Clinical trial NCT02976038
Conditions: Primary Mitochondrial Disease
Keywords: Primary Mitochondrial Disease Stealth elamipretide
Sponsor: Stealth BioTherapeutics Inc.
Start date: 2016-12-01; Completion date: 2020-04-09
Enrollment: 28 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2 Open-Label extension study to evaluate the long term safety and tolerability of daily elamipretide injections in patients with genetically confirmed Primary Mitochondrial Disease who previously participated in the SPIMM-202 Clinical Trial

Detailed description:
This open-label, non-comparative, extension trial will enroll subjects with genetically confirmed PMD who have completed the End-of-Study Visit in the SPIMM-202 trial. Subjects who do not discontinue or withdraw from the trial will receive treatment with 40 mg SC elamipretide for the shortest of the following: 260 weeks; regulatory approval and commercial availability of elamipretide in the subject's respective country; or termination of the clinical development for elamipretide in subjects with PMD.

Arms: arm 1: Open-label once daily subcutaneous injection of 40mg elamipretide
Interventions: intervention 1: elamipretide
Intervention descriptions: intervention 1: 40 mg, subcutaneous injections (in the abdomen) daily for the shortest of the following: 260 weeks; regulatory approval and commercial availability of elamipretide in the subject's respective country; or termination of the clinical development for elamipretide in subjects with PMD.

Protocol documents:
Prot_SAP_000.pdf: 
Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
00863-2.00 
1 
 
 
 
 
A MULTICENTER, OPEN-LABEL PHASE 2 EXTENSION TRIAL TO CHARACTERIZE 
THE LONG-TERM SAFETY AND TOLERABILITY OF SUBCUTANEOUS 
ELAMIPRETIDE IN SUBJECTS WITH GENETICALLY CONFIRMED PRIMARY 
MITOCHONDRIAL MYOPATHY (PMM) 
 
NCT02976038 
 
 
Final Approval Date: 29 January 2019 
 
 
 
 
 
 
 
 
 
 
 
 


Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
00863-2.00 
1 
 
 
 
CLINICAL STUDY PROTOCOL 
A MULTICENTER, OPEN-LABEL PHASE 2 EXTENSION 
TRIAL TO CHARACTERIZE THE LONG-TERM SAFETY AND 
TOLERABILITY OF SUBCUTANEOUS ELAMIPRETIDE IN 
SUBJECTS WITH GENETICALLY CONFIRMED PRIMARY 
MITOCHONDRIAL MYOPATHY (PMM) 
 
Study Phase: 
Phase 2 
 
Study Number: 
SPIMM-203 
 
Document Version: 
Version 3.0 
Final Approval Date: 
29 January 2019 
 
Sponsor: 
Stealth BioTherapeutics Inc. 
275 Grove Street, Suite 3-107 
Newton, MA 02466 
Unites States of America 
 
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. 
 


Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
2 
 
 
 
PROTOCOL APPROVAL 
 
 
Protocol Title: 
A Multicenter, Open-Label Phase 2 Extension Trial to 
Characterize the Long-term Safety and Tolerability of 
Subcutaneous Elamipretide in Subjects with Genetically 
Confirmed Primary Mitochondrial Myopathy (PMM) 
Protocol Number: 
SPIMM-203 
Protocol Date: 
29 January 2019, Version 3.0 
 
 
 
 
 
 
 
 
Jim Carr, Pharm.D. 
Chief Clinical Development Officer 
Stealth BioTherapeutics Inc. 
01/31/2019 
 
Date 


Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
3 
 
 
 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure (IB) for elamipretide (MTP-131). I have 
read the SPIMM-203 protocol and agree to conduct the study as outlined. I confirm that I will 
conduct the study in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice 
(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) 


Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
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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 Study: A Multicenter, Open-Label Phase 2 Extension Trial to Characterize the Long- 
term Safety and Tolerability of Subcutaneous Elamipretide in Subjects with Genetically 
Confirmed Primary Mitochondrial Myopathy (PMM) (SPIMM-203) 
Study Center(s): This study will be conducted in 4 centers in the United States (US) 
Objectives: 
Primary 
• 
To assess the long-term safety and tolerability of single daily subcutaneous (SC) doses 
of 40 mg elamipretide administered with the elamipretide delivery system for up to 260 
weeks 
Secondary 
• 
To obtain longitudinal efficacy data of single daily SC doses of 40 mg elamipretide 
administered with the elamipretide delivery system for up to 260 weeks on: 
o 6-Minute Walk Test (6MWT) 
o Patient Reported Outcomes (Neuro-QoL Fatigue questionnaire, Primary 
Mitochondrial Myopathy Symptom Assessment [PMMSA], Patient Global 
Assessment [PGA], EQ-5D-5L, Work Limitations Questionnaire [WLQ]) 
o Physician Global Assessment (PhGA) 


Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
5 
Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
Trial Design: 
This open-label, non-comparative, extension trial will enroll subjects with genetically 
confirmed PMM who have completed the End-of-Study Visit in the SPIMM-201 and/or 
SPIMM-202 trial (if enrolled in both trials, the End-of-Study Visits in both trials must have 
been completed). Subjects who do not discontinue or withdraw from the trial will receive 
treatment with 40 mg SC elamipretide (study drug) administered with the elamipretide delivery 
system (elamipretide injection cartridge, the elamipretide pen injector and single-use needle) 
for the shortest of the following: 260 weeks; regulatory approval and commercial availability 
of the elamipretide delivery system in the subject’s respective country; or termination of the 
clinical development for elamipretide in subjects with PMM. The Trial Schedule is presented 
in Attachment 1. 
Screening Period: The Screening Period will begin with the signature of the informed consent 
form (ICF) for this trial and will last no longer than 28 days. During the Screening Period, 
subjects will undergo screening procedures as described in the Trial Schedule. For subjects 
enrolled in SPIMM-202, the Screening Period may not begin prior to the Week 12 Visit in the 
SPIMM-202 trial. Assessments completed as part of the Week 12 Visit in SPIMM-202 that are 
within the Screening Period may serve as Screening assessments and do not need to be 
reassessed. Inclusion and exclusion criteria will be assessed using Screening assessments. 
Subjects who complete Screening and meet all trial requirements, including all inclusion and 
none of the exclusion criteria, may enter the Treatment Period. 
Treatment Period: The Treatment Period will begin on the day of the Baseline Visit, which is 
defined as Day 1. Subjects (and caregivers if needed) will be trained on the procedure for use 
of the elamipretide delivery system prior to first dose. An elamipretide delivery system training 
kit and checklist will be provided to the clinical site to assist in training. Study drug will be 
administered daily by the subject or trained caregiver in the abdomen, rotating around the four 
abdominal quadrants, or other appropriate location (after Investigator consultation with the 
Sponsor). 
Assessments completed as part of the End-of-Study Visit in SPIMM-202 and are within 24 
hours of the Baseline Visit may serve as Baseline assessments and do not need to be reassessed. 
Screening assessments that are within 24 hours of the Baseline Visit may also serve as Baseline 
assessments and do not need to be reassessed. Otherwise, Baseline assessments must be 
completed within 24 hours prior to receiving elamipretide. At the Baseline Visit, following 
completion of all Baseline procedures described in the Trial Schedule (except for the injection 
site reaction [ISR] assessment), subjects will be administered SC elamipretide at the trial center. 
Subjects (or trained caregivers) will administer elamipretide with the elamipretide delivery 
system on a daily basis at approximately the same time each day on all trial days (except for site 
visit days). Subjects will visit the trial site for the 3-Month Visit (Week 13), the 6-Month Visit 
(Week 26), and every 26 weeks afterward (additional 6- Month Visits) to administer study drug 
with the elamipretide delivery system, to complete assessments as described in the Trial 
Schedule, and to return all used trial supplies to the trial site. 
Subjects will be scheduled to have Monthly Safety Visits completed by a visiting nurse (or 
designee) in between site visits until the Week 52 site visit. Monthly safety telephone calls will 
be completed in between site visits after the Week 52 site visit. The monthly safety telephone 
call script is provided in Attachment 4. 


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CONFIDENTIAL 
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Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
 
Follow-Up Period: The Follow-Up Period will begin after completion of End-of-Therapy 
Visit (Week 260) and will last for 2 weeks. During the Follow-Up Period, subjects will 
continue to follow all study requirements. At the end of the Follow-Up Period, subjects will 
return to the trial site for the End-of-Study/Early Discontinuation Visit for final safety and 
efficacy assessments and to return used and unused trial supplies and all other study 
instruments/materials to the trial site. 
Number of Subjects (planned):  Up to 36 subjects 
Investigational Product, Dosage and Mode of Administration: 
Elamipretide injection will be supplied as a sterile 3.0 mL single-patient-use, multidose glass 
cartridge of sterile elamipretide injection solution (elamipretide HCl [80 mg/mL], phosphate 
buffer, and benzyl alcohol) for use with the elamipretide delivery system (elamipretide injection 
cartridge, the elamipretide pen injector, and needle) as described in the Pharmacy Manual and 
the 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. Additional details 
regarding the investigational product (IP) will be provided in the Pharmacy Manual. Clinical site 
staff will train subjects (and caregivers if needed) and ensure understanding of proper SC 
injection technique and use of the elamipretide delivery system prior to first dose. An 
elamipretide delivery system training kit and checklist will be provided to the clinical site to 
assist in training. On days of clinical site visits, study drug will be administered at the clinical 
site by the trained caregiver or subject. On non-visit days, the subject (or trained caregiver) will 
administer study drug 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 study drug 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 study drug, independent from the location of 
the concomitant therapy injections, should be used. 
Reference Product: There is no reference product for this open-label non-comparative trial. 


Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
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Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
 
Inclusion Criteria: 
A subject must meet ALL of the following inclusion criteria during the Screening Period: 
1. Willing and able to provide a signed informed consent form (ICF) prior to participation in 
any trial-related procedures. 
2. Investigator determines the subject can, and subject agrees to, adhere to the trial 
requirements for the length of the trial including self-administration (by subject or trained 
caregiver) of the study drug. 
3. Subject completed the End-of-Study Visit in SPIMM-201 and/or SPIMM-202 (if enrolled 
in both trials, the End-of-Study Visits in both trials must have been completed). 
4. Women of childbearing potential must agree to use 1 of the following methods of birth 
control from the date they sign the ICF through the End-of-Study Visit/ Early 
Discontinuation Visit: 
a. Abstinence, when it is in line with the preferred and usual lifestyle of the subject. 
Subject agrees to use an acceptable method of contraception should they become 
sexually active. 
b. Maintenance of a monogamous relationship with a male partner who has been 
surgically sterilized by vasectomy (the vasectomy procedure must have been 
conducted at least 60 days prior to the Screening Visit or confirmed via sperm 
analysis). 
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). 
5. Male subjects with female partners of child-bearing potential must be willing to use a 
highly effective method of contraception (see Section 9.3.11 for details) from the 
Screening Visit through the End-of-Study Visit/ Early Discontinuation Visit. 
Exclusion Criteria: 
A subject must NOT meet any of the following exclusion criteria during the Screening Period: 
1. 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. 
2. Subject has received any investigational compound (excluding elamipretide) and/or has 
participated in another interventional clinical trial within 30 days prior to the SPIMM-203 
Baseline Visit (excluding SPIMM-202) or is concurrently enrolled in any non- 
interventional research of any type judged to be scientifically or medically incompatible 
with the trial as deemed by the Investigator. 
3. Subject experienced an adverse reaction attributed to study drug resulting in permanent 
discontinuation of study drug in the SPIMM-201 or SPIMM-202 trial. 
4. Female subjects who are pregnant, planning to become pregnant, or lactating. 
5. Subject has undergone an in-patient hospitalization within the 1 month prior to the SPIMM- 
203 Baseline Visit. 


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CONFIDENTIAL 
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Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
6. Subject has a history of clinically significant hypersensitivity or allergy to any of the 
excipients contained in the study drug. 
Planned Trial Duration: 
Screening Period: Up to 28 days 
Treatment Period: Up to 260 weeks 
Follow-Up Period: Up to 2 weeks 
Criteria for Evaluation: 
Safety Endpoints 
Primary Safety Endpoint 
• 
Number of subjects experiencing adverse events/adverse device effects (AEs/ADEs) 
(including Serious Adverse Events [SAEs]/Serious Adverse Device Effects [SADEs]) 
Secondary Safety Endpoint 
• 
Changes in: 
o Vital Signs 
o Electrocardiograms (ECGs) 
o Clinical laboratory evaluations 
o Columbia Suicide Severity Rating Scale (C-SSRS) 
Efficacy Endpoints 
Primary Efficacy Endpoint 
• 
Distance walked (meters) on the 6-minute walk test (6MWT) 
Secondary Efficacy Endpoint 
• 
Patient reported outcomes 
o Neuro-QoL Fatigue questionnaire 
o Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) 
o Patient Global Assessments (PGA) 
o EQ-5D-5L 
o Work Limitations Questionnaire (WLQ) 
• 
Physician Global Assessments (PhGA) 
Statistical Methods: 
Analysis Populations 
Safety Population: All subjects who receive at least 1 dose of elamipretide. 
Efficacy Evaluable Population: All subjects receiving at least one dose with any post-dose 
efficacy evaluations. 
Safety Analyses 
Safety analyses will include incidence of AEs/ADEs and SAEs/SADEs, deaths, premature 
discontinuation from the trial due to an AE/ADE (regardless of relationship to study drug), and 
change in ECG, clinical laboratory data, and vital signs. 


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CONFIDENTIAL 
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Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
 
 
Efficacy Analyses: 
Efficacy analyses will be conducted on the Efficacy Evaluable Population and will be largely 
descriptive in nature. In general, categorical variables will be summarized by the count (N) and 
percentage of subjects (%). Continuous variables will be summarized by the number of non- 
missing observations (N), mean, standard deviation, median, minimum, and maximum values. In 
both instances, data will be summarized over time. In addition, all trial data are to be displayed 
in the datalistings. 
Additional details regarding analyses will be included in separate statistical analysis plan (SAP). 
Subject disposition summaries will include the number of subjects enrolled and the numbers 
included in the Safety Population. The number and percentage of subjects who complete or 
discontinue from the trial will be summarized by reason for discontinuation. 
Subject’s age, sex, weight, height, body mass index (BMI), and other demographic 
characteristics will be recorded and summarized. Medical history will be listed. 
Statistical analysis of this trial will be the responsibility of the Sponsor or its designee. 
Sample Size: 
This open-label extension trial will enroll up to 36 subjects with genetically confirmed PMM who 
have completed the End-of-Study Visit in the SPIMM-201 and/or SPIMM-202 trial (if enrolled in 
both trials, the End-of-Study Visits in both trials must have been completed) and who meet all 
eligibility criteria. 


Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
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Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
2. 
TABLE OF CONTENTS 
PROTOCOL APPROVAL .................................................................................................................................................. 2 
INVESTIGATOR’S AGREEMENT...................................................................................................................................... 3 
1. 
SYNOPSIS .............................................................................................................................................................. 4 
2. TABLE OF CONTENTS .......................................................................................................................................... 10 
3. ABBREVIATIONS AND DEFINITIONS ................................................................................................................... 13 
4. 
INTRODUCTION .................................................................................................................................................. 15 
4.1. 
PRIMARY MITOCHONDRIAL MYOPATHY (PMM) ................................................................................................... 15 
4.2. 
ELAMIPRETIDE RISK/BENEFIT ASSESSMENT .......................................................................................................... 16 
4.2.1. 
Potential Benefits .............................................................................................................................. 16 
4.2.1.1. 
Preclinical studies........................................................................................................................................... 16 
4.2.1.2. 
Clinical Studies ............................................................................................................................................... 17 
4.2.2. 
Potential Risks ................................................................................................................................... 17 
4.2.2.1. 
Nonclinical Study Safety Findings .................................................................................................................. 17 
4.2.2.2. 
Human Safety ................................................................................................................................................ 18 
5. 
OBJECTIVES ......................................................................................................................................................... 20 
5.1. 
PRIMARY OBJECTIVE ........................................................................................................................................ 20 
5.2. 
SECONDARY OBJECTIVES ................................................................................................................................... 20 
6. 
INVESTIGATIONAL PLAN .................................................................................................................................... 21 
6.1. 
STUDY DESIGN ................................................................................................................................................ 21 
6.2. 
STUDY SCHEDULE ............................................................................................................................................ 22 
6.2.1. 
Screening Visit/Period: Day -28 to Day -1 ......................................................................................... 22 
6.2.2. 
Treatment Period (260 weeks [± 14 days]) ........................................................................................ 22 
6.2.2.1. 
Baseline Visit (Day 1) ...................................................................................................................................... 22 
6.2.2.2. 
Monthly Safety Visits (every 4 weeks [±7 days]) ............................................................................................ 23 
6.2.2.3. 
3-Month Visit (Week 13 ± 14 days); 6-Month Visits (Week 26 and every 26 weeks after ± 14 days); End-of- 
Therapy Visit (Week 260 ± 14 days) .................................................................................................................................. 24 
6.2.2.4. 
Monthly Safety Telephone Call (every 4 weeks [±7 days]) ............................................................................ 25 
6.2.3. 
Follow-Up Period (14 days [+14 days]) .............................................................................................. 25 
6.2.3.1. 
End-of-Study Visit/ Early Discontinuation Visit (Week 262 +14 days) ............................................................ 25 
6.2.4. 
Unscheduled Visits ............................................................................................................................. 26 
6.3. 
STUDY ASSESSMENTS ....................................................................................................................................... 27 
6.3.1. 
Medical History and Physical Examination ........................................................................................ 27 
6.3.2. 
Vital signs .......................................................................................................................................... 27 
6.3.3. 
Electrocardiograms (ECGs) ................................................................................................................ 27 
6.3.4. 
Clinical Laboratory Testing ................................................................................................................ 27 
6.3.4.1. 
Blood chemistries........................................................................................................................................... 27 
6.3.4.2. 
Hematology ....................................................................................................................................................28 
6.3.4.3. 
Additional Laboratory Assessments ............................................................................................................... 28 
6.3.4.4. 
Urinalysis ....................................................................................................................................................... 28 
6.3.4.5. 
Pregnancy tests ..............................................................................................................................................28 
6.3.5. 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................................................................... 28 


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SPIMM-203 Version 3.0 
29 January 2019 
 
 
6.3.6. 
The Neuro-QoL Fatigue Questionnaire .............................................................................................. 28 
6.3.7. 
Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) .................................................. 28 
6.3.8. 
Patient Global Assessment (PGA) .......................................................................................................... 28 
6.3.9. 
EQ-5D-5L .......................................................................................................................................... 29 
6.3.10. 
Work Limitations Questionnaire (WLQ) ............................................................................................................ 29 
6.3.11. 
Physician Global Assessment (PhGA) ................................................................................................. 29 
6.3.12. 
6-Minute Walk Test (6MWT) ................................................................................................................................................. 29 
6.3.13. 
Injection Site Reaction (ISR) Assessment.................................................................................................... 29 
7. STUDY POPULATION .......................................................................................................................................... 30 
7.1. 
INCLUSION CRITERIA ........................................................................................................................................ 30 
7.2. 
EXCLUSION CRITERIA ........................................................................................................................................ 31 
7.3. 
PROHIBITED MEDICATIONS ............................................................................................................................... 31 
7.4. 
DISCONTINUATIONS ......................................................................................................................................... 31 
7.4.1. 
Discontinuation of Subjects ............................................................................................................... 31 
7.4.2. 
Discontinuation of Study Center ........................................................................................................ 32 
7.4.3. 
Discontinuation of the Study ............................................................................................................. 32 
8. 
TREATMENT ........................................................................................................................................................ 33 
8.1. 
TREATMENTS ADMINISTERED.............................................................................................................................33 
8.1.1. 
Elamipretide Pen Injector .................................................................................................................. 33 
8.1.2. 
Elamipretide Delivery System ............................................................................................................ 33 
8.2. 
MATERIALS AND SUPPLIES ................................................................................................................................. 34 
8.3. 
TREATMENT LOGISTICS AND ACCOUNTABILITY ...................................................................................................... 35 
8.4. 
RATIONALE FOR SELECTION OF DOSES IN THE STUDY .............................................................................................. 35 
8.5. 
TREATMENT COMPLIANCE................................................................................................................................. 37 
9. 
SAFETY AND EFFICACY EVALUATIONS AND APPROPRIATENESS OF MEASUREMENTS .................................... 38 
9.1. 
SAFETY MEASURES ........................................................................................................................................... 38 
9.1.1. 
Primary safety measure ..................................................................................................................... 38 
9.1.2. 
Secondary safety measure ................................................................................................................. 38 
9.2. 
EFFICACY MEASURES ....................................................................................................................................... 38 
9.2.1. 
Primary efficacy measure .................................................................................................................. 38 
9.2.2. 
Secondary efficacy measure .............................................................................................................. 38 
9.3. 
SAFETY .......................................................................................................................................................... 38 
9.3.1. 
Adverse Events (AEs)/Adverse Device Effects (ADEs) ........................................................................ 38 
9.3.2. 
Pre-Treatment Events ........................................................................................................................ 39 
9.3.3. 
Baseline Medical Conditions .............................................................................................................. 39 
9.3.4. 
Medical and Surgical Procedures ...................................................................................................... 39 
9.3.5. 
Abnormal Laboratory and Other Abnormal Investigational Findings ................................................40 
9.3.6. 
Symptomatic Overdose...................................................................................................................... 40 
9.3.7. 
Serious Adverse Events (SAEs)/Serious Adverse Device Effects (SADEs) ............................................. 40 
9.3.8. 
Recording of Adverse Events (AEs)/Adverse Device Effects (ADEs) ................................................... 41 
9.3.8.1. 
Investigator Assessments .............................................................................................................................. 41 
9.3.9. 
Adverse Event (AE)/Adverse Device Effect (ADE) Reporting Period .................................................... 43 
9.3.10. 
Serious Adverse Event (SAE)/Serious Adverse Device Effect (SADE) Expedited Reporting.................. 44 


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29 January 2019 
 
 
9.3.11. 
Pregnancy and Contraception ........................................................................................................... 45 
9.3.12. 
Responsibilities to Regulatory Authorities, Investigators and Ethics Committees ............................. 45 
9.4. APPROPRIATENESS OF MEASUREMENTS .............................................................................................................. 46 
10. 
DATA QUALITY ASSURANCE .......................................................................................................................... 47 
10.1. 
DATA CAPTURE SYSTEM ................................................................................................................................... 47 
11. 
SAMPLE SIZE AND STATISTICAL METHODS ................................................................................................... 48 
11.1. 
DETERMINATION OF SAMPLE SIZE ....................................................................................................................... 48 
11.2. 
STATISTICAL AND ANALYTICAL PLANS .................................................................................................................. 48 
11.2.1. 
General Considerations ..................................................................................................................... 48 
11.2.2. 
Subject Disposition ............................................................................................................................ 48 
11.2.3. 
Subject Characteristics....................................................................................................................... 48 
11.2.4. 
Endpoints and Methodology ............................................................................................................. 48 
11.2.4.1. 
General Considerations .................................................................................................................................. 48 
11.2.4.2. 
Analysis Populations ...................................................................................................................................... 48 
11.2.5. 
Efficacy Analyses ............................................................................................................................... 48 
11.2.6. 
Safety Analyses .................................................................................................................................. 49 
11.2.6.1. 
Adverse Events (AEs)/Adverse Device Effects (ADEs) .................................................................................... 49 
11.2.6.2. 
Deaths and Other Serious Adverse Events ..................................................................................................... 49 
11.2.6.3. 
Clinical Laboratory Evaluations ...................................................................................................................... 49 
11.2.6.4. 
Vital Signs ...................................................................................................................................................... 49 
11.2.6.5. 
Electrocardiogram (ECG) ................................................................................................................................ 50 
11.2.6.6. 
Other Safety Parameters ............................................................................................................................... 50 
12. 
INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY CONSIDERATIONS ......................................... 51 
12.1. 
INFORMED CONSENT ....................................................................................................................................... 51 
12.2. 
ETHICAL REVIEW ............................................................................................................................................. 51 
12.3. 
REGULATORY CONSIDERATIONS ......................................................................................................................... 51 
12.3.1. 
Protocol Approval .............................................................................................................................. 52 
12.3.2. 
Final Report Approval ........................................................................................................................ 52 
12.3.3. 
Study Monitoring ............................................................................................................................... 52 
12.3.4. 
Retention of Records ......................................................................................................................... 52 
12.3.5. 
Disclosure of Information .................................................................................................................. 52 
13. 
REFERENCES ................................................................................................................................................... 54 
14. 
ATTACHMENTS ............................................................................................................................................... 55 


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Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
3. 
ABBREVIATIONS AND DEFINITIONS 
Term 
Definition 
6MWT 
AE 
ADE 
ALT 
AST 
ATP 
AUC 
AUC0-last 
 
AUC0-τ 
 
BMI 
CIOMS 
Six-Minute Walk Test 
Adverse Event 
Adverse Device Effect 
Alanine aminotransferase 
Aspartate aminotransferase 
Adenosine triphosphate 
Area under the plasma concentration versus time curve 
Area under the plasma concentration vs time curve from time 0 to last 
available time point 
Area under the plasma concentration vs time curve from time 0 to end of the 
dosing interval 
Body Mass Index 
Council for International Organizations of Medical Sciences 
Cmax 
Maximumplasma concentration 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
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 
IEC 
Institutional Ethics Committee 
IFU 
Instructions for Use 
IP 
Investigational Product 


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Term 
Definition 
 
ISO 
ISR 
IV 
MedDRA 
MFD 
mL 
MTP-131 
mtDNA 
nDNA 
PK 
PGA 
PhGA 
PMD 
PMM 
PMMSA 
PT 
QMS 
RA 
SAE 
SADE 
SAP 
SC 
SOC 
SUSAR 
TDD 
TEAE 
TEADE 
UADE 
International Organization for Standardization 
Injection Site Reaction 
Intravenous 
Medical Dictionary for Regulatory Activities 
Maximum feasible dose 
milliliter 
SS-31, elamipretide, SBT-031, or Bendavia™ 
mitochondrial DNA 
nuclear DNA 
Pharmacokinetic(s) 
Patient Global Assessment 
Physician Global Assessment 
Primary MitochondrialDisease 
Primary Mitochondrial Myopathy 
Primary Mitochondrial Myopathy Symptom Assessment 
Preferred Term 
Quality Management System 
Risk Assessment 
Serious Adverse Event 
Serious Adverse Device Effect 
Statistical AnalysisPlan 
Subcutaneous 
System Organ Class 
Suspected Unexpected Serious Adverse Reaction 
Total Daily Dose 
Treatment-Emergent Adverse Event 
Treatment-Emergent Adverse Device Effect 
Unanticipated Adverse Device Effect 
WLQ 
Work Limitations Questionnaire 


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4. 
INTRODUCTION 
This study will be conducted in strict accordance with the Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, ICH GCP 
guidelines, and all applicable laws and regulations. For detailed information on the study drug 
and the nonclinical and clinical studies conducted to date, please refer to the most recent edition 
of the elamipretide Investigator’s Brochure (IB). 
 
4.1. 
Primary Mitochondrial Myopathy (PMM) 
Primary mitochondrial myopathy (PMM) are genetic disorders of the mitochondrial respiratory 
chain affecting predominantly, but not exclusively, skeletal muscle (Mancuso M, Hirano M., 
2016). They are a group of conditions with genetic mutations in nuclear DNA (nDNA) and/or 
mitochondria DNA (mtDNA) causing oxidative phosphorylation abnormalities that result in 
clinical signs and symptoms. The electron transport chain (ETC) is responsible for respiration 
and oxidative phosphorylation resulting in the production of 90% of adenosine triphosphate 
(ATP) in the body, the primary energy source for cells. Of the >25,000 genes in the nDNA 
genome, approximately 300 have been directly implicated in encoding mitochondrial ETC 
proteins and another 400 in playing a role in mitochondrial function. In addition, the 37 genes in 
the mtDNA genome encode 13 proteins critical for oxidative phosphorylation (Niyazov D, et al., 
2016; Lightowlers R, et al., 2015). PMM caused by nDNA mutations, are inherited through 
maternal and/or paternal germlines and affects all cells of the body as opposed to PMM caused 
by mtDNA mutations, which are maternally inherited and may not affect all cells. Each cell may 
contain a different percentage of wild type and mutant mtDNA, a concept known as 
heteroplasmy. When mutant heteroplasmy increases above a certain threshold, normal function 
of the cell may not be maintained leading to cell dysfunction and clinical pathology a concept 
known as the threshold effect. During embryogenesis, mutant mtDNA randomly segregates 
within developing tissue causing a segregation of the mutations in specific organs. This results in 
a wide variations in the phenotype of affected individuals (Niyazov D, et al., 2016). 
The hallmark of PMMs is the heterogeneity of the clinical presentation with multiple organ 
system involvement and poor genotype-phenotype correlation. PMM have a wide range of onset 
from birth to late adulthood and highly variable symptoms, signs, severity, and prognosis. 
Historically, the different PMM subtypes were referred to by acronyms depicting the clinical 
presentation such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes 
(MELAS), Leber’s hereditary optic neuropathy (LHON) or by physician named syndromes such 
as Kearns-Sayre (KSS). With the advent of genetic testing it became apparent that many of 
PMMs fall on the same spectrum with very variable phenotypic expressions making attempts to 
characterize genotype to phenotype correlations very challenging. Furthermore, current 
understanding of the natural history of PMM is limited (Schaefer A, et al., 2006). Although 
every organ system can be impaired in PMMs, organs with highest energy demand, such as 
skeletal muscle, heart, kidney, eye, and CNS are usually the first to be affected. Myopathy and 
exercise intolerance are prominent features in the adults and in some pediatric cases with 
Primary Mitochondrial Diseases (PMDs) causing signs and symptoms of fatigue (88%) and 
exercise intolerance (78% of the patients with PMD did not achieve internationally advised 


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levels of physical activity [10,000 steps per day]) (Gorman G, et al., 2015; Apabhai S, et al., 
2011). 
4.2. 
Elamipretide Risk/Benefit Assessment 
4.2.1. 
Potential Benefits 
 
4.2.1.1. 
Preclinical studies 
Elamipretide has not been studied in any preclinical models specific to PMM. However, 
elamipretide has been shown to be effective in restoring ATP production in preclinical models of 
both skeletal and cardiac muscle dysfunction of aged mice (Siegel M, et al., 2013). In this study, 
skeletal muscle energetics were measured in vivo one hour after injection of either elamipretide 
or saline using a combination of optical and 31P magnetic resonance spectroscopy in old and 
young mice (27 months and 5 months, respectively). ATP production in the old mice was found 
to increase and to be comparable to that in young mice one hour after a single treatment with 
elamipretide (Figure 1). These findings demonstrated a rapid reversal of age-related declines in 
resting and maximal mitochondrial ATP production, whereas, there was no observable effect on 
young, healthy muscle. In the same study, consistent results were observed after a week of 
dosing with elamipretide, with a favorable difference in the exercise tolerance of old mice, and 
again no significant effect was seen in young mice. 
Figure 1: ATP Production in Young (5 month) and Old (27 month) Mice Following a Single 
Treatment with Elamipretide 
Mean +/- SEM, n = 5 – 7 per group 
Several reports demonstrate elamipretide’s ability to prevent skeletal muscle atrophy. For 
example, in a rat model of muscle wasting, elamipretide reduced the loss of the diaphragm 
muscle function caused by 12 hours of mechanical ventilation (Powers S, et al., 2011). Similarly, 
elamipretide prevented casting-induced (i.e., immobilization) skeletal muscle atrophy via 
protecting mitochondrial function (Talbert E, et al., 2013). 


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Additionally, in a study using a mouse model, myopathy induced by the chemotherapeutic agent 
doxorubicin, which induced muscle atrophy, it was shown that elamipretide protected both 
skeletal and heart muscle atrophy via prevention of mitochondrial ROS dysfunction and 
myopathy production and is, therefore, suggesting its therapeutic potential in this setting of 
myopathy (Min K, et al., 2011). 
 
4.2.1.2. 
Clinical Studies 
The SPIMM-201 trial was a phase 1/2 multi-center, randomized, double-blind, placebo- 
controlled, multiple-ascending IV dose trial that enrolled subjects with genetically confirmed 
PMD with exercise intolerance and/or symptoms of myopathy, PMM. Three escalating IV doses 
(0.01, 0.10, and 0.25 mg/kg/hour) were studied in 3 sequential cohorts of 12 patients (one dose 
per cohort) and infused over 2 hours daily for 5 days. Within each cohort, 9 subjects were 
randomized to active drug and 3 subjects were randomized to placebo. 
An improvement over baseline in the distance walked in the 6MWT on Day 5 was observed in 
subjects treated with 0.25 mg/kg/hr elamipretide compared to placebo in the pre-specified 
analysis, with a mean change in baseline of 65.4 m vs. 20.9 m (p=0.0528). In a post-hoc analysis 
with backward elimination ANCOVA, a nominally statistically significant improvement over 
baseline in the distance walked on Day 5 was observed in subjects treated with 0.25 mg/kg/hr 
elamipretide compared to placebo, with an adjusted mean change in baseline of 51.2 m vs 3.0 m 
(p = 0.0297). The ANCOVA model also suggests the extent of improvement was a function of 
the extent of diminished capacity at baseline, with greater improvement resulting for those with 
greater diminished capacity, in a dose-related manner. 
 
4.2.2. 
Potential Risks 
 
4.2.2.1. 
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 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. 
The nonclinical GLP repeat-dose toxicity studies (IV and SC) in rats, rabbits and dogs indicated 
no elamipretide-related systemic toxicity even upon chronic administration. 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 were 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; 


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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 on fertility, embryo-fetal, or neonatal 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. When tested 
directly, both M1 and M2 were negative for gene mutation and for receptor binding. 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. 
 
4.2.2.2. 
Human Safety 
Parenteral administration of elamipretide was assessed following single and multiple IV and SC 
doses in approximately 200 healthy subjects in 11 completed clinical pharmacology studies. 
Single IV doses ranged from 0.005 mg/kg/hour to 0.25 mg/kg/hr, typically administered over 4 
hours, while 0.25 mg/kg/hr administered over 1 hour daily for 7 days was the multiple-dose 
regimen studied. Single SC doses ranged from 2 mg to 80 mg administer as 0.5 or 1 mL 
injections, while multiple-dose regimen of 6 mg to 80 mg administered as 0.25, 0.5, or 1 mL 
injections daily for 7 days were studied. 
No safety concerns have been identified with administration of IV or SC elamipretide for up to 
seven days in these studies. The only systemic AE reported in over 5% of subjects was headache 
(7.3%). Nausea and hyponatraemia were each reported in 3.0% of the subjects. All other events 
were reported with incidence of <2.0%. The majority of TEAEs were assessed by the 
investigator to be of mild severity, resolved without sequelae and did not require intervention. 
There were no significant findings for group mean clinical laboratory, vital sign, ECG, or 
physical examination parameters within or across trials. 
The SC formulation of elamipretide has been studied in both single- and multiple-dose trials in 
healthy volunteers and patient populations. Generally, injection of SC elamipretide resulted in 
mild or moderate injection site reactions (ISRs), frequently characterized by erythema, 
induration, bruising, pruritus, pain, and/or urticaria. Injection site reactions were reported 
intermittently across dosing with elamipretide, with most subjects experiencing ISRs beginning 
upon first administration of elamipretide and continuing throughout treatment, with resolution of 


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the ISRs typically occurring the day of last elamipretide administration. The resolution of ISRs, 
however, has occurred as late as 14 days after the end of elamipretide treatment in one subject. 
In subjects with renal impairment, exposure to elamipretide and both of its metabolites (M1 and 
M2), as measured by AUC, increased proportionally to the degree of renal impairment. 
However, there was no evidence of increased toxicity as a consequence of impaired renal 
function. Similarly, in the drug-drug interaction (DDI) studies carried out to date, co- 
administration of elamipretide with aspirin, with clopidogrel, or with unfractionated heparin 
(UFH) did not indicate a change in the nature, severity or frequency of AEs to the safety profile 
of either elamipretide or the comparator. 
Elamipretide, administered by parenteral routes, was also assessed in completed studies in 
multiple patient populations including subjects with stable CHF, ACS subjects who were 
undergoing primary PCI and stenting for STEMI, subjects with AKI undergoing PTRA, subjects 
with genetically confirmed mitochondrial disease with signs and symptoms of mitochondrial 
myopathy and/or exercise intolerance, subjects over 60 years of age with evidence of skeletal 
muscle mitochondrial dysfunction, and an ongoing open-label study of in subjects with AMD. 
Single and multiple IV and SC doses of elamipretide were assessed with generally no notable 
differences between the elamipretide and placebo arms in the frequency or severity of AEs, 
except for ISRs with SC elamipretide administration. Additionally, eosinophilia was reported as 
an AE and laboratory data demonstrated elevations (>0.45 cells x109/L) in eosinophils beginning 
at approximately 28 days after initiation of elamipretide treatment in numerous subjects. These 
laboratory findings have not been reported to be associated with any systemic clinical 
manifestations of eosinophilia. To date, these elevations were demonstrated to have returned to 
within normal range or to baseline levels at the follow-up visits. There were no other identified 
safety concerns in these trials with respect to other clinical laboratory results, physical 
examinations, vital signs, ECG data between the elamipretide and placebo. In general, the safety 
profile of systemic elamipretide was consistent with the pre-existing, comorbid medical 
conditions. 
Elamipretide has been studied in subjects with PMM. The SPIMM-201 trial was a phase 1/2 
multi-center, randomized, double-blind, placebo-controlled, multiple-ascending IV dose trial that 
enrolled subjects with genetically confirmed PMM. Three escalating IV doses (0.01, 0.10, and 
0.25 mg/kg/hour) were studied in 3 sequential cohorts of 12 patients (one dose per cohort) and 
infused over 2 hours daily for 5 days. Within each cohort, 9 subjects were randomized to active 
drug and 3 subjects were randomized to placebo. There were no deaths, SAEs or TEAEs 
resulting in withdrawal in this trial. Overall, there were no obvious differences in TEAEs, vital 
signs, lab values, ECG changes, or suicide assessments among the 4 treatment groups. 


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5. 
OBJECTIVES 
5.1. 
Primary Objective 
To assess the long-term safety and tolerability of single daily subcutaneous (SC) doses of 40 mg 
elamipretide administered with the elamipretide delivery system for up to 260 weeks 
 
5.2. 
Secondary Objectives 
 
• 
To obtain longitudinal efficacy data of single daily SC doses of 40 mg elamipretide 
administered with the elamipretide delivery system for up to 260 weeks on: 
o 6-Minute Walk Test (6MWT) 
o Patient Reported Outcomes (Neuro-QoL Fatigue questionnaire, Primary 
Mitochondrial Myopathy Symptom Assessment [PMMSA], Patient Global 
Assessment [PGA], EQ-5D-5L, Work Limitations Questionnaire [WLQ]) 
o Physician Global Assessment (PhGA) 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Study Design 
This open-label, non-comparative, extension trial will enroll subjects with genetically confirmed 
PMM who have completed the End-of-Study Visit in the SPIMM-201 and/or SPIMM-202 trial 
(if enrolled in both trials, the End-of-Study Visits in both trials must have been completed). 
Subjects who do not discontinue or withdraw from the trial will receive treatment with 40 mg SC 
elamipretide (study drug) administered with the elamipretide delivery system (elamipretide 
injection cartridge, the elamipretide pen injector and single-use needle) for the shortest of the 
following: 260 weeks; regulatory approval and commercial availability of the elamipretide 
delivery system in the subject’s respective country; or termination of the clinical development for 
elamipretide in subjects with PMM. The Trial Schedule is presented in Attachment 1. 
Screening Period: The Screening Period will begin with the signature of the informed consent 
form (ICF) for this trial and will last no longer than 28 days. During the Screening Period, 
subjects will undergo screening procedures as described in the Trial Schedule. For subjects 
enrolled in SPIMM-202, the Screening Period may not begin prior to the Week 12 Visit in the 
SPIMM-202 trial. Assessments completed as part of the Week 12 Visit in SPIMM-202 that are 
within the Screening Period may serve as Screening assessments and do not need to be 
reassessed. Inclusion and exclusion criteria will be assessed using Screening assessments. 
Subjects who complete the Screening Period and meet all trial requirements, including all 
inclusion and none of the exclusion criteria, may enter the Treatment Period. 
Treatment Period: The Treatment Period will begin on the day of the Baseline Visit, which is 
defined as Day 1. Subjects (and caregivers if needed) will be trained on the procedure for use of 
the elamipretide delivery system prior to first dose. An elamipretide delivery system training kit 
and checklist will be provided to the clinical site to assist in training. Study drug will be 
administered daily by the subject or trained caregiver in the abdomen, rotating around the four 
abdominal quadrants, or other appropriate location (after Investigator consultation with the 
Sponsor). Assessments completed as part of the End-of-Study Visit in SPIMM-202 and are 
within 24 hours of the Baseline Visit may serve as Baseline assessments and do not need to be 
reassessed. Screening assessments that are within 24 hours of the Baseline Visit may also serve 
as Baseline assessments and do not need to be reassessed. Otherwise, Baseline assessments must 
be completed within 24 hours prior to receiving elamipretide. At the Baseline Visit, following 
completion of all Baseline procedures described in the Trial Schedule (except for the injection 
site reaction [ISR] assessment), subjects will be administered SC elamipretide at the trial center. 
Subjects (or trained caregivers) will administer elamipretide with the elamipretide delivery 
system on a daily basis at approximately the same time each day on all trial days (except for site 
visit days). Subjects will visit the trial site for the 3-Month Visit (Week 13), the 6-Month Visit 
(Week 26), and every 26 weeks afterward (additional 6-Month Visits) to administer study drug 
with the elamipretide delivery system, to complete assessments as described in the Trial 
Schedule, and to return all used trial supplies to the trial site. Subjects will be scheduled to have 
Monthly Safety Visits completed by a visiting nurse (or designee) in between site visits until the 
Week 52 site visit. Monthly safety telephone calls will be completed in between site visits after 
the Week 52 site visit. The monthly safety telephone call script is provided in Attachment 4. 


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Follow-Up Period: The Follow-Up Period will begin after completion of End-of-Therapy Visit 
(Week 260) and will last for 2 weeks. During the Follow-Up Period, subjects will continue to 
follow all study requirements. At the end of the Follow-Up Period, subjects will return to the trial 
site for the End-of-Study/Early Discontinuation Visit for final safety and efficacy assessments 
and to return used and unused trial supplies and all other study instruments/materials to the trial 
site. 
 
6.2. 
Study Schedule 
Study procedures and their timing are summarized in the Trial Schedule (Attachment 1) and 
Study Schematic (Attachment 2). 
6.2.1. 
Screening Visit/Period: Day -28 to Day -1 
NOTE: Assessments completed as part of the Week 12 Visit in SPIMM-202 that are within the 
Screening Period may serve as Screening assessments and do not need to be reassessed. 
• 
Review and sign the ICF 
• 
Register subject for SPIMM-203 (subjects will be assigned the same subject number from 
the SPIMM-201 and/or SPIMM-202 trial) 
• 
If not concurrently enrolled in SPIMM-202 during the Screening Period, update relevant 
medical history since the End-of-Study Visit in the SPIMM-201 and/or SPIMM-202 trial 
(as described in Section 6.3.1) 
• 
If not concurrently enrolled in SPIMM-202 during the Screening Period, update 
concomitant medication/procedures (including supplements and vitamins) since the End- 
of-Study Visit in the SPIMM-201 and/or SPIMM-202 trial (as described in Section 6.3.1) 
• 
Review all inclusion and exclusion criteria 
• 
Complete a physical examination (as described in Section 6.3.1) 
• 
Collect vital signs (as described in Section 6.3.2) 
• 
Complete 12-lead resting ECG (as described in Section 6.3.3) 
• 
Draw blood for clinical laboratory testing as outlined in Attachment 3 
• 
Complete a serum pregnancy for women of child-bearing potential ONLY for subjects 
not concurrently enrolled in SPIMM-202 during the Screening Period 
• 
Collect urine for clinical urinalysis as outlined in Attachment 3 
• 
Complete the Columbia Suicide Severity Rating Scale (C-SSRS) 
“Baseline/Screening” or “Since Last Visit” as described in Section 6.3.5 and outlined 
in Attachment 10 and Attachment 11, respectively. 
 
6.2.2. 
Treatment Period (260 weeks [± 14 days]) 
 
6.2.2.1. 
Baseline Visit (Day 1) 
NOTE: Assessments completed as part of the End-of-Study Visit in SPIMM-202 and are within 
24 hours of the Baseline Visit may serve as Baseline assessments and do not need to be 


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reassessed. Screening assessments that are within 24 hours of the Baseline Visit may also serve 
as Baseline assessments and do not need to be reassessed. Otherwise, Baseline assessments must 
be completed within 24 hours prior to receiving elamipretide. All study procedures must be 
completed prior to administering study drug. Study procedures should be completed in the order 
described below. The 6MWT should be completed after all other trial procedures except study 
drug administration and ISR assessment. 
 
• Review all inclusion and exclusion criteria 
• 
If not concurrently enrolled in SPIMM-202 during the Screening Period, update relevant 
medical history that occurred/changed during the Screening Period (as described in 
Section 6.3.1) 
• 
If not concurrently enrolled in SPIMM-202 trial during the Screening Period, record AEs 
that occurred during the Screening Period (as described in Section 9.3.9) 
• 
If not concurrently enrolled in SPIMM-202 during the Screening Period, update 
concomitant medication/procedures (including supplements and vitamins) that 
occurred/changed during the Screening Period (as described in Section 6.3.1) 
• 
Complete a physical examination (as described in Section 6.3.1) 
• 
Collect vital signs (as described in Section 6.3.2) 
• 
Complete 12-lead resting ECG (as described in Section 6.3.3) 
• 
Draw blood for clinical laboratory testing as outlined in Attachment 3 
• 
Collect urine for clinical urinalysis testing as outlined in Attachment 3 
• 
Complete a urine pregnancy for women of child-bearing potential. The urine pregnancy 
test during the End-of-Study Visit in SPIMM-202 is acceptable if within the Screening 
Period 
• 
Complete the C-SSRS “Since Last Visit” (as described in Section 6.3.5 and outlined in 
Attachment 11) 
• 
Complete the Neuro-QoL Fatigue questionnaire (as described in Section 6.3.6 and as 
outlined in Attachment 5) 
• 
Complete the PMMSA (as described in Section 6.3.7 and as provided in Attachment 6) 
• 
Complete the PGA (as described in Attachment 7) 
• 
Complete the EQ-5D-5L (as described in Attachment 12) 
• 
Complete the WLQ if the subject self-reports currently working (as described in 
Attachment 13) 
• 
Complete the PhGA (as described in Attachment 8) 
• 
Conduct the 6MWT (as described in Section 6.3.12 and as outlined in Attachment 9) 
• 
Provide elamipretide delivery system supplies 
• 
Train subject (and caregivers if needed) on the procedure for administration of study drug 
with the elamipretide delivery system 


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• 
Administer (by subject or trained caregiver) study drug with the elamipretide delivery 
system 
• 
Assess for ISR 30 (± 5) minutes after study drug administration with the elamipretide 
delivery system (as described in Section 6.3.13) 
• 
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 study drug 
• 
Document any AEs/ADEs that occurred during the Baseline Visit 
• 
Schedule next site visit 
6.2.2.2. 
Monthly Safety Visits (every 4 weeks [±7 days]) 
Monthly safety visits by a visiting nurse (or designee) should occur between site visits until the 
Week 52 site visit. 
• 
Draw blood for clinical laboratory testing as outlined in Attachment 3. 
• 
Remind subject (or trained caregiver) to administer study drug with the elamipretide 
delivery system daily 
• 
Remind subject of proper elamipretide delivery system storage 
6.2.2.3. 
3-Month Visit (Week 13 ± 14 days); 6-Month Visits (Week 26 and every 26 
weeks after ± 14 days); End-of-Therapy Visit (Week 260 ± 14 days) 
NOTE: All study procedures must be completed prior to administering study drug. Study 
procedures should be completed in the order described below. The 6MWT should be completed 
after all other trial procedures except study drug administration and ISR assessment. 
• 
Document concomitant medication/procedures (including supplements and vitamins) 
since the last site visit or monthly safety telephone call 
• 
Document AEs/ADEs 
• 
Complete a physical examination (as described in Section 6.3.1) 
• 
Collect vital signs (as described in Section 6.3.2) 
• 
Complete 12-lead resting ECG (as described in Section 6.3.3) 
• 
Draw blood for clinical laboratory testing as outlined in Attachment 3 
• 
Collect urine for clinical urinalysis testing as outlined in Attachment 3 
• 
Complete the C-SSRS “Since Last Visit” (as described in Section 6.3.5 and outlined in 
Attachment 11) 
• 
Complete the Neuro-QoL Fatigue questionnaire (as described in Section 6.3.6 and as 
outlined in Attachment 5) 
• 
Complete the PMMSA (as described in Section 6.3.7 and as provided in Attachment 6) 
• 
Complete the PGA (as described in Attachment 7) 
• 
Complete the EQ-5D-5L (as described in Attachment 12) 


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• 
Complete the WLQ if the subject self-reports currently working (as described in 
Attachment 13) 
• 
Complete the PhGA (as described in Attachment 8) 
• 
Conduct the 6MWT (as described in Section 6.3.12 and as outlined in Attachment 9) 
• 
Provide elamipretide delivery system supplies 
 
• Train subject (and caregivers if needed) not previously trained on the procedure for 
administration of study drug with the elamipretide delivery system 
• 
Administer (by subject or trained caregiver) study drug with the elamipretide delivery 
system 
• 
Assess for ISR 30 (± 5) minutes after study drug administration with the elamipretide 
delivery system (as described in Section 6.3.13) 
• 
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 study drug 
• 
Schedule next site visit 
6.2.2.4. 
Monthly Safety Telephone Call (every 4 weeks [±7 days]) 
Monthly safety telephone calls will be completed in between site visits after the Week 52 site 
visit. Monthly safety telephone calls should follow the monthly telephone script provided in 
Attachment 4. 
• 
Document concomitant medication/procedures (including supplements and vitamins) 
since the last site visit or monthly safety telephone call 
• Document AEs/ADEs 
• 
Remind subject (or trained caregiver) to administer study drug daily with the elamipretide 
delivery system and to reference the Information for Use (IFU) pamphlet for any issues 
 
6.2.3. 
Follow-Up Period (14 days [+14 days]) 
 
6.2.3.1. 
End-of-Study Visit/ Early Discontinuation Visit (Week 262 +14 days) 
NOTE: Study procedures should be completed in the order described below. The 6MWT should 
be completed after all other assessments. 
• 
Document concomitant medication/procedures (including supplements and vitamins) 
since the last site visit or monthly safety telephone call 
• 
Document AEs/ADEs 
• 
Complete a physical examination (as described in Section 6.3.1) 
• 
Collect vital signs (as described in Section 6.3.2) 
• 
Complete 12-lead resting ECG (as described in Section 6.3.3) 
• 
Draw blood for clinical laboratory testing as outlined in Attachment 3 


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• 
Collect urine for clinical urinalysis testing as outlined in Attachment 3 
• 
Complete a urine pregnancy for women of child-bearing potential 
• Complete the C-SSRS “Since Last Visit” (as described in Section 6.3.5 and outlined 
in Attachment 11) 
• Complete the Neuro-QoL Fatigue questionnaire (as described in Section 6.3.6 and as 
outlined in Attachment 5) 
• 
Complete the PMMSA (as described in Section 6.3.7 and as provided in Attachment 6) 
• 
Complete the PGA (as described in Attachment 7) 
• 
Complete the EQ-5D-5L (as described in Attachment 12) 
• 
Complete the WLQ if the subject self-reports currently working (as described in 
Attachment 13) 
• 
Complete the PhGA (as described in Attachment 8) 
• 
Conduct the 6MWT (as described in Section 6.3.12 and as outlined in Attachment 9) 
• 
If applicable, collect all trial supplies not previously returned 
6.2.4. 
Unscheduled Visits 
Unscheduled Visits occur outside of pre-specified site visits. If an Unscheduled Visit occurs, 
assessments to be completed are in the judgement of the Investigator. If other assessments are 
completed, study procedures should be completed in the order described below. 
• 
Document concomitant medication/procedures (including supplements and vitamins) 
since the last site visit or monthly safety telephone call 
• Document AEs/ADEs 
• 
Complete a physical examination (as described in Section 6.3.1) 
• 
Collect vital signs (as described in Section 6.3.2) 
• 
Complete 12-lead resting ECG (as described in Section 6.3.3) 
• 
Draw blood for clinical laboratory testing as outlined in Attachment 3 
• 
Collect urine for clinical urinalysis testing as outlined in Attachment 3 
• 
Complete a urine pregnancy for women of child-bearing potential 
• 
Complete the C-SSRS “Since Last Visit” (as described in Section 6.3.5 and outlined in 
Attachment 11) 
• 
Complete the Neuro-QoL Fatigue questionnaire (as described in Section 6.3.6 and as 
outlined in Attachment 5) 
• 
Complete the PMMSA (as described in Section 6.3.7 and as provided in Attachment 6) 
• 
Complete the PGA (as described in Attachment 7) 
• 
Complete the EQ-5D-5L (as described in Attachment 12) 
• 
Complete the WLQ if the subject self-reports currently working (as described in 


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Attachment 13) 
• 
Complete the PhGA (as described in Attachment 8) 
• 
Conduct the 6MWT (as described in Section 6.3.12 and as outlined in Attachment 9) 
 
• Administer (by subject or trained caregiver) study drug with the elamipretide delivery 
system 
• 
Assess for ISR 30 (± 5) minutes after study drug administration with the elamipretide 
delivery system (as described in Section 6.3.13) 
• 
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 study drug 
 
6.3. 
Study Assessments 
The following section describes study assessments occurring during the study. Study assessments 
and procedures are presented by study visit in Attachment 1. 
6.3.1. 
Medical History and Physical Examination 
For subjects not concurrently enrolled in SPIMM-202 during the Screening Period, at the 
Baseline Visit, new medical history (including concomitant medications/procedures) since the 
End-of-Study Visit in the SPIMM-201 and/or SPIMM-202 trial will be taken. Previous medical 
history (including concomitant medications/procedures do not need to be recorded and will be 
taken from the SPIMM-201 and/or SPIMM-202 trial. 
At all site visits, a complete physical examination will be performed. This will include a full 
review of the following systems: general appearance, skin, head, eyes, ears, nose, throat, neck 
(including thyroid), lymph nodes, chest, heart, abdomen, extremities, and nervous system. 
Weight will also be collected. 
 
6.3.2. 
Vital signs 
During all study center 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 rest. 
At the Baseline Visit these vital signs measurements will be performed as part of the study 
eligibility confirmation. 
 
6.3.3. 
Electrocardiograms (ECGs) 
A 12-lead ECG will be obtained after the subject has rested quietly for 10 minutes in the supine 
position at all study center 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. 
6.3.4. 
Clinical Laboratory Testing 
Sample collection, processing and handling details are provided in the Laboratory Manual. 
 
6.3.4.1. 
Blood chemistries 


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Blood will be collected at all study center visits. Analysis will include testing for parameters 
included in Attachment 3. Blood chemistry lab parameters should also be collected 
approximately monthly at the Monthly Safety Visits by a visiting nurse (or designee) between 
site visits until the Week 52 site visit. 
 
6.3.4.2. 
Hematology 
Blood will be collected at all study center visits. Analysis will include testing for parameters 
included in Attachment 3. Hematology lab parameters should also be collected approximately 
monthly (approximately every 4 weeks) at the Monthly Safety Visits by a visiting nurse (or 
designee) between site visits until the Week 52 site visit. 
6.3.4.3. 
Additional Laboratory Assessments 
Blood will be collected at all study center visits. Analysis will include testing for parameters 
included in Attachment 3. Additional laboratory assessment parameters should also be collected 
approximately monthly (approximately every 4 weeks) at the Monthly Safety Visits by a visiting 
nurse (or designee) between site visits until the Week 52 site visit. 
 
6.3.4.4. 
Urinalysis 
Urine will be collected at all study center visits and will include testing for parameters included 
in Attachment 3. 
6.3.4.5. 
Pregnancy tests 
A serum pregnancy test is required for women of child-bearing potential at the Screening Visit 
for subjects not concurrently enrolled in SPIMM-202 during the Screening Period. Results of the 
Baseline Visit pre-dose urine pregnancy test (or urine pregnancy test during the End-of-Study 
Visit in SPIMM-202 if within the Screening Period) must be evaluated before enrollment to 
ensure eligibility. Urine pregnancy test will also be performed for women of childbearing 
potential at the End-of-Study/Early Discontinuation Visit. 
6.3.5. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
At the Screening Visit, the C-SSRS “Since Last Visit” should be completed and recorded. If the 
subject did not enroll in SPIMM-202, the C-SSRS “Baseline/Screening” should be completed 
instead (Attachment 10). At all other clinical visits, the C-SSRS “Since Last Visit” will be 
completed and recorded for all subjects. The C-SSRS “Since Last Visit” is included in 
Attachment 11. 
 
6.3.6. 
The Neuro-QoL Fatigue Questionnaire 
At all study center visits, subjects will be instructed to complete the Neuro-QoL Fatigue 
questionnaire. The Neuro-QoL Fatigue questionnaire is in Attachment 5. 
 
6.3.7. 
Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) 
At all study center visits, subjects will be instructed to complete the PMMSA. The PMMSA is in 
Attachment 6. 
 
6.3.8. 
Patient Global Assessment (PGA) 
The Investigator or designee should ask the subjects for their overall assessment of their PMM 


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symptoms. The PGA is provided in Attachment 7. 
 
6.3.9. 
EQ-5D-5L 
At all study center visits, subjects will be instructed to complete the EQ-5D-5L. The EQ-5D-5L is 
in Attachment 12. 
 
6.3.10. 
Work Limitations Questionnaire (WLQ) 
At all study center visits, subjects will be instructed to complete the WLQ if the subject self- 
reports currently working. The WLQ is in Attachment 13. 
6.3.11. 
Physician Global Assessment (PhGA) 
The Investigator or designee will provide an overall assessment of the subject’s PMM 
symptoms. The PhGA is provided in Attachment 8. The same Investigator or designee should 
administer the PhGA at each visit for a particular subject. 
6.3.12. 
6-Minute Walk Test (6MWT) 
At all study center visits, the distance walked (in meters) during the 6MWT will be recorded. 
The 6MWT instructions are provided in Attachment 9. Study centers will be provided with a 
6MWT Kit, as well as standardized training. 
 
6.3.13. 
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. The skin examination should 
occur at 30 (±5) minutes after study drug 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 
Attachment 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 9.3.8.1.4. Any ISR that 
meets any of the criteria of a SAE/serious adverse device effect (SADE) (Section 9.3.7.) should 
be reported within 24 hours of the clinical site first becoming aware of the event (as outlined in 
Section 9.3.10). 


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7. 
STUDY POPULATION 
The inclusion and exclusion criteria for participation in this study are provided below. All 
Screening procedures must be completed during the Screening Period, but may be performed on 
different days. Screening procedures should not be repeated, and subjects should not 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 study one time. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
 
7.1. 
Inclusion Criteria 
A subject must meet ALL of the following inclusion criteria during the Screening Period: 
1. Willing and able to provide a signed informed consent form (ICF) prior to participation in 
any trial-related procedures. 
2. Investigator determines the subject can, and subject agrees to, adhere to the trial 
requirements for the length of the trial including self-administration (by subject or trained 
caregiver) of the study drug. 
3. Subject completed the End-of-Study Visit in SPIMM-201 and/or SPIMM-202 (if enrolled 
in both trials, the End-of-Study Visits in both trials must have been completed). 
4. Women of childbearing potential must agree to use 1 of the following methods of birth 
control from the date they sign the ICF through the End-of-Study Visit/ Early 
Discontinuation Visit: 
a. Abstinence, when it is in line with the preferred and usual lifestyle of the subject. 
Subject agrees to use an acceptable method of contraception should they become 
sexually active. 
b. Maintenance of a monogamous relationship with a male partner who has been 
surgically sterilized by vasectomy (the vasectomy procedure must have been 
conducted at least 60 days prior to the Screening Visit or confirmed via sperm 
analysis). 
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). 
5. Male subjects with female partners of child-bearing potential must be willing to use a 
highly effective method of contraception (see Section 9.3.11 for details) from the 
Screening Visit through the End-of-Study Visit/ Early Discontinuation Visit. 


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7.2. 
Exclusion Criteria 
A subject must NOT meet any of the following exclusion criteria during the Screening Period: 
1. 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. 
2. Subject has received any investigational compound (excluding elamipretide) and/or has 
participated in another interventional clinical trial within 30 days prior to the SPIMM-203 
Baseline Visit (excluding SPIMM-202) or is concurrently enrolled in any non- 
interventional research of any type judged to be scientifically or medically incompatible 
with the trial as deemed by the Investigator. 
3. Subject experienced an adverse reaction attributed to study drug resulting in permanent 
discontinuation of study drug in the SPIMM-201 or SPIMM-202 trial. 
4. Female subjects who are pregnant, planning to become pregnant, or lactating. 
5. Subject has undergone an in-patient hospitalization within the 1 month prior to the 
SPIMM-203 Baseline Visit. 
6. Subject has a history of clinically significant hypersensitivity or allergy to any of the 
excipients contained in the study drug. 
7.3. 
Prohibited Medications 
The use of any other investigational drug except elamipretide administered with the elamipretide 
delivery system 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 medications, including over-the-counter treatments, vitamins, or supplements, are 
recommended to have been unchanged and constant for at least 1 month prior to the Baseline 
Visit. All concomitant medications/procedures 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 study will be collected and 
should be recorded in the source data and the eCRF. 
Subjects will be instructed to maintain their normal diet, daily caffeine and fiber intake 
throughout the study period. 
 
7.4. 
Discontinuations 
7.4.1. 
Discontinuation of Subjects 
Subjects may be discontinued for the following reasons: 
• 
Investigator Decision 
o The Investigator decides that the subject should be discontinued from the study 
for any reason. 


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• Subject Decision 
 
o The subject or the subject’s designee, (e.g., parents or legal guardian), requests to 
be withdrawn from the study. 
▪ Subjects who withdraw should be explicitly asked about the contribution 
of possible Adverse Events (AEs)/Adverse Device Effects (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 study center should document and sign the reason for the subject’s 
failure to withdraw consent in writing. 
o The subject is lost to follow-up after a reasonable number of attempts to contact 
the subject (including documented phone calls and/or emails, and a certified 
letter) have been completed. 
• 
Sponsor Decision 
o The Sponsor or its designee stops the study or stops the subject’s participation in 
the study for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP guidelines. 
• 
Adverse Event/Adverse Device Effect 
o If the Investigator decides that the subject should be withdrawn because of an 
AE/ADE or a clinically significant laboratory value, the elamipretide delivery 
system is to be discontinued and appropriate measures are to be taken. The 
Sponsor or its designee is to be alerted immediately. 
o Known pregnancy or breastfeeding during the study therapy administration 
period. Study center personnel must report every pregnancy as soon as possible as 
described Section 9.3.11. 
Any subject withdrawing from the study will be asked to complete the Early Discontinuation 
Visit assessments (see Attachment 1). 
 
7.4.2. 
Discontinuation of Study Center 
Study center (research center) participation may be discontinued if the Sponsor or its designee, 
the Investigator, or the Ethics Committee (EC) of the study center judges it necessary for 
medical, safety, regulatory, or other reasons consistent with applicable laws, regulations, and 
GCP guidelines. 
 
7.4.3. 
Discontinuation of the Study 
The study will be discontinued if the Sponsor or its designee judges it necessary for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and GCP 
guidelines. 


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8. 
TREATMENT 
8.1. 
Treatments Administered 
Up to 36 subjects will receive 40 mg elamipretide administered with the elamipretide delivery 
system as a single daily SC injection for the shortest of the following: 260 weeks; regulatory 
approval and commercial availability of the elamipretide delivery system in the subject’s 
respective country; or termination of the clinical development for elamipretide. 
 
Elamipretide injection will be supplied as a labeled sterile 3.0 mL single-patient-use, 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 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. 
 
8.1.1. 
Elamipretide Pen Injector 
The elamipretide pen injector was developed by Stealth BioTherapeutics exclusively for use with 
the elamipretide injection 3 mL cartridge. 
Figure 2: 
Elamipretide Pen Injector 
The elamipretide pen injector has a common classification of Piston Syringe Class II in 
accordance with 21 CFR 880.5860. The elamipretide delivery system is designated system A in 
accordance with ISO 11608-1:2014. 
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 the elamipretide injection cartridge and the pen needle 
constitute the elamipretide delivery system which will be used in SPIMM-203. The elamipretide 
delivery system is for personal use (single subject) for SC administration of a fixed dose (0.5 
mL) of elamipretide injection. The needle provided should be used. The elamipretide delivery 
system is operated mechanically and contains no electronics. The elamipretide delivery system 
major components are depicted in Figure 3. The user will assemble and use the elamipretide 


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delivery system per the IFU that will be provided to each subject. 
Figure 3: 
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 
(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 BioTherapeutics 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 first 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 study drug 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 study 
drug 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 study drug, independent from the location of the concomitant therapy 
injections, should be used. 
8.2. 
Materials and Supplies 
The elamipretide single-patient-use, multidose glass cartridge of sterile elamipretide 
injection solution and delivery system will be dispensed and stored according to the 
Pharmacy Manual. The elamipretide multidose glass cartridges are to be stored refrigerated 
at 2 to 8°C (36 to 46°F) in a secure area until dispensed. 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 


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notified in the case of an excursion. The single-patient-use, multidose cartridge, while in use 
in the elamipretide delivery system, should 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 (pen needles and 
alcohol wipes) may be stored at room temperature. 
 
Additional information will be provided in the Pharmacy Manual. An IFU pamphlet will be 
provided to assist in training. 
 
8.3. 
Treatment Logistics and Accountability 
All drug accountability records must be kept current, and the Investigator must be able to 
account for all used and unused elamipretide injection cartridges and elamipretide pen 
injectors. These records should contain the dates, quantity, and the following: 
• 
Received at study center, 
• 
Dispensed to each subject, 
• 
Returned from each subject, and 
• 
Disposed of at the study center or returned to the Sponsor or designee 
The clinical monitor responsible for the study center will provide written approval for the 
destruction or return of unused elamipretide delivery system supplies following reconciliation 
of all elamipretide delivery system supplies. 
8.4. 
Rationale for Selection of Doses in the Study 
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. Two 
similarly designed trials (SPISC-101 and SPISC-102) have been conducted to evaluate the 
safety, tolerability and PK of single (2-80 mg) and 7-day repeat-dose administration (6-80 mg) of 
ascending doses of elamipretide administered SC to healthy volunteers. In these studies, 
elamipretide was associated with no systemic safety issues. Local injection site reactions were 
limited to transient, local erythema and occasional pruritus, pain, or swelling, which resolved 
spontaneously, generally within 4 hours post-dose, without sequelae. 
The systemic exposure (in terms of mean area under the plasma concentration vs time curve 
from time 0 to end of the dosing interval (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. 
An additional clinical pharmacology study (SPICP-101) demonstrates the effect of decreased 
renal function on plasma exposure and provides guidelines for use in patients with renal 
insufficiency in addition to providing a comparison of IV to SC PK. PK, safety and theoretical 
safety margins from toxicology studies support the use of SC elamipretide up to 40 mg/day in 
patients with creatinine clearance > 30 mL/min without the need for dose adjustment. 
The SPIMM-201 study provides supporting information regarding safety and plasma exposure in 


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the PMM population following repeat-dose administration of elamipretide at 0.01, 0.1, 0.25 
mg/kg/hr as a 2-hour IV infusion (Total Daily Dose [TDD] 0.02, 0.2, 0.5 mg/kg) for 5 days. 
Elamipretide demonstrated an acceptable safety and tolerability profile. The primary efficacy 
endpoint (distance walked on the 6MWT) appeared to improve with increasing doses and the 
highest level of functional improvement was observed at 0.25 mg/kg/day, a TDD of 0.5 
mg/kg/day. PK data is presented in Table 1. 
 
Table 1: SPIMM-201:  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 
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] 
1,992 [n=5] 
M1 
183 [n=9] 
1,672 [n=5] 
M2 
39.6 [n=9] 
661 [n=8] 
0.25 mg/kg/hr given as 
a 2hr IV infusion 
59.2 
29.6 
MTP-131 
1,050 [n=9] 
4,050 [n=7] 
M1 
285 [n=9] 
2,190 [n=7] 
M2 
68.8 [n=9] 
1,169 [n=8] 
*Calculations based on nominal time points. 
Bioavailability for Cmax and area under the plasma concentration vs time curve from time 0 to last 
available time point (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 2). 
 
Table 2: SPIMM-201:  Estimated Bioavailability of SC administration (40 mg as a 1 mL 
injection) versus Two Hour IV Infusion Following Repeat Administration of 
elamipretide (MTP-131) 
PK Parameters 
following 40mg 
Estimated 
Bioavailability 
Dose 
Mean 
TDD 
(mg) 
Correction 
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 
1,418 
5,468 
1,300 
3,720 
92% 
68% 
M1 
385 
2,957 
436 
3,100 
113% 
105% 
M2 
92.9 
1,578 
88.0 
1,950 
95% 
124% 
*Calculations based on nominal time points. 
Despite 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 remain similar to or greater 
than exposure demonstrated in the SPIMM-201 study in subjects weighing <80 kg therefore, 
treatment effect is not likely to be altered by the change in dose route. 


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37 
Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
To enable chronic dosing of elamipretide, chronic (26-weeks in rat, SPI-CIT-15-03; 39-weeks in 
dog, 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 and the predominant study 
findings were related to local injection site reactions and tolerability. Safety margin calculations 
for both non-clinical species, compared to the 40 mg/day (1 mL) SC dose in man are provided in 
Table 3. 
 
Table 3: SPI-CIT-15-03, SPI-CIT-15-02: Key Summary Steady-state PK Parameters 
Days 182 (Rat) and 273 (Dog) at the NOAEL/MFD with Safety Margins vs. 
Human Exposure (SPISC-101, 40 mg/day) 
PK in Man Following 
40mg SC 
Safety Margin 
Study / 
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 
6,875 
23,850 
1,300 
3,720 
x5 
x6 
M1 
7,385 
43,000 
436 
3,100 
x17 
x14 
M2 
260 
2,470 
88.0 
1,950 
x3 
x1.8 
SPI-CIT-15-02 
10 mg/kg/day 
Dog 
MTP-131 
13,050 
21,135 
1,300 
3,720 
x10 
x6 
M1 
1,709 
5,507 
436 
3,100 
x4 
x1.8 
M2 
312 
5,093 
88.0 
1,950 
x4 
x3 
The data displayed demonstrate that exposure to elamipretide, M1 and M2 in the chronic 
toxicology studies are supportive of chronic dosing at 40 mg/day by SC injection, in human. 
8.5. 
Treatment Compliance 
During the treatment period, study drug will be administered daily by a trained caregiver or self- 
administration. Subjects will be asked about treatment compliance during the monthly safety 
telephone calls and site visits. 


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38 
Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
9. 
SAFETY AND EFFICACY EVALUATIONS AND 
APPROPRIATENESS OF MEASUREMENTS 
Study procedures and their timing are summarized in Attachment 1. 
 
9.1. 
Safety measures 
9.1.1. 
Primary safety measure 
• 
AEs/ADEs (including SAEs/SADEs) 
9.1.2. 
Secondary safety measure 
• 
Changes in: 
o Vital signs 
o ECGs 
o Clinical laboratory evaluations 
o Columbia Suicide Severity Rating Scale (C-SSRS) 
9.2. 
Efficacy Measures 
9.2.1. 
Primary efficacy measure 
• 
Distance walked (meters) on the 6MWT 
9.2.2. 
Secondary efficacy measure 
• 
Patient reported outcomes 
o Neuro-QoL Fatigue questionnaire 
o Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) 
o Patient Global Assessments (PGA) 
o EQ-5D-5L 
o Work Limitations Questionnaire (WLQ) 
• 
Physician Global Assessments (PhGA) 
9.3. 
Safety 
9.3.1. 
Adverse Events (AEs)/Adverse Device Effects (ADEs) 
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 clinical study’s post treatment follow-up period. 


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39 
Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
 
Subjects must be seen by a physician or designee (an appropriately trained healthcare 
professional) at every study 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 study in the subject’s eCRF and applicable forms. 
An AE is any untoward medical occurrence in a patient 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 unfavourable 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 instruction 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. 
Should the study drug be discontinued due to an AE/ADE deemed probably or possibly 
related to study drug/elamipretide delivery system (per Section 9.3.8.1.2), reinitiating 
(rechallange) of the study drug may be possible, after consultation with the Sponsor. 
9.3.2. 
Pre-Treatment Events 
Adverse Events that occur while the subject is concurrently enrolled in the SPIMM-202 trial and 
the SPIMM-203 Screening Period, will be collected in the SPIMM-202 trial eCRF and not as 
AEs in SPIMM-203 trial. Once the subject has completed the End-of-Study in the SPIMM-202 
trial, AEs should be reported only in the SPIMM-203 eCRF. 
For subjects not concurrently enrolled in SPIMM-202 trial during the SPIMM-203 Screening 
Period, untoward events and/or incidental diagnoses that occur prior to study drug administration 
will be assessed by the Investigator and recorded as either medical history or as an AE. If the 
event is assessed by the Investigator as related to a study procedure, related to the previous 
exposure to study drug, and/or meets seriousness criteria, it will be recorded as an AE on the AE 
eCRF, processed, and followed accordingly. 
 
9.3.3. 
Baseline Medical Conditions 
Baseline medical conditions, related or not related to the therapeutic area of 
interest/investigation, that worsen in severity or frequency during the study 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. 
 
9.3.4. 
Medical and Surgical Procedures 
Medical or surgical procedures scheduled prior to signing the ICF, but occurring during the study 
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 ICF should not be recorded as 


Stealth BioTherapeutics Inc. 
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40 
Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
 
AEs; the condition that led to the need to perform the medical or surgical procedure will be the 
AE/ADE and the procedure should be captured on the concurrent procedures pages. 
 
9.3.5. 
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, 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. 
9.3.6. 
Symptomatic Overdose 
In the event of an overdose of study 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 study Medical Monitor. 
9.3.7. 
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 inpatient 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 
A 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 patient 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 an SAE/SADE should be 
reported as a new AE/ADE and as an SAE/SADE. The start date of the SAE 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 appropriate screen(s) of the subject’s eCRF. 


Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
41 
Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
 
As part of the routine medical monitoring, the medical monitor (or designee) will review all 
SAEs/SADEs reported in the SPIMM-203 trial, looking for any safety data trends or 
elamipretide delivery system related issues. 
 
9.3.8. 
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 Adverse Event Case Report Form 
(CRF). All SAEs/SADEs must be reported using the study specific SAE Report Form, in addition 
to the Adverse Event CRF. 
It is important that each AE/ADE entry include a verbatim term along with, onset and resolution 
dates, severity, seriousness, relationship to the study drug/elamipretide delivery system, action 
taken with respect to the study drug/elamipretide delivery system, and its outcome. 
 
Investigators should use the AE/ADE definitions provided in the above sections and should 
observe the following guidelines when completing the AE pages of the CRF: 
• 
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 up to a definite diagnosis if finally, available. Similarly, a fatal event with an unknown 
cause should be recorded as “Unknown”. Please note that death is an outcome, not an event. The 
cause of death should be reported as the event. If the cause is unknown, “death, cause unknown” 
or “sudden death” can be entered as the event. When identified, the cause of death should be 
entered as the event on a follow-up form, with supporting documentation if available (e.g., death 
certificate, autopsy report). 
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. 
 
9.3.8.1. 
Investigator Assessments 
 
9.3.8.1.1. Severity/Intensity 
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: 


Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
42 
Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
 
Mild: 
Associated with no limitation of usual activities or only slight discomfort; 
generally not requiring alteration or cessation of study drug 
administration; and/or not needing therapeutic intervention. 
Moderate: Associated with limitation of usual activities or significant discomfort; 
generally requiring alteration or cessation of study drug administration; 
and/or requiring therapeutic intervention. 
Severe: 
Associated with inability of patient to carry out usual activities or very 
marked discomfort; considered to be life-threatening; resulting in 
significant disability or incapacity; and requiring therapeutic intervention. 
 
9.3.8.1.2. Relationship to the Study Drug/Elamipretide Delivery System 
Investigators must systematically assess the causal relationship of AEs/ADEs to the study 
drug 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 study drug/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 study drug/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 study drug/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. 
9.3.8.1.3. Outcomeof AdverseEvent (AE)/Adverse Device Effect (ADE) 
Investigators must follow all AEs/ADEs and SAEs/SADEs until the clinical study’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. 


Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
43 
Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
9.3.8.1.4. 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 Attachment 14. 
– Any ISR that meets any of the criteria of a SAE/SADE (Section 9.3.7) should 
be reported within 24 hours of the clinical site first becoming aware of the 
event (as outlined in Section 9.3.10). 
– 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. 
 
9.3.9. 
Adverse Event (AE)/Adverse Device Effect (ADE) Reporting Period 
The AE/ADE reporting period begins when the subject signs the ICF and continues through the 
clinical study’s post treatment follow-up period. 
After study 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. 
Adverse Events that occur while the subject is concurrently enrolled in the SPIMM-202 trial and 
the SPIMM-203 Screening Period, will be collected in the SPIMM-202 trial eCRF and not as 
AEs in SPIMM-203 trial. Once the subject has completed the End-of-Study in the SPIMM-202 
trial, AEs/ADEs should be reported only in the SPIMM-203 eCRF. 
For subjects not concurrently enrolled in SPIMM-202 trial during the SPIMM-203 Screening 
Period, untoward events and/or incidental diagnoses that occur prior to study drug administration 
will be assessed by the Investigator and recorded as either medical history or as an AE. If the 
event is assessed by the Investigator as related to a study procedure, related to the previous 
exposure to study drug, and/or meets seriousness criteria, it will be recorded as an AE on the AE 
eCRF, processed, and followed accordingly. New protocol related AEs/ADEs (caused by any 
intervention required by the protocol) and updates on all AEs/ADEs ongoing or with an 
unknown outcome must be recorded until the last subject visit required by the protocol. A last 
batch of queries will be sent after last study visit if remaining ongoing/unknown outcomes of 


Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
44 
Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
 
reported AEs/ADEs are pending. After the last batch of queries with all collected data have been 
fully processed, CRFs and database will no longer be updated. 
However, SAEs/SADEs and medically relevant ongoing/unknown outcome AEs/ADEs will be 
followed-up until resolution or stabilization by the Sponsors Pharmacovigilance department. 
Beyond this defined reporting period, any new SAE/SADE spontaneously reported to the 
Sponsor by the Investigator would be collected and processed. Additional information on 
SAE/SADE, obtained after database lock, will reside solely in the safety database. 
Within the study, all subjects who took at least 1 dose of study drug, whether they 
completed the treatment period or not, should enter the 14-day period as defined above. 
If a subject is documented as lost-to follow-up, ongoing/unknown outcome AEs will not be 
followed-up. 
For Screen failure subjects, new AEs and updates must be recorded in the SPIMM-202 eCRFs 
until the date the subject was determined to be a screen failure. Beyond that date, only 
SAEs/SADEs and medically relevant AEs/ADEs will be followed-up by the Sponsor’s 
Pharmacovigilance group and all data will be housed within the safety database. 
 
9.3.10. 
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 Sponsor as 
detailed in the Clinical Trial Pharmacovigilance Procedural Manual. 
For any SAE/SADE, the following minimum information is required as initial notification: 
• 
Investigator/Reporter with full contact information 
• 
Subject identification details (study number, site number, subject number), 
• 
Study drug administration details (dose and dates) 
• 
Event Verbatim, a brief description of signs/symptoms/or diagnosis and the date of onset, 
• 
Seriousness criteria (ion) met, and, 
• 
Relationship of the event to the study drug (e.g., the causality according to the 
Investigator) 
All SAE/SADE reports should be transmitted according to the safety management plan. 
 
Reporting procedures and timelines are the same for any new follow-up information on a 
previously reported SAE/SADE. 
 
All SAE/SADE reports must be completed as described in the eCRF completion guidelines and 
submitted through the Electronic Data Capture (EDC) system of the clinical database. Other 
relevant information from the clinical database (including demographic data, medical history, 
concomitant medications/procedures and study drug dosing information) will automatically be 
sent via the EDC system when the SAE form is submitted. 
The names, addresses, telephone and fax numbers for SAE back-up reporting (paper), are 


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45 
Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
 
included in the Safety Management Plan. 
The Investigator/Reporter must respond to any request for follow-up information (e.g., additional 
information, outcome and final evaluation, specific records where needed) or to any question the 
Sponsor may have on the AE/ADE within the same timelines as described for initial reports. This 
is necessary to permit a prompt assessment of the event by the Sponsor and (as applicable) to 
allow the Company to meet strict regulatory timelines associated with expedited safety reporting 
obligations. 
 
9.3.11. 
Pregnancy and Contraception 
Any pregnancy in a female subject or female partner of a male subject during the course of the 
study and until the last follow-up visit must be reported on the Pregnancy Report Form (Part I) 
within 24 hours of learning of the pregnancy even if no AE/ADE has occurred. If the investigator 
suspects the pregnancy has resulted from an interaction of the study medication with 
contraceptives, then the pregnancy is considered as an AE; however, all pregnancies must be 
recorded in the AE page/section of the CRF. 
The Pregnancy Report Form (Part I) must be transmitted according to the same process as 
described for SAE/SADE reporting in the Clinical Trial Pharmacovigilance Procedural Manual. 
Investigators must actively follow up, document, and report on the outcome of every pregnancy, 
even if the subject is withdrawn from the trial. 
The Investigator must notify the Sponsor of the pregnancy outcome using the Pregnancy Report 
Form (Part II). In the event of the mother experiencing an abnormal outcome which meets of the 
criteria of an SAE/SADE, the SAE Report Form must be completed. In the event of the child/fetus 
experiencing an abnormal outcome the Parent-Child/Fetus Report form must be completed. 
Any abnormal outcome must be reported in an expedited manner, while normal outcomes must 
be reported within 45 days from delivery. 
 
9.3.12. 
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 site-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 study drug or 
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. 


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Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
 
When specifically required by regulations and guidelines, the Sponsor will provide appropriate 
Safety reports directly to the concerned lead Institutional Ethics Committee (IEC)/central IRB 
and will maintain records of these notifications. When direct reporting by the Sponsor is not 
clearly defined by national or site-specific regulations, the Investigator will be responsible for 
promptly notifying the concerned IEC/IRB of any Safety reports provided by the Sponsor and for 
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 Guidance’s. 
 
9.4. 
Appropriateness of Measurements 
The measures used to assess safety in this study are consistent with those widely used and 
generally recognized as reliable, accurate, and relevant. 


Stealth BioTherapeutics Inc. 
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47 
Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
10. 
DATA QUALITY ASSURANCE 
To ensure accurate, complete, and reliable data, the Sponsor or its representatives will do the 
following: 
• 
Provide instructional material to the study centers, as appropriate 
• 
Sponsor start-up training to instruct the Investigators and study coordinators. This 
training will give instruction on the protocol, the completion of the eCRFs, and study 
procedures. 
• 
Make periodic visits to the study center 
• 
Be available for consultation and stay in contact with the study center personnel by mail, 
telephone, and/or fax 
• 
Review and evaluate eCRF data and use standard computer edits to detect errors in data 
collection 
• 
Conduct a quality review of the database 
In addition, the Sponsor or its representatives will periodically check the subject data recorded 
against source documents at the study center. The study may be audited by the Sponsor or its 
representatives, and/or regulatory agencies at any time. Investigators will be given notice before 
an audit occurs. 
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the Investigator will keep records of laboratory tests, clinical notes, and subject medical 
records in the subject files as original source documents for the study. If requested, the 
Investigator will provide the Sponsor, applicable regulatory agencies, and applicable ECs with 
direct access to original source documents. 
 
10.1. 
Data Capture System 
An EDC system will be used in this study. The study center will maintain a separate source for 
the data entered by the study center into the Sponsor-provided EDC system. 
Case report form data will be encoded and stored in a clinical study database. Data managed by a 
central vendor, such as laboratory test data, 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 study center in that center’s study file. 
Paper documentation provided by the subject may include, for example, a paper diary to collect 
subject reported outcome measures (e.g., a rating scale), a daily dosing schedule, or an event 
diary. 


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Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
11. 
SAMPLE SIZE AND STATISTICAL METHODS 
11.1. 
Determination of Sample Size 
Subject numbers (up to 36 subjects) are limited to those having previously participated in the 
SPIMM-201 and/or SPIMM-202 study, who meet all eligibility criteria. 
 
11.2. 
Statistical and Analytical Plans 
11.2.1. 
General Considerations 
All study data are to be displayed in the data listings. 
Baseline is defined as the SPIMM-203 Baseline assessments. 
Statistical analysis of this study will be the responsibility of the Sponsor or its designee. 
Additional details regarding analyses will be included in separate statistical analysis plan (SAP). 
11.2.2. 
Subject Disposition 
All subjects who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported. If known, a reason for their discontinuation will be 
given. 
 
11.2.3. 
Subject Characteristics 
Subject’s age, sex, weight, height, body mass index (BMI), and other demographic 
characteristics will be recorded and summarized. Medical history will be listed. 
 
11.2.4. 
Endpoints and Methodology 
 
11.2.4.1. 
General Considerations 
Data will be summarized using descriptive statistics (number of subjects, mean, median, standard 
deviation, minima, and maxima) for continuous variables and using frequencies and percentages 
for discrete variables. 
 
11.2.4.2. 
Analysis Populations 
The Safety Population, will include all study subjects who receive at least 1 dose of study drug. 
The Efficacy Evaluable Population will include all subjects receiving at least one dose with any 
post-dose efficacy assessments. 
 
11.2.5. 
Efficacy Analyses 
For primary and secondary efficacy endpoints, trends over time in all continuous endpoints will 
be summarized using descriptive statistics (mean, median, standard deviation, minimum, 
maximum). Categorical variables will be described using frequencies and percentages. 
Efficacy analyses will be conducted on the Efficacy Evaluable Population and will be largely 
descriptive in nature. 


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SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
 
11.2.6. 
Safety Analyses 
Safety data analysis will be conducted on all subjects in the Safety Population. 
 
11.2.6.1. 
Adverse Events (AEs)/Adverse Device Effects (ADEs) 
The number and percentage of subjects experiencing 1 or more AEs/ADEs will be summarized by 
relationship to study drug, and severity. AEs/ADEs will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) terminology. AEs/ADEs will be summarized by system organ 
class (SOC) and preferred term (PT). 
All reported AEs/ADEs will be listed, but only treatment-emergent adverse events 
(TEAEs)/Treatment-emergent adverse device effects (TEADEs) will be summarized. 
The incidence of all TEAEs/TEADEs, drug relationship with TEAEs/TEADEs, and severity of 
TEAE/TEADEs will be summarized. In the summary tables, subjects may be counted under 
multiple SOCs and PTs, but for each SOC and PT, subjects are only counted once. If a subject 
has the same AE/ADE on multiple occasions (with a treatment period), the highest severity 
(severe > moderate > mild) or drug relationship (probable > possibly related > unlikely related 
> unrelated) recorded for the AE/ADE will be presented. If severity is missing, subjects will be 
included as missing (for severity). If drug relationship is missing, subjects will be included in 
related tables (e.g., considered related). 
 
11.2.6.2. 
Deaths and Other Serious Adverse Events 
Listings will be provided for the following: 
• 
Deaths 
• 
SAEs/SADEs 
• 
AEs/ADEs leading to discontinuation of study drug/elamipretide delivery system 
11.2.6.3. 
Clinical Laboratory Evaluations 
Summary tables for laboratory parameters (including hematology, chemistry, additional 
laboratory assessments, and urinalysis) will include descriptive statistics of change relative to 
baseline where appropriate, and data listings of clinically significant abnormalities. 
Subjects with laboratory data outside the normal range will be listed with abnormal values 
flagged. 
Shift tables (e.g., tables that show the number of subjects who are low, normal, or high at 
baseline versus each post-baseline scheduled assessment) will be produced. 
The number and percentage of subjects with urinalysis results outside the normal range will be 
presented by endpoint and visit. Shift tables for urinalysis will show the number of subjects who 
are normal/abnormal at baseline and normal/abnormal at the end of study. 
 
11.2.6.4. 
Vital Signs 
Vital signs data will be summarized by changes from baseline values using descriptive statistics. 


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SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
 
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. 
11.2.6.5. 
Electrocardiogram (ECG) 
Electrocardiogram data will be summarized by changes from baseline values 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, and QT will also be listed. 
 
11.2.6.6. 
Other Safety Parameters 
Any other safety data captured on the eCRF will be listed. 


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Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
12. 
INFORMED CONSENT, ETHICAL REVIEW, 
AND REGULATORY CONSIDERATIONS 
12.1. 
Informed Consent 
The Investigator is responsible for ensuring that the subject understands the potential risks and 
benefits of participating in the study, including answering any questions the subject may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the subject willingness to continue his or her participation in the study. 
The ICF will be used to explain the potential risks and benefits of study participation to the 
subject in simple terms before the subject is entered into the study, and to document that the 
subject is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study. 
The 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 
elamipretide with the elamipretide delivery system. 
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 investigative 
study center.  All ICFs must be compliant with the ICH guideline on GCP. 
Documentation of EC approval of the protocol and the ICF must be provided to the Sponsor 
before the study may begin at the investigative study center. The EC will review the protocol as 
required. 
The study center’s EC should be provided with the following: 
• 
The current IB and updates during the course of the study 
• 
ICF 
• 
Relevant curricula vitae 
12.3. 
Regulatory Considerations 
This study will be conducted in accordance with: 
1) Consensus ethics principles derived from international ethics guidelines, including the 
CIOMS International Ethical Guidelines 
2) The ICH GCP Guideline [E6] 
3) Applicable laws and regulations 
The Investigator or designee will promptly submit the protocol to applicable EC(s). Some of the 
obligations of the Sponsor may be assigned to a third party organization. 


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SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
 
An identification code assigned to each subject will be used in lieu of the subject’s name to 
protect the subject’s identity when reporting AEs and/or other study-related data. 
 
12.3.1. 
Protocol Approval 
The Sponsor’s 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 
study. 
 
12.3.2. 
Final Report Approval 
The Sponsor’s responsible medical officer will approve the final clinical study report for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study. 
 
12.3.3. 
Study Monitoring 
The Investigators and institution(s) will permit study-related monitoring of the CRF data by 
Stealth BioTherapeutics Inc., or their assignee by providing direct access to source data and/or 
documents. The study monitor will verify the eCRFs 100% against the source documentation. 
Deviations from the protocol with regard to subject enrollment or study conduct will also be 
noted in the source documentation, in the eCRF and a complementary database. A Sponsor 
representative will visit the study center to initiate the study, prior to the first treatment of the 
first subject, and at agreed times throughout the study, including at the end of the study. Drug 
dispensing and clinical drug supply records will be 100% verified at the study center by the study 
monitor. It is understood that all subject specific information is confidential and no 
documentation that can link study information to the specific subject will be collected or retained 
by the Sponsor. 
 
12.3.4. 
Retention of Records 
All study related material including source documents, eCRFs, Central Authority, and EC 
correspondence and analyses and any other documentation required by applicable laws and 
regulations will be maintained for 15 years after completion of the study or notification from the 
Sponsor that the data can be destroyed, whichever comes first. 
 
12.3.5. 
Disclosure of Information 
Information concerning the investigational medication and patent application processes, 
scientific data or other pertinent information is confidential and remains the property of Stealth 
BioTherapeutics Inc. The Investigator may use this information for the purposes of the study 
only. It is understood by the Investigator that Stealth BioTherapeutics Inc., will use information 
developed in this clinical study in connection with the development of the investigational 
medication and therefore may disclose it as required to other clinical Investigators and to 
regulatory agencies. In order to allow the use of the information derived from this clinical study, 
the Investigator understands that he/she has an obligation to provide complete test results and all 
data developed during this study to the Sponsor. 


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Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
 
The Investigator may not submit for publication or presentation the results of this study without 
first receiving written authorization from Stealth BioTherapeutics Inc. Stealth BioTherapeutics 
Inc., agrees that before it publishes any results of the study, it shall provide the Investigator with 
at least 30 days for review of the pre-publication manuscript prior to the submission of the 
manuscript to the publisher. 


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SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
13. 
REFERENCES 
 
1. Apabhai S, Gorman GS, Sutton L, Elson JL, Plötz T, et al. Habitual Physical Activity in 
Mitochondrial Disease. 2011; 6(7): e22294. doi: 10.1371/journal.pone.0022294. 
2. Gorman G, Schaefer AM, Ng Y, et al. Prevalence of nuclear and mitochondrial DNA 
mutations related to adult mitochondrial disease. Annals of Neurology. 2015;77(5):753-759. 
doi:10.1002/ana.24362. 
3. Lightowlers RN, Taylor RW, Turnbull DM. Mutations causing mitochondrial disease: What 
is new and what challenges remain?. Science. 2015;349(6255):1494-9. 
4. Mancuso M, Hirano M. Physician Guide to Mitochondrial Myopathies. National 
Organization for Rare Disorders. 2016. Accessed on 28Jun2017. Accessible at: 
http://nordphysicianguides.org/mitochondrial-myopathies-mm/ 
5. Min K, Smuder AJ, Kwon OS, Kavazis AN, Szeto HH, Powers SK. Mitochondrial-targeted 
antioxidants protect skeletal muscle against immobilization-induced muscle atrophy. J Appl 
Physiol (1985). 2011 Nov;111(5):1459-66. 
6. Niyazov D, M, Kahler S, G, Frye R, E, Primary Mitochondrial Disease and Secondary 
Mitochondrial Dysfunction: Importance of Distinction for Diagnosis and Treatment. Mol 
Syndromol 2016;7:122-137. 
7. Powers SK, Hudson MB, Nelson WB, Talbert EE, Min K, Szeto HH, Kavazis AN, Smuder 
AJ. Mitochondria-targeted antioxidants protect against mechanical ventilation-induced 
diaphragm weakness. Crit Care Med. 2011 Jul;39(7):1749-59. 
8. Schaefer AM, Phoenix C, Elson JL, McFarland R, Chinnery PF, Turnbull DM. 
Mitochondrial disease in adults: a scale to monitor progression and treatment. Neurology. 
2006 Jun 27;66(12):1932-4. 
9. Siegel MP, Kruse SE, Percival JM, Goh J, White CC, Hopkins HC, Kavanagh TJ, Szeto HH, 
Rabinovitch PS, Marcinek DJ. Mitochondrial targeted peptide rapidly improves 
mitochondrial energetics and skeletal muscle performance in aged mice. Aging Cell. 2013 
Oct;12(5):763-771. 
10. Talbert E, Smuder A, Min K, Kwon OS, Szeto HH, Powers SK. Immobilization-induced 
activation key proteolytic systems in skeletal muscles is prevented by a mitochondria- 
targeted antioxidant.  J Appl Physiol. 115:529-538, 2013. 


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Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
 
 
14. 
ATTACHMENTS 


Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
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56 
 
 
 
 
Attachment 1 
Trial Schedule 
 
Screeninga 
Baselineb 
Treatment Period 
Follow-Up 
Period 
Unscheduled 
Parameter 
(Day -28 
to -1) 
Baseline Visit 
(Day 1) 
Monthly 
Safety 
Visits (±7 
days)c 
Monthly 
Safety 
Telephone 
Call 
(±7 days)c 
3-Month Visit 
(Week 13 ±14 days); 
6-Month Visits 
(Week 26 and every 26 
weeks after ±14 days); 
End-of-Therapy Visit 
(Week 260 ±14 days) 
End-of-Study 
Visit/Early 
Discontinuation 
Visit 
(Week 262 +14 
days) 
Unscheduled 
Visitd 
Informed Consent 
X 
Subject Registratione 
X 
Review of inclusion/exclusion criteria 
X 
X 
Demographicsf 
Relevant Medical Historyg 
X 
X 
Concomitant Medication/Procedure Reviewg 
X 
X 
X 
X 
X 
X 
Review AEs/ADEsh 
X 
X 
X 
X 
X 
Physical Exami 
X 
X 
X 
X 
X 
Vital Signsj 
X 
X 
X 
X 
X 
12-Lead ECGk 
X 
X 
X 
X 
X 
Pregnancy Testl 
X 
X 
X 
X 
Blood Chemistry, Hematology, and 
Additional Laboratory Assessmentsm 
X 
X 
X 
X 
X 
X 
Urinalysism 
X 
X 
X 
X 
X 
C-SSRS “Baseline/Screening”n 
X 
C-SSRS “Since Last Visit” 
X 
X 
X 
X 
X 
Neuro-QoL Fatigue 
X 
X 
X 
X 
PMMSA 
X 
X 
X 
X 
Patient Global Assessment 
X 
X 
X 
X 
EQ-5D-5L 
X 
X 
X 
X 
WLQo 
X 
X 
X 
X 
Physician Global Assessment 
X 
X 
X 
X 
Six Minute Walk Testp 
X 
X 
X 
X 
Study Drug Administrationq 
X 
X 
X 
X 
X 
ISR Assessmentr 
X 
X 
X 
a. 
The ICF must be signed prior to any trial related procedures are performed. Subjects, who are <18 years of age, may be required by the trial center to have a 


Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
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57 
 
 
 
 
minor assent in addition to the ICF of the parent/guardian. Assessments completed as part of the End-of-Study Visit in the SPIMM-202 trial that are within 
the Screening Period can serve as Screening assessments and do not need to be reassessed. For subjects enrolled in SPIMM-202, the Screening Period may 
not begin prior to the Week 12 Visit in the SPIMM-202 trial. 
b. 
Assessments completed as part of the End-of-Study Visit in SPIMM-202 and are within 24 hours of the Baseline Visit may serve as Baseline assessments 
and do not need to be reassessed. Screening assessments that are within 24 hours of the Baseline Visit may also serve as Baseline assessments and do not 
need to be reassessed. Otherwise, Baseline assessments must be completed within 24 hours prior to receiving elamipretide. 
c. 
Subjects will be scheduled to have Monthly Safety Visits completed by a visiting nurse (or designee) in between site visits until the Week 52 site visit. 
Monthly safety telephone calls will be completed in between site visits after the Week 52 site visit. The monthly safety telephone call script isprovided in 
Attachment 4. 
d. 
If an Unscheduled Visit occurs, assessments to be completed are in the judgement of the Investigator. 
e. 
Subject will be assigned the same subject number from SPIMM-201 and/or  SPIMM-202 trial. 
f. 
Demographic data does not need to be recorded and will be taken from the SPIMM-201 and/or SPIMM-202 trial. 
g. 
For subjects not concurrently enrolled in SPIMM-202 during the Screening Period, at the Baseline Visit, new medical history (including concomitant 
medications/procedures) since the End-of-Study Visit in the SPIMM-202 trial will be taken. Previous medical history (including concomitant medications/ 
procedures do not need to be recorded and will be taken from the SPIMM-202 trial 
h. 
For subjects not concurrently enrolled in SPIMM-202 trial during the Screening Period, record any AEs that occurred during the Screening Period (as 
described in Section 9.3.9) 
i. 
Physical examination will include: general appearance, skin, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, chest, heart, abdomen, 
extremities, and nervous system. Weight will also be collected. 
j. 
Vital signs will include HR, RR, and BP after sitting for 5 min,  andtemperature. 
k. 
All scheduled ECGs must be performed after the subject has rested quietly for at least 10 min in the supine position. 
l. 
A serum pregnancy test is required at the Screening Visit if not concurrently enrolled in SPIMM-202 during the Screening Period. Results of the Baseline 
Visit pre-dose urine pregnancy test (or urine pregnancy test during the End-of-Study Visit in SPIMM-202 if within the Screening Period) must be 
evaluated before enrollment to ensure eligibility. Urine pregnancy test will also be performed for women of childbearing potential at the End-of-Study/ 
Early Discontinuation Visit. 
m. See Attachment 3 for laboratory tests. Additional blood samples at the first 6-Month Visit will be collected and stored for assessing the immunogenicity 
potential of the study drug. 
n. 
Only to be completed if subject did not enroll in SPIMM-202. 
o. 
Only to be completed if the subject self-reports currently working. 
p. 
The 6MWT should be performed after all other trial procedures except study drug administration and ISR  assessment. 
q. 
Subjects (and caregivers if needed) will be trained on the procedure for administration of study drug with the elamipretide delivery system (elamipretide 
injection, the elamipretide pen injector, and needle). On days of trial visits, the study drug administered with the elamipretide delivery system should be 
administered at the clinical site. At site visits where elamipretide is injected, administration should occur at the study center after completion of all 
procedures, except for the ISR assessment. Elamipretide administration on days of Monthly Safety Visits and monthly safety telephone calls will be 
completed by the subject (or trained caregiver). 
r. 
The skin examination should occur at 30 (±5) minutes after study drug 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 Attachment 14. 


Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
58 
 
 
 
 
Attachment 2 
Trial Schematic 
 
 
 


Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
Stealth BioTherapeutics Inc. 
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59 
 
 
 
 
Attachment 3 
Clinical Laboratory Tests 
 
 
Clinical Hematology: 
Clinical Chemistry: 
Hemoglobin 
Sodium 
Hematocrit 
Potassium 
Erythrocyte count (RBC) 
Total bilirubin 
Leukocytes (WBC) 
Direct bilirubin 
Neutrophils, segmented 
Alkaline phosphatase (ALK-P) 
Lymphocytes 
Alanine aminotransferase (ALT) 
Monocytes 
Aspartate aminotransferase (AST) 
Eosinophils 
Blood urea nitrogen (BUN) 
Basophils 
Gamma-glutamyl transpeptidase (GGTP) 
Platelets 
Creatine kinase (CK) 
Creatinine 
Urinalysis: 
Calcium 
Specific gravity 
Glucose (non-fasting) 
pH 
Albumin 
Protein 
Chloride 
Glucose 
Triglycerides 
Ketones 
LDL 
Blood 
HDL 
Leukocyte esterase 
Venous lactate 
Additional Laboratory Assessments 
Interleukin-5 (IL-5) 
Immunoglobulin E (IgE) 


Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
Stealth BioTherapeutics Inc. 
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60 
 
 
 
 
Attachment 4 
Monthly Safety Telephone Call Script 
This page provides a sample script for the phone call that may occur approximately every 4 
weeks after the patient is enrolled in SPIMM-203 to ensure the safe and compliant use of the 
elamipretide delivery system and to appropriately collect the safety events with use of the 
elamipretide delivery system. 
The sample script below is provided to assist clinical sites with conducting monthly safety 
telephone calls. Additional questions are permitted to ensure completeness of answers. 
During each monthly safety telephone call, the following script should be followed: 
 
Script 
Hello, my name is  
, and I'm calling from (name of facility and/or Investigator’s 
name office). I am calling since it has been a month since we last spoke about your experience 
using elamipretide, the study drug in the SPIMM-203 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 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) and/or to reference the Information for Use (IFU) pamphlet for the elamipretide 
delivery system for any issues. 


Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
Stealth BioTherapeutics Inc. 
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61 
 
 
 
 
Attachment 5 
Neuro-QoL Fatigue Questionnaire 


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 


Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
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64 
 
 
 
 
Attachment 6 
Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) 
 
 
 
 
 
 
 
 
 
 
 
 
 
muscle weakness during 
 
 
 
 
 
 
 
 
abdominal discomfort (feeling 
 
 
 
 
 
 
 
 
  headache? 
 
Not at all 
Mild 
Moderate 
Severe 
1. During the past 24 hours, how 
severe was your worst feeling of 
□ 
tiredness at rest? 
□ 
□ 
□ 
2. During the past 24 hours, how 
severe was your worst feeling of 
□ 
tiredness during activities? 
□ 
□ 
□ 
3. During the past 24 hours, how 
severe was your worst feeling of 
□ 
muscle weakness at rest? 
□ 
□ 
□ 
4. During the past 24 hours, how 
severe was your worst feeling of 
□ 
activities? 
□ 
□ 
□ 
5. During the past 24 hours, how 
severe were your worst balance 
□ 
problems? 
□ 
□ 
□ 
6. During the past 24 hours, how 
severe were your worst vision 
□ 
problems? 
□ 
□ 
□ 
7. During the past 24 hours, how 
severe was your worst 
□ 
nauseous, bloated, or in pain)? 
□ 
□ 
□ 
8. During the past 24 hours, how 
severe was your worst muscle 
□ 
pain? 
□ 
□ 
□ 
9. During the past 24 hours, how 
severe was your worst 
□ 
numbness? 
□ 
□ 
□ 
10. During the past 24 hours, 
how severe was your worst 
□ 
□ 
□ 
□ 


Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
65 
 
 
 
 
Attachment 7 
Patient Global Assessment (PGA) 
The patient global assessment should be completed by the Investigator asking the patient: 
In general, would you say your health is… 
1. Excellent 
2. Very Good 
3. Good 
4. Fair 
5. Poor 


Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
66 
 
 
 
 
Attachment 8 
Physician Global Assessment (PhGA) 
Make an estimate of the overall health status of the examinee based on your findings from the 
physician’s examination, regardless of the completeness of the examination. 
1. Excellent 
2. Very Good 
3. Good 
4. Fair 
5. Poor 


Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
67 
 
 
 
 
Attachment 9 
Six-Minute Walk Test (6MWT) 


Page 1 of 8 
 
 
Six-Minute Walk Test 
 
 
PURPOSE AND SCOPE 
 
This document serves as a guideline for the 6-minute walk test (6 MWT) for the study. It 
outlines the set-up, patient preparation, step-by step procedures, and safety measures. 
 
REQUIRED EQUIPMENT 
 
1. Countdown timer (or stopwatch) 
2. Mechanical lap counter 
3. Two small cones to mark the turnaround points 
4. A chair that can be easily moved along the walking course 
5. Worksheets on a clipboard 
6. A source of oxygen 
7. Sphygmomanometer 
8. Telephone 
9. Automated electronic defibrillator 
10. Bean bag 
 
SET-UP 
 
• 
The 6MWT should be performed indoors, along a long, flat, straight, enclosed corridor 
with a hard surface that is seldom traveled. The walking course must be 30 m in length. 
A 100-ft hallway which is equivalent to 30 meters is, desirable. The length of the 
corridor should be marked every 3 m. The turnaround points should be marked with a 
cone (such as an orange traffic cone). A starting line, which marks the beginning and 
end of each 60-m lap, should be marked on the floor using brightly colored tape. 
 
• 
The patient should sit at rest in a chair, located near the starting position, for at least 
10 minutes before the test starts. During this time, check for contraindications, 
measure pulse and blood pressure, and make sure that clothing and shoes are 
appropriate. 
 
• 
A “warm-up” period before the test should not be performed. 


Page 2 of 8 
SAFETY ISSUES 
 
 
 
1. 
Testing should be performed in a location where rapid appropriate response to an 
emergency is possible. 
 
2. 
Available supplies must include oxygen, sub lingual nitroglycerine, aspirin, albuterol 
MDI. A telephone and other means should be in place to enable a call for help. 
 
3. 
The technician should be certified in cardiopulmonary resuscitation with a minimum 
of basic life support by an AHA approved CPR course or local country equivalent. 
ACLS certification is desirable. 
 
4. 
Physicians are not required to be present during all tests, and may be present 
depending on physician’s judgment. 
 
5. 
If a patient is on chronic oxygen therapy, oxygen should be given at their standard 
rate or as directed by a physician or protocol. 
 
PATIENT PREPARATION 
 
1. 
Comfortable clothing should be worn. 
2. 
Patients should not have nail polish. 
3. 
Appropriate shoes for walking should be worn. 
4. 
Patients should use their usual walking aids during the test (cane, walker, etc.). 
5. 
Patients usual medical regimen should be continued. 
6. 
A light meal is acceptable before early morning or early afternoon tests. 
7. 
Patients should not have exercised vigorously within 2 hours of beginning the test. 


Page 3 of 8 
SUPPLEMENTAL OXGEN 
 
 
 
1. 
If oxygen supplemental is needed during the walks and serial tests are planned (after 
an intervention other than oxygen therapy), then during all walks by that patient 
oxygen should be delivered in the same way with the same flow. 
 
2. 
If the flow must be increased during subsequent visits due to worsening gas 
exchange, this should be noted on the worksheet and considered during 
interpretation of the change noted in documentation. 
 
3. 
The type of oxygen delivery device should also be noted on the report. For instance, 
the patient carried liquid oxygen or received oxygen via an oxygen tank. It is not 
recommended that the patient pushes or pulls the oxygen tank themselves, nor 
should the technician walk close to the patient to pull or push the oxygen tank, as 
that may result in them “pacing” the patient and influencing the distance walked. If 
technician is walking with the oxygen tank, an extension tubing of at least 10 feet 
should be used (document that the oxygen delivery is stable) so that the technician 
is not close to the patient. Pulsed oxygen delivery is not recommended for this study; 
all oxygen delivery should be continuous. 
 
4. 
Measurements of the pulse and SpO2 should be made after waiting at 10 minutes 
after any change in oxygen delivery. 
 
RECOMMENDATIONS 
 
• 
All testing should be performed about the same time of day to minimize intraday 
variability. 
 
• 
It is preferred that the same technician perform the test for each patient. 
 
PRE-TEST 
 
1. Record start time. Provide a paper copy of the Borg scale to the patient. Have the 
patient stand and rate their baseline dyspnea and over fatigue by circling the most 
appropriate number on the Borg scale. 
 
2. Measure baseline blood pressure, respiratory rate and oxygen saturation (SpO2). 
Check pulse rate from the oximeter. Complete the first portion of the 6MWT 
worksheet. 
 
3. Set the lap counter to zero and the timer to 6 minutes. Assemble all necessary 
equipment (lap counter, timer, clip- board, Borg Scale, worksheet) and move to the 
starting point. 
 
4. Instruct the patient as follows using the exact script provided: 


Page 4 of 8 
 
 
• The object of this test is to walk as far as possible for 6 minutes. You will walk back and 
forth in this hallway. Six minutes is a long time to walk, so you will be exerting yourself. 
You will probably get out of breath or become exhausted. You are permitted to slow 
down, to stop, and to rest as necessary. You may lean against the wall while resting, but 
resume walking as soon as you are able. 
• You will be walking back and forth around the cones. You should pivot briskly around the 
cones and continue back the other way without hesitation. Now I’m going to show you. 
Please watch the way I turn without hesitation.” 
• Demonstrate by walking one lap yourself.  Walk and pivot around a cone briskly. 
• “Are you ready to do that? I am going to use this counter to keep track of the number of 
laps you complete. I will click it each time you turn around at this starting line. 
Remember that the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don’t run 
or jog. 
• Start now or whenever you are ready.” 
5. Position the patient at the starting line. You should also stand near the starting line 
during the test. Do not walk with the patient. As soon as the patient starts to walk, start 
the timer. 
7. Do not talk to anyone other than the patient during the walk. Use an even tone of voice 
when using the standard phrases of encouragement. Watch the patient. Do not get 
distracted and lose count of the laps. Each time the patient returns to the starting line, 
click the lap counter once (or mark the lap on the worksheet). Let the patient see you 
do it. Exaggerate the click using body language, like using a stop-watch at a race. 
• After the first minute, tell the patient the following (in even tones): “You are doing well. You 
have 5 minutes to go.” 
• When the timer shows 4 minutes remaining, tell the patient the following: “Keep up the 
good work. You have 4 minutes to go.” 
• When the timer shows 3 minutes remaining, tell the patient the following: “You are doing 
well. You are halfway done.” 
• When the timer shows 2 minutes remaining, tell the patient the following: “Keep up the 
good work. You have only 2 minutes left.” 
• When the timer shows only 1 minute remaining, tell the patients: “You are doingwell. 
You have only 1 minute to go.” 
 
Do not use other words of encouragement (or body language to speed up). 
• If the patient stops walking during the test and needs a rest, say this: “You can lean against 
the wall if you would like; then continue walking whenever you feel able.” Do not stop the 
timer. If the patient stops before the 6 minutes are up and refuses to continue (or you decide 


Page 5 of 8 
 
 
that they should not continue), wheel the chair over for the patient to sit on, discontinue the 
walk, and note on the worksheet the distance, the time stopped, and the reason for stopping 
prematurely. 
 
• When the timer is 15 seconds from completion, say this: “In a moment I’m going to tell 
you to stop. When I do, just stop right where you are and I will come to you.” 
• When the timer rings (or buzzes), say this: “Stop!” Walk over to the patient. Consider 
taking the chair if they look exhausted. Mark the spot where they stopped by placing a bean 
bag or a piece of tape on the floor. 
8. Note the distance walked. 
9. Reasons for stopping the 6MWT immediately: 
 
Chest Pain 
Intolerable dyspnea 
Leg cramps, staggering 
Diaphoresis, pale or ashen appearance 
There are no specific limits of oxygen saturation or heart rate that automatically 
mandate cessation of the test; the Tester is to observe the patient throughout the 
walk for clinical signs of severe desaturation or tachycardia. 
• 
Tester’s judgment that it is unsafe to continue, if there is doubt whether a test 
should be stopped early because of patient symptoms, it is better to err on the side 
of safety and stop the test early. 
 
o Have a chair available near the course for the patient to sit in and recover. 
o If a severe prolonged desaturation occurs, consult with the supervising 
physician as needed and treat the patient as needed, e.g., provide 
supplemental oxygen. 
 
Post-Test: 
 
1. 
Record stop time. Immediately upon stopping, provide a paper copy of the Borg 
scale for patient to complete. Have the patient circle the most appropriate number 
on the scale for the post walk Borg dyspnea and fatigue levels and ask this: “How 
did you feel during the test? What if anything kept you from walking further? 
2. 
Measure blood pressure and respiratory rate. Complete the second portion of the 
6MWT worksheet. 
3. 
Measure SpO2 and check for at least 20 seconds. Record and check pulse rate from 
the oximeter.  Oxygen should be administered as appropriate. 
 
4. 
It is not necessary to report all the reasons for stopping the 6MWT as adverse events, 
medical judgment should be employed for making this determination. 


Page 6 of 8 
 
 
5. 
Record the number of laps from the counter (or tick marks on the worksheet). 
6. 
Record the additional distance covered (the number of meters in the final partial lap) 
using the markers on the wall as distance guides. Calculate the total distance walked, 
rounding to the nearest meter, and record it on the worksheet. 
7. 
Congratulate the patient on good effort and offer a drink of water. 


Page 7 of 8 
 
 
THE BORG SCALE 
 
0 
Nothing at all 
0.5 Very, very slight (just noticeable) 
1 
Very slight 
2 
Slight (light) 
3 
Moderate 
4 
Somewhat severe 
5 
Severe (heavy) 
6 
7 
Very severe 
8 
9 
10 
Very, very severe (maximal) 
 
At the beginning of the 6-Minute exercise, the patient will be given a paper copy of the 
Borg scale with the following instructions given in the writing at the time the scale is 
administered. “Please grade your level of shortness of breath using this scale.” 
Then ask this:  “Please grade your level of fatigue using this scale.” 
After the post-test recovery period, remind the patient of the breathing number that they 
chose before the exercise and ask the patient to grade their breathing level again. Then 
ask the patient to grade their level of fatigue, after reminding them their grade before the 
exercise. 


 
Six-Minute Walk Test Worksheet 
 
 
Patient ID#:  
 
Visit Name:  
 
Date:    
 
 
 
□Not Done 
If 6 MWT not done, mark applicable box:   Specify:   
 
 
Supplemental oxygen during the test: 
□ Yes  □ No 
If yes, specify O2 flow:  
L/min 
Type:   
 
 
Time 
Pre-walk 
  
: 
 
Post-walk 
  
: 
 
Blood Pressure 
  
 
  
 
Heart Rate 
  
 
  
 
Respiratory Rate 
  
 
  
 
SpO2 
  
% 
  
% 
Dyspnea (Borg Scale) 
  
 
  
 
Fatigue (Borg Scale) 
  
 
  
 
Stopped during the test? 
□ Yes  □ No 
If yes, mark applicable box: 
□ Diaphoresis 
□ Angina 
□ Light headedness 
 
□ Leg cramps 
□ Intolerable dyspnea 
□ Mental confusion/headache 
□ Other (specify):   
 
 
 
Number of laps:  
(x 60 meters) + final partial lap:  
meters = 
Total distance walked in 6 minutes:  
meters 
 
 
Tech Comments: 
 
 
 
Name and signature of technician:  
 
Date:   
 
 
 
 
 
 
 
 
Page 8 of 8 


 
Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
Attachment 10 
Columbia-Suicide Severity Rating Scale (C-SSRS) “Baseline/Screening” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
 
76 


 
 
 
 
 
 
 
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 
 


 
Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
Attachment 11 
Columbia-Suicide Severity Rating Scale (C-SSRS) “Since Last Visit” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
 
80 


 
 
 
 
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-SSRS-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 
 


 
Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
Attachment 12 
EQ-5D-5L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
 
84 


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


 
Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
Attachment 13 
Work Limitations Questionnaire (WLQ) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stealth BioTherapeutics Inc. 
CONFIDENTIAL 
 
88 


 
CONFIDENTIAL 
 
 
 
 
 
Work Limitations Questionnaire© 
 
Self-Administered  Long-Form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Work Limitations Questionnaire, © 1998, The Health Institute, Tufts Medical Center f/k/a New England 
Medical Center Hospitals, Inc.; Debra Lerner, Ph.D.; Benjamin Amick III, Ph.D.; and GlaxoWellcome, Inc. 
All Rights Reserved. 


16ST7I0007 USA Subj. Quest..doc 
1 
 
 
Cover page WLQ-25 Updated 2011 


16ST7I0007 USA Subj. Quest..doc 
2 
 
 
Fill in Today’s Date 
Month 
Day 
Year 
 
 
 
 
Instructions 
 
Health problems can make it difficult for working people to perform certain parts of their jobs. 
We are interested in learning about how your health may have affected you at work during the 
past 2 weeks. 
 
(1) The questions will ask you to think about your physical health or emotional problems. 
These refer to any ongoing or permanent medical conditions you may have and the 
effects of any treatments you are taking for these. Emotional problems may include 
feeling depressed or anxious. 
 
(2) Most of the questions are multiple choice. They ask you to answer by placing a mark in a 
box. 
 
For example: 
 
 
 
How satisfied are you with each of the following . . .? 
 
(Mark one box on each line a. and b.) 
Not At All 
Satisfied 
Moderately 
Satisfied 
Very 
Satisfied 
a. 
Your local schools. . . . . . . . . . . 
1 
2 
◼3 
b. 
Your local police department. . . 
1 
◼2 
3 
 
 
 
These marks tell us you are very satisfied with your local schools and 
moderately satisfied with your local police department. 


16ST7I0007 USA Subj. Quest..doc 
3 
 
 
OPTIONAL PAGE 
 
 
3. 
Before you begin answering any questions, we would like you to write some 
information on the calendar. 
 
• 
Find today’s date.  Mark that box. 
• 
Count back 2 weeks and mark that box too. 
 
This 2-week period is the subject of most of the questions. Feel free to mark other important 
dates such as birthdays, family events, or work deadlines. Please use the calendar to help 
you answer correctly. 
 
 
 
Insert calendar here. 


16ST7I0007 USA Subj. Quest..doc 
4 
 
 
 
 
 
 
 
1. In the past 2 weeks, how much of the time did your physical health or 
emotional problems make it difficult for you to do the following? 
 
(Mark one box on each line a. through e.) 
Difficult 
all of the 
time 
(100%) 
Difficult 
most of 
the time 
Difficult 
some of 
the time 
(about 
50%) 
Difficult 
a slight 
bit of the 
time 
Difficult 
none of 
the time 
(0%) 
Does not 
apply to 
my job 
a. work the required 
number of hours 
? 1 
? 2 
? 3 
? 4 
? 5 
? 6 
b. get going easily at 
the beginning of 
the workday 
? 1 
? 2 
? 3 
? 4 
? 5 
? 6 
c. start on your job 
as soon as you 
arrived at work 
? 1 
? 2 
? 3 
? 4 
? 5 
? 6 
d. do your work 
without stopping 
to take breaks or 
rests 
? 1 
? 2 
? 3 
? 4 
? 5 
? 6 
e. stick to a routine 
or schedule 
? 1 
? 2 
? 3 
? 4 
? 5 
? 6 
Questions 1 through 5 ask about how your health has affected you at work during the 
past 2 weeks. Please answer these questions even if you missed some workdays. 
• Mark the “Does not apply to my job” box only if the question describes something 
that is not part of your job. 
• If you have more than one job, report on your main job only. 


16ST7I0007 USA Subj. Quest..doc 
5 
 
 
PLEASE READ CAREFULLY 
 
 
 
 
 
2. a. In the past 2 weeks, how much of the time were you able to walk or move 
around different work locations (for example, go to meetings), without 
difficulty caused by physical health or emotional problems? 
 
(Mark one box.) 
Able most of the time 
? 2 
 
Able a slight bit of the time 
? 4 
Does not apply to my job 
? 6 
 
 
 
b. In the past 2 weeks, how much of the time were you able to lift, carry, or 
move objects at work weighing more than 10 lbs., without difficulty caused 
by physical health or emotional problems? 
 
(Mark one box.) 
Able most of the time 
? 2 
 
Able a slight bit of the time 
? 4 
Does not apply to my job 
? 6 
Able some of the time (about 
50%) 
? 3 
Able some of the time (about 
50%) 
? 3 
These questions ask you to rate the amount of time you were 
able to handle certain parts of your job without difficulty. 
Able all of the time (100%) 
? 1 
Able none of the time (0%) 
? 5 
Able all of the time (100%) 
? 1 
Able none of the time (0%) 
? 5 


16ST7I0007 USA Subj. Quest..doc 
6 
 
 
c. In the past 2 weeks, how much of the time were you able to sit, stand, or 
stay in one position for longer than 15 minutes while working, without 
difficulty caused by physical health or emotional problems? 
 
(Mark one box.) 
Able most of the time 
? 2 
 
Able a slight bit of the time 
? 4 
Does not apply to my job 
? 6 
 
 
 
d. In the past 2 weeks, how much of the time were you able to repeat the 
same motions over and over again while working, without difficulty caused 
by physical health or emotional problems? 
 
(Mark one box.) 
Able most of the time 
? 2 
 
Able a slight bit of the time 
? 4 
Does not apply to my job 
? 6 
Able some of the time (about 
50%) 
? 3 
Able some of the time (about 
50%) 
? 3 
Able all of the time (100%) 
? 1 
Able none of the time (0%) 
? 5 
Able all of the time (100%) 
? 1 
Able none of the time (0%) 
? 5 


16ST7I0007 USA Subj. Quest..doc 
7 
 
 
e. In the past 2 weeks, how much of the time were you able to bend, twist, or 
reach while working, without difficulty caused by physical health or emotional 
problems? 
(Mark one box.) 
Able most of the time 
? 2 
 
Able a slight bit of the time 
? 4 
Does not apply to my job 
? 6 
 
 
 
f. In the past 2 weeks, how much of the time were you able to use hand-held 
tools or equipment (e.g., a phone, pen, keyboard, computer mouse, drill, 
hairdryer, or sander), without difficulty caused by physical health or 
emotional problems? 
 
(Mark one box.) 
Able most of the time 
? 2 
 
Able a slight bit of the time 
? 4 
Does not apply to my job 
? 6 
Able some of the time (about 
50%) 
? 3 
Able some of the time (about 
50%) 
? 3 
Able all of the time (100%) 
? 1 
Able none of the time (0%) 
? 5 
Able all of the time (100%) 
? 1 
Able none of the time (0%) 
? 5 


16ST7I0007 USA Subj. Quest..doc 
8 
 
 
PLEASE READ CAREFULLY 
 
 
 
 
 
 
 
3. In the past 2 weeks, how much of the time did your physical health or 
emotional problems make it difficult for you to do the following? 
 
(Mark one box on each line a. through f.) 
Difficult 
all of the 
time 
(100%) 
Difficult 
most of 
the time 
Difficult 
some of 
the time 
(about 
50%) 
Difficult 
a slight 
bit of the 
time 
Difficult 
none of 
the time 
(0%) 
Does 
not 
apply to 
my job 
a. keep your mind on 
your work 
? 1 
? 2 
? 3 
? 4 
? 5 
? 6 
b. think clearly when 
working 
? 1 
? 2 
? 3 
? 4 
? 5 
? 6 
c.  do work carefully 
? 1 
? 2 
? 3 
? 4 
? 5 
? 6 
d. concentrate on your 
work 
? 1 
? 2 
? 3 
? 4 
? 5 
? 6 
e. work without losing 
your train of 
thought 
? 1 
? 2 
? 3 
? 4 
? 5 
? 6 
f. easily read or use 
your eyes when 
working 
? 1 
? 2 
? 3 
? 4 
? 5 
? 6 
These questions ask about difficulties you may have had at work. 


16ST7I0007 USA Subj. Quest..doc 
9 
 
 
 
 
 
 
 
 
4. In the past 2 weeks, how much of the time did your physical health or 
emotional problems make it difficult for you to do the following? 
 
(Mark one box on each line a. through c.) 
Difficult 
all of the 
time 
(100%) 
Difficult 
most of 
the time 
Difficult 
some of 
the time 
(about 
50%) 
Difficult 
a slight 
bit of the 
time 
Difficult 
none of 
the time 
(0%) 
Does 
not 
apply to 
my job 
a. speak with people 
in-person, in 
meetings or on the 
phone 
? 1 
? 2 
? 3 
? 4 
? 5 
? 6 
b. control your temper 
around people 
when working 
? 1 
? 2 
? 3 
? 4 
? 5 
? 6 
c. help other people to 
get work done 
? 1 
? 2 
? 3 
? 4 
? 5 
? 6 
The next questions ask about difficulties in relation to the people you came in contact 
with while working. These may include employers, supervisors, coworkers, clients, 
customers, or the public. 


16ST7I0007 USA Subj. Quest..doc 
10 
 
 
 
 
 
 
 
 
 
5. In the past 2 weeks, how much of the time did your physical health or 
emotional problems make it difficult for you to do the following? 
 
(Mark one box on each line a. through e.) 
Difficult 
all of the 
time 
(100%) 
Difficult 
most of 
the time 
Difficult 
some of 
the time 
(about 
50%) 
Difficult 
a slight 
bit of the 
time 
Difficult 
none of 
the time 
(0%) 
Does not 
apply to 
my job 
a. handle the 
workload 
? 1 
? 2 
? 3 
? 4 
? 5 
? 6 
b.  work fast enough 
? 1 
? 2 
? 3 
? 4 
? 5 
? 6 
c.  finish work on time 
? 1 
? 2 
? 3 
? 4 
? 5 
? 6 
d. do your work 
without making 
mistakes 
? 1 
? 2 
? 3 
? 4 
? 5 
? 6 
e. feel you’ve done 
what you are 
capable of doing 
? 1 
? 2 
? 3 
? 4 
? 5 
? 6 
These questions ask about how things went at work overall. 


 
Elamipretide (MTP-131 for SC Injection) 
SPIMM-203 Version 3.0 
29 January 2019 
 
Attachment 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 tenderness 
Pain or tenderness 
Pain or 
Pain or tenderness causing 
Pain or 
causing no or minimal 
causing greater than 
tenderness 
inability to perform basic 
Tenderness 
limitation of use of 
minimal limitation 
causing inability 
self-care  function OR 
limb 
of use of limb 
to perform 
Hospitalization indicated 
usual social 
& functional 
activities 
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 
Potentially life- 
threatening 
consequences (eg, 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
OR Drainage OR 
Symptoms 
causing inability 
to perform usual 
social & 
functional 
activities 
Injection Site 
Same as for Injection 
Same as for 
Same as for 
Same as for Injection 
Induration or 
Site Erythema or 
Injection Site 
Injection Site 
Site Erythema or 
Swelling 
Redness 
Erythema or 
Erythema or 
Redness 
Redness 
Redness 
Injection Site 
Itching localized to the 
Itching beyond the 
Generalized 
NA 
Pruritus 
injection site that  is 
injection site that is 
itching causing 
relieved spontaneously or 
not generalized OR 
inability to 
in < 48 hours of 
Itching localized to 
perform usual 
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 
 
100 


 
VMRKBNJ2HIBCGUBANGXN66 
 
 
 
Jim Carr 
Party ID: 2H2HANIG4JD93NXRJ4SR98 
IP Address: 50.203.117.38 
jim.carr@stealthbt.com 
 
 
 
 
Multi-Factor 
Digital Fingerprint Checksum 
 
aa0f9b9d48495b0b1d9cd54cd33d791c053f1f03 
 
 
Timestamp 
Audit 
2019-01-31 04:56:17 -0800 
All parties have signed document. Signed copies sent to: John J. Jones, Jim 
Carr, and Quality Systems. 
2019-01-31 04:56:17 -0800 
Document signed by Jim Carr (jim.carr@stealthbt.com) with drawn signature. - 
50.203.117.38 
2019-01-31 04:55:52 -0800 
Document viewed by Jim Carr (jim.carr@stealthbt.com). - 50.203.117.38 
2019-01-30 14:11:06 -0800 
Document created by Quality Systems (qualitysystems@stealthbt.com). - 
96.230.125.25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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