period. 
 
6.1.1.2. 
PART 1 Treatment Period 
The Treatment Period will begin on the day of the Baseline Visit, which is defined as Day 1, and 
lasts for 24 weeks. Subjects (and caregivers if needed) will be trained on the procedure for 
administration of the elamipretide delivery system (the investigational medicinal product [IMP] 
[elamipretide or placebo], the elamipretide pen injector, and needle), and recording of the 
location (injection in the abdomen, rotating around the four abdominal quadrants, or other 
appropriate location [after Investigator consultation with the Sponsor]) and time (at 
approximately the same time each day [e.g., early morning, noon, or early afternoon]) of the IMP 
administration daily in the electronic or paper diary. An elamipretide delivery system training kit 
and checklist will be provided to the clinical site to assist in training. At the Baseline Visit, 
following completion of all Baseline procedures described in the PART 1 Schedule of 
Assessments, subjects or trained caregivers will administer IMP at the clinical site. On non-visit 
days, subjects (or trained caregivers) will administer the IMP daily during the Treatment Period. 
The subject will return to the clinical site for the Week 4, Week 12, and Week 24 Visits for 
assessments, to administer the IMP (subject or trained caregiver), and to return all used IMP 
supplies. During the Treatment Period, subjects will continue to follow all trial requirements, 
including recording the location and time of the IMP administration daily and completing the 
PMMSA daily. The Treatment Period will conclude with a visit to the clinical site at the Week 
24 Visit when subjects will return all trial-related supplies. 
At the Week 24 Visit, if the subject confirms they are willing and able to continue to adhere to 
trial requirements and the Investigator determines the subject meets the Continuation Criteria the 
subject may continue into Part 2. If the subject continues into PART 2, the subject will continue 
(or start, for subjects treated with placebo in PART 1) elamipretide therapy the day of the Week 
24 Visit (using the PART 2 supply of IMP) and continue trial activities as described in the PART 
2 Schedule of Assessments (Appendix 2). Subjects who will not continue into PART 2 will not 
be administered IMP and will enter the PART 1 Follow-Up Period. 
For all subjects, it is the intent that subjects who discontinue IMP (at any time) for any reason 
will continue to be followed for all protocol-planned trial visits through the completion of the 
PART 1 Treatment Period, and will have all endpoints (including efficacy) collected 
accordingly. In the interest of the subject, subjects who withdraw consent or are withdrawn from 
the trial by the investigator should be encouraged to complete an Early Discontinuation Visit as 
soon as possible and an effort should be made to complete and report the observations as 
thoroughly as possible up to the date of withdrawal. 
 
6.1.1.3. 
PART 1 Follow-Up Period (for subjects not continuing into PART 2) 
The PART 1 Follow-Up Period will begin after completion of the Week 24 Visit and will last for 
4 weeks. Subjects will return to the clinical site for the PART 1 End-of-Trial Visit for final safety 
assessments, as described in the PART 1 Schedule of Assessments, and return all remaining trial- 
related supplies not previously returned. 

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6.1.2. 
PART 2 
 
6.1.2.1. 
PART 2 Treatment Period 
The Treatment Period will begin on the day of the PART 1 Week 24 Visit (at the administration 
of IMP) using the PART 2 supply of IMP. Subjects (or trained caregivers) will administer the 
IMP daily during the Treatment Period. The subject will return to the clinical site for the Week 
28, Week 36, and Week 48 Visits for assessments, to administer the IMP (subject or trained 
caregiver), and to return all used IMP supplies. Additional visits will occur every 24 weeks for 
the remainder of the Treatment Period, with phone calls to the subject every 12 weeks between 
clinical site visits. During the Treatment Period, subjects will continue to follow all trial 
requirements. 
In the interest of the subject, subjects who withdraw consent or are withdrawn from the trial by 
the investigator should be encouraged to complete an Early Discontinuation Visit as soon as 
possible and an effort should be made to complete and report the observations as thoroughly as 
possible up to the date of withdrawal. 
 
6.1.2.2. 
PART 2 Follow-Up Period 
The PART 2 Follow-Up Period will begin after completion of the Week 168 Visit and will last 
for 4 weeks. Subjects will continue to follow all trial requirements. Subjects will return to the 
clinical site for the PART 2 End-of-Trial Visit for final safety assessments, as described in the 
PART 2 Schedule of Assessments, and return all remaining trial-related supplies not previously 
returned. 
 
6.2. 
Schedule of Visit Assessments 
The Schedule of Assessments is described first for PART 1, which includes an up-to 4-week 
screening period, a 24-week double-blind treatment period, and a 4-week post-treatment follow- 
up period for subjects not continuing to PART 2. The Schedule of Assessments for PART 2 is 
then described, and includes an up-to 144 week PART 2 Treatment Period and a 4-week post- 
treatment follow-up period. 
 
6.2.1. 
PART 1 
Trial procedures and their timing are summarized in the PART 1 Schedule of Assessments 
(Appendix 1) and Trial Schematic (Appendix 3). All clinical site visits should occur at 
approximately (±2 hours) the same time during the day and subjects should have at least 1 hour 
of fasting (e.g., no large meals) prior to the 6MWT. Trial Days are relative to the Baseline Visit, 
and thus Day 1 is the first day of treatment with double-blind IMP, while Day -1 is the day 
immediately prior. 
 
6.2.1.1. 
Screening Visit/Period: Day -28 to Day -1 (minimum of 7 days) 
NOTE: The PMMSA at the Screening Visit should be the last trial assessment completed. 
The 6MWT at the Screening Visit should be completed prior to the PMMSA. 
• 
Review and sign the Informed Consent Form (ICF). 
• 
Record demographics (age, gender, ethnicity, race). 

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• 
Review all Inclusion and Exclusion Criteria. 
• 
Record medical/surgical history and from subjects not previously enrolled in SPIMM- 
300, including previous genetic testing results (as described in Section 6.3.1). NOTE: 
genetic testing will not be provided as part of the SPIMM-301 trial. 
• 
Record concomitant medication (including supplements and vitamins) (as described 
in Section 6.3.1). 
• 
During the screening period, assess for any pre-treatment event and record as medical 
history or AE (as described in Sections 9.3). 
• 
Complete a physical examination (as described in Section 6.3.2). 
• 
Collect vital signs (as described in Section 6.3.4). 
• 
Complete 12-lead resting ECG (as described in Section 6.3.5). 
• 
Complete the Columbia Suicide Severity Rating Scale (C-SSRS) 
“Baseline/Screening” (as described in Section 6.3.3 and provided in Appendix 5). 
• 
Draw blood and collect urine for clinical laboratory testing and urinalysis as outlined 
in Appendix 4 (and as described in Section 6.3.6). 
• 
Complete serum pregnancy test (only for women of childbearing potential). 
• 
Provide subject with the electronic or paper diary and train subject on the procedure 
to complete the PMMSA. Complete the PMMSA (as described in Section 6.3.8 and 
as outlined in Appendix 8) and collect results in the electronic or paper diary. The 
PMMSA should be completed daily during the Screening Period. 
• 
Complete the Neuro-QoL Fatigue (as described in Section 6.3.9 and as provided in 
Appendix 9). 
• 
Complete the EQ-5D-5L (as described in Section 6.3.10 and as provided in 
Appendix 10). 
• 
Complete the Patient Global Impression (PGI) Scales (as described in Section 6.3.11 
and as provided in Appendix 11). 
• 
Complete the Clinician Global Impression (CGI) Scales (as described in 
Section 6.3.12 and as provided in Appendix 12). 
• 
Conduct the 6MWT (as described in Section 6.3.13 and as outlined in Appendix 13). 
6.2.1.2. 
Baseline Visit (Day 1) 
NOTE: Subjects who have been deemed eligible during Screening Period will return for 
randomization and the following procedures will be performed. The 6MWT must be completed 
after all other trial assessments. On days of trial visits, the IMP should be administered at the 
clinic. At Baseline Visit, the IMP administration will occur after the completion of all Visit 
procedures. 
• 
Review all Inclusion Criteria and Exclusion Criteria. 

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• 
Assess AEs/ADEs related to a trial procedure and/or meet seriousness criteria that 
occurred since the signing of the informed consent form as Section 9.9.2. 
• 
Update medical/surgical history during the Screening Period (as described in 
Section 6.3.1). 
• 
Update concomitant medication/procedures (including supplements and vitamins) 
during the Screening Period (as described in Section 6.3.1). 
• 
Complete a physical examination (as described in Section 6.3.2). 
• 
Collect vital signs (as described in Section 6.3.4). 
• 
Complete 12-lead resting ECG (as described in Section 6.3.5). 
• 
Complete the C-SSRS “Since Last Visit” (as described in Section 6.3.3 and provided 
in Appendix 6). 
• 
Draw blood and collect urine for clinical laboratory testing and urinalysis as outlined 
in Appendix 4 (and as described in Section 6.3.6). An additional blood sample will be 
collected and stored for assessing the immunogenicity potential of the IMP. 
• 
Complete urine pregnancy test (only for women of childbearing potential). 
• 
Complete the PMMSA (as described in Section 6.3.8 and as outlined in Appendix 8) 
and collect results in the electronic or paper diary. The PMMSA should be completed 
daily during the Treatment Period. 
• 
Complete the Neuro-QoL Fatigue (as described in Section 6.3.9 and as provided in 
Appendix 9). 
• 
Complete the EQ-5D-5L (as described in Section 6.3.10 and as provided in 
Appendix 10). 
• 
Complete the Patient Global Impression (PGI) Scales (as described in Section 6.3.11 
and as provided in Appendix 11). 
• 
Complete the Clinician Global Impression (CGI) Scales (as described in 
Section 6.3.12 and as provided in Appendix 12). 
• 
Conduct the 6MWT (as described in Section 6.3.13 and as outlined in Appendix 13). 
If the subject meets all SPIMM-301 eligibility criteria and has completed all baseline 
assessments, the subject may be randomized (as described in Section 8.5). Following 
randomization: 
• 
Provide elamipretide delivery system supplies. 
• 
Train subject (and caregivers if needed) on the procedure for administration of the 
elamipretide delivery system, and recording of the location (injection in the abdomen, 
rotating around the four abdominal quadrants, or other appropriate location [after 
Investigator consultation with the Sponsor]) and time (at approximately the same time 
each day [e.g., early morning, noon, or early afternoon]) of the IMP administration in 
the electronic or paper diary. 

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• 
Administer (by subject or trained caregiver) IMP with the elamipretide delivery 
system, recording the location, date, and time of the IMP administration in the 
electronic or paper diary. 
• 
Assess for ISR 30 (±5) minutes after the IMP administration with the elamipretide 
delivery system (as described in Section 6.3.15). 
 
6.2.1.3. 
Double-Blind Treatment Period 
• 
Complete the PMMSA (as described in Section 6.3.8 and as outlined in Appendix 13) 
daily during Treatment Period. 
• 
Subjects (or trained caregivers) will administer IMP with the elamipretide delivery 
system, recording the location, date, and time of the IMP administration in the 
electronic or paper diary. 
 
6.2.1.4. 
Week 4 (Day 29 ±2), Week 12 (Day 85 ±4), and Week 24 (Day 169 +14 days) 
Visits 
NOTE: The 6MWT must be completed after all other trial assessments. On days of trial 
visits, the IMP should be administered at the clinical site. At the Week 4, Week 12, and Week 24 
Visits, the IMP administration should occur after all other trial procedures. At the Week 24 Visit, 
IMP administration will only occur if the subject is continuing to PART 2 of the SPIMM-301 
trial. 
• 
Collect all used IMP supplies (Week 4 and Week 12 Visits) and all trial-related 
supplies in addition to all elamipretide delivery system supplies (Week 24 Visit) and 
assess compliance. 
• 
Provide new IMP supplies (Week 4 and Week 12). At the Week 24 Visit, if the 
subject is continuing to PART 2, provide new elamipretide delivery system supplies. 
• 
Update concomitant medication/procedures (including supplements and vitamins) 
during the Treatment Period (as described in Section 6.3.1). 
• 
Assess AEs/ADEs. 
• 
Complete a physical examination (as described in Section 6.3.2). 
• 
Collect vital signs (as described in Section 6.3.4). 
• 
Complete 12-lead resting ECG (as described in Section 6.3.5). 
• 
Complete the C-SSRS “Since Last Visit” (as described in Section 6.3.3 and provided 
in Appendix 6). 
• 
Draw blood and collect urine for clinical laboratory testing and urinalysis as outlined 
in Appendix 4 (and as described in Section 6.3.6). At the Week 24 Visit, an additional 
blood sample will be collected and stored for assessing the immunogenicity potential 
of the IMP. 
• 
Draw blood for PK testing as described in Section 6.3.14: 
– Week 4: 1 hour post dose (± 10 min) 

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– Week 12: 30 min, 2 hours, and 4 hours post dose (± 10 min) 
– Week 24: pre-dose (-10 min) 
• 
Complete the PMMSA (as described in Section 6.3.8 and as outlined in Appendix 8) 
and collect results in the electronic or paper diary. The PMMSA should be completed 
daily during the Treatment Period. 
• 
Complete the Neuro-QoL Fatigue (as described in Section 6.3.9 and as provided in 
Appendix 9). 
• 
Complete the EQ-5D-5L (as described in Section 6.3.10 and as provided in 
Appendix 10). 
• 
Complete the Patient Global Impression (PGI) Scales (as described in Section 6.3.11 
and as provided in Appendix 11). 
• 
Complete the Clinician Global Impression (CGI) Scales (as described in 
Section 6.3.12 and as provided in Appendix 12). 
• 
Conduct the 6MWT (as described in Section 6.3.13 and as outlined in Appendix 13). 
• 
Administer (by subject or trained caregiver) IMP with the elamipretide delivery 
system, recording the location, date, and time of the IMP administration in the 
electronic or paper diary. This is not performed at Week 24 Visit unless the subject is 
continuing into PART 2. If the subject continues into PART 2, the subject will 
continue (or start, for subjects treated with placebo in PART 1) elamipretide therapy 
the day of the Week 24 Visit (using the PART 2 supply of IMP). 
Note: Administration of PART 2 IMP at the Week 24 Visit is the start of PART 2 
Treatment Period. 
• 
Assess for ISR 30 (±5) minutes after the IMP administration with the elamipretide 
delivery system (as described in Section 6.3.15). This is not performed at Week 24 
Visit unless the subject is continuing into PART 2. 
• 
Remind women of childbearing potential and male subjects with female partners of 
child-bearing potential to use a highly effective method of contraception until 28 days 
after the last dose of IMP (Week 24 Visit). 
• 
Review all PART 2 Continuation Criteria (Week 24 Visit). 
• 
Schedule next center visit: 
– Post-treatment follow-up visit for subjects not continuing into PART 2. 
– Week 28 visit for subjects continuing into PART 2. 
6.2.1.5. 
PART 1 Post-Treatment Follow-Up Period (4 weeks [+7 days]) 
At the Week 24 Visit, the subject and the Investigator will determine whether the subject will 
continue into PART 2 (confirming the subject meeting the Continuation Criteria). Subjects who 
will not continue into PART 2 will complete the PART 1 Follow-Up Period and PART 1 End-of- 
Trial Visit. 

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For subjects not continuing into PART 2, the PART 1 Follow-Up Period will begin after 
completion of the Week 24 Visit and will last for 4 weeks. Subjects will return to the clinical site 
for the PART 1 End-of-Trial Visit for final safety assessments, as described in the PART 1 
Schedule of Assessments, and return all remaining trial-related supplies not previously returned. 
 
6.2.1.5.1.  PART 1 End-of-Trial Visit (for subjects not continuing into PART 2) (Day 197 + 
7 days)/Early Discontinuation Visit 
• 
Collect all remaining trial-related supplies 
• 
Document concomitant medication (including supplements and vitamins). 
• 
Assess AEs/ADEs. 
• 
Complete a physical examination (as described in Section 6.3.2). 
• 
Collect vital signs (as described in Section 6.3.4). 
• 
Complete 12-lead resting ECG (as described in Section 6.3.5). 
• 
Complete the C-SSRS “Since Last Visit” (as described in Section 6.3.3 and provided 
in Appendix 6). 
• 
Draw blood and collect urine for clinical laboratory testing and urinalysis as outlined 
in Appendix 4 (and as described in Section 6.3.6). At the Early Discontinuation Visit 
(if applicable), an additional blood sample will be collected and stored for assessing 
the immunogenicity potential of the IMP. 
• 
Complete urine pregnancy test (only for women of childbearing potential). 
• 
If applicable, collect all trial-related supplies not previously returned. 
• 
If an Early Discontinuation Visit, remind women of childbearing potential and male 
subjects with female partners of child-bearing potential to use a highly effective 
method of contraception until 28 days after the last dose of IMP. 
 
6.2.2. 
PART 2 
Trial procedures and their timing for PART 2 are summarized in the PART 2 Schedule of 
Assessments (Appendix 2) and Trial Schematic (Appendix 3). While there is no screening period 
for PART 2, subjects continuing into PART 2 must meet the PART 2 Continuation Criteria. 
Subjects who decide not to continue in the PART 2 at the PART 1 Week 24 Visit are not eligible 
to participate in PART 2. 
Note: Administration of PART 2 IMP at the Week 24 Visit in PART 1 is the start of PART 2 
Treatment Period. 
During PART 2, an up-to 144-week Treatment Period is followed by a 4-week post-treatment 
Follow-Up Period and PART 2 End-of-Trial Visit that will close out each subject’s participation 
in the trial. Trial weeks will be relative to the start of treatment in PART 1. 

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6.2.2.1. 
PART 2 Treatment Period 
The treatment period during PART 2 will include both clinical site visits and phone calls from 
the site. 
 
6.2.2.1.1. Clinical Site Visits: Week 28 (± 1 week), 36, 48, 72, 96, 120, 144, and 168 (± 2 
weeks for each visit) 
At all clinical site visits during the PART 2 Treatment Period visits, subjects will return used 
IMP supplies. At the Week 168 visit, subjects will return all trial-related supplies. On days of 
trial visits, the IMP should be administered with the elamipretide delivery system at the clinical 
site. 
• 
Collect all used IMP supplies (all trial-related supplies at Week 168) and assess 
compliance. Collect the elamipretide pen injector at the Week 72 and 120 Visits. 
• 
Provide new IMP supplies (except at the Week 168 visit) and a new elamipretide pen 
injector at the Week 72 and 120 Visits. 
• 
Update concomitant medication/procedures (including supplements and vitamins) 
during the Treatment Period (as described in Section 6.3.1). 
• 
Assess AEs/ADEs. 
• 
Complete a physical examination (as described in Section 6.3.2). 
• 
Collect vital signs (as described in Section 6.3.4). 
• 
Complete 12-lead resting ECG (as described in Section 6.3.5). 
• 
Complete the C-SSRS “Since Last Visit” (as described in Section 6.3.3 and provided 
in Appendix 6). 
• 
Draw blood and collect urine for clinical laboratory testing and urinalysis as outlined 
in Appendix 4 (and as described in Section 6.3.6). 
• 
Administer IMP with the elamipretide delivery system (except at the Week 168 
Visit). 
• 
Assess for ISR 30 (±5) minutes after the IMP administration with the elamipretide 
delivery system (as described in Section 6.3.15) (except at the Week 168 Visit). 
• 
Remind women of childbearing potential and male subjects with female partners of 
child-bearing potential to use a highly effective method of contraception until 28 days 
after the last dose of IMP (Week 168 Visit). 
 
6.2.2.1.2.   Phone Calls: Weeks 60, 84, 108, 132, 156 (± 2 weeks for each) 
A phone call from the site will be made to the subject to assess AEs/ADEs and concomitant 
medications (see Appendix 7 for a sample of the telephone script to use). 
 
6.2.2.2. 
PART 2 Post-Treatment Follow-Up Period (4 weeks [+7 days]) 
The PART 2 Follow-Up Period will begin after completion of the Week 168 Visit and will last 
for 4 weeks. Subjects will continue to follow all trial requirements. Subjects will return to the 

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clinical site for the PART 2 End-of-Trial Visit for final safety assessments, as described in the 
PART 2 Schedule of Assessments, and return all remaining trial-related supplies not previously 
returned. 
 
6.2.2.2.1. PART 2 End-of-Trial Visit (Week 172 + 7 days)/Early Discontinuation Visit 
• 
Document concomitant medication (including supplements and vitamins). 
• 
Assess AEs/ADEs. 
• 
Complete a physical examination (as described in Section 6.3.2). 
• 
Collect vital signs (as described in Section 6.3.4). 
• 
Complete 12-lead resting ECG (as described in Section 6.3.5). 
• 
Complete the C-SSRS “Since Last Visit” (as described in Section 6.3.3 and provided 
in Appendix 6). 
• 
Draw blood and collect urine for clinical laboratory testing and urinalysis as outlined 
in Appendix 4 (as described in Section 6.3.6). At the Early Discontinuation Visit (if 
applicable), an additional blood sample will be collected and stored for assessing the 
immunogenicity potential of the IMP. 
• 
Complete urine pregnancy test (only for women of childbearing potential). 
• 
If applicable, collect all trial-related supplies not previously returned. 
• 
If an Early Discontinuation Visit, remind women of childbearing potential and male 
subjects with female partners of child-bearing potential to use a highly effective 
method of contraception until 28 days after the last dose of IMP. 
 
6.3. 
Description of Trial Procedures 
The following sections describe trial procedures occurring during the trial. Trial procedures and 
their timing are summarized in the Schedules of Assessments (for PART 1, Appendix 1, and for 
PART 2, Appendix 2). 
 
6.3.1. 
Medical/Surgical History and Concomitant Medications/Procedures 
Medical history and any concomitant medications will be recorded during the Screening Visit. At 
the Baseline Visit, a review of any additional medical history and/or new concomitant 
medication/procedures that occurred during the Screening Period will be completed. 
Concomitant medications/procedures should be updated and recorded at each clinical site visit. 
Subjects not previously enrolled in SPIMM-300 must have previous genetic testing information 
available, which will be reviewed by an Adjudication Committee, to determine eligibility for 
study enrollment. NOTE: genetic testing will not be provided as part of the SPIMM-301 trial. 
 
6.3.2. 
Physical Examination 
During all clinical site visits, a complete physical examination will be performed. The physical 
examination will include a full review of the following systems: general appearance, skin, head, 

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eyes, ears, nose, throat, neck (including thyroid), lymph nodes, chest, heart, abdomen, 
extremities, nervous system, and weight. Height will only be measured at the Screening Visit. 
 
6.3.3. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
At the Screening Visit, the C-SSRS “Baseline/Screening” will be completed and recorded. The 
C-SSRS “Baseline/Screening” is included in Appendix 5. At all other clinical site visits, the C- 
SSRS “Since Last Visit” will be recorded. The C-SSRS “Since Last Visit” is included in 
Appendix 6. Subjects who score positive on any C-SSRS will have appropriate referrals made 
either for a mental health evaluation or to the emergency room if necessary, in the opinion of the 
Investigator. 
 
6.3.4. 
Vital Signs 
During all clinical site visits, the vital signs measurements will include temperature, heart rate, 
respiration rate, and blood pressure, recorded in the sitting position after at least 5 minutes of 
rest. 
 
6.3.5. 
Electrocardiograms (ECGs) 
A 12-lead ECG will be obtained after the subject has rested quietly for 5 minutes in the supine 
position at all clinical site visits. ECG intervals (PR, RR, QRS, QT), heart rate and ECG findings 
will be recorded for each subject. Based on signs or symptoms, additional 12-lead ECGs may be 
performed. The QT interval will be corrected programmatically in the clinical database. 
 
6.3.6. 
Clinical Laboratory Testing 
Sample collection, processing, and handling details are provided in the Laboratory Manual. 
Blood and urine will be drawn and collected at clinical site visits. Analysis will include testing 
for parameters included in Appendix 4. Additional blood samples at the Baseline, Week 24 Visit, 
and Early Discontinuation Visit (if applicable) will be collected and stored for assessing the 
immunogenicity potential of the IMP. 
 
6.3.7. 
Pregnancy Tests 
Women of child-bearing potential will have a serum pregnancy test performed at the Screening 
Visit. Women of child-bearing potential will have a urine pregnancy test at the Baseline Visit 
and the results of the Baseline Visit pre-dose pregnancy test must be evaluated before 
randomization to ensure eligibility. A urine pregnancy test will also be performed for women of 
childbearing potential at the PART 1 or PART 2 End-of-Trial or Early Discontinuation Visit. 
 
6.3.8. 
Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) 
The Primary Mitochondrial Myopathy Symptom Assessment© (PMMSA) [2018] Stealth 
BioTherapeutics Inc. is a novel, daily patient-reported outcome measure, used to better 
understand the subject’s perspective and disease experience during the trial. The PMMSA 
assesses 10 symptoms experienced by subjects with PMM, each on a 4-point scale. The Total 
Fatigue score comprises a subset of symptoms (including tiredness and muscle weakness). Each 
question in the PMMSA has 4 response options: 1=Not at all, 2=Mild, 3=Moderate, and 
4=Severe. A daily total score will be calculated based on the daily average score of the questions 

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answered multiplied by the number of questions for the Total Fatigue score. PMMSA data for a 
minimum of 4 of the 7 days before Baseline and before each visit are necessary to calculate the 
PMMSA Total Fatigue Score. 
During PART 1, starting at the Screening Visit, subjects will be instructed to complete the 
PMMSA daily during the Screening and Treatment Periods. At the Screening Visit, subjects will 
be provided with the electronic or paper diary and trained on the procedure to complete the 
PMMSA daily in the diary. At the Screening Visit, subjects will also identify which of the 
symptoms on the PMMSA is their most bothersome symptom of their PMM. The PMMSA is in 
Appendix 8. 
 
6.3.9. 
The Neuro-QoL Fatigue 
At all clinical site visits, subjects will be instructed to complete the Neuro-QoL Fatigue. The 
Neuro-QoL Fatigue is in Appendix 9. 
 
6.3.10. 
EQ-5D-5L 
At all clinical site visits, subjects will be instructed to complete the EQ-5D-5L. The EQ-5D-5L 
questionnaire is in Appendix 10. 
 
6.3.11. 
Patient Global Impression (PGI) Scales 
The PGI Scales will be completed to assess their overall assessment of their symptoms related to 
their diagnosis of PMM. The PGI Scales are provided in Appendix 11. 
 
6.3.12. 
Clinician Global Impression (CGI) Scales 
The Investigator (or designee) will provide an overall assessment of the subject’s symptoms 
related to their diagnosis of PMM at all clinical site visits. The CGI Scales are provided in 
Appendix 12. 
 
6.3.13. 
6-Minute Walk Test (6MWT) 
At all clinical site visits, the distance walked (in meters) during the 6MWT will be recorded. The 
6MWT instructions are provided in Appendix 13. 
Sites will be trained by CPC Clinical Research on the conduct of the 6MWT. CPC Clinical 
Research will develop trial specific material, train clinical sites, and ensure consistency and 
accuracy of conduct and data from the 6MWT across multiple sites. In order to obtain evaluable 
data on the 6MWT, the conduct of the 6MWT must be standardized across all participating sites. 
CPC Clinical Research will conduct a Site Endpoint Evaluation Visit (SEEV) which will 
include: 
• 
Training each individual expected to conduct the 6MWT during the trial. Training will 
include education on the 6MWT, passing a brief quiz, and performing a mock test with 
the SEEV specialist. This must occur before conducting the test with trial subjects. 
• 
Evaluating the physical location of the 6MWT course to ensure it meets standard criteria. 
• 
Review of trial specific source documentation. 
• 
Answering any questions regarding the conduct of the 6MWT. 

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The purpose of the SEEV is to ensure standards by which the 6MWT is performed do not differ 
from person to person within a site as well as helping to create consistency across this 
multicenter trial. 
Additionally, the 6MWT should be administered by a clinical site staff member trained on the 
conduct of the 6MWT and not involved in other aspects of the study. 
 
6.3.14. 
Pharmacokinetic (PK) Sampling 
To characterize the PK of elamipretide, PK sampling will be conducted at defined time points. 
PK sampling will identify and characterize the influence of demographic factors (e.g., age, 
gender, race), health status, drug-drug interaction and other covariates on the PK of elamipretide. 
The PK sampling schedule is as follows: 
• 
Week 4: 1 hour post dose (± 10 min) 
• 
Week 12: 30 min, 2 hours, and 4 hours post dose (± 10 min) 
• 
Week 24: pre-dose (-10 min) 
6.3.15. 
Injection Site Reaction (ISR) Assessment 
A skin examination of the injection site (abdomen, rotating around the four abdominal quadrants, 
or other appropriate location [after Investigator consultation with the Sponsor]) will be 
performed by the Investigator (or designee) at all clinical site visits during the Treatment Period 
in PART 1 (Baseline, Week 4, Week 12, and Week 24 Visits) and PART 2 (Week 28, Week 36, 
Week 48, Week 72, Week 96, Week 120, Week 144, Week 168). The skin examination should 
occur at 30 (±5) minutes after the IMP administration with the elamipretide delivery system. The 
presence and severity of pain, erythema, swelling, and pruritus at the injection site will be 
assessed. Scoring of erythema, swelling, pruritus and pain will be done using a 5-point scale 
using the “Table for Grading the Severity of Site Reactions to Injections” provided in 
Appendix 14: 
• 
None = 0 
• 
Mild = 1 
• 
Moderate = 2 
• 
Severe = 3 
• 
Potentially life-threatening = 4 
NOTE: Any ISR captured as part of this assessment should be reported as an AE/ADE, as per the 
judgement of the Investigator, according to guidelines detailed in Section 9.9.1.4. Any ISR that 
meets any of the criteria of a SAE/serious adverse device effect (SADE) (Section 9.8) should be 
reported within 24 hours of the clinical site first becoming aware of the event (as outlined in 
Section 9.10). 

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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
The inclusion and exclusion criteria for participation in PART 1 and PART 2 are provided 
below. All screening assessments must be completed during the SPIMM-301 Screening Period, 
but may be performed on different days. Screening assessments should not be repeated, and 
subjects cannot be re-screened without the Sponsor’s approval. If a subject is re-screened, they 
will maintain their original screening number. Subjects may only be enrolled into the trial one 
time. 
Prospective approval of protocol deviations to enrollment criteria, also known as protocol 
waivers or exemptions, are not permitted. 
While there is no screening period for PART 2, subjects continuing into PART 2 must meet the 
PART 2 Continuation Criteria. Subjects who decide not to continue in the PART 2 at the PART 
1 Week 24 Visit are not eligible to participate in PART 2. 
 
7.1. 
SPIMM-301 Eligibility 
7.1.1. 
Subject Inclusion Criteria 
A subject must meet all of the following Inclusion Criteria at the Baseline Visit to be eligible for 
inclusion in the SPIMM-301 trial: 
1. Willing and able to provide a signed informed consent form (ICF) prior to participation in 
any trial-related procedures. 
2. Agrees and is able to adhere to the trial requirements for the length of the trial, including 
the use of the elamipretide delivery system. 
3. Subject is ≥16 and ≤80 years of age. In Germany, subjects must be ≥18 years of age. 
4. Enrolled (signed ICF) in SPIMM-300 or have prior approval from the Sponsor to enroll 
without SPIMM-300 participation. 
5. Diagnosed with PMM in the opinion of the Investigator, consisting of: 
a. Molecular genetic abnormality of the mitochondrial respiratory chain, and 
b. Subject reported symptoms (i.e., exercise intolerance, fatigue, muscle weakness) 
or physical examination findings of myopathy that are the predominant symptoms 
of the subject’s mitochondrial respiratory chain disorder. 
6. The subject’s molecular genetic abnormality is consistent with PMM as confirmed by the 
Adjudication Committee. 
7. Women of childbearing potential must agree to use 1 of the following methods of birth 
control from the date they sign the ICF until 28 days after the last dose of IMP: 
a. Abstinence, when it is in line with the preferred and usual lifestyle of the subject. 
Subject agrees to use a highly effective method of contraception should they 
become sexually active. 

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b. Relationships with male partners who have been surgically sterilized by 
vasectomy (the vasectomy procedure must have been conducted at least 60 days 
prior to the Screening Visit). 
c. 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. 
Note: 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). 
8. Male subjects with female partners of child-bearing potential must be willing to use a 
highly effective method of contraception from the date they sign the ICF until 28 days 
after the last dose of IMP. 
 
7.1.2. 
SPIMM-301 Exclusion Criteria 
A subject CANNOT meet any of the following Exclusion Criteria at the SPIMM-301 Baseline 
Visit to be eligible for inclusion in the trial: 
1. Subject has myopathic signs and/or symptoms due to a neuropathic process (i.e. 
cerebellar dysfunctions and peripheral neuropathies) or a gait problem that would 
interfere with the 6MWT, in the opinion of the Investigator. 
2. Female subjects who are pregnant, planning to become pregnant, or 
breastfeeding/lactating. 
3. Walks < 100 meters or > 450 meters during the 6MWT at either the Screening Visit OR 
Baseline Visit. 
4. At the Baseline Visit, the estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 
m2, using the Screening Visit value with the Modification of Diet in Renal Disease 
(MDRD) Study equation. 
5. Subject has undergone an in-patient hospitalization within the 30 days prior to the 
Baseline Visit or has a planned hospitalization or a surgical procedure during the trial. 
6. Subject has clinically significant respiratory disease and/or cardiac disease (medical 
history or current clinical findings), in the opinion of the Investigator, or prior 
interventional cardiac procedure (e.g., cardiac catheterization, angioplasty/percutaneous 
coronary intervention, balloon valvuloplasty, etc.) within 3 months of the Baseline Visit. 
7. Subject has a pacemaker, implantable cardioverter-defibrillator, or cardiac 
resynchronization therapy device OR QTc elongation (using the correction factor utilized 
at the clinical site) defined as a QTc >450 msec in male subjects and >480 msec in 
female subjects. 
Note: At the initial electrocardiogram (ECG), if QTc exceeds these parameters, the ECG 
may be repeated 2 more times (during the same visit), and the average of the 3 QTc 
values used to determine the subject’s eligibility. 

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8. ECG evidence of acute ischemia, atrial fibrillation, or active conduction system 
abnormalities with the exception of any of the following: 
a. First degree AV-block 
b. Second degree AV-block Type 1 (Mobitz Type 1 / Wenckebach type) 
c. Right bundle branch block 
9. Subject has severe vision impairment that, in the opinion of the Investigator, may 
interfere with their ability to complete all trial requirements 
10. Subject has a seizure disorder that, in the opinion of the Investigator, may interfere with 
their ability to complete all trial requirements. 
11. Active malignancy or any other cancer from which the subject has been disease-free for < 
2 years. 
12. Subject has a solid organ transplant and/or is currently receiving treatment with therapy 
for immunosuppression, in the opinion of the Investigator. 
13. Subject has been previously diagnosed with human immunodeficiency virus (HIV), 
hepatitis B, or hepatitis C infection. 
14. Subject has a history of a systemic eosinophilic illness and/or an eosinophil count >1,000 
cells x106/L at the Screening Visit. 
15. Subject is currently participating or has participated in an interventional clinical trial (i.e., 
investigational product or device, stem cell therapy, gene therapy) within 30 days of the 
Baseline Visit; or is currently enrolled in a non-interventional clinical trial (except for 
SPIMM-300) at the Baseline Visit which, in the opinion of the Investigator, may be 
potentially confounding to the results of the current trial (e.g. exercise therapy trial). 
16. Subject has previously received elamipretide (MTP-131), for any reason. 
17. Subject has a history of active substance abuse during the year before the Baseline Visit, 
in the opinion of the Investigator. 
18. Subject has any prior or current medical condition that, in the judgment of the 
Investigator, would prevent the subject from safely participating in and/or completing all 
trial requirements. 
 
7.2. 
PART 2 Eligibility 
7.2.1. 
PART 2 Subject Continuation Criteria 
A subject must meet all of the following PART 2 Continuation Criteria at the Week 24 Visit in 
PART 1 to be eligible for PART 2: 
1. Subjects must continue to be able and willing to adhere to the trial requirements. 
2. Subject is appropriate to continue in PART 2 (i.e. subject was compliant in SPIMM-301), 
in the opinion of the Investigator. 
3. Subject has not had a serious adverse event (SAE)/serious adverse device effect (SADE) 
attributed to the elamipretide delivery system. 

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4. Subject has not permanently discontinued the elamipretide delivery system. 
7.3. 
Prohibited Medications 
The use of any other investigational drug except elamipretide is prohibited during the conduct of 
the current trial. 
The concurrent use of sacubitril (an antihypertensive drug used in combination with valsartan 
marketed under the brand name, Entresto®, in the US and EU) is prohibited, due to a lack of 
current information regarding possible drug interactions. 
All attempts should be made to keep all medications, including over-the-counter treatments, 
vitamins, or supplements constant during the SPIMM-301 trial and to not initiate new therapy 
during the trial, unless in response to an AE. All concomitant medications will be recorded in the 
source data and the Electronic Case Report Form (eCRF). Changes in dosages of current 
medications (including over-the-counter vitamins or supplements) during the conduct of the trial 
will be discouraged, unless required to treat an AE/ADE. 
Subjects will be instructed to maintain their normal diet, daily caffeine, and fiber intake 
throughout the trial period. 
 
7.4. 
Criteria for Subject or Trial Discontinuation 
7.4.1. 
Discontinuation of Subjects 
Subjects may be discontinued from the trial for the following reasons: 
• 
Investigator Decision 
– The Investigator decides that the subject should be discontinued from the trial for 
any reason (e.g., the eGFR is <30 mL/min/1.73 m2, using the MDRD study 
equation). 
• 
Subject Decision 
– The subject or the subject’s designee, (e.g., parents or legal guardian), requests to 
be withdrawn from the trial. 
– Subjects who withdraw should be explicitly asked about the contribution of 
possible AEs/ADEs to their decision to withdraw consent, and any AE/ADE 
information elicited should be documented. 
Preferably the subject should withdraw consent in writing and, if the subject or 
the subject’s representative refuses or is physically unavailable, the clinical site 
should document and sign the reason for the subject’s failure to withdraw consent 
in writing. 
– 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 

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– The Sponsor or its designee stops the trial or stops the subject’s participation in 
the trial for medical, safety, regulatory, or other reasons consistent with applicable 
laws, regulations, and GCP guidelines. 
• 
Adverse Event (AE)/ADE 
– If the Investigator decides that the subject should be withdrawn because of an 
AE/ADE or 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. 
For all subjects, it is the intent that subjects who discontinue IMP (at any time) for any reason 
will continue to be followed for all protocol-planned trial visits through the completion of the 
PART 1 Treatment Period, and will have all endpoints (including efficacy) collected 
accordingly. In the interest of the subject, subjects who withdraw consent or are withdrawn from 
the trial by the investigator should be encouraged to complete an Early Discontinuation Visit as 
soon as possible and an effort should be made to complete and report the observations as 
thoroughly as possible up to the date of withdrawal. 
 
7.4.2. 
Discontinuation of Clinical Site Participation 
A clinical site participation may be discontinued if the Sponsor or its designee, the Investigator, 
the Regulatory Authority, or the Ethics Committee (EC) judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP guidelines. 
 
7.4.3. 
Discontinuation of the Trial 
The trial may 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. 

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8. 
INVESTIGATIONAL MEDICINAL PRODUCT MATERIALS 
AND MANAGEMENT 
8.1. 
Treatments Administered 
PART 1 is a 24-week, randomized, double-blind, parallel-group, placebo-controlled trial will 
enroll approximately 202 subjects who have PMM. Subjects will be randomized (1:1) to one of 
two groups: 24 weeks of single daily SC doses of 40 mg elamipretide administered with the 
elamipretide delivery system or 24 weeks of single daily SC doses of placebo. 
PART 2 is an up to 144-week, open-label assessment of the long-term safety and tolerability of 
single daily SC doses of 40 mg elamipretide administered with the elamipretide delivery system 
in subjects with PMM. Subjects who continue into PART 2 will receive treatment with 40 mg 
SC elamipretide for up to 144 weeks. 
Elamipretide injection and placebo will be supplied as a labeled sterile 3.0 mL multidose glass 
cartridge (containing an elastomeric plunger and an elastomeric septum secured with a crimped 
aluminum cap) for use with the elamipretide delivery system. Each cartridge contains 2.5 mL of 
sterile elamipretide solution for up to five (5) 40 mg doses (0.5 mL per injection of 80 mg/mL 
sterile elamipretide solution) per injection. Elamipretide solution is an aqueous sterile solution of 
80 mg/mL elamipretide HCl formulated in sodium phosphate buffer and benzyl alcohol. The 
placebo solution is composed of sodium chloride, sodium phosphate buffer, and benzyl alcohol. 
 
8.1.1. 
Elamipretide Pen Injector 
The elamipretide pen injector was developed by Stealth BT exclusively for use with the 
elamipretide injection or placebo 3mL cartridge. 
The elamipretide pen injector has a common classification of Piston Syringe Class II in 
accordance with 21 CFR 880.5860 and a classification of IIa in accordance with Medical Device 
Directive 93/42/EEC Annex IX. The elamipretide delivery system is designated system A in 
accordance with ISO 11608-1:2014. 
In accordance with MDD 93/42/EEC, Annex IX, Classification Criteria, I. Definitions, the 
elamipretide pen injector is transient (normally intended for continuous use for less than 60 
minutes) and surgically invasive device (penetration other than through an established body 
orifice), sections 1.1 and 1.2, respectively. In accordance with Annex IX, Section III 
Classification, Rule 6, the elamipretide pen injector is Class IIa, “all surgically invasive devices 
for transient use are in Class IIa”. Further to Rule 6, the elamipretide pen injector is intended to 
administer medicines by means of a delivery system, but not done in a manner that is potentially 
hazardous taking account the mode of application. This classification is further supported by the 
fact that the device (elamipretide pen injector) is intended to administer a daily fixed dose of 
medicine where the dosage level and nature of the medicinal product is not critical, i.e., 
elamipretide has demonstrated an acceptable safety profile at the proposed fixed daily clinical 
dose. 
In Canada, the reusable elamipretide pen injector is considered a surgically invasive device 
classified as Class II by rule 1(1) of the Medical Device Regulations (SOR/98-282) Rule 1 states: 

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Rule 1: 
1. Subject to sub-rules (2) and (3), all surgically invasive devices are classified as Class II. 
2. A surgically invasive device that is intended to diagnose, monitor, control or correct a 
defect of the central cardiovascular system or the central nervous system or of a fetus in 
utero is classified as Class IV. 
A surgically invasive device that is intended to be absorbed by the body, or that is normally 
intended to remain in the body for at least 30 consecutive days, is classified as Class III. 
The elamipretide pen injector is designed, manufactured and controlled in accordance with 
21CFR 820, ISO 13485 and ISO 14971, as appropriate. Specifically, the elamipretide pen 
injector is manually assembled, in a single-piece flow process (by a single operator), at the 
facilities of Haselmeier in accordance with cGMPs, ISO 13485, and Quality Management 
System (QMS). 
 
8.1.2. 
Elamipretide Delivery System 
The elamipretide pen injector along with IMP cartridge and the pen needle constitutes the 
elamipretide delivery system which will be used in SPIMM-301. The elamipretide delivery 
system is for personal use (single subject) for SC administration of a fixed dose (0.5 mL) of 
elamipretide injection or placebo. The needle provided should be used. The elamipretide delivery 
system is operated mechanically and contains no electronics. The elamipretide delivery system is 
depicted in Figure 4. The user will assemble and use the elamipretide delivery system per the 
IFU that will be provided to each subject. 
Figure 4: 
Elamipretide Delivery System (expanded view of major components) 
The materials used in the elamipretide delivery system are standard materials for medical 
devices. Materials that may come in contact with the subject have been assessed for 
biocompatibility in accordance with ISO 10993-1; the elamipretide delivery system is 
biocompatible when used as intended. The manufacturer of the elamipretide pen injector 

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(Haselmeier) had conducted a device design Risk Assessment (RA) for the elamipretide pen 
injector with an insulin cartridge and concluded that the elamipretide pen injector is safe for use. 
Stealth has conducted a design risk RA and a use-related RA for the elamipretide delivery 
system and concluded that the elamipretide delivery system is safe for use as intended. 
Each subject or caregiver will be trained in the use of the elamipretide delivery system per the 
IFU prior to administration of the dose. An elamipretide delivery system training kit and 
checklist will be provided to the clinical site to assist in training. 
The subject (or trained caregiver) will administer the IMP with the elamipretide delivery system 
via daily SC injections in the abdomen, rotating around the four abdominal quadrants, or other 
appropriate location (after Investigator consultation with the Sponsor). The time of the IMP 
administration should be approximately the same time each day (e.g., early morning, noon, or 
early afternoon). If a subject is concurrently receiving another SC therapy, unique locations for 
injections for the IMP, independent from the location of the concomitant therapy injections, 
should be used. At the Baseline Visit, the IMP will be administered with the elamipretide 
delivery system after completion of all baseline procedures (Section 6.2.1.2). 
 
8.2. 
Materials and Supplies 
The placebo and elamipretide multidose glass cartridge and delivery system will be dispensed 
and stored according to the Pharmacy Manual. The placebo and elamipretide multidose glass 
cartridges are to be stored refrigerated at 2 to 8°C (36 to 46°F) in a secure area. Temperature 
records must be maintained and temperature excursions reported as soon as they are discovered. 
Short term excursions (less than 72 hours) in storage temperature up to room temperature (15 to 
30°C or 59 to 86°F) during shipping, storage, handling, and patient transport may be acceptable 
and will not compromise the usability of the investigative product supply. The sponsor should be 
notified in the case of an excursion. The multi-use cartridge, while in use in the elamipretide 
delivery system, may be stored at room temperature in the elamipretide pen injector for up to 
five (5) days. 
The elamipretide pen injector should be stored at room temperature and not refrigerated, even 
when assembled and in-use with a multi-dose cartridge. The ancillary supplies may be stored at 
room temperature. 
Additional information will be provided in the Pharmacy Manual. An Instructions for Use (IFU) 
pamphlet will be provided to assist in training. 
 
8.3. 
Investigational Medicinal Product Accountability 
IMP will be assigned for both PART 1 and PART 2 through an Interactive Web Response 
System (IWRS). All drug accountability records must be kept current, and the Investigator must 
be able to account for all used and unused elamipretide delivery system supplies. These records 
should contain the dates, quantity, and elamipretide delivery system: 
• 
Received at clinic 
• 
Administered to each subject 
• 
Dispensed to each subject 

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• 
Returned from each subject 
• 
Disposed of at the clinical site or returned to the Sponsor or designee 
The clinical monitor responsible for the clinical site will provide written approval for the 
destruction or return of used and unused elamipretide delivery system supplies following 
reconciliation of all clinical supplies. 
 
8.4. 
Treatment Compliance 
During the treatment period, IMP will be administered with the elamipretide delivery system 
daily by a trained caregiver, or self-administration. A diary will be used to document 
administration. 
 
8.5. 
Randomization 
The randomization for PART 1 will be based on a 1:1 ratio of elamipretide to matching placebo. 
The randomization will be centrally administered through an IWRS. Subjects will be stratified by 
the subclassification of the mutation determined to be the primary cause of the subject’s PMM 
(DiMauro 2003) as determined by the Adjudication Committee: 
• 
Disorders involving mtDNA mutations that impair mitochondrial protein synthesis in 
toto 
• 
Disorders involving mtDNA mutations that affect the subunits of the respiratory 
chain 
• 
Disorders involving nDNA mutations in genes encoding subunits or ancillary proteins 
of the respiratory chain 
• 
Disorders involving nDNA mutations causing defects of intergenomic signaling 
• 
Disorders involving nDNA mutations causing defects of mitochondrial protein 
importation 
• 
Disorders involving nDNA mutations causing alterations of the lipid milieu of the 
inner mitochondrial membrane 
• 
Disorders involving nDNA mutations causing alterations of mitochondrial motility or 
fission 
There is no randomization for PART 2. 
 
8.6. 
Blinding and Unblinding Procedures 
Trial personnel and subjects will be blinded to treatment in PART 1 until the PART 1 database is 
locked. 
The Investigator will contact the Sponsor prior to unblinding any subject’s treatment sequence 
unless in the instance of a medical emergency. 
In case of an immediate medical emergency or if directed by the Sponsor, and only if the 
information is required by the Investigator to manage a subject’s AE, is a subject’s treatment 
assignment to be unblinded prematurely. In cases of medical emergency, the Investigator may 

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unblind a subject’s treatment assignment using the computerized system according to the 
instructions received. The Sponsor must be notified as soon as possible regarding the reason for 
unblinding. 
Whenever the treatment assignment of an individual subject is unblinded, the individual who 
performed the unblinding, the date, time and reason for the unblinding must be logged in the 
computerized unblinding system (IWRS) and also included in source documentation. The name 
of the individual who broke the blind must be included in the clinic’s source documentation. 
The Sponsor designated CRO will control and document, according to the appropriate Standard 
Operating Procedures, the disclosure of treatment assignments, and treatment identity. These 
procedures ensure that no blinded staff (CRO, clinical site staff, Sponsor) will have premature 
access to the subjects’ treatment assignments. 

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9. 
EFFICACY AND SAFETY EVALUATIONS AND 
APPROPRIATENESS OF MEASUREMENTS 
9.1. 
Efficacy Endpoints 
Efficacy will only be assessed for PART 1. 
 
9.1.1. 
Primary Endpoints 
The primary endpoints are: 
• 
Distance walked (meters) during the 6MWT 
• 
Total Fatigue score on the PMMSA 
9.1.2. 
Secondary Endpoints 
The secondary endpoints are: 
• 
Fatigue During Activities score on the PMMSA 
• 
Neuro-QoL Fatigue Short Form score 
• 
Most bothersome symptom score on the PMMSA 
• 
Neuro-QoL Fatigue activities of daily living (specific items from the Neuro-QoL Item 
Bank) 
 
9.1.3. 
Exploratory Endpoints 
There will be a number of exploratory endpoints investigated, including: 
• 
Individual symptom scores on the PMMSA 
• 
Alternate version of the PMMSA Total Fatigue Score 
• 
Individual item scores of the Neuro-QoL Fatigue 
• 
EQ-5D-5L scores 
• 
Patient Global Impression (PGI) Scales 
– PGI of Symptom scores 
– PGI of Change scores 
• 
Clinician Global Impression (CGI) Scales 
– CGI of Symptom scores 
– CGI of Change scores 
9.1.4. 
Pharmacokinetic (PK) Endpoints 
The PK endpoints are: 
• 
PK parameters 

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9.2. 
Safety Endpoints 
For both PART 1 and PART 2, safety will be assessed through collection of the following data: 
• 
AEs/ADEs 
• 
Vital Signs 
• 
Electrocardiograms 
• 
Clinical laboratory evaluations 
• 
C-SSRS 
The safety profile of elamipretide will be assessed through the recording, reporting, and 
analyzing of AEs/ADEs, clinical evaluations, and laboratory tests. 
Comprehensive assessment of AEs/ADEs experienced by the subject will be performed from the 
time of the subject’s signature of informed consent, throughout the course of the trial, and until 
the conclusion of the post treatment follow-up period. 
Subjects must be seen by a physician or designee (an appropriately trained healthcare 
professional) at every trial visit and the evaluation must be documented. Clinical site staff will 
report any AE/ADEs, whether observed by the Investigator (or designee), or reported by the 
subject. 
The Investigator is responsible for promptly documenting and reporting all AEs/ADEs observed 
during the trial in the subject’s eCRF and applicable forms. The reporting period for AEs/ADEs 
is described in Section 9.9.2. 
The Sponsor will periodically review trial safety data as outlined in the Medical Monitoring 
Plan. 
 
9.2.1. 
Adverse Events (AEs)/Adverse Device Effects (ADEs) 
Any untoward medical occurrence in a subject or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
An ADE is an AE related to the use of an investigational medical device. This includes any event 
resulting from insufficient or inadequate instructions for use, deployment, installation, or 
operation, or any malfunction of the investigational medical device or any event resulting from 
user error or from intentional misuse of the investigational medical device. 
The safety profile will be assessed through the recording, reporting, and analyzing of AEs/ADEs, 
clinical evaluations, and laboratory tests. 
Comprehensive assessment of AEs/ADEs experienced by the subject will be performed from the 
time of the subject’s signature of informed consent, throughout the course of the trial, and until 
the conclusion of the clinical trial’s post treatment follow-up period. 

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Subjects must be seen by a physician or designee (an appropriately trained healthcare 
professional) at every trial visit and the evaluation must be documented. Trial site personnel will 
report any AE/ADE, whether observed by the Investigator (or designee), or reported by the 
subject. 
The Investigator is responsible for promptly documenting and reporting all AEs/ADEs observed 
during the trial in the subject’s eCRF and applicable forms. 
Should the IMP be discontinued due to an AE/ADE deemed probably or possibly related to the 
IMP (per Section 9.9.1.2), reinitiating (rechallange) of the IMP may be possible, after 
consultation with the Sponsor. 
 
9.3. 
Pre-Treatment Adverse Events 
Untoward events that occur prior to the first IMP administration (pre-treatment event) and 
assessed by the Investigator as related to a trial procedure and/or meeting seriousness criteria will 
be recorded as an AE/SAE on the subject’s electronic case report form (eCRF) and applicable 
forms, processed, and followed accordingly. AEs/SAEs that occur prior to IMP administration 
are by definition, unrelated to the IMP and will be reported as such in the data listings. 
9.4. 
Medical History Conditions 
Pre-treatment events or diagnoses not related to a trial procedure and/or meeting seriousness 
criteria will be recorded as medical history on the subject’s eCRF. Medical history conditions, 
related or not related to the therapeutic area of interest/investigation, that worsen in severity or 
frequency during the trial in a way that is not consistent with natural disease progression, in the 
opinion of the Investigator, should be recorded and reported as AEs/ADEs. 
 
9.5. 
Medical and Surgical Procedures 
Medical or surgical procedures (including hospitalizations) scheduled prior to signing the 
informed consent, but occurring during the trial should not be captured as AEs. The condition 
leading to the procedure should be listed in the medical history and the procedure should be 
captured on the concurrent procedures page. Medical or surgical procedures not scheduled prior 
to signing the informed consent should not be recorded as AEs; the condition that led to the need 
to perform the medical or surgical procedure will be the AE/ADE or SAE/SADE and the 
procedure should be captured on the concurrent procedures page. 
 
9.6. 
Abnormal Laboratory and Other Abnormal Investigational Findings 
Abnormal laboratory findings or other objective measurements, deemed clinically significant by 
the Investigator should be reported as an AE/ADE. 
When reporting an abnormal laboratory finding as an AE/ADE or SAE/SADE, the description of 
the abnormality, rather than the abnormal value itself, should be recorded. A clinical diagnosis 
should be reported if the Investigator believes the finding is consistent with a disease process. 

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9.7. 
Symptomatic Overdose 
In the event of an overdose of trial medication, the Investigator should use clinical judgment in 
treating the signs and symptoms of the overdose. The signs and symptoms should be reported as 
AEs/ADEs. Overdoses must be reported immediately to the trial Medical Monitor (or designee). 
 
9.8. 
Serious Adverse Events (SAEs)/Serious Adverse Device Effect 
(SADEs) 
A SAE/SADE is any AE/ADE that: 
• 
Results in death. 
• 
Is life-threatening. The term “life-threatening” refers to a situation 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 in-patient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity. 
• 
Is a congenital anomaly/birth defect. 
• 
Is a medically important event or reaction. 
An SADE is an ADE that might have led to the SADE, in a participant, user or other person if a) 
suitable action had not been taken or b) intervention had not been made or c) if circumstances 
had been less fortunate. They are handled under the SAE reporting system. 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should 
also usually be considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias, or convulsions that do 
not result in hospitalization; or development of drug dependency or drug abuse. 
Any non-serious AE/ADE that worsens and meets the criteria for a SAE/SADE should be 
reported as a SAE/SADE. The start date of the SAE/SADE should be the date the AE/ADE 
worsened to meet the criteria for a SAE/SADE. 
The Investigator is expected to take all therapeutic measures necessary for resolution of the 
SAE/SADE. Any medications or procedures necessary for treatment of the SAE/SADE must be 
recorded on the subject’s eCRF. 
As part of the routine medical monitoring, the medical monitor (or designee) will review all 
SAEs/SADEs reported in the SPIMM-301 trial, looking for any safety data trends or trial IMP- 
related issues. 
9.9. 
Recording of Adverse Events (AEs)/Adverse Device Effects (ADEs) 
Complete and accurate data on all AEs/ADEs experienced for the duration of the reporting 
period (defined below) will be recorded on an ongoing basis on the subject’s eCRF. All 

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SAEs/SADEs must be reported using the trial specific SAE Report Form, in addition to the 
subject’s eCRF. 
It is important that each AE/ADE entry include a verbatim term along with, onset and resolution 
dates, severity, seriousness, relationship to the IMP, action taken with respect to the IMP, and its 
outcome. 
Investigators should use the AE/ADE definitions provided in the above sections and should 
observe the following guidelines when completing the subject’s eCRF: 
• 
Whenever possible, recognized medical terms should be used to describe AEs/ADEs 
rather than colloquialisms (for example, ‘influenza’ rather than ‘flu’), and 
abbreviations should be avoided. 
• 
Adverse events/ADEs should be described using a specific clinical diagnosis, if this is 
available, rather than a list of signs or symptoms (for example, ‘congestive heart 
failure’ rather than ‘dyspnea, rales, and cyanosis’). However, signs/symptoms that are 
not associated with an identified disease or syndrome, or for which an overall 
diagnosis is not yet available, should be reported as individual AEs/ADEs. 
• 
Provisional diagnosis (e.g., “suspected Myocardial Infarction”) is acceptable but 
should be followed with a definite diagnosis (if available). Similarly, a fatal event 
with an unknown cause should be recorded as “Unknown” 
• 
In cases of surgical or diagnostic procedures, the condition/illness leading to such a 
procedure is considered as the AE/ADE rather than the procedure itself. 
 
9.9.1. 
Investigator Assessments 
 
9.9.1.1. 
Severity 
Severity, which is a description of the intensity of manifestation of the AE/ADE, is distinct from 
the regulatory definition of seriousness. The Investigator is required to grade the severity of each 
AE/ADE according to the following guidelines. 
Investigators must assess the severity/intensity of AEs/ADEs according to the following 
qualitative toxicity scale: 
• 
Mild: Associated with no limitation of usual activities or only slight discomfort; 
generally not requiring alteration or cessation of IMP administration; and/or not 
needing therapeutic intervention. 
• 
Moderate: Associated with limitation of usual activities or significant discomfort; 
generally requiring alteration or cessation of IMP administration; and/or requiring 
therapeutic intervention. 
• 
Severe: Associated with inability of subject to carry out usual activities or very 
marked discomfort; considered to be life-threatening; resulting in significant 
disability or incapacity; and requiring therapeutic intervention. 

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9.9.1.2. 
Relationship to the Investigational Medicinal Product (IMP)/Elamipretide 
Delivery System 
Investigators must systematically assess the causal relationship of AEs/ADEs to the IMP or 
elamipretide delivery system according to the following guidelines: 
• 
Probable: A causal relationship is clinically/biologically highly plausible, there is a 
plausible time sequence between onset of the AE/ADE and administration of the 
IMP/use of the elamipretide delivery system, the event is unlikely to be attributed to 
underlying/concurrent disease, other drugs, or other factors, and there is a reasonable 
response on withdrawal. 
• 
Possible: A causal relationship is clinically/biologically plausible and there is a 
plausible time sequence between onset of the AE/ADE and administration of the 
IMP/use of the elamipretide delivery system. 
• 
Unlikely: A causal relationship is improbable and/or another documented cause of 
the AE/ADE is most plausible. 
• 
Unrelated: A causal relationship is clinically/biologically improbable, there is not a 
plausible time sequence between onset of the AE/ADE and administration of the 
IMP/use of the elamipretide delivery system, the event is likely to be attributed to 
underlying/concurrent disease, other drugs, or other factors, and there is no 
reasonable response on withdrawal. 
 
9.9.1.3. 
Outcome of an Adverse Event (AE)/Adverse Device Effect (ADE) 
Investigators must follow all AEs/ADEs and SAEs/SADEs until the clinical trial’s post treatment 
follow-up period until resolution, stabilization, or withdrawal of consent. Resolution is defined 
as: 
• 
Recovered/Resolved; 
• 
Recovering/Resolving; 
• 
Not recovered/Not resolved; 
• 
Recovered/Resolved with sequelae; 
• 
Fatal; or 
• 
Unknown. 
9.9.1.4. 
Investigator Injection Site Reaction (ISR) Assessment 
Any ISR following SC administration, should be reported as an AE/ADE. To standardize the 
reporting of ISRs, the following guidance should be followed when reporting an ISR as an 
AE/ADE: 
– The ISR should be assessed for severity using the “Table for Grading the Severity 
of Site Reactions to Injections” provided in Appendix 14. 

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– Any ISR that meets any of the criteria of a SAE/SADE (Section 9.8) should be 
reported within 24 hours of the clinical site first becoming aware of the event (as 
outlined in Section 9.10). 
– The ISR should be reported as the characteristic of the ISR, rather than the 
general term of “Injection Site Reaction”. For instance, erythema associated with 
an ISR should be reported as “injection site erythema” or “redness at injection 
site” rather than the broad term “injection site reaction”. 
– For ISRs which reoccur following a subsequent SC injection, only one event 
should be recorded on the eCRF, with the overall duration to include the start date 
of the first reported event and the end date of the last recurrent event. The severity 
grade should be the most severe of the recurrent event during this period. 
The AEs/ADEs reported as a result of an ISR should be recorded on the subject’s ISR AE/ADE 
eCRF. The Investigator is expected to use their clinical judgement regarding treatments for ISRs. 
Any medications or procedures necessary for treatment of the ISR signs and/or symptoms must 
be recorded on the subject’s eCRF. 
 
9.9.2. 
Adverse Event (AE)/Adverse Device Effect (ADE) Reporting Period 
The AE/ADE reporting period begins when the subject signs the informed consent and continues 
through the clinical trial post treatment follow-up period. Note that AEs that occur between the 
time subject signs the ICF and the time the subject is dosed with IMP will be summarized in the 
medical history eCRF and not as an AE unless the event meets the definition of a SAE or is 
related to a trial procedure. 
After trial completion, all SAEs/SADEs with an ongoing/unknown outcome will be followed-up 
until resolution or stabilization. Additional information on SAEs/SADEs, obtained after database 
lock, will reside solely in the safety database. 
 
9.10. 
Serious Adverse Event (SAE)/Serious Adverse Device Effect (SADE) 
Expedited Reporting 
In the event of a SAE/SADE occurring during the reporting period, the Investigator must 
immediately (within 24 HOURS after becoming aware of the SAE/SADE) inform the Sponsor 
by telephone, by fax or by e-mail as detailed in the SAE form, completion instructions, eCRF 
completion guidelines, and/or Safety Management Plan (SMP). Reporting responsibilities for 
SAEs/SADEs are detailed in the SMP. For sites in Germany, see Appendix 15. 
For any SAE/SADE, the following minimum information is required as initial notification: 
• 
Investigator/Reporter with full contact information, 
• 
Subject identification details (trial number, center number, subject number), 
• 
IMP administration details (dose and dates), 
• 
Event Verbatim, a brief description of signs/symptoms/or diagnosis and the date of 
onset, 
• 
Seriousness criteria (ion) met. 

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Within 24 hours, the relationship of the event to the IMP (e.g., the causality according to the 
Investigator) and/or to the elamipretide delivery system (serial number) and needle (e.g., the 
causality according to the Investigator) should be provided. 
All SAE/SADE reports should be transmitted according to the Safety Management Plan. 
The Investigator/Reporter must provide follow-up information as available or requested by the 
Sponsor. 
 
9.10.1. 
Pregnancy and Contraception 
For male subjects with female partners of child-bearing potential, highly effective methods of 
contraception must be adhered to from the date they sign the ICF until 28 days after the last dose 
of IMP. 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 trial) 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 from 
the start of treatment until 28 days after the last dose of IMP. Sperm or egg donation by subjects 
is not permitted from the start of treatment until 28 days after the last dose of IMP. 
Any pregnancy in a female partner of a male subject during the course of the trial and until the 
last follow-up visit must be reported even if no AE/ADE has occurred, as detailed in the Safety 
Management Plan. If the investigator suspects the pregnancy has resulted from an interaction of 
the trial medication with contraceptives, then the pregnancy is considered as an AE. 
The Investigator must notify the Sponsor of any pregnancy using the Pregnancy Notification 
Form and the reporting procedure as described in the Safety Management Plan. Investigators 
must actively follow up, document, and report on the outcome of every pregnancy, even if the 
subject is withdrawn from the trial, as detailed in the Safety Management Plan. 
 
9.10.2. 
Responsibilities to Regulatory Authorities, Investigators and Ethics Committees 
The Sponsor will send appropriate safety notifications to regulatory authorities in accordance 
with applicable laws and regulations. 
The Investigator must comply with (and inform the Sponsor of) any applicable center-specific 
requirements related to the reporting of SAEs/SADEs involving his/her subjects to the Ethics 
Committee/Institutional Review Board (EC/IRB) that approved the trial. 
In accordance with ICH GCP guidelines, the Sponsor will inform the Investigator of findings 
that could adversely affect the safety of subjects, impact the conduct of the trial, or alter the 
EC’s/IRB’s approval/favorable opinion to continue the trial. In particular, and in line with 
respective regulations, the Sponsor will inform the Investigator of AEs/ADEs that are both 
serious and unexpected and are considered to be related to the administered IMP/elamipretide 
delivery system (“suspected unexpected serious adverse reactions” or SUSARs, or “unanticipated 
adverse device effects”, or UADEs). The Investigator should place copies of these Safety reports 
in the Investigator Site File. National regulations with regard to Safety report notifications to 
Investigators will be taken into account. 
When specifically required by regulations and guidelines, the Sponsor will provide appropriate 
Safety reports directly to the concerned lead IEC/central IRB and will maintain records of these 

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notifications. When direct reporting by the Sponsor is not clearly defined by national or center- 
specific regulations, the Investigator will be responsible for promptly notifying the concerned 
IEC/IRB of any Safety reports provided by the Sponsor and of filing copies of all related 
correspondence in the Investigator Site File. 
For trials covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/SUSARs/UADEs will be carried out in accordance with that 
Directive and with the related detailed Guidances. 

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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 clinics, as appropriate 
• 
Sponsor start-up training to instruct the Investigators and trial coordinators. This 
training will give instruction on the protocol, the completion of the eCRFs, and trial 
procedures. 
• 
Make periodic visits to the clinic 
• 
Be available for consultation and stay in contact with the clinical site staff by mail, 
telephone, and/or fax 
• 
Review and evaluate eCRF data and use standard computer edits to detect errors in 
data collection 
• 
Conduct a quality review of the database 
In addition, the Sponsor or its representatives will periodically check subject data recorded 
against source documents at the clinic. The trial may be audited by the Sponsor or its 
representatives, and/or regulatory agencies at any time. Investigators will be given notice before 
an audit occurs. 
To ensure the safety of participants in the trial, and to ensure accurate, complete, and reliable 
data, the Investigator will keep records of laboratory tests, clinical notes, and subject medical 
records in the subject files as original source documents for the trial. If requested, the 
Investigator will provide the Sponsor, applicable regulatory agencies, and applicable ECs with 
direct access to original source documents. 
 
10.1. 
Data Capture System 
An electronic data capture system (eDC) will be used in this trial. The clinical site will maintain 
a separate source for the data entered by the clinical site into the Sponsor-provided electronic 
data capture system. 
Case report form data will be encoded and stored in a clinical trial database. Data managed by a 
central vendor, such as laboratory test data or ECG data, or any data for which electronic 
documentation is provided by the subject, will be stored electronically in the central vendor’s 
database system. 
Any data for which paper documentation provided by the subject will serve as a source 
document will be identified and documented by each clinical site in that center’s trial file. Paper 
documentation provided by the subject may include, for example, a paper diary to collect subject 
reported outcome measures (e.g., a rating scale), a daily dosing schedule, or an event diary. 

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11. 
SAMPLE SIZE AND STATISTICAL METHODS 
11.1. 
Determination of Sample Size 
The sample size of 202 subjects provides 90% power to detect a 30-meter difference between 
treatment groups in the 6MWT and also 90% power to detect a one unit difference in the 
PMMSA Total Fatigue Score, assuming standard deviations of 60 meters for 6MWT and 2 units 
for the PMMSA Total Fatigue Score, at an alpha-level of 0.025. The two-sided alpha-level of 
0.025 is to account for a possible multiplicity adjustment as given in Section 11.2.5.5. 
 
11.2. 
Statistical and Analytical Plans 
11.2.1. 
General Considerations 
Data will be tabulated (by treatment group) using descriptive statistics (number of subjects, 
mean, median, standard deviation, minima, and maxima) for continuous variables and using 
frequencies and percentages for discrete variables. Inferential statistics will be presented where 
specified. A comprehensive statistical analysis plan (SAP) will be written and approved prior to 
database lock. This SAP will detail how missing values are to be handled, windows for trial 
visits, and how other analysis considerations will be addressed. 
Statistical tests (where performed) will be 2-sided at the alpha=0.05 level of significance, except 
where otherwise noted to adjust for multiplicity. 
 
11.2.2. 
Analysis Populations 
Statistical analysis will be performed using the following populations: 
• 
Safety Population – Includes all trial subjects who receive at least 1 dose of IMP. 
Subjects will be analyzed according to the actual treatment they receive. 
• 
Intent-to-Treat (ITT) Population – Includes all trial subjects who receive at least one 
dose of IMP. Subjects will be analyzed according to the treatment group they were 
randomized to and generally included in efficacy analyses for which post-baseline 
data are available. 
• 
Per-Protocol (PP) Population – Includes all ITT subjects without major protocol 
violations/deviations. The list of major protocol violations/deviations will be 
identified and specified in the SAP prior to final database lock for the trial that would 
lead to exclusion for the PP analysis. 
• 
Pharmacokinetic (PK) Population - Includes all trial subjects who have at least one 
PK sample taken during their participation. 
 
11.2.3. 
Subject Disposition 
Subject disposition (including the number and percent of subjects who are randomized, who 
receive randomized treatment, who are included in each analysis population, who prematurely 
discontinue and reasons for discontinuation, and who complete the trial) will be tabulated by 
treatment group. The number and percentage of subjects by exposure duration will be tabulated. 

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11.2.4. 
Subject Characteristics 
Subject’s age, sex, weight, height, body mass index (BMI), and other demographic 
characteristics will be recorded and summarized. Medical history will be listed. 
 
11.2.5. 
Efficacy Analyses 
Details regarding the final analyses will be included in a comprehensive SAP, which will be written 
and approved prior to database lock. 
 
11.2.5.1. Primary Efficacy Endpoints 
The distance walked (meters) during the 6MWT and Total Fatigue score on the PMMSA 
constitute the primary endpoint family. Efficacy analyses will be conducted on the ITT 
population. 
For the analysis of the primary endpoint family, the following two-sided hypotheses will be 
carried out to evaluate the treatment effect of elamipretide group against the placebo group in the 
6MWT and Total Fatigue score on the PMMSA (i=1 and 2, respectively): 
where µiPLB is the mean change from baseline on either the 6MWT (i=1) or the Total Fatigue 
score on the PMMSA [4 item] (i=2) at the end of the treatment period (Week 24) for the placebo 
treatment group, and µiMTP is the respective mean change from baseline at the end of the 
treatment period (Week 24) for the elamipretide treatment group. 
Analyses of continuous endpoints will be conducted utilizing a mixed model repeated measures 
(MMRM) approach, with fixed effects for treatment, genetic abnormality subclassification strata, 
visit, the treatment-by-visit interaction, and subject as a random effect. The outcome is the 
change from baseline to each on-treatment time point. The baseline value for the endpoint and a 
baseline by visit interaction term will be included as covariates. The primary time point is at 
Week 24; however, all protocol-scheduled time points will be included in the model. The exact 
details of the model, including variance-covariance structure and denominator degrees of 
freedom will be specified in the SAP. 
 
11.2.5.2. Secondary Efficacy Endpoints 
The secondary endpoints are: 
• 
Fatigue During Activities score on the PMMSA 
• 
Neuro-QoL Fatigue Short Form score 
• 
Most bothersome symptom score on the PMMSA 
• 
Neuro-QoL Fatigue activities of daily living (specific items from the Neuro-QoL Item 
Bank) 
These endpoints will be assessed in a similar manner as the primary efficacy endpoints. 

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11.2.5.3. Exploratory Endpoints 
There will be a number of exploratory endpoints investigated, including: 
• 
Individual symptom scores on the PMMSA 
• 
Alternate version of the PMMSA Total Fatigue Score 
• 
Individual item scores of the Neuro-QoL Fatigue 
• 
EQ-5D-5L scores 
• 
Patient Global Impression (PGI) Scales 
– PGI of Symptom scores 
– PGI of Change scores 
• 
Clinician Global Impression (CGI) Scales 
– CGI of Symptom scores 
– CGI of Change scores 
These endpoints will be assessed in a similar manner as the primary efficacy endpoints. 
 
11.2.5.4. Pharmacokinetic (PK) Endpoints 
The PK endpoints are: 
• 
PK parameters 
11.2.5.5. Adjustments for Multiplicity 
A family-wise alpha level of 0.05 will be maintained for the primary endpoint family, using 
Hochberg’s procedure at the primary time point of 24 weeks. If both primary endpoints are 
significantly different from placebo at the 0.05 (two-sided) level of significance (in favor of 
treatment), then both will be considered statistically significant. Otherwise the endpoint with the 
smaller p-value of the two will be considered statistically significant, if statistically significant at 
the 0.025 (two-sided) level of significance. 
Select secondary and exploratory endpoints will be alpha-level protected in a hierarchical 
fashion, conditional upon the statistical significance of both endpoints in the primary endpoint 
family. Additional details will be specified in the SAP. 
 
11.2.5.6. Handling of Missing Data 
A significant amount of missing data are not anticipated, given characteristics of the subject 
population from which subjects will be enrolled. In addition, the mixed model repeated measures 
approach is valid under a missing at random (MAR) missingness mechanism. Nevertheless, 
depending on the extent of missing data, additional sensitivity analyses may be considered. 

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11.2.6. 
Pharmacokinetics (PK) 
Elamipretide plasma concentration data collected on repeated occasions in all subjects (Week 4, 
Week 12 and Week 24) will be used in a non-linear mixed effects model to assess the 
characteristics of elamipretide PK in the PK population. 
The PK model will be generated and validated using data reported from historical, thorough PK 
studies. Where sufficient data allows, covariates will include age, gender, race, renal function (as 
described by eGFR), ordinal grouping of genetic abnormalities, intercurrent conditions and 
concomitant medications. 
Plasma samples will be analyzed for elamipretide using a validated liquid chromatography/ 
tandem mass spectrometry assay. Pharmacokinetic modelling will be performed using 
NONMEM computer software. 
All model assumptions, validation and data analysis will be detailed in the PK Analysis Plan 
prior to database lock. 
 
11.2.7. 
Safety Analyses 
Safety data analysis will be conducted for the Safety Population. 
 
11.2.7.1. 
Adverse Events (AEs)/Adverse Device Effects (ADEs) 
All AEs/ADEs will be coded to system organ class (SOC) and preferred term (PT) using the 
latest Medical Dictionary for Regulatory Activities coding dictionary. All reported AEs/ADEs 
will be listed, but only treatment-emergent AEs (TEAEs)/treatment-emergent adverse device 
effects (TEADEs) will be summarized. 
The incidence of all TEAEs/TEADEs, drug relationship with TEAEs, device relationship with 
TEADEs, and severity of TEAEs/TEADEs will be summarized by treatment group. In the 
summary tables, subjects may be counted under multiple SOCs and PTs, but for each SOC and 
PT, subjects are only counted once for each treatment group. If a subject has the same AE/ADE 
on multiple occasions, the highest severity (severe > moderate > mild) or drug relationship 
(probable > possibly related > unlikely related > unrelated) recorded for the event will be 
presented. If severity is missing, subjects will be included as missing (for severity). If drug 
relationship is missing, subjects will be included in related tables (i.e., considered related). 
Summary tables will be organized by SOC, then PT. 
Local tolerability (pain/tenderness, erythema, induration/swelling, and pruritus) of the injection 
site will be evaluated as an AE and summarized. 
 
11.2.7.2. 
Deaths and Other Serious Adverse Events (SAEs)/Serious Adverse Device 
Effects (SADEs) 
Listings will be provided for the following: 
• 
Deaths 
• 
SAEs/SADEs 
• 
AEs/ADEs leading to discontinuation of double-blind IMP 

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11.2.7.3. 
Clinical Laboratory Evaluations 
Summary tables for laboratory parameters included in Appendix 4 (including clinical 
hematology and chemistry laboratory parameters, 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 parameter and visit for each treatment group. Shift tables for urinalysis will show 
the number of subjects who are normal/abnormal at baseline and normal/abnormal at the end of 
trial. 
 
11.2.7.4. 
Vital Signs 
Vital signs data will be summarized by changes from baseline values at each treatment group 
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. 
 
11.2.7.5. 
Electrocardiogram 
ECG data will be summarized by changes from baseline values at each treatment group using 
descriptive statistics. 
Electrocardiogram results (normal versus abnormal) and an assessment of the clinical 
significance of any abnormalities, in the opinion of the Investigator, will be listed for individual 
subjects. Intervals of PR, RR, QRS, QT, and QTcF will also be listed. 
Similar data will be reported for ambulatory arrhythmias. 
 
11.2.7.6. 
Other Safety Parameters 
Any other safety data captured on the eCRF will be listed. 

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12. 
INFORMED CONSENT, ETHICAL REVIEW, AND 
REGULATORY CONSIDERATIONS 
12.1. 
Informed Consent 
The Investigator is responsible for identifying potential subjects from the SPIMM-300 study or 
subjects that otherwise meets trial Inclusion/Exclusion Criteria. The Investigator is responsible 
for ensuring that the subject understands the potential risks and benefits of participating in the 
trial, including answering any questions the subject may have throughout the trial and sharing in 
a timely manner any new information that may be relevant to the subject willingness to continue 
his or her participation in the trial. 
The ICF will be used to explain the potential risks and benefits of trial participation to the subject 
in simple terms before the subject is entered into the trial, and to document that the subject is 
satisfied with his or her understanding of the risks and benefits of participating in the trial and 
desires to participate in the trial. 
The Investigator is responsible for ensuring that informed consent is given by each subject or 
legal representative. This includes obtaining the appropriate signatures and dates on the ICF prior 
to the performance of any protocol procedures and prior to the administration of investigational 
product. 
As used in this protocol, the term “informed consent” includes all consent and assent given by 
subject or their legal representatives. 
 
12.2. 
Ethical Review 
The Sponsor or its representatives must approve all ICFs before they are used at a clinical site. 
All ICFs must be compliant with the ICH guideline on GCP. 
Documentation of EC approval of the protocol and the ICFs must be provided to the Sponsor, or 
designee before the trial may begin at the clinical site. 
 
12.3. 
Regulatory Considerations 
This trial will be conducted in accordance with: 
1. Consensus ethics principles derived from international ethics guidelines, including the 
CIOMS International Ethical Guidelines 
1. The ICH GCP Guideline [E6] 
2. European Directive 2001/20/EC 
3. Applicable laws and regulations 
The Investigator, Sponsor, or designee will promptly submit the protocol to applicable EC(s), 
IRBs, Regulatory Authorities and other Regulatory bodies as required. Some of the obligations 
of the Sponsor may be assigned to a third-party organization. Clinical sites will not commence 
enrollment until Regulatory Authority submission/approval and site EC/IRB favorable 
opinion/approval are granted. 

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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/ADEs and/or other trial-related data. 
 
12.3.1. 
Protocol Approval 
The Sponsor’s responsible 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 trial. 
 
12.3.2. 
Final Report Approval 
The Sponsor’s responsible medical officer will approve the final clinical trial report for this trial, 
confirming that, to the best of his or her knowledge, the report accurately describes the conduct 
and results of the trial. 
 
12.3.3. 
Trial Monitoring 
The Investigators and institution(s) will permit trial-related monitoring of the eCRF data by 
Stealth BioTherapeutics Inc., or their assignee by providing direct access to source data and/or 
documents. The trial monitor will verify the eCRFs 100% against the source documentation. 
Deviations from the protocol with regard to subject enrollment or trial conduct will be noted in a 
database. Serious/major protocol deviations may be reported to EC(s), IRBs, Regulatory 
Authorities and other Regulatory bodies as required. A Sponsor representative will visit the 
clinical site to initiate the trial, prior to the first treatment of the first subject, and at agreed times 
throughout the trial, including at the end of the trial. Drug dispensing and clinical drug supply 
records will be 100% verified at the clinical site by the trial monitor. It is understood that all 
subject specific information is confidential and no documentation that can link trial information 
to the specific subject will be collected or retained by the Sponsor. Additional details will be 
provided in a Clinical Monitoring Plan. 
 
12.3.4. 
Retention of Records 
All trial-related material including source documents, eCRFs, Central Authority, EC 
correspondence, and analyses and any other documentation required by applicable laws and 
regulations will be maintained for 15 years after completion of the trial 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 trial only. 
It is understood by the Investigator that Stealth BioTherapeutics Inc., will use information 
developed in this clinical trial in connection with the development of the 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 trial, 
the Investigator understands that he/she has an obligation to provide complete test results and all 
data developed during this trial to the Sponsor. 
The Investigator may not submit for publication or presentation the results of this trial without 
first receiving written authorization from Stealth BioTherapeutics Inc. Stealth BioTherapeutics 

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Inc., agrees that before it publishes any results of the trial, 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. 
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Fry M, Green DE. Cardiolipin requirement for electron transfer in complex I and III of the 
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Society's Committee on Diagnosis. The in-depth evaluation of suspected mitochondrial disease. 
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Karaa A, Krieger J, Holbert A, Grier J, Thompson JL, Parikh S, Hirano M. Mitochondrial 
disease patients' perception of dietary supplements' use. Mitochondrion. 2015(24):S26-7. 
Mancuso M, Hirano M. Physician Guide to Mitochondrial Myopathies. National Organization 
for Rare Disorders. 2016. Accessed on 12Mar2017. Accesible at: 
http://nordphysicianguides.org/mitochondrial-myopathies-mm/ 
Min K, Smuder AJ, Kwon OS, Kavazis AN, Szeto HH, Powers SK. Mitochondrial-targeted 
antioxidants protect skeletal muscle against immobilization-induced muscle atrophy. Journal of 
Applied Physiology. 2011 Nov 1;111(5):1459-66. 
Ng YS, Turnbull DM. Mitochondrial disease: genetics and management. Journal of neurology. 
2016 Jan 1;263(1):179-91. 
Parikh S, Goldstein A, Koenig MK, Scaglia F, Enns GM, Saneto R, Anselm I, Cohen BH, Falk 
MJ, Greene C, Gropman AL, Haas R, Hirano M, Morgan P, Sims K, Tarnopolsky M, Van Hove 
JLK, Wolfe L, DiMauro S. Diagnosis and Management of Mitochondrial Disease: A consensus 
Statement from the Mitochondrial Medicine Society. Genetics in Medicine 2015; 17(9):689-701. 
Pfeffer G, Chinnery P. Diagnosis and treatment of mitochondria myopathies. Ann Med. 2013; 
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Powers SK, Hudson MB, Nelson WB, Talbert EE, Min K, Szeto HH, Kavazis AN, Smuder AJ. 
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weakness. Critical care medicine. 2011 Jul 1;39(7):1749-59. 
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a transgenic short hairpin RNA-induced murine model of Tafazzin deficiency. Human gene 
therapy. 2010 Dec 13;22(7):865-71. 
Suomalainen A, Elo JM, Pietilainen KH, et al. FGF-21 as a biomarker for muscle-manifesting 
mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol 2011;10:806– 
818. 
Taivassalo T, Gardner JL, Taylor RW, Schaefer AM, Newman J, Barron MJ, Haller RG, 
Turnbull DM. Endurance Training and Detraining in Mitochondrial Myopathies Due to Single 
Large-Scale mtDNA Deletions. Brain 2006; 129:3391-3401. 
Taivassalo T, Jensen TD, Kennaway N, DiMauro S, Vissing J, Haller RG. The spectrum of 
exercise tolerance in mitochondrial myopathies: a study of 40 patients. Brain. 2003 Feb;126(Pt 
2):413-23 
Talbert EE, Smuder AJ, Min K, Kwon OS, Szeto HH, Powers SK. Immobilization-induced 
activation of key proteolytic systems in skeletal muscles is prevented by a mitochondria-targeted 
antioxidant. Journal of applied physiology. 2013 Aug 15;115(4):529-38. 
Tarnopolsky M. Exercise Testing as a Diagnostic Entity in Mitochondrial Myopathies. 
Mitochondrion 4 2004; 529-542 
Yatsuga S, Fujita Y, Ishii A, Fukumoto Y, Arahata H, Kakuma T, Kojima T, et al. Growth 
differentiation factor 15 as a useful biomarker for mitochondrial disorders. Ann Neurol. 2015 
;78(5):814-23. 
Yeske P, et al. Mitochondrial Disease Clinical Trials Working Group. Challenges of Research on 
Therapeutics in Mitochondrial Diseases. Presented at: FDA Critical Path Innovation Meeting; 
October 19, 2015; Silver Spring, MD. Available at: 
https://www.fda.gov/drugs/developmentapprovalprocess/druginnovation/ucm395888.htm. 
Accessed June 27, 2017. 
Zorov DB, Filburn CR, Klotz LO, Zweier JL, Sollott SJ. Reactive oxygen species (Ros-Induced) 
Ros release a new phenomenon accompanying induction of the mitochondrial permeability 
transition in cardiac myocytes. The Journal of experimental medicine. 2000 Oct 2;192(7):1001- 
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Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial ROS-induced ROS release: an update and 
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APPENDIX 1. PART 1 SCHEDULE OF ASSESSMENTS 
 
Period 
Screening 
Perioda 
Treatment Period 
Follow-Up 
Period 
Visitb 
Visit 1 
(Screening) 
Visit 2 
(Baseline/Day 1)c 
Visit 3 
(Week 4) 
Visit 4 
(Week 12) 
Visit 5 
(Week 24) 
Visit 6A 
(End-of-Trial 
or Early DC) 
Window 
-28 Day to -1 
Day 1 
Day 29 ±2 
Day 85 ± 4 
Day 169 + 14 
Day 197 +14 
Informed Consentd 
X 
Demographics 
X 
Review Inclusion/Exclusion Criteria 
X 
X 
Review PART 2 Continuation Criteria 
X 
Medical/Surgical Historyn 
X 
X (update) 
Concomitant Medication/Procedure Review 
X 
X (update) 
X 
X 
X 
X 
Review AEs/ADEs 
X 
X 
X 
X 
X 
X 
Physical Examinatione 
X 
X 
X 
X 
X 
X 
Vital Signsf 
X 
X 
X 
X 
X 
X 
12-Lead ECGg 
X 
X 
X 
X 
X 
X 
C-SSRS “Baseline/Screening” 
X 
C-SSRS “Since Last Visit” 
X 
X 
X 
X 
X 
Clinical chemistry and hematology 
laboratory parametersh 
X 
X 
X 
X 
X 
X 
Clinical Urinalysish 
X 
X 
X 
X 
X 
X 
Pregnancy Testi 
X 
X 
X 
PK Samplesj 
X 
X 
X 
PMMSA 
Xo------------------------------------Daily ------------------------------------ X 
Neuro-QoL Fatigue 
X 
X 
X 
X 
X 
EQ-5D-5L 
X 
X 
X 
X 
X 
PGI Scales 
X 
X 
X 
X 
X 
CGI Scales 
X 
X 
X 
X 
X 
6MWTk 
X 
X 
X 
X 
X 
IMP Administrationl 
X--------------------Daily ------------------- X 
ISR Assessmentm 
X 
X 
X 
X 
a. 
Screening will begin with the subject’s signature of the informed consent form (ICF) and will last a minimum of 7 days to a maximum of 28 days. Subjects 
not previously enrolled in SPIMM-300, however, may have a longer screening period for review by the Adjudication Committee to determine their 
eligibility for study enrollment. 
b. 
All clinical site visits should occur at approximately (±2 hours) the same time during the day and subjects should have at least 1 hour of fasting (e.g. no large 
meals) prior to the 6MWT. Trial Days are relative to the Baseline Visit (Day 1). 

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c. 
Baseline assessments must be completed within 24 hours prior to receiving IMP. 
d. 
The ICF must be signed prior to any trial-related procedures are performed. 
e. 
Height will only be measured at the Screening Visit, and used in the trial to calculate BMI. Physical examination will include: general appearance, skin, 
head, eyes, ears, nose, throat, neck  (including thyroid), lymph nodes, chest, heart, abdomen, extremities, nervous system, and weight. 
f. 
Vital signs will include HR, RR, and BP after sitting for 5 min, and temperature. 
g. 
All scheduled ECGs must be performed after the subject has rested quietly for at least 5 min in the supine position. 
h. 
Blood samples will be collected prior to the IMP administration on the Baseline Visit. Analysis will include testing for parameters included in Appendix 4. 
Additional blood samples at the Baseline, Week 24 Visit, and Early Discontinuation Visit (if applicable) will be collected and stored for assessing the 
immunogenicity potential of the IMP. 
i. 
Serum pregnancy test will be done for women of childbearing potential at the Screening Visit. Results of the Baseline Visit pre-dose urine pregnancy test 
must be evaluated before randomization to ensure eligibility. Urine pregnancy test will also be performed for women of childbearing potential at the End-of- 
Trial/Early Discontinuation Visit. 
j. 
PK Schedule: Week 4: 1 hour post dose (± 10 min); Week 12: 30 min, 2 hours, and 4 hours post dose (± 10 min); Week 24: pre-dose (-10 min). 
k. 
The 6MWT should be performed after all other trial procedures (except for PMMSA at the Screening Visit and the IMP administration at the Baseline Visit). 
The 6MWT instructions are provided in Appendix 13. 
l. 
Subjects (and caregivers if needed) will be trained on the procedure for administration of the elamipretide delivery system (the investigational medicinal 
product [IMP] [elamipretide or placebo], the elamipretide pen injector, and needle). On days of trial visits, the IMP administered with the elamipretide 
delivery system should be administered at the clinical site. At Baseline Visit, the IMP administration will occur after the completion of all Visit procedures. 
At the Week 4, Week 12, and Week 24 Visits, the IMP administration should occur after all other trial procedures. The location (injection in the abdomen, 
rotating around the four abdominal quadrants, or other appropriate location [after Investigator consultation with the Sponsor]) and time (at approximately the 
same time each day [e.g., early morning, noon, or early afternoon]) of the IMP administration will be recorded daily in a diary. Supplies will be collected, 
compliance will be assessed, and new supplies will be provided at clinical site visits. For subjects continuing into PART 2 of the trial, IMP administration 
the day of the Week 24 Visit will use the PART 2 supply of IMP. Subjects not continuing into PART 2 will not be administered IMP at the Week 24 Visit. 
m. The skin examination should occur at 30 (±5) minutes after the IMP administration with the elamipretide delivery system. The presence and severity of pain, 
erythema, swelling, and pruritus at the injection site will be assessed. Scoring of erythema, swelling, pruritus and pain will be done using a 5-point scale 
using the “Table for Grading the Severity of Site Reactions to Injections” provided in Appendix 14. 
n. 
Obtain previous genetic testing results from subjects not previously enrolled in SPIMM-300. 
o. 
The PMMSA at the Screening Visit should be the last trial assessment completed. 

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APPENDIX 2. PART 2 SCHEDULE OF ASSESSMENTS 
 
Period 
Treatment Period 
Follow-Up Period 
Visit 
Visit 6B 
(Week 28) 
Visit 7 
(Week 36) 
Visit 8 
(Week 48) 
Visits 9-13 
(Week 72, 96, 
120, 
144, 168) 
Phone Call 
(Week 60, 84, 
108, 
132, 156) 
Visit 14 
(Week 172) 
End-of-Trial or 
Early DC 
Window 
± 1 week 
± 2 weeks 
± 2 weeks 
± 2 weeks 
± 2 weeks 
+ 7 days 
Concomitant 
Medication/Procedure Review 
X 
X 
X 
X 
X 
X 
Review AEs/ADEs 
X 
X 
X 
X 
X 
X 
Physical Examinationa 
X 
X 
X 
X 
X 
Vital Signsb 
X 
X 
X 
X 
X 
12-Lead ECGc 
X 
X 
X 
X 
X 
C-SSRS “Since Last Visit” 
X 
X 
X 
X 
X 
Clinical chemistry and hematology 
laboratory parametersd 
X 
X 
X 
X 
X 
Clinical Urinalysisd 
X 
X 
X 
X 
X 
Urine Pregnancy Teste 
X 
IMP Administrationf 
X--------------------Daily ------------------- X 
ISR Assessmentg 
X 
X 
X 
X 
a. 
Physical examination will include: general appearance, skin, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, chest, heart, abdomen, 
extremities, nervous system, and weight. 
b. 
Vital signs will include HR, RR, and BP after sitting for 5 min, and temperature. 
c. 
All scheduled ECGs must be performed after the subject has rested quietly for at least 5 min in the supine position. 
d. 
See Appendix 4 for clinical laboratory tests. Additional blood samples at the Early Discontinuation Visit (if applicable) will be collected and stored for 
assessing the immunogenicity potential of the IMP. 
e. 
Urine Pregnancy test will be performed for women of childbearing potential at the End-of-Trial/Early Discontinuation Visit. 
f. 
On days of trial visits, the IMP administered with the elamipretide delivery system should be administered at the clinical site. The location (injection in the 
abdomen, rotating around the four abdominal quadrants, or other appropriate location [after Investigator consultation with the Sponsor]) and time (at 
approximately the same time each day [e.g., early morning, noon, or early afternoon]) of the IMP administration will be recorded daily in a diary. Supplies 
will be collected, compliance will be assessed, and new supplies will be provided at clinical site visits. 
g. 
The skin examination should occur at 30 (±5) minutes after the IMP administration with the elamipretide delivery system. The presence and severity of pain, 
erythema, swelling, and pruritus at the injection site will be assessed. Scoring of erythema, swelling, pruritus and pain will be done using a 5-point scale 
using the “Table for Grading the Severity of Site Reactions to Injections” provided in Appendix 14. 

SPIMM-301 Version 4.0 
15 June 2018 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
85 
 
 
 
APPENDIX 3. TRIAL DESIGN SCHEMATIC 
PART 1 
Trial site(s): Multicenter (North America and Europe); approximately 27 sites 
 
 
PART 2 
 

SPIMM-301 Version 4.0 
15 June 2018 
86 
 
 
 
 
 
APPENDIX 4. LIST OF CLINICAL LABORATORY TESTS TO BE 
PERFORMED 
 
Hematology: 
Chemistry: 
Haemoglobin 
Sodium 
Haematocrit 
Potassium 
Erythrocyte count (RBC) 
Total bilirubin 
MCH 
Direct bilirubin 
MCHC 
Indirect bilirubin 
MCV 
Bicarbonate 
RBC morphology 
Alkaline phosphatase (ALK-P) 
Leukocytes (WBC) 
Alanine aminotransferase (ALT) 
Neutrophils (ANC, segmented %) 
Aspartate aminotransferase (AST) 
Lymphocytes (absolute, %) 
Blood urea nitrogen (BUN) 
Monocytes (absolute, %) 
Gamma-glutamyl transpeptidase (GGTP) 
Eosinophils (absolute, %) 
Creatine kinase (CK) 
Basophils (absolute, %) 
Creatinine 
Platelets 
LDH 
Uric Acid 
Urinalysis: 
Phosphate 
Color & Clarity 
Total Protein 
Specific Gravity 
Globulin 
pH 
Magnesium 
Protein 
Calcium 
Glucose 
Glucose (non-fasting) 
Ketones 
Albumin 
Bilirubin 
Chloride 
Urobilinogen 
Triglycerides 
Blood 
Cholesterol 
Nitrite 
HDL 
Leukocyte esterase 
LDL 
VLDL 
Lactate 
Immunogenicity sample (Baseline and 
Week 24 ONLY) 
eGFR 
 
 
 
 
 
 
 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 

SPIMM-301 Version 4.0 
15 June 2018 
87 
 
 
 
APPENDIX 5. COLUMBIA-SUICIDE SEVERITY RATING SCALE (C- 
SSRS) “BASELINE/SCREENING” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 

 
 
 
 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Baseline/Screening Version 
Version 1/14/09 
 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J. 
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained in 
the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of suicidal 
ideation or behavior depends on the judgment of the individual administering the scale. 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History Form, 
developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
 
 
 
C-SSRS Baseline Screening - United States/English - Mapi. 
C-SSRS-BaselineScreening_AU5.1_eng-USori.doc 

© 2008 Research Foundation for Mental Hygiene, Inc. 
C-SSRS—Baseline/Screening (Version 1/14/09) 
Page 1 of 2 
 
 
SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” section. If the answer to 
question 2 is “yes”, ask questions 3, 4 and 5. If the answer to question 1 and/or 2 is “yes”, complete 
“Intensity of Ideation” section below. 
Lifetime: Time 
He/She Felt 
Most Suicidal 
Past 
Months 
1.  Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
If yes, describe: 
Yes 
No 
Yes 
No 
2.  Non-Specific Active Suicidal Thoughts 
General non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of 
ways to kill oneself/associated methods, intent, or plan during the assessment period. 
Have you actually had any thoughts of killing yourself? 
If yes, describe: 
Yes 
No 
Yes 
No 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific 
plan with time, place or method details worked out (e.g., thought of method to kill self but not a specific plan). Includes person who would 
say, “I thought about taking an overdose but I never made a specific plan as to when, where or how I would actually do it… and I would 
never go through with it.” 
Have you been thinking about how you might do this? 
If yes, describe: 
Yes 
No 
Yes 
No 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts 
but I definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them? 
If yes, describe: 
Yes 
No 
Yes 
No 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
If yes, describe: 
Yes 
No 
Yes 
No 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e.,1-5 from above, with 1 being 
the least severe and 5 being the most severe). Ask about time he/she was feeling the most suicidal. 
Lifetime - 
Most Severe Ideation:     
 
  
 
Type # (1-5) 
Description of Ideation 
Past X Months - 
Most Severe Ideation:     
 
  
 
Type # (1-5) 
Description of Ideation 
Most Severe 
Most 
Severe 
Frequency 
How many times have you had these thoughts? 
(1) Less than once a week 
(2) Once a week 
(3) 2-5 times in week 
(4) Daily or almost daily 
(5) Many times each day 
 
 
Duration 
When you have the thoughts how long do they last? 
(1) Fleeting - few seconds or minutes 
(4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time 
(5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time 
  
 
  
 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts 
(4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty 
(5) Unable to control thoughts 
(3) Can control thoughts with some difficulty 
(0) Does not attempt to control thoughts 
  
 
  
 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or 
acting on thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide 
(4) Deterrents most likely did not stop you 
(2) Deterrents probably stopped you 
(5) Deterrents definitely did not stop you 
(3) Uncertain that deterrents stopped you 
(0) Does not apply 
  
 
  
 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself? Was it to end the pain or 
stop the way you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or 
was it to get attention, revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others 
(4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others 
living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others and to 
(5) Completely to end or stop the pain (you couldn’t go on 
end/stop the pain 
 
living with the pain or how you were feeling) 
(0) Does not apply 
  
 
  
 
 

© 2008 Research Foundation for Mental Hygiene, Inc. 
C-SSRS—Baseline/Screening (Version 1/14/09) 
Page 2 of 2 
 
 
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Lifetime 
Past 
Years 
Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill 
oneself. Intent does not have to be 100%. If there is any intent/desire to die associated with the act, then it can be considered an actual suicide 
attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in 
mouth but gun is broken so no injury results, this is considered an attempt. 
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, 
a highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of 
a high floor/story). Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred. 
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you  
as a way to end your life? 
Did you want to die (even a little) when you  
 ? 
Were you trying to end your life when you  
? 
Or did you think it was possible you could have died from  
? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, 
get sympathy, or get something else to happen)? (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes 
No 
 
 
Total # of 
Attempts 
 
Yes 
No 
Yes 
No 
Total # of 
Attempts 
Yes 
No 
Interrupted Attempt: 
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt 
would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an attempt rather than an interrupted 
attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. 
Once they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from 
ledge. Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you 
before you actually did anything? 
If yes, describe: 
Yes 
No 
 
 
Total # of 
interrupted 
Yes 
No 
Total # of 
interrupted 
Aborted Attempt: 
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self- 
destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by 
something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
Yes 
No 
 
 
Total # of 
aborted 
Yes 
No 
Total # of 
aborted 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as 
assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a 
suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, 
getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
Yes 
No 
Yes 
No 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes 
No 
Yes 
No 
Answer for Actual Attempts Only 
Most Recent 
Attempt 
Date: 
Most Lethal 
Attempt 
Date: 
Initial/First 
Attempt 
Date: 
Actual Lethality/Medical Damage: 
0. No physical damage or very minor physical damage (e.g., surface scratches). 
1. Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2. Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel). 
3. Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with 
reflexes intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4. Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third- 
degree burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5. Death 
Enter Code 
Enter Code 
Enter Code 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had 
potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying 
on train tracks with oncoming train but pulled away before run over). 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
Enter Code 
Enter Code 
Enter Code 
 

 
SPIMM-301 Version 4.0 
15 June 2018 
 
 
APPENDIX 6. COLUMBIA-SUICIDE SEVERITY RATING SCALE (C- 
SSRS) “SINCE LAST VISIT” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
 
 
91 

 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit 
Version 1/14/09 
 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J. 
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained in 
the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of suicidal 
ideation or behavior depends on the judgment of the individual administering the scale. 
 
 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History Form, 
developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
 
 
 
C-SSRS Since Last Visit - United States/English - Mapi. 
C-S SRS-SinceLastVisit_AU5.1_eng-USori.doc 

© 2008 Research Foundation for Mental Hygiene, Inc. 
C-SSRS—Since Last Visit (Version 1/14/09) 
Page 1 of 2 
 
 
SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes”, 
ask questions 3, 4 and 5. If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below. 
Since Last 
Visit 
1.  Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
If yes, describe: 
Yes 
No 
2.  Non-Specific Active Suicidal Thoughts 
General non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan during the assessment period. 
Have you actually had any thoughts of killing yourself? 
If yes, describe: 
Yes 
No 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g., thought of method to kill self but not a specific plan). Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it…..and I would never go through with it”. 
Have you been thinking about how you might do this? 
If yes, describe: 
Yes 
No 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I definitely 
will not do anything about them”. 
Have you had these thoughts and had some intention of acting on them? 
If yes, describe: 
Yes 
No 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
If yes, describe: 
Yes 
No 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e.,1-5 from above, with 1 being the least severe 
and 5 being the most severe). 
Most Severe Ideation: 
   
 
  
 
 
Type # (1-5) 
Description of Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts? 
(1) Less than once a week 
(2) Once a week 
(3) 2-5 times in week 
(4) Daily or almost daily 
(5) Many times each day 
 
Duration 
When you have the thoughts how long do they last? 
(1) Fleeting - few seconds or minutes 
(2) Less than 1 hour/some of the time 
(3) 1-4 hours/a lot of time 
(4) 4-8 hours/most of day 
(5) More than 8 hours/persistent or continuous 
 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts 
(4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty 
(5) Unable to control thoughts 
(3) Can control thoughts with some difficulty 
(0) Does not attempt to control thoughts 
 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting on 
thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide 
(4) Deterrents most likely did not stop you 
(2) Deterrents probably stopped you 
(5) Deterrents definitely did not stop you 
(3) Uncertain that deterrents stopped you 
(0) Does not apply 
 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself? Was it to end the pain or stop the way 
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention, 
revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others 
(4) Mostly to end or stop the pain (you couldn’t go on living with the pain or 
(2) Mostly to get attention, revenge or a reaction from others 
how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others and to 
(5) Completely to end or stop the pain (you couldn’t go on living with the 
end/stop the pain 
 
pain or how you were feeling) 
(0) Does not apply 
  
 
 

© 2008 Research Foundation for Mental Hygiene, Inc. 
C-SSRS—Since Last Visit (Version 1/14/09) 
Page 2 of 2 
 
 
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since 
Last Visit 
Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
Yes 
No 
does not have to be 100%. If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury 
results, this is considered an attempt. 
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly 
lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). 
Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred. 
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Total # of 
Attempts 
Did you  
as a way to end your life? 
Did you want to die (even a little) when you  
? 
 
Were you trying to end your life when you  
? 
Or Did you think it was possible you could have died from  
? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get 
sympathy, or get something else to happen)? (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
Yes 
No 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
 
Interrupted Attempt: 
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred). 
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around 
neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything? 
If yes, describe: 
Yes 
No 
 
 
Total # of 
interrupted 
Aborted Attempt: 
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you actually did 
anything? 
If yes, describe: 
Yes 
No 
 
 
Total # of 
aborted 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a 
specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, 
giving valuables away or writing a suicide note)? 
If yes, describe: 
Yes 
No 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes 
No 
Suicide: 
Yes 
No 
Answer for Actual Attempts Only 
Most Lethal 
Attempt 
Date: 
Actual Lethality/Medical Damage: 
0. No physical damage or very minor physical damage (e.g., surface scratches). 
1. Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2. Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree burns; bleeding of major vessel). 
3. Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes intact; third-degree burns 
less than 20% of body; extensive blood loss but can recover; major fractures). 
4. Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree burns over 20% of body; 
extensive blood loss with unstable vital signs; major damage to a vital area). 
5. Death 
Enter Code 
  
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for very serious 
lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away 
before run over). 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 2 
= Behavior likely to result in death despite available medical care 
Enter Code 
 

SPIMM-301 Version 4.0 
15 June 2018 
95 
 
 
 
APPENDIX 7. SAMPLE SAFETY TELEPHONE CALL SCRIPT 
This page provides a sample script for the phone call that will be made to the subject occur 
approximately every 12 weeks between clinical site visits after the subject is enrolled in PART 2 
to ensure the safe and compliant use of the study drug and to appropriately collect the safety 
events with use of the study drug. 
The sample script below is provided to assist clinical sites with conducting safety telephone 
calls. Additional questions are permitted to ensure completeness of answers. 
During each safety telephone call, the following script should be followed: 
Script 
Hello, my name is  
, and I'm calling from (name of facility and/or Investigator’s 
name office). I am calling since it has been about 3 months since we last spoke about your 
experience using elamipretide, the study drug in the PART 2 trial you are involved in. May I ask 
you a few questions about your experience? 
Have you or a trained caregiver been administering the study drug daily? 
How many days since (our last telephone call or your last site visit) have you missed 
administering the study drug? 
Do you have any questions/concerns regarding administering the study drug? 
Have you had any problems with the study drug device? 
Have you experienced any worsening of your health or any new problems/conditions while on 
the study drug since (our last telephone call or your last site visit)? 
Have you started or changed any medications since (our last telephone call or your last site 
visit)? 
Could we schedule the next (telephone call or site visit)? (schedule telephone call or site visit) 
Do you have any additional questions? 
Thank you for speaking with me today. If you have any additional questions, please call me at 
(phone number). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 

SPIMM-301 Version 4.0 
15 June 2018 
96 
 
 
 
APPENDIX 8. PRIMARY MITOCHONDRIAL MYOPATHY SYMPTOM 
ASSESSMENT (PMMSA) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 

Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
 
 
 
Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) 
 
 
 
 
 
was your worst feeling of tiredness 
 
 
 
was your worst feeling of tiredness 
 
 
was your worst feeling of muscle 
 
 
 
was your worst feeling of muscle 
 
 
were your worst balance problems? 
were your worst vision problems? 
was your worst abdominal 
 
 
was your worst muscle pain? 
was your worst numbness? 
was your worst headache? 
Not at all 
Mild 
Moderate 
Severe 
1.   During the past 24 hours, how severe 
□ 
at rest (for example, when sitting or 
lying down)? 
□ 
□ 
□ 
2.   During the past 24 hours, how severe 
□ 
during activities? 
□ 
□ 
□ 
3.   During the past 24 hours, how severe 
□ 
weakness at rest (for example, when 
sitting or lying down)? 
□ 
□ 
□ 
4.   During the past 24 hours, how severe 
□ 
weakness during activities? 
□ 
□ 
□ 
5.   During the past 24 hours, how severe 
□ 
□ 
□ 
□ 
6.   During the past 24 hours, how severe 
□ 
□ 
□ 
□ 
7.   During the past 24 hours, how severe 
□ 
discomfort (feeling nauseous, 
bloated, or in pain)? 
□ 
□ 
□ 
8.   During the past 24 hours, how severe 
□ 
□ 
□ 
□ 
9.   During the past 24 hours, how severe 
□ 
□ 
□ 
□ 
10. During the past 24 hours, how severe 
□ 
□ 
□ 
□ 

Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
 
 
 
 
 
At Screening Visit Only: 
Of the symptoms included in the list below, which do you consider to be your most bothersome 
symptom? Please select only one response from the options listed below. 
• 
Tiredness at rest (for example, when sitting or lying down) 
• 
Tiredness during activities 
• 
Muscle weakness at rest (for example, when sitting or lying down) 
• 
Muscle weakness during activities 
• 
Balance problems 
• 
Vision problems 
• 
Abdominal discomfort (feeling nauseous, bloated, or in pain) 
• 
Muscle pain 
• 
Numbness 
• 
Headache 

 
SPIMM-301 Version 4.0 
15 June 2018 
 
 
APPENDIX 9. NEURO-QOL FATIGUE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
 
 
99 

Neuro-QOL Item Bank v1.0 –Fatigue 
©2008-2013 David Cella and the PROMIS Health Organization on behalf of the National Institute for Neurological 
Disorders and Stroke (NINDS). Used with permission. 
English 
November 4, 2014 
Page 1 of 2 
 
 
 
 
Fatigue 
 
Please respond to each question or statement by marking one box per row. 
 
In the past 7 days… 
Never 
Rarely 
Sometimes 
Often 
Always 
NQFTG13 
I felt exhausted…………………………... 
I felt that I had no energy………………... 
I felt fatigued…………………………….. 
I was too tired to do my household chores. 
I was too tired to leave the house………... 
I was frustrated by being too tired to do 
the things I wanted to do………………… 
I felt tired………………………………… 
I had to limit my social activity because I 
was tired…………………………………. 
I needed help doing my usual activities 
because of my fatigue……………………. 
I needed to sleep during the day…………. 
I had trouble starting things because I was 
too tired………………………………….. 
I had trouble finishing things because I 
was too tired……………………………... 
I was too tired to take a short walk………. 
I was too tired to eat…………………....... 
I was so tired that I needed to rest during 
the day…………………………………… 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
1 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
2 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
3 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
5 
 
5 
 
5 
 
5 
 
5 
 
5 
 
5 
 
5 
 
5 
 
5 
 
5 
 
5 
 
5 
 
5 
 
5 
NQFTG11 
NQFTG15 
NQFTG06 
NQFTG07 
NQFTG10 
NQFTG14 
NQFTG02 
 
NQFTG01 
NQFTG03 
NQFTG04 
 
NQFTG05 
NQFTG08 
NQFTG09 
NQFTG12 
NQFTG16 
I felt weak all over……………………….. 
 
1 
 
2 
 
3 
 
4 
 
5 

Neuro-QOL Item Bank v1.0 –Fatigue 
©2008-2013 David Cella and the PROMIS Health Organization on behalf of the National Institute for Neurological 
Disorders and Stroke (NINDS). Used with permission. 
English 
November 4, 2014 
Page 2 of 2 
 
 
 
 
In the past 7 days… 
Never 
Rarely 
Sometimes 
Often 
Always 
NQFTG17 
I needed help doing my usual activities 
because of weakness……………………... 
 
1 
 
2 
 
3 
 
4 
 
5 
 
NQFTG18 
I had to limit my social activity because I 
was physically weak……………………... 
 
1 
 
2 
 
3 
 
4 
 
5 
NQFTG20 
I had to force myself to get up and do 
things because I was physically too weak.. 
 
1 
 
2 
 
3 
 
4 
 
5 

SPIMM-301 Version 4.0 
15 June 2018 
 
 
 
APPENDIX 10. EQ-5D-5L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
 
 
102 

USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Health Questionnaire 
English version for the USA 

2 
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 
 
Under each heading, please check the ONE box that best describes your health TODAY. 
MOBILITY 
I have no problems walking 
❑ 
I have slight problems walking 
❑ 
I have moderate problems walking 
❑ 
I have severe problems walking 
❑ 
I am unable to walk 
❑ 
SELF-CARE 
I have no problems washing or dressing myself 
❑ 
I have slight problems washing or dressing myself 
❑ 
I have moderate problems washing or dressing myself 
❑ 
I have severe problems washing or dressing myself 
❑ 
I am unable to wash or dress myself 
❑ 
USUAL ACTIVITIES (e.g. work, study, housework, family or 
leisure activities) 
I have no problems doing my usual activities 
❑ 
I have slight problems doing my usual activities 
❑ 
I have moderate problems doing my usual activities 
❑ 
I have severe problems doing my usual activities 
❑ 
I am unable to do my usual activities 
❑ 
PAIN / DISCOMFORT 
I have no pain or discomfort 
❑ 
I have slight pain or discomfort 
❑ 
I have moderate pain or discomfort 
❑ 
I have severe pain or discomfort 
❑ 
I have extreme pain or discomfort 
❑ 
ANXIETY / DEPRESSION 
I am not anxious or depressed 
❑ 
I am slightly anxious or depressed 
❑ 
I am moderately anxious or depressed 
❑ 
I am severely anxious or depressed 
❑ 
I am extremely anxious or depressed 
❑ 

3 
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 
 
 
 
 
• We would like to know how good or bad your health is TODAY. 
 
• This scale is numbered from 0 to 100. 
 
• 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
 
• Mark an X on the scale to indicate how your health is TODAY. 
 
• Now, please write the number you marked on the scale in the box 
below. 
The best health 
you can imagine 
 
 
 
 
90 
 
85 
 
 
 
 
 
 
 
YOUR HEALTH TODAY = 
 
 
 
 
 
 
 
 
 
 
5 
 
0 
The worst health 
you can imagine 
65
100 
95
80
75
60
55
45
40
35
30
25
20
15
10
50
70

 
SPIMM-301 Version 4.0 
15 June 2018 
 
 
APPENDIX 11.  PATIENT GLOBAL IMPRESSION (PGI) SCALES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
 
 
106 

SPIMM-301 
Version 1.0 
 
 
 
 
 
Patient Global Impression of Symptoms 
 
Date Completed:   
 
 
The following questions ask you about your primary mitochondrial myopathy symptoms 
OVER THE PAST WEEK. 
 
1. Please choose the response below that best describes the severity of your primary 
mitochondrial myopathy symptoms over the past week. 
 No Symptoms 
 Mild Symptoms 
 Moderate Symptoms 
 Severe Symptoms 
 Very Severe Symptoms 
 
2. Please choose the response below that best describes the severity of your fatigue 
(tiredness and muscle weakness) over the past week. 
 No Fatigue 
 Mild Fatigue 
 Moderate Fatigue 
 Severe Fatigue 
 Very Severe Fatigue 
 
3. Please choose the response below that best describes the severity of your tiredness 
at rest over the past week. 
 No Tiredness 
 Mild Tiredness 
 Moderate Tiredness 
 Severe Tiredness 
 Very Severe Tiredness 
 
4. Please choose the response below that best describes the severity of your tiredness 
during activities over the past week. 
 No Tiredness 
 Mild Tiredness 
 Moderate Tiredness 
 Severe Tiredness 
 Very Severe Tiredness 
 
5. Please choose the response below that best describes the severity of your muscle 
weakness at rest over the past week. 
 No Muscle Weakness 
 Mild Muscle Weakness 

SPIMM-301 
Version 1.0 
 
 
 
 Moderate Muscle Weakness 
 Severe Muscle Weakness 
 Very Severe Muscle Weakness 
 
6. Please choose the response below that best describes the severity of your muscle 
weakness during activities over the past week. 
 No Muscle Weakness 
 Mild Muscle Weakness 
 Moderate Muscle Weakness 
 Severe Muscle Weakness 
 Very Severe Muscle Weakness 
 
7. Please choose the response below that best describes the severity of your balance 
problems over the past week. 
 No Balance Problems 
 Mild Balance Problems 
 Moderate Balance Problems 
 Severe Balance Problems 
 Very Severe Balance Problems 
 
8. Please choose the response below that best describes the severity of your vision 
problems over the past week. 
 No Vision Problems 
 Mild Vision Problems 
 Moderate Vision Problems 
 Severe Vision Problems 
 Very Severe Vision Problems 
 
9. Please choose the response below that best describes the severity of your 
abdominal discomfort (feeling nauseous, bloated, or in pain) over the past week. 
 No Abdominal Discomfort 
 Mild Abdominal Discomfort 
 Moderate Abdominal Discomfort 
 Severe Abdominal Discomfort 
 Very Severe Abdominal Discomfort 
 
10. Please choose the response below that best describes the severity of your muscle 
pain over the past week. 
 No Muscle Pain 
 Mild Muscle Pain 
 Moderate Muscle Pain 
 Severe Muscle Pain 
 Very Severe Muscle Pain 

SPIMM-301 
Version 1.0 
 
 
 
 
11. Please choose the response below that best describes the severity of your numbness 
over the past week. 
 No Numbness 
 Mild Numbness 
 Moderate Numbness 
 Severe Numbness 
 Very Severe Numbness 
 
12. Please choose the response below that best describes the severity of your headache 
over the past week. 
 No Headache 
 Mild Headache 
 Moderate Headache 
 Severe Headache 
 Very Severe Headache 

SPIMM-301 
Version 1.0 
 
 
 
Patient Global Impression of Change 
Date Completed:   
 
Please think about how your primary mitochondrial myopathy symptoms have changed 
from the time just before you started the study medication to today. The following 
questions ask you about how your symptoms have changed SINCE THE TIME JUST BEFORE 
YOU STARTED THE STUDY MEDICATION TO TODAY. 
 
 
1. Please choose the response below that best describes the overall change in your 
primary mitochondrial myopathy symptoms since you started taking the study 
medication. My primary mitochondrial myopathy symptoms are: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
 
2. Please choose the response below that best describes the overall change in your 
fatigue (tiredness and muscle weakness) since you started taking the study 
medication. My fatigue is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
 
3. Please choose the response below that best describes the overall change in your 
tiredness at rest since you started taking the study medication. My feeling of 
tiredness at rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 

SPIMM-301 
Version 1.0 
 
 
 
4. Please choose the response below that best describes the overall change in your 
tiredness during activities since you started taking the study medication. My feeling 
of tiredness during activities is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
 
5. Please choose the response below that best describes the overall change in your 
feeling of muscle weakness at rest since you started taking the study medication. My 
feeling of muscle weakness at rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
 
6. Please choose the response below that best describes the overall change in your 
feeling of muscle weakness during activities since you started taking the study 
medication. My feeling of muscle weakness during activities is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
 
7. Please choose the response below that best describes the overall change in your 
balance problems since you started taking the study medication. My balance 
problems are: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 

SPIMM-301 
Version 1.0 
 
 
 
8. Please choose the response below that best describes the overall change in your 
vision problems since you started taking the study medication. My vision problems 
are: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
 
9. Please choose the response below that best describes the overall change in your 
abdominal discomfort (feeling nauseous, bloated, or in pain) since you started 
taking the study medication. My abdominal discomfort is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
 
10. Please choose the response below that best describes the overall change in your 
muscle pain since you started taking the study medication. My feeling of muscle pain 
is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
 
11. Please choose the response below that best describes the overall change in your 
numbness since you started taking the study medication. My feeling of numbness is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 

SPIMM-301 
Version 1.0 
 
 
 
12. Please choose the response below that best describes the overall change in your 
headache since you started taking the study medication. My feeling of headache is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 

 
SPIMM-301 Version 4.0 
15 June 2018 
 
 
APPENDIX 12.  CLINICIAN GLOBAL IMPRESSION (CGI) SCALES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
 
 
114 

SPIMM-301 
Version 1.0 
 
 
 
Clinician Global Impression of Symptoms 
Date Completed:   
 
1. Overall, how severe are the patient’s primary mitochondrial myopathy symptoms 
today? 
 No Symptoms 
 Mild Symptoms 
 Moderate Symptoms 
 Severe Symptoms 
 Very Severe Symptoms 
2. Overall, how severe is the patient’s fatigue (tiredness and muscle weakness) today? 
 No Fatigue 
 Mild Fatigue 
 Moderate Fatigue 
 Severe Fatigue 
 Very Severe Fatigue 

SPIMM-301 
Version 1.0 
 
 
 
 
Clinician Global Impression of Change 
 
Date Completed:   
 
Please think about how the patient’s primary mitochondrial myopathy symptoms have 
changed from the time just before he/she started the study drug in SPIMM-301 to today. 
The following questions ask you about how the patient’s symptoms have changed SINCE 
THE TIME JUST BEFORE HE/SHE STARTED THE STUDY DRUG IN SPIMM-301 TO TODAY. 
 
1. Please choose the response below that best describes the overall change in the 
patient’s primary mitochondrial myopathy symptoms since he/she started taking 
the study drug in SPIMM-301. The patient’s primary mitochondrial myopathy 
symptoms are: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
 
2. Please choose the response below that best describes the overall change in the 
patient’s fatigue (tiredness and muscle weakness) since he/she started taking the 
study drug in SPIMM-3どな. The patient’s fatigue is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 

SPIMM-301 Version 4.0 
15 June 2018 
117 
 
 
 
APPENDIX 13.  6-MINUTE WALK TEST (6MWT) 
A 6MWT will be performed to assess the distance a subject is able to walk in six minutes on a 
fixed course length. The subject will be instructed to walk as far as possible for 6 minutes. 
Subjects may stop to rest as needed but should continue walking as soon as they are able. 
If a test is unusable the Core Lab will instruct the site to repeat the test, if possible. 
CPC Clinical Research (CPC) will provide training to all individuals who will be administering 
the 6MWT for this trial and pre-approving the 6MWT course at each clinical site. Subjects 
should only be walked on a course that is approved by CPC. 
The following instructions should be provided to the subject prior to each visit that includes a 
6MWT: 
1. Do not eat or smoke within 1 hour prior to the test, 
2. Wear comfortable, low-heeled walking shoes for the test, and 
3. Bring your usual walking aid (cane, walker, etc.) with you to the visit. 
Please refer to the Study Manual and CPC 6MWT Reference Tool for the full instruction on how 
to conduct the 6MWT. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 

SPIMM-301 Version 4.0 
15 June 2018 
118 
 
 
 
APPENDIX 14. TABLE FOR GRADING THE SEVERITY OF INJECTION 
SITE REACTIONS 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Injection Site 
Pain or 
Pain or tenderness 
Pain or 
Pain or tenderness 
Pain or 
tenderness 
causing greater than 
tenderness 
causing inability to 
Tenderness 
causing no or 
minimal limitation 
causing inability 
perform basic self-care 
minimal 
of use of limb 
to perform 
function OR 
limitation of use 
of limb 
usual social 
& functional 
activities 
Hospitalization 
indicated 
Injection Site 
Erythema or 
Redness 
2.5 to < 5 cm in 
diameter OR 6.25 
to < 25 cm2 surface 
area AND 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
≥ 5 to < 10 cm in 
diameter OR ≥ 25 to < 
100 cm2 surface 
area OR Symptoms 
causing greater than 
minimal 
interference with 
usual social & 
functional activities 
≥ 10 cm in 
diameter OR ≥ 
100 cm2 surface 
area OR 
Ulceration OR 
Secondary 
infection OR 
Phlebitis OR 
Sterile abscess 
OR Drainage OR 
Symptoms 
Potentially life- 
threatening 
consequences (eg, 
abscess, 
exfoliative 
dermatitis, 
necrosis 
involving dermis 
or deeper tissue) 
causing inability 
to perform usual 
social & 
functional 
activities 
Injection Site 
Same as for 
Same as for 
Same as for 
Same as for 
Induration or 
Injection Site 
Injection Site 
Injection Site 
Injection Site 
Swelling 
Erythema or 
Erythema or 
Erythema or 
Erythema or 
Redness 
Redness 
Redness 
Redness 
Injection Site 
Itching localized to 
Itching beyond the 
Generalized 
NA 
Pruritus 
the injection site 
injection site that is 
itching causing 
that is relieved 
not generalized OR 
inability to 
spontaneously or in 
Itching localized to 
perform usual 
< 48 hours of 
treatment 
the injection site 
requiring ≥ 48 
hours treatment 
social 
& functional 
activities 
Adapted from Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Version 2.0, November 2014. 
 
 
 
 
 
 
 
 
 
 
 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 

SPIMM-301 Version 4.0 
15 June 2018 
119 
 
 
 
APPENDIX 15.  COUNTRY-SPECIFIC APPENDIX--GERMANY 
 
The SAE definition and reporting of SAEs will conform to the Medical Devices Safety Plan 
Ordinance (Medizinprodukte-Sicherheitsplanverordnung) that is valid for Germany. 
 
SAE definition: 
 
“Ein Schwerwiegendes unerwünschtes Ereignis” ist jedes in einer genehmigungspflichtigen 
klinischen Prüfung oder einer genehmigungspflichtigen Leistungsbewertungsprüfung auftretende 
ungewollte Ereignis, das unmittelbar oder mittelbar zum Tod oder zu einer schwerwiegenden 
Verschlechterung des Gesundheitszustands eines Probanden, eines Anwenders oder einer 
anderen Person geführt hat, geführt haben könnte oder führen könnte ohne zu berücksichtigen, 
ob das Ereignis vom Medizinprodukt verursacht wurde; das Vorgesagte gilt entsprechend für 
schwerwiegende unerwünschte Ereignisse, die in einer klinischen Prüfung oder 
Leistungsbewertungsprüfung, für die eine Befreiung von der Genehmigungspflicht nach § 20 
Absatz 1 Satz 2 des Medizinproduktegesetzes erteilt wurde, aufgetreten sind. 
 
SAE reporting responsibilities for Germany are detailed in the SMP. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 

 
ISIGDKIKWKCMSZ6EU6J2KI 
 
 
 
Jim Carr 
Party ID: ZWGEDHILMKK6HHEGVJI747 
IP Address: 76.234.40.165 
jim.carr@stealthbt.com 
 
 
 
 
Multi-Factor 
Digital Fingerprint Checksum 
 
acbf6568f7b30334c7688a41be3ae9297502afa7 
 
 
Timestamp 
Audit 
2018-06-15 15:04:07 -0700 
All parties have signed document. Signed copies sent to: Anthony Aiudi, Jim 
Carr, and Virginia Viau. 
2018-06-15 15:04:06 -0700 
Document signed by Jim Carr (jim.carr@stealthbt.com) with drawn signature. - 
76.234.40.165 
2018-06-15 15:03:33 -0700 
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2018-06-15 14:33:36 -0700 
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