Clinical trial NCT03098797
Conditions: Barth Syndrome
Keywords: Barth Syndrome elamipretide MTP-131 Stealth Stealth BT BTHS
Sponsor: Stealth BioTherapeutics Inc.
Start date: 2017-07-05; Completion date: 2021-10-11
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
A randomized, double-blind cross over trial to evaluate the safety, efficacy, and tolerability of elamipretide in subjects with Barth syndrome.

Detailed description:
A phase 2 randomized, double-blind, placebo-controlled crossover trial to evaluate the safety, tolerability, and efficacy of subcutaneous injections of elamipretide in subjects with genetically confirmed Barth syndrome followed by open-label treatment extension. Part 1 was a randomized, double-blind, placebo-controlled, crossover trial to assess safety, tolerability, and efficacy single daily subcutaneous (SC) doses of 40 mg elamipretide administered for 12 weeks in subjects with Barth syndrome. Part 2: This was an open-label extension trial to assess the long-term safety, tolerability, and longitudinal trends in efficacy single daily SC doses of 40 mg elamipretide for up to 192 weeks.

Arms: arm 1: Experimental Part 1: 12 weeks of single daily SC doses of 40 mg elamipretide in Treatment Period 1 followed by 12 weeks of treatment with placebo in Treatment Period 2 (separated by a 4 week washout period).

Experimental Open Label Extension Part 2: All subjects will receive Elamipretide 40mg SC daily injections for up to 168 weeks arm 2: Placebo Comparator Part 1: 12 weeks of single daily SC doses of placebo in Treatment Period 1 followed by 12 weeks of treatment with 40 mg elamipretide in Treatment Period 2 (separated by a 4 week washout period).

Placebo Comparator Open Label Extension Part 2: All subjects will receive Elamipretide 40mg SC daily injections for up to 168 weeks
Interventions: intervention 1: Elamipretide intervention 2: Placebo
Intervention descriptions: intervention 1: 40 mg daily subcutaneous injection for 12 weeks intervention 2: daily subcutaneous injection for 12 weeks

Protocol documents:
Prot_SAP_000.pdf: 
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A PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBOCONTROLLED 
CROSSOVER TRIAL TO EVALUATE THE SAFETY,  
TOLERABILITY, AND EFFICACY OF SUBCUTANEOUS INJECTIONS OF 
ELAMIPRETIDE (MTP-131) IN SUBJECTS WITH GENETICALLY  
CONFIRMED BARTH SYNDROME FOLLOWED BY AN OPEN-LABEL 
TREATMENT EXTENSION 
 
 
NCT03098797 
 
23 April 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 


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CLINICAL TRIAL PROTOCOL  
A PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBOCONTROLLED 
CROSSOVER TRIAL TO EVALUATE THE SAFETY,  
TOLERABILITY, AND EFFICACY OF SUBCUTANEOUS INJECTIONS 
OF ELAMIPRETIDE (MTP-131) IN SUBJECTS WITH GENETICALLY  
CONFIRMED BARTH SYNDROME FOLLOWED BY AN OPEN-LABEL 
TREATMENT EXTENSION 
 
Trial Phase: 
Phase 2 
 
Trial Number: 
SPIBA-201 
 
Document Version: 
Version 4.1 
 
Final Approval Date:  
23 April 2021  
 
Sponsor: 
Stealth BioTherapeutics, Inc. 
140 Kendrick Street, Building C-West Needham,  
MA 02494 United States 
of America 
Jim Carr, Pharm.D. 
Sponsor Chief Clinical  
Chief Clinical Development Officer 
Development Officer: 
Jim.Carr@StealthBT.com 
+1 617-762-2503 
Sandrin Bergheanu, M.D., Ph.D. 
Sponsor Medical  
Medical Monitor 
Monitor:  
Sandrin.Bergheanu@StealthBT.com 
+1 617-762-2595 or +31 (0) 641 476 460 
Confidentiality Statement 
 
The information contained in this document is confidential and is the property of Stealth  


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BioTherapeutics, Inc.  No part of it may be transmitted, reproduced, published, or used by 
anyone without the written permission of Stealth BioTherapeutics, Inc.  
 
1 
PROTOCOL APPROVAL 
 Protocol Title: 
A Phase 2 Randomized, Double-Blind, Placebo- 
Controlled Crossover Trial to Evaluate the Safety,  
Tolerability, and Efficacy of Subcutaneous Injections of  
Elamipretide (MTP-131) in Subjects with Genetically  
Confirmed Barth Syndrome Followed by an Open-Label  
Treatment Extension   
Protocol Number: 
SPIBA-201 Protocol Date: 
23 April 2021 
 
 Jim Carr, Pharm.D. 
Date 
Chief Clinical Development Officer 
Stealth BioTherapeutics, Inc.  
04/23/2021 


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INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochure for elamipretide (MTP-131).  I have 
read the SPIBA-201 protocol v4.1 and agree to conduct the trial as outlined.  I confirm that I 
will conduct the trial in accordance with ICH GCP guidelines.  I will also ensure that 
subInvestigator(s) and other relevant members of my staff have access to copies of this 
protocol, and the ICH GCP guidelines to enable them to work in accordance with the 
provisions of these documents.  I agree to maintain the confidentiality of all information 
received or developed in connection with this protocol. 
   
 
  
  
  
  
  
  
  
  
  
  
  
Printed Name of Investigator  
   
 
  
  
  
  
  
  
  
  
  
  
  
Signature of Investigator  
    
  
  
  
  
  
Date (DD/MMM/YYYY) 


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1. 
SYNOPSIS 
Name of Sponsor/Company:  Stealth BioTherapeutics, Inc. 
Investigational Medicinal Product:  Elamipretide (MTP-131) 
Title of Trial: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Crossover Trial to  
Evaluate the Safety, Tolerability, and Efficacy of Subcutaneous Injections of Elamipretide  
(MTP-131) in Subjects with Genetically Confirmed Barth Syndrome Followed by an 
OpenLabel Treatment Extension 
Objectives: This trial is designed with 2 parts, SPIBA-201 (Part 1) and SPIBA-201 OLE 
(Part 2). The objectives of each part are consistent with the trial design. 
x Part 1 is a 28-week, randomized, double-blind, placebo-controlled crossover 
assessment of the efficacy and safety of single daily subcutaneous (SC) doses of 40 
mg elamipretide (vs placebo) as a treatment for subjects with Barth Syndrome. 
x Part 2 is an up to 192-week, open-label assessment of the long-term safety and 
tolerability of single daily SC doses of 40 mg elamipretide in subjects with Barth 
Syndrome.  
Part 1 objectives are:   
Primary 
x To evaluate the effect of single daily subcutaneous (SC) doses of 40 mg elamipretide 
administered for 12 weeks in subjects with Barth Syndrome on:  
o Distance walked (meters) during the 6-Minute Walk Test (6MWT) o 
Total Fatigue on the BarTH Syndrome Symptom Assessment (BTHS-SA)  
Secondary 
x To evaluate the effect of single daily SC doses of 40 mg elamipretide administered for 
12 weeks in subjects with Barth Syndrome as measured by change in:  
o 
Muscle strength as measured by handheld dynamometry (HHD)  o Five 
Times Sit-to-Stand Test (5XSST) o 2-D and 3-D Echocardiographic 
measurements o Accelerometry counts o SWAY Application Balance 
Assessment o Patient Reported Outcomes o Clinician Global Impression (CGI) 
Scales  
o 
Caregiver Global Impression (CaGI) Scales 
o 
Biomarkers 
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x To evaluate the safety and tolerability of single daily SC doses of 40 mg elamipretide 
administered for 12 weeks in subjects with Barth Syndrome 
Part 2 objectives are: 
Primary 
x To assess the long-term safety and tolerability of single daily SC doses of 40 mg 
elamipretide for up to 192 weeks 
Secondary x To evaluate longitudinal trends of single daily SC doses of 40 mg 
elamipretide administered for up to 192 weeks in subjects with Barth Syndrome as 
measured by: o 6MWT  
o 
Total Fatigue on the BTHS-SA 
o 
Muscle strength as measured by HHD 
o 
5XSST 
o 
2-D and 3-D Echocardiographic measurements o SWAY Application 
Balance Assessment o Patient Reported Outcomes 
o 
CGI Scales o CaGI Scales o Biomarkers 
Pharmacokinetic (PK) x To assess PK via 
a population model 
Methodology:  
This randomized, double-blind, placebo-controlled crossover trial followed by an open-label 
treatment extension assessment will enroll approximately 12 subjects who have genetically 
confirmed Barth Syndrome. There are 2 parts to this trial. 
x Part 1 is a 28-week, randomized, double-blind, placebo-controlled crossover 
assessment of the efficacy and safety of single daily SC doses of 40 mg elamipretide 
(vs placebo) in subjects with Barth Syndrome. Subjects will be randomized (in a ratio 
of 1:1) to one of two sequence groups:   
 
 
12-weeks of single daily subcutaneous (SC) doses of 40 mg elamipretide in  
Treatment Period 1 followed by 12-weeks of treatment with placebo in Treatment 
Period 2 (separated by 4-week washout period)  
 
 
12-weeks of single daily subcutaneous (SC) doses of placebo in Treatment  
Period 1 followed by 12-weeks of treatment with 40 mg elamipretide in 
Treatment Period 2 (separated by 4-week washout period) x Part 2 is an up to 192-
week, open-label assessment of the long-term safety and tolerability of single daily 
SC doses of 40 mg elamipretide in subjects with Barth  


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Syndrome. Subjects who continue into Part 2 will receive treatment with 40 mg SC 
elamipretide for up to 192 weeks. 
Note that the duration of Part 2 treatment for each subject will be the shortest of the following: 
x 192 weeks 
x Date of enrollment in another Stealth BioTherapeutics (SBT) follow-on clinical trial in 
Barth syndrome or expanded access program (EAP) x Regulatory approval and 
commercial availability of elamipretide 
x Termination of the clinical development for elamipretide in subjects with Barth 
Syndrome. 
Part 1 
This randomized, double-blind, placebo-controlled crossover trial will enroll approximately 
12 subjects who have genetically confirmed Barth Syndrome. Subjects will be randomized 
(1:1) to one of two sequence groups: 12-weeks of single daily subcutaneous (SC) doses of 40 
mg elamipretide in Treatment Period 1 followed by 12-weeks of treatment with placebo in 
Treatment Period 2 (separated by 4-week washout period), or vice versa. The Part 1 Trial 
Schematic is presented in Attachment 3. 
Screening Period: The Screening Period will begin with the signature of the informed consent 
form (ICF) and will last for at least 7 days and no more than 28 days and will include a 
Screening Visit. During the Screening Period, subjects will undergo all screening procedures 
as described in the Part 1 Schedule of Assessment (Attachment 1) including applying and 
wearing the AVIVO™ MPM System daily for approximately 7 consecutive days and 
completing the age appropriate BarTH Syndrome Symptom Assessment (BTHS-SA) daily. 
Confirmation of Barth Syndrome will incorporate a review of the Investigator submitted 
diagnosis and genetic results. Confirmation of Barth Syndrome must be made prior to  
randomizing the subject. Subjects who complete all screening procedures during the 
Screening Period and continue to meet all trial requirements, including all inclusion and none 
of the exclusion criteria, will be randomized and enter Treatment Period 1.   
Treatment Period 1:  Treatment Period 1 will begin on the day of Treatment Period 1 Baseline  
(Pre-dose) Visit, which is defined as Treatment Period 1 Day 1.  At the Treatment Period 1  
Baseline Visit, following completion of all Baseline procedures described in the Trial  
Schedule, the subject will be administered investigational medicinal product (IMP)  
(elamipretide or placebo) subcutaneously at the trial center. The Investigator (or designee) 
will also place a new AVIVO™ MPM System on the subject’s chest and instruct the subject 
to continue to wear the System for approximately 7 consecutive days.  At the discretion of 
the Investigator, the subject may return to the trial center on Treatment Period 1 Days 2 
through 5 to receive a daily subcutaneous injection of the IMP.  At the Treatment Period 1 
Baseline Visit, subjects (and caregivers) will be trained on the procedure for self-
administration of IMP. The IMP should be administered at approximately the same time each 
day (e.g. early morning, noon, early afternoon, or evening). The Visiting Nurse will complete 
assessments at the  


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Treatment Period 1 Week 1, 4, and 8 Nurse Visits as described in the Schedule of Visiting 
Nurse Assessments (Attachment 2). The trial center and Visiting Nurse will remind subjects 
to complete the age appropriate BTHS-SA daily throughout Treatment Period 1 and to apply 
and wear a new AVIVO™ MPM System daily for approximately 7 consecutive days 
immediately  


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prior to the Treatment Period 1 Week 12 Visit. Treatment Period 1 will conclude with the 
Treatment Period 1 Week 12 visit at the trial center where the subjects will return all used 
vials, unused vials, and used AVIVO™ MPM Systems to the trial center.  
Washout Period: The Washout will begin after the Treatment Period 1 Week 12 Visit and will 
last for at least 28 days (+7 days). During the Washout Period, subjects will continue to 
follow all trial requirements, including completing the age appropriate BTHS-SA daily.    
Treatment Period 2: Treatment Period 2 will begin on the day of Treatment Period 2 Pre-dose  
Visit, which is defined as Treatment Period 2 Day 1.  At the Treatment Period 2 Pre-dose 
Visit, following completion of all Pre-dose procedures described in the Trial Schedule, the 
subject will be administered IMP subcutaneously at the trial center. The Investigator (or 
designee) will also place a new AVIVO™ MPM System on the subject’s chest and instruct 
the subject to continue to wear the System for approximately 7 consecutive days.  At the 
discretion of the Investigator, the subject may return to the trial center on Treatment Period 2 
Days 2 through 5 to receive a daily subcutaneous injection of IMP.  The IMP should be 
administered at approximately the same time each day (e.g. early morning, noon, early 
afternoon, or evening). The Visiting Nurse will complete assessments at the Treatment Period 
2 Week 1, 4, and 8 Nurse Visits as described in the Schedule of Visiting Nurse Assessments 
(Attachment 2). The trial center and Visiting Nurse will remind subjects to complete the age 
appropriate  
BTHS-SA daily throughout Treatment Period 2 and to apply and wear a new AVIVO™ MPM  
System daily for approximately 7 consecutive days immediately prior to the Treatment 
Period 2 Week 12 Visit. Treatment Period 2 will conclude with the Treatment Period 2 Week 
12 visit at the trial center where the subjects will return all used vials, unused vials, and used 
AVIVO™ MPM Systems to the trial center. 
Part 1 Follow-Up Period: At the Treatment Period 2 Week 12 Visit, the subject and the 
Investigator will determine whether the subject will continue into Part 2 (confirming the 
subject meeting the Continuation Criteria). Subjects who will not continue into Part 2 will 
complete the Part 1 Follow-Up Period and Part 1 End-of-Trial Visit. The Part 1 Follow-Up 
Period will begin after completion of Treatment Period 2 Week 12 and will last for 28 days 
(+7 days).  During the Part 1 Follow-Up Period, subjects will continue to follow all trial 
requirements, including completing the age appropriate BTHS-SA daily.  At the end of the 
Part 1 Follow-Up Period, subjects will return to the trial center for the Part 1 End-
ofTrial/Early Discontinuation Visit for final safety and efficacy assessments as described in 
the Trial Schedule, and to return all trial materials/equipment 
For Part 1, an external Data and Safety Monitoring Board (DSMB) will be established to 
review safety data on a regular basis to ensure safety of all subjects enrolled. 
Part 2 
While there is no screening period for Part 2, subjects must meet the Part 2 Continuation 
Criteria. Subjects who decide not to continue to Part 2 at the Treatment Period 2 Week 12 
Visit of Part 1 are not eligible to participate in Part 2. The Part 2 Schedule of Assessments is 
provided in Attachment 1. The Part 2 Trial Schematic is presented in Attachment 3.  


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Part 2 Treatment Period: The Part 2 Treatment Period will begin on the day after the 
Treatment Period 2 Week 12 Visit of Part 1. Subjects (or trained caregivers) will administer 
the IMP daily during the Part 2 Treatment Period. The subject will return to the clinical site 
for the Part  
2 Week 12, 24, 36, 48, 72, 96, 120, 144, 168 and 192 Visits for assessments, to administer the  
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IMP (subject or trained caregiver), and to return all used IMP supplies. Phone calls (or other 
forms of communication) will be made to the subject every 12 weeks between clinical site 
visits (i.e. weeks 60, 84, 108, 132, 156, 180). During the Treatment Period, subjects will 
continue to follow all trial requirements.  
Subjects who withdraw consent or are withdrawn from the trial by the investigator should be 
encouraged to complete an Early Discontinuation Visit as soon as possible and an effort 
should be made to complete and report the assessments as thoroughly as possible up to the 
date of withdrawal. 
The Part 2 Treatment Period will end with the Part 2 End of Treatment (EOT) Visit.  This will 
occur after completion of the Week 192 Visit, or anytime between the Week 144 - Week 192 
Visits during Part 2 when the subject and Investigator determine that the subject will enroll in 
another SBT follow-on clinical trial in Barth Syndrome or EAP.  
Part 2 Follow-Up Period: The Part 2 Follow-Up Period will begin after completion of the Part  
2 Week EOT Visit and will last for 4 weeks. Subjects will continue to follow all trial 
requirements. Subjects will return to the clinical site for the Part 2 End-of-Trial Visit for final 
safety assessments, as described in the Part 2 Schedule of Assessments, and return all 
remaining trial-related supplies not previously returned. Subjects enrolling in another SBT 
follow-on clinical trial in Barth Syndrome or EAP will not participate in the Part 2 Follow-Up 
Period, and the Part 2 EOT Visit will be considered the end-of-trial visit. 
Number of Subjects (planned): Approximately 12 subjects will be randomized 1:1 to one of 
two sequence groups, to receive subcutaneous placebo then subcutaneous elamipretide, or 
vice-versa, in this 2-period cross-over trial followed by an open-label treatment extension 
assessment. 
Investigational Product, Dosage and Mode of Administration 
Elamipretide (MTP-131) will be supplied as a sterile solution for subcutaneous injection.  The 
dose of elamipretide will be 40 mg administered as a once daily SC injection. Additional 
details regarding the IMP will be provided in the Pharmacy Manual. IMP should be 
administered by either a trained caregiver or the subject via daily SC injection in the abdomen 
(rotating around the four abdominal quadrants) or thigh, provided that it is at least 5 cm from 
the previous day’s location of administration, at approximately the same time each day (e.g. 
early morning, noon, early afternoon, or evening). 


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Reference Product: The placebo for this trial will be composed of the excipients used to 
manufacture the investigational drug but without the active drug substance. The placebo will 
be handled and administered identically to active drug. 
Inclusion Criteria:  
A subject must meet ALL of the following Inclusion Criteria at the Baseline Visit: 
1. Willing and able to provide signed informed consent form (ICF) prior to participation in 
any trial-related procedures. If applicable, informed consent in writing from parent(s) or 
legally-acceptable representative(s) and, informed assent from subject (if age appropriate 
according to local requirements) should be provided  
2. Agrees to adhere to the trial requirements for the length of the trial 
3. Genetically confirmed Barth Syndrome in the opinion of the Investigator 4. Male aged ≥ 
12 years  
8 
5. At the Screening Visit, subject body weight and estimated glomerular filtration rate 
(eGFR) meeting one of the following:  
a. Body weight >30 kg AND eGFR ≥ 90 mL/min/1.73 m2 at the Screening visit 
b. Body weight >40 kg AND eGFR ≥ 60 mL/min/1.73 m2 at the Screening visit 
eGFR will be calculated using the Modification of Diet in Renal Disease (MDRD) 
equation: 
eGFR (mL/min/1.73 m2) = 175 x (SCr*)-1.154 x (Age)-0.203 x (0.742 if 
female) x (1.212 if African American)            *=serum creatinine 
6. Ambulatory and impaired, in the opinion of the Investigator, during the 6-Minute Walk 
Test at the Baseline Visit 
7. Subject has been on stable (unchanged and constant) medications (including over-
thecounter treatments, vitamins, or supplements), or medications that will not impact the 
safety or efficacy endpoints of the trial, in the opinion of the Investigator for at least 30 
days prior to the Baseline Visit 
8. Male subjects with female partners of child-bearing potential must be willing to use a 
highly effective method of contraception (see Section 9.11.1 for details) from the  
Screening Visit through at least 2 months following the last injection 


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Exclusion Criteria: 
A subject must NOT meet any of the following exclusion criteria at the Baseline Visit: 
1. Participated in another interventional clinical trial within 30 days of or is currently 
enrolled in a non-interventional clinical trial at the Baseline Visit judged by Investigator 
to be potentially confounding with the current trial  
2. 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 
3. Undergone an in-patient hospitalization within 30 days prior to the Baseline Visit or is 
likely to need in-patient hospitalization or surgical procedure during the course of the trial  
4. Subject is undergoing an apparent pubertal growth spurt in the opinion of the Investigator  
5. Subject has uncontrolled hypertension in the judgment of the Investigator (e.g. 
consistently elevated above >160 mmHg systolic or >100 mmHg diastolic despite 
appropriate treatment) 
6. Subject has a history of clinically significant hypersensitivity or allergy to any of the 
excipients contained in the investigational medicinal product (IMP)  
7. Subject has a history of active substance abuse during the year before the Baseline Visit, 
or is thought, for any reason, likely not to be compliant in the opinion of the Investigator  
8. History of heart transplantation or current placement (or within the past year) on the 
waiting list for a heart transplantation 
9. a. For subjects with an implantable cardioverter defibrillator (ICD): the known occurrence 
of ICD therapy/discharge in the 3 months prior to the Baseline Visit and/or expected to 
undergo re-implantation during the conduct of the study   
b. For subjects without an implantable cardioverter defibrillator (ICD): expected to 
undergo an implantation of an ICD during the conduct of the study 
9 
10. Currently receiving treatment with chemotherapeutic agents or immunosuppressant agents 
or has received prior radiation therapy to the chest 
11. Recipient of stem cell or gene therapy or is currently being treated by a therapeutic 
investigational device  
Part 2 Continuation Criteria  
A subject must meet all of the following Part 2 Continuation Criteria at the Treatment Period 2 
Week 12 Visit of Part 1 to be eligible for Part 2: 
1. Subjects must continue to be able and willing to adhere to the trial requirements  
2. Subject is appropriate to continue in Part 2 (i.e. subject was compliant in Part 1), in the 
opinion of the Investigator  
3. Subject has not had a serious adverse event (SAE) related to the IMP 
4. Subject has not permanently discontinued the IMP 


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Planned Trial Duration: Up to 228 weeks 
This trial is designed with 2 parts, Part 1 and Part 2.  
Part 1: Up to 32 weeks (up to 36 weeks if not continuing into Part 2) 
Screening: At least 7 days and no more than 28 days  
Treatment Period 1: 12 weeks  
Washout: 4 weeks 
Treatment Period 2: 12 weeks  
Part 1 Follow-Up: 4 weeks (for subjects not continuing into Part 2).  
Part 2: Up to 196 weeks 
Part 2 Treatment Period: 192 weeks 
Part 2 Follow-Up: 4 weeks  
Criteria for Evaluation: 
Primary Endpoints x Distance walked (meters) during the 6-Minute 
Walk Test (6MWT) x Total Fatigue on the BTHS-SA 
Secondary Endpoints x Muscle strength as measured by handheld 
dynamometry (HHD)  x Five Times Sit-to-Stand Test score x 2-D 
and 3-D Echocardiographic measurements x Accelerometry 
counts 
x SWAY Application Balance Assessment x 
Patient reported outcomes o PROMIS 
Short Form Fatigue 
o Fatigue During Activities on the BTHS-SA  o 
Patient Global Impression (PGI) Scales  
 PGI of Symptoms  
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 PGI of Change  
o EQ-5D x Clinician Global 
Impression (CGI) Scales o CGI of 
Symptoms o CGI of Change  x Caregiver 
Global Impression (CaGI) Scales  o CaGI of 
Symptoms o CaGI of Change   
x Biomarkers o MLCL: L4-
CL Ratio 
o Plasma and blood biomarkers (GDF-15, FGF-21, glutathione/reduced 
glutathione)  
o Urine biomarkers (8-isoprostane,8-hydroxy-2-deoxyguanosine, 
3methylgutaconic acid)  
o Plasma and urine metabolomics o Exploratory biomarkers  
x Adverse Events (AEs) x Vital 
signs x Electrocardiograms 
(ECGs) x Ambulatory 
arrhythmias x Clinical laboratory 
evaluations 
x Columbia-Suicide Severity Rating Scale (C-SSRS) 
Pharmacokinetic (PK) Endpoints x 
Assessment of PK via a population model 


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Statistical Methods: 
Analysis Populations  
Safety Population: All subjects who receive at least 1 dose of IMP, according to the treatment 
received.   
Intention-to-Treat (ITT) Population: All subjects who receive at least 1 dose of IMP will be 
included, according to the treatment sequence group to which they were randomized. Per-
Protocol (PP) Population: Includes all ITT subjects without major protocol 
violations/deviations. The list of major protocol violations/deviations will be identified and 
specified prior to final database lock for the trial that would lead to exclusion for the PP 
analysis. 
Pharmacokinetic (PK) Population: Includes all trial subjects who have at least 1 PK sample 
taken during their participation.  
Safety Analyses   
Safety analyses will include incidence of AEs and SAEs, deaths, premature discontinuation 
from the trial due to an AE (regardless of relationship to IMP), and change in ECG, clinical 
laboratory data, and vital signs.   
Efficacy Analyses  
Efficacy analyses will be conducted on the ITT population. In general, categorical variables 
will be summarized by the count (N) and percentage of subjects (%). Continuous variables 
will be  
11 
summarized by the number of non-missing observations (N), mean, standard deviation, 
median, minimum, and maximum values.  All trial data are to be displayed in the data 
listings. Subject disposition summaries will include the number of subjects enrolled and the 
numbers included in the ITT populations. 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. 
Two primary endpoints are included in the primary endpoint family (6MWT and BTHS-SA - 
Total Fatigue).  Hochberg’s procedure will be used to control the family-wise Type I error 
rate at 0.05 (two-sided).  No adjustments will be made to alpha levels to account for 
secondary efficacy measures. Statistical analysis of this trial will be the responsibility of the 
Sponsor or its designee. 
Additional details regarding analyses will be included in separate statistical analysis plan 
(SAP). 
Sample Size 
For this Phase 2, randomized, double-blind, placebo-controlled crossover trial followed by an 
open-label treatment extension assessment, a sample size of approximately 12 subjects is 
planned. Assuming an underlying standard deviation of paired differences of 50 meters for 
the 6MWT distance and 1.3 points for the BTHS-SA Total Fatigue score12 subjects provides 
for nearly 80% power to detect a mean improvement of 50 meters in the 6MWT or 1.3 points 
for the BTHS-SA Total Fatigue score, with each potentially tested at the 0.025 (two-sided) 
level of significance (associated with a potential adjustment via Hochberg’s procedure), in 


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Part 1. Subject numbers are restricted by feasibility considerations (availability of subjects) 
but that recruitment could be greater if subjects are available (up to 16 subjects). 
12 
 
2. 
TABLE OF CONTENTS 
PROTOCOL APPROVAL ........................................................................................................ 
2 INVESTIGATOR’S AGREEMENT 
......................................................................................... 3  
1. 
SYNOPSIS........................................................................................................................
.... 4  
2. 
TABLE OF CONTENTS 
.................................................................................................. 13  
3. 
ABBREVIATIONS AND DEFINITIONS 
...................................................................... 17  
4. 
INTRODUCTION 
............................................................................................................. 19  
4.1. 
Barth Syndrome 
............................................................................................................. 19  


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4.2. 
Pharmacologic Basis for Elamipretide as a Potential Treatment for BTHS 
............ 20  
4.3. 
Elamipretide Risk/Benefit Assessment 
........................................................................ 21  
4.3.1. 
Potential 
Benefits 
...................................................................................................... 21  
4.3.1.1. 
Pre-clinical studies ............................................................................................ 
21  
4.3.1.2. 
Clinical Studies in Other Genetically Confirmed Mitochondrial Diseases ....... 
23  
4.3.2. 
Potential 
Risks 
.......................................................................................................... 25  
4.3.2.1. 
Nonclinical Study Safety Findings .................................................................... 
25  
4.3.2.2. 
Human Safety .................................................................................................... 
26  
4.3.3. 
Conclusions 
.............................................................................................................. 28  
5. 
OBJECTIVES 
.................................................................................................................... 29  
5.1. 
Part 1 Objectives 
............................................................................................................ 29  
5.1.1. 
Primary 
Objective 
..................................................................................................... 29  
5.1.2. 
Secondary 
Objectives 
............................................................................................... 29  
5.2. 
Part 2 Objectives 
............................................................................................................ 30  
5.2.1. 
Primary 
Objective 
..................................................................................................... 30  
5.2.2. 
Secondary 
Objectives 
............................................................................................... 30  
5.2.3. 
Pharmacokinetics 
(PK) 
............................................................................................. 30  
6. 
INVESTIGATIONAL PLAN 
........................................................................................... 31  
6.1. 
Trial Design 
.................................................................................................................... 31  
6.1.1. 
Part 
1 
......................................................................................................................... 31  


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6.1.2. 
Part 
2 
......................................................................................................................... 33  
6.2. 
Discussion of Design and Control 
................................................................................. 34  
6.3. 
Trial Schedule 
................................................................................................................ 34  
6.3.1. 
Part 
1 
......................................................................................................................... 34  
6.3.1.1. 
Screening Period: Day -28 to Day -1 (minimum of 7 days) ............................. 
34  
6.3.1.2. 
Treatment Period 1 ............................................................................................ 
36  
6.3.1.3. 
Washout Period (28 days +7) ............................................................................ 
39  
6.3.1.4. 
Treatment Period 2 ............................................................................................ 
39  
6.3.1.5. 
Part 1 Follow-Up Period (28 days +7) (for subjects not continuing into Part 2) 
 
  
42  
6.3.2. 
Part 
2 
......................................................................................................................... 43  
6.3.2.1. 
Part 2 Treatment Period ..................................................................................... 
43  
6.3.2.2. 
Part 2 Follow-Up Period (4 weeks [+7 days]) .................................................. 
45  
6.4. 
Trial Assessments 
........................................................................................................... 46 
13 
6.4.1. 
Medical 
History 
and 
Concomitant 
Medications/Procedures 
.................................... 46 
6.4.2. 
Physical 
Examination 
............................................................................................... 47  
6.4.3. 
Vital 
signs 
................................................................................................................. 47  
6.4.4. 
Electrocardiograms 
(ECGs) 
...................................................................................... 47  
6.4.5. 
Clinical 
Laboratory 
Testing 
...................................................................................... 47  


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6.4.5.1. 
Blood Chemistries ............................................................................................. 
47  
6.4.5.2. 
Hematology ....................................................................................................... 
47  
6.4.5.3. 
Urinalysis .......................................................................................................... 
47  
6.4.6. 
Biomarker 
Testing 
.................................................................................................... 47 6.4.7. Blood 
Spot ................................................................................................................ 48 
6.4.8. 
2-D 
and 
3-D 
Echocardiographs 
................................................................................ 48  
6.4.9. AVIVO™ Mobile Patient Management (MPM) System ......................................... 49 
6.4.10. Columbia Suicide Severity Rating Scale (C-SSRS) ............................................. 49 
6.4.11. PROMIS Short Form Fatigue ............................................................................... 50  
6.4.12. 
BarTH Syndrome Symptom Assessment (BTHS-SA) ......................................... 
50  
6.4.13. 
Patient Global Impression (PGI) Scales ............................................................... 
50  
6.4.14. 
Clinician Global Impression (CGI) Scales ........................................................... 
50  
6.4.15. 
Caregiver Global Impression (CaGI) Scales ......................................................... 
50 
6.4.16. 
EQ-5D 
................................................................................................................... 51  
6.4.17. 6-Minute Walk Test (6MWT) ............................................................................... 51 
6.4.18. 5X Sit to Stand Test (5XSST) ............................................................................... 51  
6.4.19. 
Handheld Dynamometry (HHD) ........................................................................... 
51  
6.4.20. 
SWAY Application Balance Assessments ............................................................ 
52  
6.4.21. 
Pharmacokinetic (PK) Sampling ........................................................................... 
52  
6.5. 
Data and Safety Monitoring Board 
.............................................................................. 52  
7. 
TRIAL POPULATION 
..................................................................................................... 53  
7.1. 
Inclusion Criteria 
........................................................................................................... 53  
7.2. 
Exclusion Criteria 
.......................................................................................................... 54  
7.3. 
Part 2 Continuation Criteria 
........................................................................................ 54  


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7.4. 
Prohibited Medications 
................................................................................................. 55  
7.5. 
Discontinuations 
............................................................................................................. 55  
7.5.1. 
Discontinuation 
of 
Subjects 
...................................................................................... 55 7.5.2. Discontinuation 
of Trial Center ................................................................................ 56  
 
7.5.3.  Discontinuation of the Trial ...................................................................................... 56  
8. 
TREATMENT 
................................................................................................................... 57  
8.1. 
Treatments Administered 
............................................................................................. 57  
8.2. 
Materials and Supplies 
.................................................................................................. 57  
8.2.1. 
Elamipretide 
.............................................................................................................. 57  
8.2.2. 
Placebo 
...................................................................................................................... 57  
8.3. 
Treatment Logistics and Accountability 
...................................................................... 58  
8.4. 
Rationale for Selection of Doses in the Trial 
............................................................... 58  
8.5. 
Treatment Compliance 
.................................................................................................. 61  
8.6. 
Continued Access to Investigational Medicinal Product 
............................................ 61 
14 
8.7. 
Blinding and Unblinding Procedures 
........................................................................... 61 
9. 
EFFICACY AND SAFETY EVALUATIONS AND APPROPRIATENESS OF  
MEASUREMENTS .................................................................................................................. 
62  
9.1. 
Efficacy Endpoints 
......................................................................................................... 62  
9.1.1. 
Primary 
Endpoints 
.................................................................................................... 62  


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9.1.2. 
Secondary 
Endpoints 
................................................................................................ 62  
9.1.3. 
Pharmacokinetic 
(PK) 
Endpoints 
............................................................................. 63  
9.2. 
Safety Endpoints 
............................................................................................................ 63  
9.3. 
Adverse Events 
............................................................................................................... 64  
9.4. 
Pre-Treatment Events 
................................................................................................... 64  
9.5. 
Baseline Medical Conditions 
......................................................................................... 64  
9.6. 
Medical and Surgical Procedures 
................................................................................. 64  
9.7. 
Abnormal Laboratory and Other Abnormal Investigational Findings 
.................... 64  
9.8. 
Symptomatic Overdose 
.................................................................................................. 65  
9.9. 
Serious Adverse Events (SAE) 
...................................................................................... 65  
9.10. 
Recording of Adverse Events .................................................................................... 
65  
9.10.1. 
Investigator Assessments ...................................................................................... 
66  
9.10.1.1. Severity .............................................................................................................. 
66  
9.10.1.2. Relationship to the Investigational Medicinal Product (IMP) .......................... 
66  
9.10.1.3. Outcome of an Adverse Event .......................................................................... 
67  
9.10.1.4. Reporting of Injection Site Reactions (ISR) ..................................................... 
67  
9.10.2. 
Adverse Event Reporting Period .......................................................................... 
68  
9.11. 
Serious Adverse Event Expedited Reporting ........................................................... 
68  
9.11.1. 
Pregnancy and Contraception ............................................................................... 
68  
9.11.2. 
Responsibilities to Regulatory Authorities, Investigators and Ethics Committees 
 
  
69  


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9.12. 
Appropriateness of Measurements ........................................................................... 
69  
10. 
DATA QUALITY ASSURANCE ................................................................................. 
70  
10.1. 
Data Capture System ................................................................................................. 
70  
11. 
SAMPLE SIZE AND STATISTICAL METHODS .................................................... 
71  
11.1. 
Determination of Sample Size ................................................................................... 
71  
11.2. 
Statistical and Analytical Plans ................................................................................. 
71  
11.2.1. 
General Considerations ......................................................................................... 
71  
11.2.2. 
Subject Disposition ............................................................................................... 
71  
11.2.3. 
Subject Characteristics .......................................................................................... 
71  
11.2.4. 
Endpoints and Methodology ................................................................................. 
71  
11.2.4.1. General Considerations ..................................................................................... 
71  
11.2.4.2. Analysis Populations ......................................................................................... 
72  
11.2.5. 
Efficacy Analyses ................................................................................................. 
72  
11.2.5.1. Handling of Missing Data ................................................................................. 
72  
11.2.6. 
Pharmacokinetic (PK) Analysis ............................................................................ 
73  
11.2.7. 
Safety Analyses ..................................................................................................... 
73 
15 
11.2.7.1. Adverse Events .................................................................................................. 
73 
11.2.7.2. Deaths and Other Serious Adverse Events ........................................................ 
73  


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11.2.7.3. Clinical Laboratory Evaluations ........................................................................ 
74  
11.2.7.4. Vital Signs ......................................................................................................... 
74  
11.2.7.5. Electrocardiogram ............................................................................................. 
74  
11.2.7.6. Other Safety Parameters .................................................................................... 
74  
12. 
INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY  
CONSIDERATIONS ................................................................................................................ 
75  
12.1. 
Informed Consent ....................................................................................................... 
75  
12.2. 
Ethical Review ............................................................................................................ 
75  
12.3. 
Regulatory Considerations ........................................................................................ 
75  
12.3.1. 
Protocol Approval ................................................................................................. 
76  
12.3.2. 
Final Report Approval .......................................................................................... 
76  
12.3.3. 
Trial Monitoring.................................................................................................... 
76  
12.3.4. 
Retention of Records ............................................................................................. 
76  
12.3.5. 
Disclosure of Information ..................................................................................... 
76  
13. 
REFERENCES ............................................................................................................... 
78  
14. 
ATTACHMENTS .......................................................................................................... 
80  


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16 
 
3. 
ABBREVIATIONS AND DEFINITIONS 
Term 
Definition 
 
5XSST 
5X Sit to Stand Test 
6MWT 
6-Minute Walk Test 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATP 
Adenosinetriphosphate 
AUC 
Area under the plasma concentration versus time curve 
AUC0-τ 
Area under the plasma concentration vs time curve from time 0 to end of the 
dosing interval  
AUC0-inf 
Area under the plasma concentration curve from baseline to infinity  
AUC0-24 
Area under the plasma concentration curve from baseline to 24 hours postdose  
BTHS-SA 
BarTH Syndrome Symptom Assessment  
BMI 
Body mass index  
CaGI 
Caregiver Global Impression Scales 
CIOMS 
Council for International Organizations of Medical Sciences 
CGI 
Clinician Global Impression Scales 
Cmax 
Maximum plasma concentration 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
Electronic data capture 
EF 
Ejection fraction 
ETC 
Electron Transport Chain 
FGF-21  
Fibroblast Growth Factor 21  
GCP 
Good Clinical Practice 
GDF-15 
Growth Differentiation Factor 15 


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HHD 
handheld dynamometry 
IB 
Investigator’sBrochure 
17 
Term 
Definition 
 
ICD 
Implantable cardioverter defibrillator 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IMM 
Inner mitochondrial membrane  
IMP 
Investigational medicinal product 
ISR 
Injection site reaction 
IV 
Intravenous 
ITT 
Intention-to-treat 
L4-CL 
Tetralinoleyl-cardiolipin 
LV 
Left ventricular  
MFD 
Maximum feasible dose  
mL 
Milliliter 
MLCL 
Monolyso-cardiolipin 
MTP-131  
SS-31, elamipretide, or Bendavia™ 
mtDNA 
Mitochondrial DNA 
nDNA 
Nuclear DNA 
OLE 
Open-label extension 
PGI 
Patient Global Impression Scales 
PK 
Pharmacokinetic(s) 
PMM 
Primary mitochondrial myopathy 
PT 
Preferred term 
ROS 
Reactive oxygen species  
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 


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TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
18 
 
4. 
INTRODUCTION 
This trial 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 
investigational medicinal product (IMP) 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. 
Barth Syndrome 
Barth Syndrome (BTHS, 3-methylglutaconic aciduria type II, MIM 300394) is a rare X-
linked disorder with an estimated prevalence of 1/300,000–400,000 live births and 
characterized by cardiomyopathy, skeletal myopathy, neutropenia, and growth abnormalities, 
among other features (Ades L, et al., 1993). BTHS is caused by defects in TAZ (G4.5), which 
encodes for Tafazzin, an acyltransferase involved in the remodeling of the mitochondrial 
phospholipid cardiolipin. Cardiolipin has important roles in mitochondrial function including 
maintaining cristae structure, supporting electron transport chain efficiency, and in apoptosis. 
(Hoch F., 1992). Deficiency of tafazzin results in abnormal cardiolipin content, a reduction of 
structurally mature tetralinoleyl-cardiolipin (L4-CL) and an increase in structurally immature 
monolysocardiolipin (MLCL) (Vreken P, et al., 2000).  Alterations in cardiolipin structure, 
content, and acyl chain composition are associated with mitochondrial dysfunction (Paradies 
G, et al., 2014). This dysfunction results in reduced function and efficiency of the electron 
transport chain (ETC), affecting oxidative phosphorylation (OXPHOS) and results in reduced 
ATP and likely increased reactive oxygen species (ROS) production. Presumably, 
disorganized oxidative phosphorylation and other aspects of mitochondrial dysfunction lead 
to signs and symptoms of disease.   
The diagnosis of BTHS is suggested by typical clinical findings and an increase (5- to 20-
fold) in urinary 3-methylglutaconic acid (3-MGC) and other urinary metabolites. The 
diagnosis is established via detection of a TAZ pathogenic variant on molecular genetic 
testing and/or a diagnostic assay measuring the elevation of the MLCL to L4-CL ratio 
(MLCL/L4-CL), which is both a highly sensitive and specific diagnostic measurement in 
bloodspots, nucleated cells, and tissues (Clark S, et al., 2013; Sandlers Y, et al., 2016). 
BTHS is a complex inborn error of metabolism and affects many systems of the body 
(Jefferies J., 2013).  Though not always present, cardinal characteristics of this multi-system 
disorder often include combinations and varying degrees of:  
• 
Cardiomyopathy (usually dilated cardiomyopathy [DCM] with undulating 
hypertrophic cardiomyopathy [HCM], sometimes with left ventricular noncompaction 
[LVNC]  
and/or endocardial fibroelastosis [EFE]). This can result in ventricular 
arrhythmias/sudden cardiac death (SCD) 


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• 
Skeletal muscle myopathy (usually proximal myopathy, low muscle mass, and muscle 
weakness) resulting in exercise intolerance due to extreme fatigue 
• 
Growth delay (short stature in the early years, followed by accelerated growth in mid- 
to late puberty)  
19 
• 
Neutropenia (can be chronic, intermittent, cyclic, or not present) resulting in 
lifethreatening bacterial infections 
• 
Feeding problems (e.g., difficulty sucking, swallowing, or chewing; aversion to some 
food textures; selective or picky eating; frequent vomiting)  
• 
Biochemical abnormalities (cardiolipin composition abnormalities and variable 
3methylglutaconic aciduria and 3-methylglutaconic acidemia)  
No treatment is approved for the treatment of individuals with BTHS  
4.2. 
Pharmacologic Basis for Elamipretide as a Potential Treatment for  
BTHS 
As previously described, alterations in cardiolipin structure, content, and acyl chain 
composition are associated with mitochondrial dysfunction (Paradies G, et al., 2014). This 
dysfunction results in reduced function and efficiency of the electron transport chain (ETC), 
affecting oxidative phosphorylation (OXPHOS) and results in reduced ATP and likely 
increased reactive oxygen species (ROS) production. This increase in ROS may reach a 
threshold and trigger additional increased ROS generation by the ETC, an effect termed 
“ROSinduced ROS release (RIRR)” (Zorov, D. et al., 2000; Zorov, D, et al., 2006).  These 
effects constitute a positive feedback mechanism for enhanced ROS production leading to 
potentially additional significant mitochondrial structural abnormalities, dysfunction and 
cellular injury. At a certain level of mitochondrial dysfunction (decreased ATP and increased 
ROS productions), patients experience signs and symptoms of their disease.  
Reactive Oxygen Species also attack and denature a number of components within the 
mitochondria, including the protein components of the ETC, membrane lipids (particularly 
cardiolipin), and mtDNA. In particular, the denaturing of cardiolipin has been associated with 
abnormal morphology of the inner mitochondrial membrane (IMM), less association of the 
ETC complexes within that membrane, a decline in activity of the ETC (ATP production), 
and the release of cytochrome c which initiates apoptotic signaling (Fry, M, et al., 1981; 
Chicco A, et al., 2007). 
Studies of BTHS patient tissues and animal models of TAZ depletion have reported 
structurally abnormal mitochondria with inefficient oxidative phosphorylation, resulting in 
decreased ATP and increased ROS levels (Saric A, et al., 2015). Elamipretide may help to 


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stabilize the limited number of mature L4-CL and allow them to function properly, rather 
than becoming dysfunctional due to being preferentially targeted by the higher levels of ROS 
that BTHS patients have due to the dysfunctional mitochondria.  The association of 
elamipretide with cardiolipin has been shown to normalize key cardiolipin properties that are 
modified during oxidative stress. The proposed interaction of elamipretide with the limited 
mature cardiolipin that exists in patients with BTHS may preserve the optimal interaction of 
the protein complexes of the ETC, improve electron flow, increase ATP production, and 
decrease ROS generation.  
20 
4.3. 
Elamipretide Risk/Benefit Assessment 
4.3.1. 
Potential Benefits 
4.3.1.1. 
Pre-clinical studies 
4.3.1.1.1. Skeletal and cardiac muscle dysfunction of aged mice 
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 agerelated 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.   


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Figure 1:  ATP Production in Young (5 month) and Old (27 month) Mice Following a Single 
Treatment with Elamipretide 
 
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). 
21 
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).  
  
4.3.1.1.2. Cardiac muscle dysfunction of tafazzin (TAZ) knockdown (TAZKD) mice 
A pre-clinical mouse model of Barth Syndrome has been used to assess potential side effects 
and efficacy of elamipretide (Soustek, M. S., et al. 2010). Upon induction of the TAZ-
specific shRNA in vivo by doxycycline, TAZ mRNA levels in transgenic mice are reduced by 
>89% in cardiac and skeletal muscle. At week 8, elamipretide (5 mg/kg/day) or saline is 
administered via Alzet minipump for a period of 6 weeks. Cardiac echocardiograms are 
performed at weeks 8 (prior to treatment), week 11 (3 weeks treatment) and week 14 (6 
weeks treatment) (Figure 2). 
Mean +/- SEM, n = 5 – 7 per group 
Single 3mg/kg dose of elamipretide  
C  1200   
assessed after one hour  
0   
.: ;  
Control  
CJ 
:::, 1000   
•  Elamipretide  
'O  e  800   
p<0.05  
a.  
a.  
 600   
ni  400   
E  
·x 200   
ca 
:ii: 
0   
 months  
5 
27 months  
Age  


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At week 14, the animals are sacrificed. The TAZKD mice had a 90% reduction in cardiolipin 
and approximately 10-fold increase in MLCL. Treatment with elamipretide did not alter this 
distribution. Importantly, favorable findings regarding heart function, including 
improvements in fractional shortening (Figure 3), and histology (ventricle diameter and 
degree of fibrosis) were initially observed (Figure 4). These changes were not significant 
across the full cohort due to variability resulting from sex and genotype (hetero vs. 
homozygotes), and point to the difficulty in developing an animal model for Barth which will 
allow efficient and timely testing of compounds.  
22 
Figure 2:  Study Schedule of Events 
Birth  
t  
t  
t  
Week8  
Week11  
Week 14  
Cardiac Echo  
Cardiac Echo  
Sacrifice  


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Figure 3:  Mean Fractional Shortening (FS)   
 
Figure 4:  Picosirius Red Staining for Fibrosis of a Section of Left Ventricle 
 
4.3.1.2. 
Clinical Studies in Other Genetically Confirmed Mitochondrial Diseases  
No previous studies have been conducted with elamipretide in subjects with Barth Syndrome.  
The SPIMM-201 trial was a phase 1/2 multi-center, randomized, double-blind, 
placebocontrolled, multiple ascending IV dose trial that enrolled subjects ≥16 and ≤65 years 
with primary mitochondrial myopathy (PMM). Three escalating doses (0.01, 0.10, and 0.25 
mg/kg/hour infused for 2 hours) were studied (one dose per cohort) and infused daily for 5 
days. The primary efficacy endpoint was distance walked during the 6MWT after 5 days of 
treatment.  
Five days of daily IV elamipretide was well tolerated with no increase in adverse events or 
laboratory abnormalities compared to placebo. The most common TEAE overall was 
headache in 6 (16.7%) subjects, followed by dizziness in 3 subjects. There were no 
treatment-related TEAEs that were severe in intensity. 
n=10 
=14 
Mean(FS)  &  FS vs. tlmePt  
Treatment  
- Mean  
60 
elamipretide  
Vehicle  
C: FS  
n  10 
n  1
50 
40 
30 
FS  
20 
10 
0 
-10 
0 
3 
6 
0 
3 
6 
timePt  
DOX  + Saline  
09 x  + elamipretide  


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23 
The primary efficacy measure of interest was the change from Baseline in distance walked 
(meters) on the 6-minute walk test (6MWT).  In addition to the 6MWT, the efficacy of 
elamipretide was explored using Cardiopulmonary Exercise Testing (CPET) parameters, 
patient reported outcomes (Newcastle Mitochondrial Disease Adult Scale [NMDAS] and a 
Daily Symptom Questionnaire [DSQ]), and plasma and urinary biomarkers.  
The highest dose of elamipretide examined in this trial, 0.25 mg/kg/hr, was associated with 
improvement in skeletal muscle function compared to placebo, as measured by the 6MWT 
(Table 1).   
Table 1:  
Summary of Change from Baseline on Days 5 and 7 in Distance Walked (meters) 
on 6MWT 
 
 
Elamipretide 
 
Placebo 
(N = 9) 
0.01 mg/kg/hr 
(N = 9) 
0.10 mg/kg/hr 
(N = 9) 
0.25 mg/kg/hr 
(N = 9) 
Baseline 
Mean (SD)2 
363.9 (143.15) 
421.9 (66.85) 
360.2 (100.99) 
369.8 (96.82) 
Change on Day 51 
Mean (SD) 
LS Mean 
LSM Diff2 (90% CI)3 
p-value3 
14.2 (49.40) 
13.5 
-7.0 (-44.1, 30.1) 
0.7523 
34.3 (43.46) 
36.5 
16.1 (-21.6, 53.8) 
0.4746 
65.4 (45.71) 
64.5 
44.1 (7.0, 81.2) 
0.0528 
20.9 (45.18) 
20.4 
Change on Day 71 
Mean (SD) 
LS Mean 
LSM Diff2 (90% CI)3 
p-value3 
31.8 (41.10) 
30.3 
-8.3 (-53.0, 36.5) 
0.7561 
35.1 (56.56) 
39.5 
1.0 (-44.5, 46.4) 
0.9718 
63.6 (63.30) 
61.7 
23.1 (-21.6, 67.9) 
0.3872 
39.4 (60.74) 
38.5 
Abbreviations: 6MWT = 6-minute walk test; CI = Confidence interval; LS = Least squares; LSM Diff = Least 
Squares Mean Difference; SD = Standard deviation. 
1. 
Change from Baseline = value at Visit – value at Baseline Visit. 
2. 
LSM Difference is elamipretide dose (0.01, 0.10, or 0.25 mg/kg/hr) minus placebo. 
3. 
P-value and 90% CI of the difference are based on the ANCOVA model which included treatment as a factor 
and Baseline measure as a covariate. 
Additionally, there was a positive dose response with increasing dose of elamipretide as 
indicated in the linear trend test (p=0.014 on Day 5).  
In a post-hoc analysis which adjusted for sex and baseline disease walked, allowing magnitude 
of treatment benefit to be related to baseline, subjects treated with the highest dose of 
elamipretide walked an adjusted mean (i.e., LS mean) distance of 48 meter further on Day 5, 


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than subjects in the placebo group in the 6MWT compared to their Baseline assessment 
(p=0.03) (Table 2).   
24 
Table 2:  
Summary of Change from Baseline in Distance Walked (meters) in the 6MWT at  
Day 5 – Using Backward Elimination (ITT Population) 
 
Elamipretide 
Placebo 
(N = 9) 
0.01 mg/kg/hr 
(N = 9) 
0.10 mg/kg/hr 
(N = 9) 
0.25 mg/kg/hr 
(N = 9) 
Baseline 
Mean (SD) 
363.9 (143.15) 
421.9 (66.85) 
360.2 (100.99) 
369.8 (96.82) 
Change on Day 51 
Mean (SD) 
LS Mean 
LSM Diff2 (90% CI)3 
p-value3 
14.2 (49.40) 
3.1 
0.1 (-34.9, 35.1) 
0.9967 
34.3 (43.46) 
28.3 
25.2 (-12.9, 63.4) 
0.2702 
65.4 (45.71) 
51.2 
48.2 (12.5, 84.0) 
0.0297 
20.9 (45.18) 
3.0 
Abbreviations: 6MWT = 6-minute walk test; CI = Confidence interval; LS = Least squares; LSM Diff = Least 
Squares Mean Difference; SD = Standard deviation. 
1. Change from Baseline = value at visit – value at baseline visit. 
2. LSM Difference is elamipretide dose (0.01, 0.10, or 0.25 mg/kg/hr) minus placebo. 
3. Based on the ANCOVA model with treatment, baseline 6MWT, baseline 6MWT-by-treatment interaction, 
screening 6MWT, sex baseline height, baseline weight, and randomization cohort included in the model. 
Backward elimination was used to include only factors with Significance Level to Stay (SLS) <=0.1 in the 
final ANCOVA model and presented in this table. Final Model for Day 5 included Baseline 6MWT, 
treatment, baseline 6MWT-by-treatment interaction, and sex. 
Subgroup analysis of the 6MWT suggest that elamipretide is more effective in subjects with 
greater impairment at Screening, as those who initially walked <350 meter showed greater 
improvement following treatment compared to those who initially walked ≥350 meter.  
CPET was used to assess skeletal muscle function. For all treatment groups, including 
placebo, there was an increase in aerobic capacity (peak VO2 max) and a decrease in 
ventilatory efficiency (peak VE/VCO2 slope). No CPET parameters were significantly 
different than placebo for any dose of elamipretide. Adjusted mean modified NMDAS total 


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scores for current function and current clinical assessment did not change over time. Changes 
in biomarker data  
(plasma glutathione, plasma FGF-21, urine 8-isoprostane, and urine 8-hydroxy-
2deoxyguanosine) were not significantly different than placebo. Pharmacokinetics of 
elamipretide were unchanged from normal subjects in this patient population.  
4.3.2. 
Potential Risks 
4.3.2.1. 
Nonclinical Study Safety Findings 
The nonclinical testing of elamipretide encompasses a program of studies in pharmacology, 
metabolism, pharmacokinetics (PK), and toxicology.   
Elamipretide was effective in multiple models of cardio-renal disease and skeletal muscle 
dysfunction and has been active across all species tested to date, including rat, guinea pig, 
rabbit, dog, sheep, and pig.  The effective dose range was 0.05 to 0.5 mg/kg/day.  Based on  
25 
results from a battery of secondary and safety pharmacology studies, elamipretide is not 
expected to cause any adverse off-target pharmacodynamic effects at therapeutic 
concentrations.    
Elamipretide did not cause end-organ toxicity at any dosage tested in either rats or dogs.  
Systemic toxicity at high doses was manifested primarily by acute and transient clinical 
signs, which are mediated by histaminergic-like reactions.  Effects were associated with 
maximum elamipretide plasma concentration (Cmax) and were rapidly reversible as plasma 
concentrations of elamipretide (and histamine) decreased.  Dose administration was not 
associated with any adverse effects on cardiovascular, respiratory or central nervous system 
function; off-target non-adverse effects were limited to transient decrease of blood pressure 
and heart rate, consistent with histaminergic-like reactions.  In all studies, the severity of the 
effects was proportional to Cmax for elamipretide; thus, the safety margin is estimated based 
on Cmax, and not area under the plasma-concentration-time curve (AUC).  The plasma 
elamipretide threshold concentration for clinically-relevant adverse effects appears to be 
~20,000 ng/mL in both rats and dogs, which is more than 10-fold higher than the maximum 
observed human exposures at clinical doses. 
Intravenous administration of elamipretide to rats and dogs was well tolerated at the 
administration site.  Local injection site reactions evident upon SC administration varied with 
species, dose and dose concentration.    
Elamipretide was negative for genotoxicity in the full battery of tests and caused no 
significant hemolysis or inhibition of receptor binding. Elamipretide did result in the release 
of histamine from rat mast cells at a concentrations ≥ 390 µg/mL. Elamipretide was not 
associated with adverse effects on fertility or embryo-fetal development.   


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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, for 
receptor binding, and rat mast cell degranulation. Systemic exposure to the metabolites in rats 
and dogs was not related to any toxicity in acute, subchronic, or chronic studies.  Neither M1 
nor M2 metabolites showed biological activity when evaluated in an ex vivo guinea pig heart 
model.  At a concentration of 1 μM, neither metabolite provided myocardial protection 
against ischemic reperfusion injury. 
4.3.2.2. 
Human Safety 
Parenteral administration of elamipretide was assessed following single and multiple IV and 
SC doses in approximately 230 healthy subjects in 12 completed clinical pharmacology 
studies with data available. Single IV doses ranged from 0.005 mg/kg/hour to 0.25 mg/kg/hr, 
and were typically administered over 4 hours. Multiple-dose regimens ranged from 0.25 
mg/kg/hr administered over 1 hour daily for 7 days to 140 mg administered over 1 hour daily 
for 5 days. Single SC doses ranged from 2 mg to 80 mg and were administered as 0.5 or 1 
mL injections, while multiple-dose regimens of 6 mg to 80 mg were administered as 0.25, 
0.5, or 1 mL injections daily for 7 days.  
26 
No safety concerns have been identified with administration of IV or SC elamipretide for up 
to seven days in these studies. The only systemic adverse event reported in over 5% of 
subjects was headache (8.8%).  Nausea (2.6%), hyponatraemia (2.6%), and dizziness (2.2%) 
were also reported. 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, electrocardiogram (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 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.   


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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 studies carried out to date, co-administration 
of elamipretide with aspirin, with clopidogrel, or with unfractionated heparin 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 chronic heart failure, subjects with 
acute coronary syndrome who were undergoing primary percutaneous coronary intervention 
and stenting for ST-elevation myocardial infarction, subjects with acute kidney injury 
undergoing percutaneous transluminal renal angioplasty, subjects with PMM, subjects over 
60 years of age with evidence of skeletal muscle mitochondrial dysfunction, and in ongoing 
openlabel studies of in subjects with PMM and age-related macular degeneration. Single and 
multiple IV and SC doses of elamipretide were assessed with generally no notable 
differences between the elamipretide and placebo arms in the frequency or severity of 
adverse events, except for ISRs with SC elamipretide administration. Additionally, mild 
eosinophilia was reported as an adverse event in numerous subjects. Laboratory data 
demonstrated elevations (>0.45 cells x109/L) in eosinophils beginning at approximately 3-4 
weeks after initiation of elamipretide treatment in a majority of subjects. These laboratory 
findings have not been reported to be associated with any systemic clinical manifestations of 
eosinophilia. In general, these elevations appear to trend downward after longer duration of 
treatment (16 weeks) and were demonstrated to have returned to within normal range or to 
baseline levels at the followup visit (up to 28 days after the end of elamipretide treatment). 
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.   
27 
Across all studies, both IV and SC formulations, there have been no reported pregnancies, no 
exposures during lactation, no overdoses, and no abuses or misuses reported   
4.3.3. 
Conclusions 
In summary, based on the clinical and nonclinical study data, acceptable safety risks are 
expected for the proposed current trial. Subjects will have an opportunity to report any safety 
concerns; hence the benefit:risk ratio of this trial is considered favorable.  


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5. 
OBJECTIVES 
This trial is designed with 2 parts, SPIBA-201 (Part 1) and SPIBA-201 OLE (Part 2). The 
objectives of each part are consistent with the trial design. 
x Part 1 is a 28-week, randomized, double-blind, placebo-controlled crossover assessment 
of the efficacy and safety of single daily subcutaneous (SC) doses of 40 mg 
elamipretide (vs placebo) as a treatment for subjects with Barth Syndrome. 
x Part 2 is an up to 192-week, open-label assessment of the long-term safety and 
tolerability of single daily SC doses of 40 mg elamipretide in subjects with Barth 
Syndrome.  
5.1. 
Part 1 Objectives 
5.1.1. 
Primary Objective 
To evaluate the effect of single daily subcutaneous (SC) doses of 40 mg elamipretide 
administered for 12 weeks in subjects with Barth Syndrome on the:  
x Distance walked (meters) during the 6-Minute Walk Test (6MWT) x Total 
Fatigue on the BarTH Syndrome Symptom Assessment (BTHS-SA) 
5.1.2. 
Secondary Objectives 
x To evaluate the effect of single daily SC doses of 40 mg elamipretide administered for 
12 weeks in subjects with Barth Syndrome as measured by change in: o Muscle 
strength as measured by handheld dynamometry (HHD)  o Five Times Sit-to-Stand 
Test (5XSST) o 2-D and 3-D Echocardiographic measurements o Accelerometry 
counts o SWAY Application Balance Assessment o Patient Reported Outcomes o 
Clinician Global Impression (CGI) Scales o Caregiver Global Impression (CaGI) 
Scales o Biomarkers 
x To evaluate the safety and tolerability of single daily SC doses of 40 mg elamipretide 
administered for 12 weeks in subjects with Barth Syndrome 


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5.2. 
Part 2 Objectives  
5.2.1. 
Primary Objective  
To assess the long-term safety and tolerability of single daily SC doses of 40 mg elamipretide 
for up to 192 weeks 
5.2.2. 
Secondary Objectives  
To evaluate longitudinal trends of single daily SC doses of 40 mg elamipretide 
administered for up to 192 weeks in subjects with Barth Syndrome as measured by: x 
6MWT  
x Total Fatigue on the BTHS-SA x 
Muscle strength as measured by HHD 
x 5XSST 
x 2-D and 3-D Echocardiographic measurements 
x SWAY Application Balance Assessment x 
Patient Reported Outcomes x CGI Scales x CaGI 
Scales x Biomarkers 
5.2.3. 
Pharmacokinetics (PK) 
x To assess PK via a population model   


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Trial Design 
This randomized, double-blind, placebo-controlled crossover trial followed by an open-label 
treatment extension assessment will enroll approximately 12 subjects who have genetically 
confirmed Barth Syndrome. There are 2 parts to this trial. 
x Part 1 is a 28-week, randomized, double-blind, placebo-controlled crossover assessment 
of the efficacy and safety of single daily SC doses of 40 mg elamipretide (vs placebo) 
in subjects with Barth Syndrome. Subjects will be randomized (in a ratio of 1:1) to 
one of two sequence groups: 
o 12-weeks of single daily subcutaneous (SC) doses of 40 mg elamipretide in 
Treatment Period 1 followed by 12-weeks of treatment with placebo in 
Treatment Period 2 (separated by 4-week washout period) o 12-weeks 
of single daily subcutaneous (SC) doses of placebo in Treatment Period 1 
followed by 12-weeks of treatment with 40 mg elamipretide in Treatment 
Period 2 (separated by 4-week washout period) 
x Part 2 is an up to 192-week, open-label assessment of the long-term safety and 
tolerability of single daily SC doses of 40 mg elamipretide in subjects with Barth 
Syndrome. Subjects who continue into Part 2 will receive treatment with 40 mg SC 
elamipretide for up to 192 weeks. 
Note that the duration of Part 2 treatment for each subject will be the shortest of the 
following: 
o 192 weeks 
o Date of enrollment in another SBT follow-on clinical trial in Barth syndrome 
or 
EAP 
o Regulatory approval and commercial availability of elamipretide o 
Termination of the clinical development for elamipretide in subjects with 
Barth Syndrome. 
6.1.1. 
Part 1   
This randomized, double-blind, placebo-controlled crossover trial will enroll approximately 
12 subjects who have genetically confirmed Barth Syndrome. Subjects will be randomized 
(1:1) to one of two sequence groups: 12-weeks of single daily subcutaneous (SC) doses of 40 
mg elamipretide in Treatment Period 1 followed by 12-weeks of treatment with placebo in 


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Treatment Period 2 (separated by 4-week washout period), or vice versa. The Part 1 Trial 
Schematic is presented in Attachment 3. 
Screening Period:  The Screening Period will begin with the signature of the informed 
consent form (ICF) and will last for at least 7 days and no more than 28 days and will include 
a Screening Visit. During the Screening Period, subjects will undergo all screening 
procedures as described in the Part 1 Schedule of Assessments (Attachment 1) including 
applying and  
31 
wearing the AVIVO™ MPM System daily for approximately 7 consecutive days and 
completing the age appropriate BarTH Syndrome Symptom Assessment (BTHS-SA) daily. 
Confirmation of Barth Syndrome will incorporate a review of the Investigator submitted 
diagnosis and genetic results. Confirmation of Barth Syndrome must be made prior to 
randomizing the subject. Subjects who complete all screening procedures during the 
Screening Period and continue to meet all trial requirements, including all inclusion and none 
of the exclusion criteria, will be randomized and enter Treatment Period 1.   
Treatment Period 1: Treatment Period 1 will begin on the day of Treatment Period 1  
Baseline (Pre-dose) Visit, which is defined as Treatment Period 1 Day 1.  At the Treatment  
Period 1 Baseline Visit, following completion of all Baseline procedures described in the 
Trial  
Schedule, the subject will be administered IMP subcutaneously at the trial center. The 
Investigator (or designee) will also place a new AVIVO™ MPM System on the subject’s 
chest and instruct the subject to continue to wear the System for approximately 7 consecutive 
days.  At the discretion of the Investigator, the subject may return to the trial center on 
Treatment  
Period 1 Days 2 through 5 to receive a daily subcutaneous injection of IMP.  At the Treatment 
Period 1 Baseline Visit, subjects (and caregivers) will be trained on the procedure for 
selfadministration of IMP. The IMP should be administered at approximately the same time 
each day (e.g. early morning, noon, early afternoon, or evening). The Visiting Nurse will 
complete assessments at the Treatment Period 1 Week 1, 4, and 8 Nurse Visits as described in 
the Schedule of Visiting Nurse Assessments (Attachment 2). The trial center and Visiting 
Nurse will remind subjects to complete the age appropriate BTHS-SA daily throughout 
Treatment Period 1 and to apply and wear a new AVIVO™ MPM System daily for 
approximately 7 consecutive days immediately prior to the Treatment Period 1 Week 12 
Visit. Treatment Period 1 will conclude with the Treatment Period 1 Week 12 visit at the trial 
center where the subjects will return all used vials, unused vials, and used AVIVO™ MPM 
Systems to the trial center. 
Washout Period: The Washout will begin after the Treatment Period 1 Week 12 Visit and 
will last for 28 days (+7 days). During the Washout Period, subjects will continue to follow 
all trial requirements, including completing the age appropriate BTHS-SA daily.  


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Treatment Period 2: Treatment Period 2 will begin on the day of Treatment Period Pre-dose 
Visit, which is defined as Treatment Period 2 Day 1. At the Treatment Period 2 Pre-dose 
Visit, following completion of all Pre-dose procedures described in the Trial Schedule, the 
subject will be administered IMP subcutaneously at the trial center. The Investigator (or 
designee) will also place a new AVIVO™ MPM System on the subject’s chest and instruct 
the subject to continue to wear the System for approximately 7 consecutive days.  At the 
discretion of the Investigator, the subject may return to the trial center on Treatment Period 2 
Days 2 through 5 to receive a daily subcutaneous injection of IMP.  The IMP should be 
administered at approximately the same time each day (e.g. early morning, noon, early 
afternoon, or evening). The Visiting Nurse will complete assessments at the Treatment Period 
2 Week 1, 4, and 8 Nurse Visits as described in the Schedule of Visiting Nurse Assessments 
(Attachment 2). The trial center and Visiting Nurse will remind subjects to complete the age 
appropriate BTHS-SA daily throughout Treatment Period 2 and to apply and wear a new 
AVIVO™ MPM System daily for approximately 7 consecutive days immediately prior to the 
Treatment Period 2 Week 12 Visit. Treatment Period 2 will conclude with the Treatment 
Period 2 Week 12 visit at the trial center where the subjects will return all used vials, unused 
vials, and used AVIVO™  
32 
MPM Systems to the trial center. 
Part 1 Follow-Up Period: At the Treatment Period 2 Week 12 Visit, the subject and the 
Investigator will determine whether the subject will continue into Part 2 (confirming the 
subject meeting the Continuation Criteria). Subjects who will not continue into Part 2 will 
complete the Part 1 Follow-Up Period and Part 1 End-of-Trial Visit.  
The Part 1 Follow-Up Period will begin after completion of Treatment Period 2 Week 12 and 
will last for 28 days (+7 days).  During the Part 1 Follow-Up Period, subjects will continue to 
follow all trial requirements, including completing the age appropriate BTHS-SA daily.  At 
the end of the Part 1 Follow-Up Period, subjects will return to the trial center for the Part 1 
End-ofTrial/Early Discontinuation Visit for final safety and efficacy assessments as described 
in the Trial Schedule, and to return all trial materials/equipment. 
For Part 1, an external Data and Safety Monitoring Board (DSMB) will be established to 
review safety data on a regular basis to ensure safety of all subjects enrolled. 
6.1.2. 
Part 2 
While there is no screening period for Part 2, subjects must meet the Part 2 Continuation 
Criteria. Subjects who decide not to continue to Part 2 at the Treatment Period 2 Week 12 
Visit of Part 1 are not eligible to participate in Part 2. The Part 2 Schedule of Assessments is 
provided in Attachment 1. The Part 2 Trial Schematic is presented Attachment 3.  


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Part 2 Treatment Period: The Part 2 Treatment Period will begin on the day after the  
Treatment Period 2 Week 12 Visit of Part 1. Subjects (or trained caregivers) will administer 
the  
IMP daily during the Part 2 Treatment Period. The subject will return to the clinical site for 
the Part 2 Week 12, 24, 36, 48, 72, 96, 120, 144, 168 and 192 Visits for assessments, to 
administer the IMP (subject or trained caregiver), and to return all used IMP supplies. Phone 
calls (or other forms of communication) will be made to the subject every 12 weeks between 
clinical site visits (i.e. weeks 60, 84, 108, 132, 156, 180). During the Treatment Period, 
subjects will continue to follow all trial requirements.  
Subjects who withdraw consent or are withdrawn from the trial by the investigator should be 
encouraged to complete an Early Discontinuation Visit as soon as possible and an effort 
should be made to complete and report the assessments as thoroughly as possible up to the 
date of withdrawal. 
The Part 2 Treatment Period will end with the Part 2 EOT Visit.  This will occur after 
completion of the Week 192 Visit, or anytime between the Week 144 – 192 Visits during Part 
2 when the subject and Investigator determine that the subject will enroll in another SBT 
follow-on clinical trial in Barth syndrome or EAP. 
Part 2 Follow-Up Period: The Part 2 Follow-Up Period will begin after completion of the 
Part 2 EOT Visit and will last for 4 weeks. Subjects will continue to follow all trial 
requirements. Subjects will return to the clinical site for the Part 2 End-of-Trial Visit for final 
safety assessments, as described in the Part 2 Schedule of Assessments, and return all 
remaining trialrelated supplies not previously returned.  Subjects enrolling another SBT 
follow-on clinical  
33 
trial in Barth syndrome or EAP will not participate in the Part 2 Follow-Up Period, and the 
Part 2 EOT Visit will be considered the end-of-trial visit. 
6.2. 
Discussion of Design and Control 
This is a randomized, double-blind, placebo-controlled, two-period crossover trial in subjects 
with genetically confirmed Barth Syndrome, followed by an open-label treatment extension. 
Subjects will be randomized (1:1) to one of two sequence groups: 12-weeks of treatment with 
SC elamipretide in Treatment Period 1 followed by 12-weeks of treatment with placebo in 
Treatment Period 2 (separated by 4-week washout period), or vice versa.   
A 4-week washout was selected to considerably reduce the likelihood of a carryover effect 
based on the known pharmacokinetics of elamipretide and anticipated turnover of 
mitochondria.  The crossover design was selected because of the additional anticipated power 


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due to subjects serving as their own control, given the anticipated scarcity of available 
subjects to participate in this study, due to the ultra-rare nature of this disease. 
Blinded treatment will be used to reduce potential bias during data collection and evaluation 
of endpoints.  
Part 2 is an open-label, uncontrolled treatment in which all subjects will receive elamipretide 
treatment for up to 192 weeks. This treatment period will allow for assessment of longer-term 
safety and tolerability in the target population, as well as allow for detection of less-frequent 
AEs. 
The Part 1 and Part 2 Trial Schematics are presented in Attachment 3.  
6.3. 
Trial Schedule 
Trial procedures and their timing are summarized in the Part 1 and Part 2 Schedule of 
Assessments (trial center visits) (Attachment 1), Part 1 Schedule of Visiting Nurse Assessments 
(Attachment 2), and the Part 1 and Part 2 Trial Schematics (Attachment 3). A list of all clinical 
laboratory tests to be performed is found in Attachment 4. All study center visits should occur 
at approximately (±2 hours) the same time and after at least 3 hours of fasting. Days and Weeks 
are relative to the Pre-dose Visit of the respective Treatment Period in both Part 1 and Part 2.  
6.3.1. 
Part 1   
6.3.1.1. 
Screening Period: Day -28 to Day -1 (minimum of 7 days) x Complete 
the age appropriate BTHS-SA (as described in Section 6.4.12) daily during the 
Screening Period 
6.3.1.1.1. Screening Visit 
NOTE: The 6MWT, 5XSST, HHD, and SWAY Application Balance Assessments should 
be completed in the order described below and on the same day. x Review and sign the 
Informed Consent Form (ICF) x Record demographics (age, gender, ethnicity, race)  
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Review all inclusion and exclusion criteria x Record relevant medical history (as 
described in Section 6.4.1) x Record concomitant medication (including supplements and 
vitamins) (as described in Section 6.4.1) x Complete a physical examination (as described 
in Section 6.4.2) x Collect vital signs (as described in Section 6.4.3) x Complete 12-lead 
resting ECG (as described in Section 6.4.4) x Draw blood and urine for clinical laboratory 
testing and urinalysis as outlined in Attachment 4 (as described in Section 6.4.5) x Collect 
blood and urine for biomarker testing, as outlined in Attachment 4 (as described in 
Section 6.4.6) 
x Collect blood spot (as described in Section 6.4.7) 
x Complete the 2-D and 3-D echocardiograms (as described in Section 6.4.8) x Complete 
the Columbia Suicide Severity Rating Scale (C-SSRS) “Lifetime Recent” (as described in 
Section 6.4.10 and outlined in Attachment 5)  
x Complete the age appropriate PROMIS Short Form Fatigue assessment (as described in 
Section 6.4.11) x Complete the age appropriate Patient Global Impression (PGI) Scales 
(as described in Section 6.4.13) x Complete the Clinician Global Impression (CGI) Scales 
(as described in Section 6.4.14) x Complete the age appropriate Caregiver Global 
Impression (CaGI) Scales (as described in Section 6.4.15)  
x Complete the age appropriate EQ-5D instrument (as described in Section 6.4.16) x 
Conduct the 6MWT (as described in Section 6.4.17 and as outlined in Attachment 14) x 
Complete the 5XSST which should be started after completion of 6MWT and after at 
least 5 minutes rest (should not be more than 30 minutes) (as described in Section 6.4.18 
and as outlined in Attachment 15) x Complete the HHD testing which should be started 
after completion of 5XSST and after at least 5 minutes rest (should not be more than 30 
minutes) (as described in Section 6.4.19) x Complete the SWAY Application Balance 
Assessments (as described in Section 6.4.20 and outlined in Attachment 13) which should 
be performed after completion of the  
HHD and at least 5 minutes rest (should not be more than 30 minutes)  
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Train subject on application of the AVIVO™ MPM System. Apply AVIVO™ MPM 
System to the subject’s chest.  The AVIVO™ MPM System should be used for 
approximately 7 consecutive days following the visit (as described in Section 6.4.9)  
x Schedule next center visit   
6.3.1.2. Treatment Period 1 x Complete the age appropriate BTHS-SA (as described in 
Section 6.4.11) daily during Treatment Period 1 x Subjects (or trained caregivers) will 
administer IMP on a daily basis at approximately the same time each day (e.g. early 
morning, noon, early afternoon, or evening)   
x Subjects will be instructed and reminded at approximately Week 11, to apply and wear a 
new AVIVO™ MPM System for approximately 7 consecutive days immediately prior 
to the Treatment Period 1 Week 12 Visit   
6.3.1.2.1. Treatment Period 1 Baseline (Pre-dose) Visit (Day 1)   
NOTE:  Subjects who have been deemed eligible during Screening Period will return for 
randomization and the following procedures will be performed. All trial procedures must be 
completed prior to administering IMP. The decision to have a subject return for the Days 2 
through 5 Visits and on the schedule of Visiting Nursing Visits for both Treatment Period 1 
and Treatment Period 2 should be made and documented prior to the Treatment Period 1 
Baseline Visit. The 6MWT, 5XSST, HHD, and SWAY Application Balance Assessments 
should be completed in the order described below and on the same day.  
x Review all inclusion and exclusion criteria  
x Document AEs related to a trial procedure and/or meet seriousness criteria that occurred 
since the signing of the informed consent form as described in Section 9.11 
x Update relevant medical history during the Screening Period (as described in Section 
6.4.1) x Update concomitant medication/procedures (including supplements and 
vitamins) during the Screening Period (as described in Section 6.4.1) x Randomize 
subject 
x Complete a physical examination (as described in Section 6.4.2) x Collect vital 
signs (as described in Section 6.4.3) x Complete 12-lead resting ECG (as 
described in Section 6.4.4) x Draw blood and urine for clinical laboratory testing 
and urinalysis as outlined in Attachment 4 (as described in Section 6.4.5) x Collect 
blood and urine for biomarker testing, and metabolomics as outlined in 


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Attachment 4 (as described in Section 6.4.6) (urine metabolomics should be first 
morning void urine sample)  
36 
Collect blood spot (as described in Section 6.4.7) x Complete the 2-D and 
3-D echocardiograms (as described in Section 6.4.8)  
x Complete the C-SSRS “Since Last Visit” (as described in Section 6.4.10 and outlined in 
Attachment 6) x Complete the age appropriate PROMIS Short Form Fatigue assessment 
(as described in Section 6.4.11) x Complete the age appropriate PGI Scales (as described 
in Section 6.4.13) x Complete the CGI Scales (as described in Section 6.4.14)  
x Complete the age appropriate CaGI Scales (as described in Section 6.4.15) x Complete 
the age appropriate EQ-5D instrument (as described in Section 6.4.16) x Conduct the 
6MWT (as described in Section 6.4.17 and as outlined in Attachment 14) x Complete the 
5XSST which should be started after completion of 6MWT and after at least 5 minutes 
rest (should not be more than 30 minutes) (as described in Section 6.4.18 and as outlined 
in Attachment 15) x Complete the HHD testing which should be started after completion 
of 5XSST and after at least 5 minutes rest (should not be more than 30 minutes) (as 
described in Section 6.4.19) x Complete the SWAY Application Balance Assessments (as 
described in Section 6.4.20 and outlined in Attachment 13) which should be performed 
after completion of the HHD and at least 5 minutes rest (should not be more than 30 
minutes) x Inject the IMP 
x Apply a new AVIVO™ MPM System to the subject’s chest.  The new AVIVO™ MPM 
System should be used for approximately 7 consecutive days following the visit (as 
described in Section 6.4.9)  
x Schedule next center visit and discuss visit schedule and how to schedule the Visiting 
Nurse service 
6.3.1.2.2. Treatment Period 1 Days 2 through 5 Visits (optional) 
x Document AEs x Inject the IMP 


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6.3.1.2.3. Treatment Period 1 Visiting Nurse Visits: Week 1 (Day 8 ± 1), Week 4 (Day 
29 ± 2), and Week 8 (Day 57 ± 2)  
A Visiting Nurse will visit the subject at the Treatment Period 1 Week 1 (Day 8 ± 1), Week 4 
(Day 29 ± 2), and Week 8 (Day 57 ± 2). The Visiting Nurse will compete assessments as 
described in the Schedule of Visiting Nurse Assessments (Attachment 2). 
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6.3.1.2.4. Treatment Period 1 Week 12 Visit (Day 85 ±7)  
NOTE:  Subjects will be instructed and reminded at approximately Week 11, to apply and 
wear a new AVIVO™ MPM System for approximately 7 consecutive days immediately prior 
to the Treatment Period 1 Week 12 Visit. Subjects should be instructed to administer the IMP 
on the day of Treatment Period 1 Week 12 Visit, prior to returning to the trial center. The 
6MWT, 5XSST, HHD, and SWAY Application Balance Assessments should be completed in 
the order described below and on the same day. 
x Update concomitant medication/procedures (including supplements and vitamins) 
during the Screening Period (as described in Section 6.4.1)  
x Document AEs  
x Complete a physical examination (as described in Section 6.4.2) x Collect vital 
signs (as described in Section 6.4.3) x Complete 12-lead resting ECG (as 
described in Section 6.4.4) x Draw blood and urine for clinical laboratory testing 
and urinalysis as outlined in Attachment 4 (as described in Section 6.4.5) x Collect 
blood and urine for biomarker testing, and metabolomics as outlined in 
Attachment 4 (as described in Section 6.4.6) (urine metabolomics should be first 
morning void urine sample)  
x Collect blood spot (as described in Section 6.4.7) 
x Complete the 2-D and 3-D echocardiograms (as described in Section 6.4.8)  
x Complete the C-SSRS “Since Last Visit” (as described in Section 6.4.10 and outlined in 
Attachment 6) x Complete the age appropriate PROMIS Short Form Fatigue assessment 
(as described in Section 6.4.11) x Complete the age and Treatment Period appropriate 
PGI Scales (as described in Section 6.4.13) x Complete the Treatment Period appropriate 
CGI Scales (as described in Section 6.4.14) x Complete the age and Treatment Period 
appropriate CaGI Scales (as described in Section 6.4.15) x Complete the age appropriate 
EQ-5D instrument (as described in Section 6.4.16) x Conduct the 6MWT (as described in 
Section 6.4.17 and as outlined in Attachment 14) x Complete the 5XSST which should be 
started after completion of 6MWT and after at least 5 minutes rest (should not be more 
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x Complete the HHD testing which should be started after completion of 5XSST and after 
at least 5 minutes rest (should not be more than 30 minutes) (as described in Section 
6.4.19) x Complete the SWAY Application Balance Assessments (as described in Section 
6.4.20 and outlined in Attachment 13) which should be performed after completion of the 
HHD and at least 5 minutes rest (should not be more than 30 minutes) x Collect all used 
and unused IMP vials from the subject x Schedule next center visit  
6.3.1.3. 
Washout Period (28 days +7)  
Washout will be 28 days (+7 days) in duration. If all used and unused vials were not returned 
at the Treatment Period 1 Week 12 Visit, an unscheduled Visiting Nurse Visit may be 
scheduled to collect all remaining vials. The age appropriate BTHS-SA (as described in 
Section 6.4.12) should be completed daily during the Washout Period.   
6.3.1.4. Treatment Period 2 x Complete the age appropriate BTHS-SA (as described in 
Section 6.4.11) daily during Treatment Period 2 x Subjects (or trained caregivers) will 
administer IMP on a daily basis at approximately the same time each day (e.g. early 
morning, noon, early afternoon, or evening)   
x Subjects will be instructed and reminded at approximately Week 11, to apply and wear a 
new AVIVO™ MPM System for approximately 7 consecutive days immediately prior 
to the Treatment Period 2 Week 12 Visit  
6.3.1.4.1. Treatment Period 2 Pre-dose Visit (Day 1)   
NOTE:  All trial procedures must be completed prior to administering IMP. The 6MWT, 
5XSST, HHD, and SWAY Application Balance Assessments should be completed in the 
order described below and on the same day. x Document AEs 
x Update concomitant medication/procedures (including supplements and vitamins) (as 
described in Section 6.4.1)  
x Complete a physical examination (as described in Section 6.4.2) x Collect vital 
signs (as described in Section 6.4.3) x Complete 12-lead resting ECG (as 
described in Section 6.4.4) x Draw blood and urine for clinical laboratory testing 
and urinalysis as outlined in Attachment 4 (as described in Section 6.4.5)  
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x Collect blood and urine for biomarker testing, and metabolomics as outlined in 
Attachment 4 (as described in Section 6.4.6) (urine metabolomics should be first 
morning void urine sample)  
x Collect blood spot (as described in Section 6.4.7) 
x Complete the 2-D and 3-D echocardiograms (as described in Section 6.4.8)  
x Complete the C-SSRS “Since Last Visit” (as described in Section 6.4.10 and outlined in 
Attachment 6) x Complete the age appropriate PROMIS Short Form Fatigue assessment 
(as described in Section 6.4.11) x Complete the age appropriate PGI Scales (as described 
in Section 6.4.13) x Complete the CGI Scales (as described in Section 6.4.14)  
x Complete the age appropriate CaGI Scales (as described in Section 6.4.15) x Complete 
the age appropriate EQ-5D instrument (as described in Section 6.4.16) x Conduct the 
6MWT (as described in Section 6.4.17 and as outlined in Attachment 14) x Complete the 
5XSST which should be started after completion of 6MWT and after at least 5 minutes rest 
(should not be more than 30 minutes) (as described in Section 6.4.18 and as outlined in 
Attachment 15) x Complete the HHD testing which should be started after completion of 
5XSST and after at least 5 minutes rest (should not be more than 30 minutes) (as described 
in Section 6.4.19) x Complete the SWAY Application Balance Assessments (as described 
in Section 6.4.20 and outlined in Attachment 13) which should be performed after 
completion of the HHD and at least 5 minutes rest (should not be more than 30 minutes) x 
Inject IMP  
x Apply a new AVIVO™ MPM System to the subject’s chest.  The new AVIVO™ MPM 
System should be used for approximately 7 consecutive days following the visit (as 
described in Section 6.4.9)  
x Schedule next center visit and discuss home (or other Investigator agreed upon location) 
visit schedule by the Visiting Nurse 
6.3.1.4.2. Treatment Period 2 Days 2 through 5 Visits (optional) 
x Document AEs x Inject IMP 
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6.3.1.4.3. Treatment Period 2 Visiting Nurse Visits: Week 1 (Day 8 ± 1), Week 4 (Day 
29 ± 2), and Week 8 (Day 57 ± 2)  
A Visiting Nurse will visit the subject at the Treatment Period 2 Week 1 (Day 8 ± 1), Week 4 
(Day 29 ± 2), and Week 8 (Day 57 ± 2). The Visiting Nurse will compete assessments as 
described in the Schedule of Visiting Nurse Assessments (Attachment 2). 
6.3.1.4.4. Treatment Period 2 Week 12 Visit (Day 85 ± 7)   
NOTE:  Subjects will be instructed and reminded at approximately Week 11, to apply and 
wear a new AVIVO™ MPM System for approximately 7 consecutive days immediately prior 
to the Treatment Period 2 Week 12 Visit. Subjects should be instructed to administer the IMP 
on the day of Treatment Period 2 Week 12 Visit, prior to returning to the trial center.  The 
6MWT, 5XSST, HHD, and SWAY Application Balance Assessments should be completed in 
the order described below and on the same day. 
x Update concomitant medication/procedures (including supplements and vitamins) 
during the Screening Period (as described in Section 6.4.1)  
x Document AEs  
x Complete a physical examination (as described in Section 6.4.2) x Collect vital 
signs (as described in Section 6.4.3) x Complete 12-lead resting ECG (as 
described in Section 6.4.4) x Draw blood and urine for clinical laboratory testing 
and urinalysis as outlined in Attachment 4 (as described in Section 6.4.5) x Collect 
blood and urine for biomarker testing, and metabolomics as outlined in 
Attachment 4 (as described in Section 6.4.6) (urine metabolomics should be first 
morning void urine sample)  
x Collect blood spot (as described in Section 6.4.7) 
x Complete the 2-D and 3-D echocardiograms (as described in Section 6.4.8)  
x Complete the C-SSRS “Since Last Visit” (as described in Section 6.4.10 and outlined in 
Attachment 6) x Complete the age appropriate PROMIS Short Form Fatigue assessment 
(as described in Section 6.4.11) x Complete the age and Treatment Period appropriate 
PGI Scales (as described in Section 6.4.13) x Complete the Treatment Period appropriate 
CGI Scales (as described in Section 6.4.14) x Complete the age and Treatment Period 
appropriate CaGI Scales (as described in Section 6.4.15) x Complete the age appropriate 
EQ-5D instrument (as described in Section 6.4.16) x Conduct the 6MWT (as described in 
Section 6.4.17 and as outlined in Attachment 14)  


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x Complete the 5XSST which should be started after completion of 6MWT and after at 
least 5 minutes rest (should not be more than 30 minutes) (as described in Section 6.4.18 
and as outlined in Attachment 15) x Complete the HHD testing which should be started 
after completion of 5XSST and after at least 5 minutes rest (should not be more than 30 
minutes) (as described in Section 6.4.19) x Complete the SWAY Application Balance 
Assessments (as described in Section 6.4.20 and outlined in Attachment 13) which should 
be performed after completion of the HHD and at least 5 minutes rest (should not be more 
than 30 minutes) x Collect all used and unused IMP vials from the subject x Schedule 
next center visit o Post-treatment Part 1 Follow-Up Visit for subjects not continuing into 
Part 2. o Week 28 visit for subjects continuing into Part 2.  
6.3.1.5. 
Part 1 Follow-Up Period (28 days +7) (for subjects not continuing into Part 2) 
At Treatment Period 2 Week 12 Visit, the subject and the Investigator will determine whether 
the subject will continue into Part 2 (confirming the subject meeting the Continuation 
Criteria). Subjects who will not continue into Part 2 will complete the Part 1 Follow-Up 
Period and Part 1 End-of-Trial Visit.  
For subjects not continuing into Part 2, the Part 1 Follow-Up Period will begin after 
completion of the Treatment Period 2 Week 12 Visit.   
The Part 1 Follow-Up Period will be 4 weeks in duration. If all used and unused vials were 
not returned at the Treatment Period 2 Week 12 Visit, an unscheduled Visiting Nurse Visit 
may be scheduled to collect all remaining vials.  The age appropriate BTHS-SA (as described 
in Section 6.4.12) should be completed daily during the Part 1 Follow-up Period. Subjects 
will return to the clinical site for the Part 1 End-of-Trial Visit for final safety assessments, as 
described in the Part 1 Schedule of Assessments, and return all remaining trial-related 
supplies not previously returned.  
6.3.1.5.1. End-of-Trial/Early Discontinuation Visit (Day 113 + 7 days) /Early 
Discontinuation (for subjects not continuing into Part 2) 
NOTE: The 6MWT, 5XSST, HHD, and SWAY Application Balance Assessments should be 
completed in the order described below and on the same day.  
x Update concomitant medication/procedures (including supplements and vitamins) since 
the last visit (as described in Section 6.4.1)  
x Document AEs  
x Complete a physical examination (as described in Section 6.4.2) x 
Collect vital signs (as described in Section 6.4.3)  


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x Complete 12-lead resting ECG (as described in Section 6.4.4) x Draw blood and 
urine for clinical laboratory testing and urinalysis as outlined in Attachment 4 (as 
described in Section 6.4.5) x Collect blood and urine for biomarker testing, and 
metabolomics as outlined in Attachment 4 (as described in Section 6.4.6) (urine 
metabolomics should be first morning void urine sample)  
x Collect blood spot (as described in Section 6.4.7) 
x Complete the 2-D and 3-D echocardiograms (as described in Section 6.4.8)  
x Complete the C-SSRS “Since Last Visit” (as described in Section 6.4.10 and outlined in 
Attachment 6) x Complete the age appropriate PROMIS Short Form Fatigue assessment 
(as described in Section 6.4.11) x Complete the age appropriate PGI Scales (as described 
in Section 6.4.13) x Complete the CGI Scales (as described in Section 6.4.14)  
x Complete the age appropriate CaGI Scales (as described in Section 6.4.15) x Complete 
the age appropriate EQ-5D instrument (as described in Section 6.4.16) x Conduct the 
6MWT (as described in Section 6.4.17 and as outlined in Attachment 14) x Complete the 
5XSST which should be started after completion of 6MWT and after at least 5 minutes 
rest (should not be more than 30 minutes) (as described in Section 6.4.18 and as outlined 
in Attachment 15) x Complete the HHD testing which should be started after completion 
of 5XSST and after at least 5 minutes rest (should not be more than 30 minutes) (as 
described in Section 6.4.19) x Complete the SWAY Application Balance Assessments (as 
described in Section 6.4.20 and outlined in Attachment 13) which should be performed 
after completion of the HHD and at least 5 minutes rest (should not be more than 30 
minutes) x Collect all used and unused vials from the subject 
6.3.2. 
Part 2 
6.3.2.1. 
Part 2 Treatment Period  
The Part 2 Treatment Period will include both clinical site visits and phone calls (or other 
forms of communication) from the site staff.   
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6.3.2.1.1. Clinical Site Visits: Weeks12 (±1week), and Weeks24, 36, 48, 72, 96, 120, 144, 
168, and 192 (± 2 weeks for each visit) 
At all clinical site visits during the Part 2 Treatment Period visits, subjects will return used 
IMP supplies. At the Part 2 Week 192 visit, subjects will return all trial-related supplies. On 
the day of the Visit that the PK samples are collected (at the earliest clinical site visit in Part 2 
[at or after the Week 12 Visit in Part 2]), subjects should be instructed to administer the IMP 
at the trial center. 
NOTE: The 6MWT, 5XSST, HHD, and SWAY Application Balance Assessments should be 
completed in the order described below and on the same day.  
x Update concomitant medication/procedures (including supplements and vitamins) since 
the last visit (as described in Section 6.4.1) 
x Document AEs 
x Complete a physical examination (as described in Section 6.4.2) x Collect vital 
signs (as described in Section 6.4.3) x Complete 12-lead resting ECG (as 
described in Section 6.4.4) x Draw blood and urine for clinical laboratory testing 
and urinalysis as outlined in Attachment 4 (as described in Section 6.4.5) x Collect 
blood and urine for biomarker testing, and metabolomics as outlined in 
Attachment 4 (as described in Section 6.4.6) (urine metabolomics should be first 
morning void urine sample) 
x Collect blood spot (as described in Section 6.4.7) 
x Complete the 2-D and 3-D echocardiograms (as described in Section 6.4.8) 
x Complete the C-SSRS “Since Last Visit” (as described in Section 6.4.10 and outlined in 
Attachment 6) x Complete the age appropriate BTHS-SA (as described in Section 6.4.12) 
x Complete the age appropriate PROMIS Short Form Fatigue assessment (as described in 
Section 6.4.11) x Complete the age appropriate PGI Scales (as described in Section 
6.4.13) x Complete the CGI Scales (as described in Section 6.4.14) 
x Complete the age appropriate CaGI Scales (as described in Section 6.4.15) x 
Complete the age appropriate EQ-5D instrument (as described in Section 6.4.16) x 
Conduct the 6MWT (as described in Section 6.4.17 and as outlined in Attachment 14) x 
Complete the 5XSST which should be started after completion of 6MWT and after at 
least 5 minutes rest (should not be more than 30 minutes) (as described in Section 
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x Complete the HHD testing which should be started after completion of 5XSST and after 
at least 5 minutes rest (should not be more than 30 minutes) (as described in Section 
6.4.19) x Complete the SWAY Application Balance Assessments (as described in Section 
6.4.20 and outlined in Attachment 13) which should be performed after completion of the 
HHD and at least 5 minutes rest (should not be more than 30 minutes) x Collect all used 
and unused vials from the subject 
x Draw blood for PK testing as described in Section 6.4.21 (at the earliest clinical site 
visit in Part 2 (at or after the Week 12 Visit in Part 2): o Pre-dose (-30 min) o 
0.5h (± 5 min) o 1h (± 10 min) o 2h (± 15 min) o 4h (± 15 min) 
6.3.2.1.2. Phone Calls (or other forms of communication): Part 2 Weeks 60, 84, 108, 
132, 156, 180 (± 2 weeks for each visit) 
A phone call (or other forms of communication) from the site will be made to the subject to 
assess AEs/ADEs and concomitant medications (see Attachment 17 for a sample of the 
telephone script to use). 
6.3.2.2. 
Part 2 Follow-Up Period (4 weeks [+7 days])  
The Part 2 Follow-Up Period will begin after completion of the Part 2 EOT Visit and will last 
for 4 weeks. Subjects will continue to follow all trial requirements. Subjects will return to the 
clinical site for the Part 2 End-of-Trial Visit for final assessments, as described in the Part 2 
Schedule of Assessments, and return all remaining trial-related supplies not previously 
returned.  Subjects enrolling another SBT follow-on clinical trial in Barth syndrome or EAP 
will not participate in the Part 2 Follow-Up Period, and the Part 2 EOT Visit will be 
considered the end-of-trial visit. 
6.3.2.2.1. Part 2 End-of-Trial/Early Discontinuation Visit (Week 196 +7 days)  
NOTE: The 6MWT, 5XSST, HHD, and SWAY Application Balance Assessments should be 
completed in the order described below and on the same day.  
x Update concomitant medication/procedures (including supplements and vitamins) since 
the last visit (as described in Section 6.4.1)  
x Document AEs  
x Complete a physical examination (as described in Section 6.4.2) x 
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x Complete 12-lead resting ECG (as described in Section 6.4.4) x Draw blood and 
urine for clinical laboratory testing and urinalysis as outlined in Attachment 4 (as 
described in Section 6.4.5) x Collect blood and urine for biomarker testing, and 
metabolomics as outlined in Attachment 4 (as described in Section 6.4.6) (urine 
metabolomics should be first morning void urine sample)  
x Collect blood spot (as described in Section 6.4.7) 
x Complete the 2-D and 3-D echocardiograms (as described in Section 6.4.8)  
x Complete the C-SSRS “Since Last Visit” (as described in Section 6.4.10 and outlined in 
Attachment 6) x Complete the age appropriate BTHS-SA (as described in Section 6.4.12) 
x Complete the age appropriate PROMIS Short Form Fatigue assessment (as described in 
Section 6.4.11) x Complete the age appropriate PGI Scales (as described in Section 
6.4.13) x Complete the CGI Scales (as described in Section 6.4.14)  
x Complete the age appropriate CaGI Scales (as described in Section 6.4.15) x Complete 
the age appropriate EQ-5D instrument (as described in Section 6.4.16) x Conduct the 
6MWT (as described in Section 6.4.17 and as outlined in Attachment 14) x Complete the 
5XSST which should be started after completion of 6MWT and after at least 5 minutes 
rest (should not be more than 30 minutes) (as described in Section 6.4.18 and as outlined 
in Attachment 15) x Complete the HHD testing which should be started after completion 
of 5XSST and after at least 5 minutes rest (should not be more than 30 minutes) (as 
described in Section 6.4.19) x Complete the SWAY Application Balance Assessments (as 
described in Section 6.4.20 and outlined in Attachment 13) which should be performed 
after completion of the HHD and at least 5 minutes rest (should not be more than 30 
minutes) x Collect all used and unused vials from the subject 
6.4. 
Trial Assessments  
The following section describes trial assessments occurring during the trial. Trial assessments 
and their timing are summarized in the Part 1 and Part 2 Schedule of Assessments (trial center 
visits) (Attachment 1) and the Schedule of Visiting Nurse Assessments (Attachment 2).   
6.4.1. 
Medical History and Concomitant Medications/Procedures 
Relevant medical history (in the opinion of the Investigator) and any concomitant 
medications will be recorded during the Screening Visit.  At the Baseline Visit, a review of 
any additional  
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medical history and/or new concomitant medication/procedures that occurred during the 
Screening Period will be taken. Concomitant medications/procedures should be updated and 
recorded at each center visit.   
6.4.2. 
Physical Examination  
During all trial center visits, a complete physical examination will be performed at each 
center visit. The physical examination 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, and weight. Height will be 
measured during all physical examinations. 
6.4.3. 
Vital signs 
During all trial center visits and Visiting Nurse 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.  
6.4.4. 
Electrocardiograms (ECGs) 
A 12-lead ECG will be obtained after the subjects has rested quietly for 10 minutes in the 
supine position. 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.  
6.4.5. 
Clinical Laboratory Testing 
Sample collection, processing and handling details are provided in the Laboratory Manual.   
6.4.5.1. 
Blood Chemistries 
Blood will be collected at trial center visits and Visiting Nurse Visits. Analysis will include 
testing for parameters included in Attachment 4.  
6.4.5.2. 
Hematology 
Blood will be collected at trial center visits and Visiting Nurse Visits. Analysis will include 
testing for parameters included in Attachment 4.  
6.4.5.3. 
Urinalysis 
Urine will be collected at trial center visits and Visiting Nurse Visits. Analysis will include 
testing for parameters included in Attachment 4.  
6.4.6. 
Biomarker Testing  
Sample collection, processing and handling details are provided in the Laboratory Manual.  


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Blood and urine will be collected for analysis of biomarkers as outlined in Attachment 4. 
Urine metabolomics should be first morning void urine sample. Additional blood samples 
will be collected and stored, for assessing the immunogenicity potential of the IMP, at the 
Baseline  
47 
Visit of Treatment Period 1, Treatment Period 2 Week 12 Visit, and (if applicable) Part 1 or 
Part 2 Early Discontinuation Visits. 
6.4.7. 
Blood Spot 
A blood spot test will be completed at trial center visits. Analysis will include testing for 
parameters included in Attachment 4. 
6.4.8. 
2-D and 3-D Echocardiographs 
2-D and 3-D echocardiograms will be performed. Parameters to be assessed include: 
2-D x Left ventricular (LV) end-diastolic volume (mL) 
x LV end-systolic volumes (mL) x LV ejection 
fraction (EF) (%) x LV dimensions o LVSd (cm) 
o LVSs (cm) o LVIDd (cm) o LVIDs (cm) o 
LVPWd (cm) o LVPWs (cm) 
x LV fractional shortening (%) x LV global 
longitudinal strain (triplane) (%) x LV peak 
systolic strain o apical 4 chamber view (%) 
o apical 2 chamber view (%) o apical LAX 
view (%) 
x Left atrial volume (mL) x LV mass 
(g) x Diastology  o Peak E (m/s) o 
Peak A (m/s) o Medial MV annulus 
e (m/s) o Medial MV annulus a 
(m/s) 


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o Lateral MV annulus e (m/s) 
o Lateral MV annulus a (m/s)  
x Measurement of non-compaction (Chin and Jenni methods): 
o Chin: ratio (X/Y) at LV apex at end-diastole o 
Jenni: ratio (NC/C) at LV apex at end-systole         
x Aortic valve regurgitation (semi-quantitative) (trivial, mild, moderate, severe) 
x Mitral regurgitation (semi-quantitative) (trivial, mild, moderate, severe) x 
Tricuspid regurgitation (semi-quantitative) (trivial, mild, moderate, severe) x 
Structural abnormalities 
3-D x LV end-diastolic volume (mL) 
x LV end-systolic volumes (mL) 
x LV EF% 
6.4.9. 
AVIVO™ Mobile Patient Management (MPM) System  
The AVIVO™ Mobile Patient Management (MPM) System is intended to continuously 
measure, record and periodically transmit physiological data including, but not limited to, 
ECG and activity (accelerometry).  
In Part 1, starting at the Screening Visit, subjects will be provided with an AVIVO™ MPM  
System which will be applied, as instructed in the product manual, at trial center visits by the 
Investigator (or designee) or subject (or trained caregiver). The Investigator (or designee) will 
educate the subject on appropriate application and use of the AVIVO™ MPM System. A new 
AVIVO™ MPM System will also be provided and applied at the trial center at Treatment 
Period 1 Baseline and Treatment Period 2 Pre-dose Visits. Subjects will be instructed and 
reminded to apply and wear a new AVIVO™ MPM System at approximately Week 11, 
immediately prior to the Treatment Period 1 Week 12 Visit and the Treatment Period 2 Week 
12 Visit.  Subjects will be instructed to wear each AVIVO™ MPM System for approximately 
7 consecutive days after each application. Subjects will return all AVIVO™ MPM Systems 
by the completion of his/her participation in the trial. 
The AVIVO™ MPM System will not be used in Part 2.  
6.4.10. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
At the Screening Visit, the C-SSRS “Lifetime Recent” will be completed and recorded. The 
C- 


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SSRS “Lifetime Recent” is included in Attachment 5. At all other trial center visits, the 
CSSRS “Since Last Visit” will be recorded.  The C-SSRS “Since Last Visit” is included in 
Attachment 6. 
49 
6.4.11. 
PROMIS Short Form Fatigue  
The age appropriate PROMIS Short Form Fatigue should be completed. The age appropriate 
PROMIS Short Form Fatigue instruments are provided in Attachment 7. For subjects ≥ 18 
years of age at the Screening Visit, the PROMIS Adult Short Form Fatigue should be 
completed. Subjects 12-17 years of age at the Screening Visit, the PROMIS Pediatric Short 
Form Fatigue should be completed for the duration of the trial.  
6.4.12. 
BarTH Syndrome Symptom Assessment (BTHS-SA) 
In Part 1, the age appropriate BTHS-SA should be completed daily by the subject in a diary 
starting at the Screening Visit and continued until the Part 1 Treatment Period 2 Week 12 
Visit (for subjects continuing into Part 2) or Part 1 End-of-Trial/Early Discontinuation Visit 
(for subjects not continuing into Part 2). In Part 2, the age appropriate BTHS-SA should be 
completed ONLY at the clinical site visits. The age appropriate BTHS-SAs are provided in 
Attachment 8. For subjects ≥ 16 years of age at the Screening Visit, the BTHS-SA Adult 
should be completed. Subjects 12-15 years of age at the Screening Visit, the BTHS-SA 
Adolescent should be completed for the duration of the trial.  
6.4.13. 
Patient Global Impression (PGI) Scales 
The age appropriate PGI Scales should be completed to assess their overall assessment of 
their symptoms related to their diagnosis of Barth Syndrome. The age appropriate PGI Scales 
are provided in Attachment 9. For subjects ≥ 16 years of age at the Screening Visit, the PGI 
Adult should be completed. Subjects 12-15 years of age at the Screening Visit, the PGI 
Adolescent should be completed for the duration of the trial. The age and Treatment Period 
appropriate PGI of Change Scales should be completed only at Week 12 of Treatment Period 
1 and Week 12 of Treatment Period 2.   
6.4.14. 
Clinician Global Impression (CGI) Scales  
The Investigator or designee will provide an overall assessment of the subject’s symptoms 
related to their diagnosis of Barth Syndrome at all trial center visits. The CGI Scales are 
provided in Attachment 10.  The same Investigator or designee should administer the CGI at 
each visit for a particular subject. The Treatment Period appropriate CGI of Change Scale 


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should be completed only at Week 12 of Treatment Period 1 and Week 12 of Treatment 
Period 2. 
6.4.15. 
Caregiver Global Impression (CaGI) Scales  
The age appropriate CaGI Scales should be completed (if applicable) by a caregiver of the 
subject to assess the caregiver’s overall assessment of the subject’s symptoms related to their 
diagnosis of Barth Syndrome. The age appropriate CaGI Scales are provided in Attachment 
11. The same caregiver should complete the age appropriate CaGI at each visit for a 
particular subject. For subjects ≥ 16 years of age at the Screening Visit, the CaGI Adult 
should be completed by the caregiver. Subjects 12-15 years of age at the Screening Visit, the 
CaGI Adolescent should be completed by the caregiver for the duration of the trial. The age 
and Treatment Period appropriate CaGI of Change Scales should be completed only at Week 
12 of Treatment Period 1 and Week 12 of Treatment Period 2.   
50 
6.4.16. 
EQ-5D  
An age appropriate EQ-5D should be completed. The age appropriate EQ-5D instrument is 
provided in Attachment 12. For subjects ≥ 16 years of age at the Screening Visit, the EQ-
5D5L should be completed. Subjects 12-15 years of age at the Screening Visit, the EQ-5D-Y 
should be completed for the duration of the trial. 
6.4.17. 
6-Minute Walk Test (6MWT) 
At all trial center visits, the distance walked (in meters) during the 6MWT will be recorded.  
The 6MWT instructions are provided in Attachment 14.  The Investigator (or designee) 
conducting the 6MWT should not be the same Investigator (or designee) completing the 
safety assessments for a particular subject.  
6.4.18. 
5X Sit to Stand Test (5XSST)  
At all trial center visits, the time (in seconds) to complete the 5XSST will be recorded.  The 
5XSST instructions are provided in Attachment 15. The 5XSST Test should be performed 
after completion of the 6MWT and at least 5 minutes rest (should not be more than 30 
minutes). The Investigator (or designee) conducting the 5XSST should not be the same 
Investigator (or designee) completing the safety assessments for a particular subject. 
6.4.19. 
Handheld Dynamometry (HHD)   
The day of assessment the handheld dynamometer will be calibrated using a 2-kg weight:  
1. Using a 2-kg weight:  
2. Turn the handheld dynamometer on with the round flat transducer head up and the 
reading frame facing tester. Place in foam carrying case.  


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3. Press reset button. 
4. Place calibration weight on the transducer pad. Verify the weight is centered and 
stable.  
5. Read force reading displayed in “read force” LCD while weight is resting on the 
transducer pad.  
If there is more than a 5% difference, contact manufacturer and do not conduct the HHD 
testing with that dynamometer. At all trial center visits, HHD assessments will be completed 
and recorded.  The HHD assessments should be performed after completion of the 5XSST 
and at least 5 minutes rest (should not be more than 30 minutes). Handheld dynamometry 
will assess the knee extensors of both legs. Subjects should be positioned in a short sitting 
position on adjustable height treatment mat with hips and knee flexed to 90 degrees with feet 
unsupported. The handheld dynamometer should be positioned on the anterior surface of 
lower leg, just proximal to the ankle. The tester position should be kneeling in front of the 
subject. Subject will be provided with the following instructions: “Straighten your knee, 
push, push, push.” Strength will be assessed via “make technique” where tester will 
resist/match the maximum isometric contraction for 5 seconds to allow full muscle fiber 
recruitment. Perform on right lower extremity and then left and repeat (right, left, right, left). 
The average of the two attempts for each extremity will be analyzed.  
51 
The Investigator (or designee) conducting the HHD should not be the same Investigator (or 
designee) completing the safety assessments for a particular subject. 
6.4.20. 
SWAY Application Balance Assessments 
The SWAY Application Balance Assessments will be complete and recorded. The SWAY  
Application Balance Assessments instructions are provided in Attachment 13. The 
Investigator  
(or designee) conducting the SWAY Application Balance Assessments should not be the same  
Investigator (or designee) completing the safety assessments for a particular subject. The 
SWAY Application Balance Assessments should be performed after completion of the HHD 
and at least 5 minutes rest (should not be more than 30 minutes).  
6.4.21. 
Pharmacokinetic (PK) Sampling 
To characterize the PK of elamipretide and metabolites, PK sampling will be conducted at 
defined time points at the earliest clinical site visit in Part 2 (at or after the Week 12 Visit in 
Part 2). To reduce trial procedure burden, PK sampling may be completed during the earliest 
scheduled clinical site visit in Part 2 (at or after the Week 12 Visit in Part 2) or at an 
independent clinical site visit. Additionally, to reduce the need for multiple venipunctures, in 


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the opinion of the Investigator, a venous catheter may be used for PK sample collection. 
Blood samples for PK determinations of elamipretide and metabolites concentrations will be 
collected as follows:  
x Pre-dose (-30 min) 
x 0.5h (± 5 min) x 1h 
(± 10 min) x 2h (± 15 
min) x 4h (± 15 min)   
Sample collection, processing and handling details are provided in the Laboratory Manual.  
6.5. 
Data and Safety Monitoring Board 
For Part 1, an external DSMB meeting is to be held at regular intervals to evaluate the safety 
of this study. The role of the DSMB members is to evaluate the safety within each treatment 
group on an ongoing basis in order to determine whether any undue safety concerns are 
observed, and thus whether the study should be allowed to continue enrollment.   
A detailed DSMB charter will be prepared by the Sponsor and agreed to by all DSMB members 
before initiation of enrollment in this study. This charter will document the timing, membership, 
analysis content, and review procedures for each DSMB meeting.  Safety analyses will include, 
at a minimum, summaries of study disposition and all TEAEs, SAEs, deaths, and 
discontinuations due to AEs, laboratory results, and individual subject listings of selected safety 
data. 
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 7. 
TRIAL POPULATION 
The inclusion and exclusion criteria for participation in this trial are provided below. All 
screening assessments must be completed during the Screening Period, but may be performed 
on different days. Screening assessments should not be repeated, and subjects cannot be 
rescreened without the Sponsor’s approval.  If a subject is re-screened, they will maintain 
their original screening number. Subjects may only be enrolled into the trial one time.  
Prospective approval of protocol deviations to 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 at the Baseline Visit: 


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1. Willing and able to provide signed informed consent form (ICF) prior to participation 
in any trial-related procedures. If applicable, informed consent in writing from 
parent(s) or legally-acceptable representative(s) and, informed assent from subject (if 
age appropriate according to local requirements) should be provide  
2. Agrees to adhere to the trial requirements for the length of the trial 
3. Genetically confirmed Barth Syndrome in the opinion of the Investigator   
4. Male aged ≥ 12 years  
5. At the Screening Visit, subject body weight and estimated glomerular filtration rate 
(eGFR) meeting one of the following: 
a. Body weight >30 kg AND eGFR ≥ 90 mL/min/1.73 m2 at the Screening visit 
b. Body weight >40 kg AND eGFR ≥ 60 mL/min/1.73 m2 at the Screening visit 
eGFR will be calculated using the Modification of Diet in Renal Disease (MDRD)  
equation:  
eGFR (mL/min/1.73 m2) = 175 x (SCr*)-1.154 x (Age)-0.203 x (0.742 
if female) x (1.212 if African American)            *=serum creatinine  
6. Ambulatory and impaired, in the opinion of the Investigator, during the 6-Minute 
Walk Test at the Baseline Visit 
7. Subject has been on stable (unchanged and constant) medications (including over-
thecounter treatments, vitamins, or supplements), or medications that will not impact 
the safety or efficacy endpoints of the trial, in the opinion of the Investigator for at 
least 30 days prior to the Baseline Visit 
8. Male subjects with female partners of child-bearing potential must be willing to use a 
highly effective method of contraception (see Section 9.11.1 for details) from the  
Screening Visit through at least 2 months following the last injection 
53 
7.2. 
Exclusion Criteria 
A subject must NOT meet any of the following exclusion criteria at the Baseline Visit: 
1. Participated in another interventional clinical trial within 30 days of or is currently 
enrolled in a non-interventional clinical trial at the Baseline Visit judged by the 
Investigator to be potentially confounding with the current trial 


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2. 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 
3. Undergone an in-patient hospitalization within 30 days prior to the Baseline Visit or is 
likely to need in-patient hospitalization or surgical procedure during the course of the 
trial 
4. Subject is undergoing an apparent pubertal growth spurt in the opinion of the 
Investigator  
5. Subject has uncontrolled hypertension in the judgment of the Investigator (e.g. 
consistently elevated above >160 mmHg systolic or >100 mmHg diastolic despite 
appropriate treatment) 
6. Subject has a history of clinically significant hypersensitivity or allergy to any of the 
excipients contained in the investigational medicinal product (IMP)  
7. Subject has a history of active substance abuse during the year before the Baseline 
Visit, or is thought, for any reason, likely not to be compliant in the opinion of the 
Investigator  
8. History of heart transplantation or current placement (or within the past year) on the 
waiting list for a heart transplantation  
9. a. For subjects with an implantable cardioverter defibrillator (ICD): the known 
occurrence of ICD therapy/discharge in the 3 months prior to the Baseline Visit and/or 
expected to undergo re-implantation during the conduct of the study   
b. For subjects without an implantable cardioverter defibrillator (ICD): expected to 
undergo an implantation of an ICD during the conduct of the study  
10. Currently receiving treatment with chemotherapeutic agents or immunosuppressant 
agents or has received prior radiation therapy to the chest  
11. Recipient of stem cell or gene therapy or is currently being treated by a therapeutic 
investigational device    
7.3. 
Part 2 Continuation Criteria  
A subject must meet all of the following Part 2 Continuation Criteria at the Treatment Period 
2 Week 12 Visit of Part 1 to be eligible for Part 2: 
1. Subjects must continue to be able and willing to adhere to the trial requirements   
2. Subject is appropriate to continue in Part 2 (i.e. subject was compliant in Part 1), in 
the opinion of the Investigator  
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3. Subject has not had a serious adverse event (SAE) related to the IMP 
4. Subject has not permanently discontinued the IMP  
7.4. 
Prohibited Medications 
The use of any other investigational drug except elamipretide is prohibited during the conduct 
of the current trial.  
The concurrent use of sacubitril (an antihypertensive drug used in combination with valsartan 
marketed under the brand name, Entresto, in the US) is prohibited, due to a lack of current 
information regarding possible drug interactions.  
All medications, including over-the-counter treatments, vitamins, or supplements, must have 
been stable, in the opinion of the Investigator, for at least 30 days prior to the Baseline Visit 
and is not planning on beginning new therapy during the trial. All concomitant medications 
will be recorded in the source data and the Electronic Case Report Form (eCRF). Changes in 
dosages of current medications (including over-the-counter vitamins or supplements) during 
the conduct of the trial will be discouraged, unless required to treat an Adverse Event.  
Subjects will be instructed to maintain their normal diet, daily caffeine, and fiber intake 
throughout the trial period.    
7.5. 
Discontinuations 
7.5.1. 
Discontinuation of Subjects 
Subjects may be discontinued for the following reasons:  
x Investigator Decision o The Investigator decides that the subject should be 
discontinued from the trial for any reason.  
x Subject Decision  o The subject or the subject’s designee, (e.g., parents or legal 
guardian), requests to be withdrawn from the trial.   
 Subjects who withdraw should be explicitly asked about the 
contribution of possible adverse events to their decision to withdraw 
consent, and any adverse event 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 trial 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. 


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x Sponsor Decision  
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o The Sponsor or its designee stops the trial or stops the subject’s participation in 
the trial for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP guidelines.  
x Adverse Event  o If the Investigator decides that the subject should be withdrawn 
because of an AE or a clinically significant laboratory value, the investigational 
product is to be discontinued and appropriate measures are to be taken.  The 
Sponsor or its designee is to be alerted immediately.   
Any subject withdrawing from the trial will be asked to complete the Part 1 or Part 2 Early 
Discontinuation Visit assessments (Attachment 1), as appropriate.    
7.5.2. 
Discontinuation of Trial Center  
Trial center (research center) participation may be discontinued if the Sponsor or its designee, 
the Investigator, or the Ethics Committee (EC) of the trial center judges it necessary for 
medical, safety, regulatory, or other reasons consistent with applicable laws, regulations, and 
GCP guidelines.  
7.5.3. 
Discontinuation of the Trial 
The trial will be discontinued if the Sponsor or its designee judges it necessary for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and GCP 
guidelines.  


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 8. 
TREATMENT 
8.1. 
Treatments Administered 
This randomized, double-blind, placebo-controlled crossover trial followed by an open-label 
treatment extension assessment will enroll approximately 12 subjects who have genetically 
confirmed Barth Syndrome. Subjects will be randomized (1:1) to one of two sequence 
groups: 12-weeks of single daily subcutaneous (SC) doses of 40 mg elamipretide in 
Treatment Period 1 followed by 12-weeks of treatment with placebo in Treatment Period 2 
(separated by 4-week washout period), or vice versa. Subjects who will continue into Part 2 
will receive up to 192 weeks of single daily SC doses of 40 mg elamipretide. The Part 1 and 
Part 2 Trial Schematics are presented in Attachment 3. IMP may be administered daily to the 
subject in the abdomen (rotating around the four abdominal quadrants) or thigh, provided that 
it is at least 5 cm from the previous day’s location of administration, by either a trained 
caregiver or the subject. Administration of IMP will occur at approximately the same time 
every day (e.g. early morning, noon, early afternoon, or evening) during each Treatment 
Period.   
At the Treatment Period 1 Baseline and Treatment Period 2 Pre-dose Visits, IMP will be 
administered after completion of all specified procedures (Section 6.3.1.2.1 and Section 
6.3.1.4.1).  Subjects or caregivers will receive instruction on scheduling daily home (or other 
Investigator agreed upon location) visits with the Visiting Nurse and may be assigned a 
Visiting Nurse to administer IMP subcutaneously at the Treatment Period 1 Week 1, Week 4, 
and Week 8 Visiting Nurse Visits and Treatment Period 2 Week 1, Week 4, and Week 8 
Visiting Nurse Visits. Subjects (or caregivers) will be trained on the procedure for 
administration of IMP and will administer IMP on a daily basis at approximately the same 
time each day (e.g. early morning, noon, early afternoon, or evening).    
If, for any reason, a subject (or trained caregiver) is unable/unwilling to administer IMP, a 
Visiting Nurse or clinical site staff may administer IMP. 
8.2. 
Materials and Supplies 
IMP (elamipretide and placebo for Part 1 and only elamipretide for Part 2) will be dispensed, 
stored, and administered according to the Pharmacy Manual.  
8.2.1. 
Elamipretide 
Elamipretide drug product will be provided as a sterile solution for administration by SC 
injection. Additional details regarding the IMP will be provided in the Pharmacy Manual.    
8.2.2. 
Placebo 
Placebo will be provided as a sterile solution for administration by SC injection. Additional 
details regarding the IMP will be provided in the Pharmacy Manual.    


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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 vials of IMP.  These records should contain the dates, 
quantity, and IMP:  
x Received at trial center x 
Administered to each subject x 
Dispensed to each subject x 
Returned from each subject 
x Disposed of at the trial center or returned to the Sponsor or designee  
The clinical monitor responsible for the trial center will provide written approval for the 
destruction or return of unused IMP vials following reconciliation of all clinical supplies. 
8.4. 
Rationale for Selection of Doses in the Trial 
Multiple clinical pharmacology studies have been conducted to date, 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 
pharmacokinetics (PK) of single (2-80 mg) and 7-day repeat-dose administration (6-80 mg) 
of ascending doses of elamipretide administered subcutaneously (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 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.  
The SPIMM-201 trial provides supporting information regarding safety and plasma exposure 
in the PMD 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.  


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Elamipretide demonstrated an acceptable safety and tolerability profile. The primary efficacy 
endpoint (distance walked during 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 3.    
58 
Table 3: SPIMM-201:  Mean Steady-State PK Parameters* on Day 5 (males and females 
combined) Following Repeat Administration of elamipretide (MTP131) 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] 
1992  [n=5] 
M1 
183  [n=9] 
1672  [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 
1050  [n=9] 
4050  [n=7] 
M1 
285  [n=9] 
2190  [n=7] 
M2 
68.8 [n=9] 
1169  [n=8] 
*Calculations based on nominal time points.  Data is draft and QC’d. 
Bioavailability for Cmax and AUC0-last following administration of a TDD of 40 mg 
elamipretide as a two hour, IV infusion and as a single SC injection can be estimated by 
applying a correction factor to the IV parameters to normalize TDD to 40 mg (assumes 
proportionality of relationship between dose levels and exposure parameters for elamipretide, 
M1 and M2, as previously described) and deriving percentage exposures (Table 4). 


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Table 4: 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 SC 
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 
1418 
5468 
1,300 
3,720 
92% 
68% 
M1 
385 
2957 
436 
3,100 
113% 
105% 
M2 
92.9 
1578 
88.0 
1,950 
95% 
124% 
*Calculations based on nominal time points.  Data is draft and QC’d. 
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 trial in subjects weighing <80 kg 
therefore, treatment effect is not likely to be altered by the change in dose route. 
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  
59 
daily. No systemic toxicity was apparent at any elamipretide dose tested and the predominant 
trial 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 5.   
Table 5: 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 
Trial / NOAEL 
Species 
Analyte 
Cmax 
(ng/mL) 
AUC0-last 
(ng.h/mL) 
Cmax 
(ng/mL) 
AUC0-last 
(ng.h/mL) 
By 
Cmax 
By  
AUC 
SPI-CIT-15-03 
15 mg/kg/day 
Rat 
MTP-131 
6875 
23,850 
1,300 
3,720 
x5 
x6 
M1 
7385 
43,000 
436 
3,100 
x17 
x14 
M2 
260 
2470 
88.0 
1,950 
x3 
x1.8 
Dog 
MTP-131 
13050 
21135 
1,300 
3,720 
x10 
x6 


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SPI-CIT-15-02 
10 mg/kg/day 
M1 
1709 
5507 
436 
3,100 
x4 
x1.8 
M2 
312 
5093 
88.0 
1,950 
x4 
x3 
The data displayed demonstrate that exposure to elamipretide, M1 and M2 in the chronic 
toxicology studies are supportive of chronic dosing at 40 mg/day by SC injection, in human, 
assuming an average body weight of approximately 75 kg and normal renal function (GFR > 
90 mL/min). 
The PK of elamipretide is body weight dependent.  In a clinical pharmacology study 
assessing the safety and PK of elamipretide administered as SC injection, once daily for 7 
days (SPISC102), body weight plotted against Cmax and AUC0-last of elamipretide and its’ 
metabolites demonstrated negative correlation; as body weight increases, Cmax and AUC0-last 
will decrease in an approximately linear manner.  These data indicate that an individual with 
a body weight of 40 kg may be expected to have 25% greater exposure to elamipretide and 
M1 and 45% greater exposure to M2 than an individual with a body weight of 75 kg at the 
same dose level of study drug.  Safety margins displayed in Table 3 demonstrate that an 
individual with a body weight of 30 kg administered 40 mg elamipretide SC would be 
expected to remain within acceptable ranges of exposure to elamipretide, M1 and M2 and are 
therefore included in the study population.  Patients with body weight < 30 kg are excluded 
from participation.  
Elamipretide and its’ metabolites are excreted by the kidney, therefore decreased renal 
function impacts the PK of the compounds.  A clinical pharmacology trial in subjects with 
normal renal function or mild, moderate or severe renal impairment (SPICP-101) 
demonstrates a negative correlation between GFR and exposure to elamipretide, M1 and M2; 
as GFR decreases Cmax and AUC0-last will increase in an approximately linear manner.  
Exposure to elamipretide is expected to be approximately 2.3-fold higher in a subject with 
GFR < 30 mL/min compared to the corresponding exposure in a subject with normal renal 
function while M1 and M2 increase approximately 3.9-fold and 8.4-fold respectively in the 
same comparison.  Safety margins displayed in Table 3 demonstrate that in order to maintain 
adequate toxicity exposure for dose levels in human, a dose level of 40 mg elamipretide SC 
would be expected to remain within acceptable ranges of exposure to elamipretide, M1 and 
M2 in subjects with GFR >60 mL/min,  
60 
assuming average body weight (75 kg).  Subjects with GFR < 60 mL/min are excluded from 
participation.  
Taken together, body weight and renal function effects on exposure of elamipretide and its’ 
metabolites allow the following inclusion criteria in this study: 
a. Patient body weight > 30 kg with GFR ≥ 90 mL/min/1.73 m2 OR 


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b. Patient body weight > 40 kg with GFR ≥ 60 mL/min/1.73 m2. 
8.5. 
Treatment Compliance 
During the treatment period, IMP will be administered daily by a trained caregiver or 
selfadministration. In Part 1, a diary will be used to document administration. 
8.6. 
Continued Access to Investigational Medicinal Product 
Trial subjects may be eligible for an open-label extension trial following the conclusion of the 
trial. 
8.7. 
Blinding and Unblinding Procedures 
The trial personnel and subjects will be blinded to treatment until the database is locked.   
The Investigator will contact the Sponsor prior to unblinding any subject’s treatment 
sequence unless in the instance of a medical emergency. 
In case of an immediate medical emergency or if directed by the Sponsor, and only if the 
information is required by the Investigator to manage a subject’s AE, is a subject’s treatment 
assignment to be unblinded prematurely. In cases of medical emergency, the Investigator may 
unblind a subject’s treatment assignment using the computerized system according to the 
instructions received. The Sponsor must be notified as soon as possible regarding the reason 
for unblinding.  
Whenever the treatment assignment of an individual subject is unblinded, the individual who 
performed the unblinding, the date, time and reason for the unblinding must be logged in the 
computerized unblinding system (IWRS) and also included in source documentation. The 
name of the individual who broke the blind must be included in the trial center’s source 
documentation.   
The Sponsor designated CRO will control and document, according to the appropriate 
Standard Operating Procedures, the disclosure of treatment assignments, and treatment 
identity. These procedures ensure that no blinded staff (CRO, trial center, Sponsor) will have 
premature access to the subjects’ treatment assignments.  
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9. 
EFFICACY AND SAFETY EVALUATIONS AND 
APPROPRIATENESS OF MEASUREMENTS 
Trial procedures and their timing are summarized in Attachment 1, Attachment 2, and 
Attachment 3. 
9.1. 
Efficacy Endpoints   
9.1.1. 
Primary Endpoints 
x Distance walked (meters) during the 6-Minute Walk Test (6MWT) x Total Fatigue on 
the BarTH Syndrome Symptom Assessment (BTHS-SA) o The Total Fatigue score on 
a given day is the sum of Q1 [tiredness at rest], Q2 [tiredness during activities], and Q4 
[muscle weakness during activities]. The calculated value of the endpoint is the average 
of the 7 days prior to the office visit.  If any of the 3 questions are not answered on any 
given day, then the Total Fatigue score for that day will be set to missing.  
9.1.2. 
Secondary Endpoints x Muscle strength as measured by 
handheld dynamometry (HHD)  x Five Times Sit-to-Stand Test 
score x 2-D and 3-D Echocardiographic measurements x 
Accelerometry counts 
x SWAY Application Balance Assessment x Patient 
reported outcomes o PROMIS Short Form Fatigue 
o Fatigue During Activities on the BTHS-SA 
 The Fatigue During Activities score on a given day is the sum of Q2 
[tiredness during activities] and Q4 [muscle weakness during 
activities]. The calculated value of the endpoint is the average of the 7 
days prior to the office visit.  If either of the questions is not answered 
on any given day, then the Fatigue During Activities score for that day 
will be set to missing. 
o Patient Global Impression (PGI) Scales  
 PGI of Symptoms  
 PGI of Change  o EQ-5D  
x Clinician Global Impression (CGI) Scales o 
CGI of Symptoms  


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o CGI of Change   
x Caregiver Global Impression (CaGI) Scales  
o CaGI of Symptoms  o CaGI of 
Change   
x Biomarkers o MLCL: L4-
CL Ratio 
o Plasma and blood biomarkers (GDF-15, FGF-21, glutathione/reduced 
glutathione)  
o Urine biomarkers (8-isoprostane, 8-hydroxy-2-deoxyguanosine, 
3methylgutaconic acid)  
o Plasma and urine metabolomics o Exploratory biomarkers 
9.1.3. 
Pharmacokinetic (PK) Endpoints 
Assessment of PK via a population model (see Section 11.2.6)  
9.2. 
Safety Endpoints 
The safety and tolerability endpoints will be assessed by: 
x AEs  
x Vital signs 
x ECGs 
x Ambulatory arrhythmias x 
Clinical laboratory evaluations 
x Columbia-Suicide Severity Rating Scale (C-SSRS) 
The safety profile of elamipretide will be assessed through the recording, reporting, and 
analyzing of adverse events, clinical evaluations, and laboratory tests.   
Comprehensive assessment of adverse events experienced by the subject will be performed 
from the time of the subject’s signature of informed consent, throughout the course of the 
trial, and until the conclusion of the clinical trial’s post treatment follow-up period.   
Subjects must be seen by a physician or designee (an appropriately trained healthcare 
professional) at every trial visit and the evaluation must be documented. Trial center 
personnel will report any adverse event (AE), whether observed by the Investigator (or 
designee), or reported by the subject.  


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The Investigator is responsible for promptly documenting and reporting all AEs observed 
during the trial in the subject’s eCRF and applicable forms. The reporting period for AEs is 
described in Section 9.10.2. 
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9.3. 
Adverse Events 
Any untoward medical occurrence in a subject or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment.  
An adverse event (AE) can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with 
the use of a medicinal product, whether or not considered related to the medicinal product.  
9.4. 
Pre-Treatment Events 
Untoward events and/or incidental diagnoses that occur prior to IMP administration are by 
definition, unrelated to the IMP and will be reported as such in the data listings. Pre-treatment 
events or incidental diagnoses will be recorded on the past medical history electronic case 
report form (eCRF).  However, if a pre-treatment event is assessed by the Investigator as 
related to a trial procedure and/or meets seriousness criteria, it will be recorded as an AE on 
the AE eCRF, processed, and followed accordingly.  
9.5. 
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 trial in a way that is not 
consistent with natural disease progression, in the opinion of the Investigator, should be 
recorded and reported as AEs. 
9.6. 
Medical and Surgical Procedures  
Medical or surgical procedures (including hospitalizations) scheduled prior to signing the 
informed consent, but occurring during the trial should not be captured as AEs. The condition 
leading to the procedure should be listed in the medical history and the procedure should be 
captured on the concurrent procedures page. Medical or surgical procedures not scheduled 
prior to signing the informed consent should not be recorded as adverse events; the condition 
that led to the need to perform the medical or surgical procedure will be the AE or SAE and 
the procedure should be captured on the concurrent procedures page.  


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9.7. 
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.  
When reporting an abnormal laboratory finding as an AE or SAE, 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. 
64 
9.8. 
Symptomatic Overdose 
In the event of an overdose of trial medication, the Investigator should use clinical judgment 
in treating the signs and symptoms of the overdose.  The signs and symptoms should be 
reported as AEs.  Overdoses must be reported immediately to the trial Medical Monitor. 
9.9. 
Serious Adverse Events (SAE) 
A SAE is any AE that: 
x Results in death.  
x 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. 
x Requires inpatient hospitalization or prolongation of existing hospitalization. 
x Results in persistent or significant disability/incapacity. 
x Is a congenital anomaly/birth defect. 
Medical and scientific judgement should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also usually be considered serious. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. 


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Any non-serious AE that worsens and meets the criteria for an SAE should be reported as a 
new AE and as an SAE. The start date of the SAE should be the date the AE worsened to 
meet the criteria for a SAE. 
The Investigator is expected to take all therapeutic measures necessary for resolution of the 
SAE. Any medications or procedures necessary for treatment of the SAE must be recorded on 
the appropriate screen(s) of the subject’s eCRF. 
9.10. 
Recording of Adverse Events 
Complete and accurate data on all AEs 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 must be reported using the trial specific SAE Report Form, in 
addition to the Adverse Event CRF.  
It is important that each AE entry include a verbatim term along with, onset and resolution 
dates, severity, seriousness, relationship to the IMP, action taken with respect to the IMP, and 
its outcome.  
Investigators should use the adverse event definitions provided in the above sections and 
should observe the following guidelines when completing the AE pages of the CRF:  
65 
x Whenever possible, recognized medical terms should be used to describe AEs rather 
than colloquialisms (for example, ‘influenza’ rather than ‘flu’), and abbreviations 
should be avoided.  
x Adverse events 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.   
x 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”  
x In cases of surgical or diagnostic procedures, the condition/illness leading to such a 
procedure is considered as the AE rather than the procedure itself.  


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9.10.1. 
Investigator Assessments 
9.10.1.1. Severity 
Severity, which is a description of the intensity of manifestation of the AE, is distinct from the 
regulatory definition of seriousness. The Investigator is required to grade the severity of each 
adverse event according to the following guidelines.  
Investigators must assess the severity/intensity of adverse events according to the following 
qualitative toxicity scale:  
Mild: 
Associated with no limitation of usual activities or only slight discomfort; 
generally not requiring alteration or cessation of IMP administration; and/or 
not needing therapeutic intervention.  
Moderate:
Associated with limitation of usual activities or significant discomfort; 
generally requiring alteration or cessation of IMP administration; and/or 
requiring therapeutic intervention. 
Severe: 
Associated with inability of subject to carry out usual activities or very marked 
discomfort; considered to be life-threatening; resulting in significant disability 
or incapacity; and requiring therapeutic intervention.  
9.10.1.2. Relationship to the Investigational Medicinal Product (IMP) 
Investigators must systematically assess the causal relationship of AEs to the IMP(s) 
according to the following guidelines:  
Probable: 
A causal relationship is clinically/biologically highly plausible, there is 
a plausible time sequence between onset of the AE and administration 
of the IMP, the event is unlikely to be attributed to 
underlying/concurrent disease, other drugs, or other factors, and there 
is a reasonable response on withdrawal.  
66 
Possible: 
A causal relationship is clinically/biologically plausible and there is a 
plausible time sequence between onset of the AE and administration of 
the IMP. 
Unlikely: 
A causal relationship is improbable and/or another documented cause of 
the AE is most plausible.  
Unrelated: 
A causal relationship is clinically/biologically improbable, there is not a 
plausible time sequence between onset of the AE and administration of 
the IMP, the event is likely to be attributed to underlying/concurrent 
disease, other drugs, or other factors, and there is no reasonable 
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9.10.1.3. Outcome of an Adverse Event  
Investigators must follow all AEs and SAEs as described in Section 9.10.2. Outcome is 
defined as: 
x Recovered/Resolved;    x 
Recovering/Resolving x Not 
recovered/Not resolved x 
Recovered/Resolved with sequelae; x 
Fatal; or x Unknown.  
9.10.1.4. Reporting of Injection Site Reactions (ISR) 
Local ISRs have been frequently experienced with SC elamipretide administration. 
Characteristics of these injection site reactions were mild erythema, mild swelling, and mild 
pruritus, commencing within the first hour of the injection and generally resolving within 4 
hours.   
In order to standardize the reporting of ISRs, the following guidance should be 
followed: x Any ISR following SC administration should be reported as an AE.   
o The ISR should be assessed for severity using the “Table for Grading the 
Severity of Site Reactions to Injections” provided in Attachment 16. 
o Any ISR that meets any of the criteria of an SAE (Section 9.9) should be 
reported within 24 hours of the study center first becoming aware of the event 
(as outlined in Section 9.11). 
o 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”. 
67 
o 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.   


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9.10.2. 
Adverse Event Reporting Period 
The adverse event reporting period begins when the subject signs the informed consent and 
continues through the clinical trial’s post treatment follow-up period.  
After trial completion, all SAEs with an ongoing/unknown outcome will be followed-up until 
resolution or stabilization.  Additional information on SAEs, obtained after database lock, 
will reside solely in the safety database.   
9.11. 
Serious Adverse Event Expedited Reporting 
In the event of a SAE occurring during the reporting period, the Investigator must 
immediately (within 24 HOURS after becoming aware of the SAE) inform the Sponsor by 
telephone, by fax or by e-mail as detailed in the SAE form, completion instructions, CRF 
completion guidelines, and/or Safety Management Plan.   
For any SAE, the following minimum information is required as initial 
notification: x Investigator/Reporter with full contact information 
x Subject identification details (trial number, center number, subject number), x 
IMP administration details (dose and dates) 
x Event Verbatim, a brief description of signs/symptoms/or diagnosis and the date of 
onset,   
x Seriousness criteria (ion) met, and, 
x Relationship of the event to the IMP (e.g., the causality according to the Investigator) 
All SAE reports should be transmitted according to the Safety Management Plan.    
The Investigator/Reporter must provide follow-up information as available or requested by 
the Sponsor.   
9.11.1. 
Pregnancy and Contraception 
For male subjects with female partners of child-bearing potential, highly effective methods of 
contraception must be adhered to prior to entry into the study and for at least 2 months after 
last dose of study drug. Highly effective methods of contraception is defined as the usage by 
the female partner of any form of hormonal contraception or intra-uterine device (which 
should be established prior to the start of the study) plus usage by one of the partners of an 
additional spermicide-containing barrier method of contraception. Male subjects with 
pregnant partners must use a condom with spermicide from the start of treatment until at least 
2 months after the  


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last dose of study drug. Sperm or egg donation by subjects is not permitted from the start of 
treatment until 2 months after the study drug was administered. 
Any pregnancy in a female partner of a male subject during the course of the trial and until 
the last follow-up visit must be reported within 24 hours of learning of the pregnancy even if 
no AE has occurred, as detailed in the Safety Management Plan. If the investigator suspects 
the pregnancy has resulted from an interaction of the trial medication with contraceptives, 
then the pregnancy is considered as an AE; however, all pregnancies must be recorded in the 
AE page/section of the CRF.   
Investigators must actively follow up, document, and report on the outcome of every 
pregnancy, even if the subject is withdrawn from the trial, as detailed in the Safety 
Management Plan. 
9.11.2. 
Responsibilities to Regulatory Authorities, Investigators and Ethics 
Committees 
The Sponsor will send appropriate safety notifications to regulatory authorities in accordance 
with applicable laws and regulations.  
The Investigator must comply with any applicable center-specific requirements related to the 
reporting of SAEs 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 adverse events that are 
both serious and unexpected and are considered to be related to the administered IMP 
(“suspected unexpected serious adverse reactions” or SUSARs). The Investigator should 
place copies of these Safety reports in the Investigator Site File. National regulations with 
regard to Safety report notifications to Investigators will be taken into account.  
When specifically required by regulations and guidelines, the Sponsor will provide 
appropriate Safety reports directly to the concerned lead IEC/central IRB and will maintain 
records of these notifications. When direct reporting by the Sponsor is not clearly defined by 
national or centerspecific regulations, the Investigator will be responsible for promptly 
notifying the concerned IEC/IRB of any Safety reports provided by the Sponsor and of filing 
copies of all related correspondence in the Investigator Site File. 
For trials covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/SUSARs will be carried out in accordance with that 
Directive and with the related detailed Guidances. 


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9.12. 
Appropriateness of Measurements  
The measures used to assess safety in this trial are consistent with those widely used and 
generally recognized as reliable, accurate, and relevant. 
69 
 10. 
DATA QUALITY ASSURANCE 
To ensure accurate, complete, and reliable data, the Sponsor or its representatives will do the 
following: 
x Provide instructional material to the trial centers, as appropriate 
x Sponsor start-up training to instruct the Investigators and trial coordinators.  This 
training will give instruction on the protocol, the completion of the eCRFs, and trial 
procedures.  
x Make periodic visits to the trial center 
x Be available for consultation and stay in contact with the trial center personnel by mail, 
telephone, and/or fax  
x Review and evaluate eCRF data and use standard computer edits to detect errors in data 
collection 
x Conduct a quality review of the database  
In addition, the Sponsor or its representatives will periodically check a sample of the subject 
data recorded against source documents at the trial center. The trial may be audited by the 
Sponsor or its representatives, and/or regulatory agencies at any time.  Investigators will be 
given notice before an audit occurs.  
To ensure the safety of participants in the trial, and to ensure accurate, complete, and reliable 
data, the Investigator will keep records of laboratory tests, clinical notes, and subject medical 
records in the subject files as original source documents for the trial.  If requested, the 
Investigator will provide the Sponsor, applicable regulatory agencies, and applicable ECs 
with direct access to original source documents. 
10.1. 
Data Capture System 
An electronic data capture system (eDC) will be used in this trial. The trial center will 
maintain a separate source for the data entered by the trial center into the Sponsor-provided 
electronic data capture system.  


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Case report form data will be encoded and stored in a clinical trial database. Data managed by 
a central vendor, such as laboratory test data or ECG data, or any data for which electronic 
documentation is provided by the subject, will be stored electronically in the central vendor’s 
database system.  
Any data for which paper documentation provided by the subject will serve as a source 
document will be identified and documented by each trial center in that center’s trial file. 
Paper documentation provided by the subject may include, for example, a paper diary to 
collect subject reported outcome measures (e.g., a rating scale), a daily dosing schedule, or an 
event diary.   
70 
 
11. 
SAMPLE SIZE AND STATISTICAL METHODS 
11.1. 
Determination of Sample Size 
For this Phase 2, randomized, double-blind, placebo-controlled crossover trial followed by an 
open-label treatment extension assessment, a sample size of approximately 12 subjects is 
planned. Assuming an underlying standard deviation of paired differences of 50 meters for 
the 6MWT distance and 1.3 points for the BTHS-SA Total Fatigue score, 12 subjects 
provides for nearly 80% power to detect a mean improvement of 50 meters in the 6MWT or 
1.3 points for the BTHS-SA Total Fatigue score, with each potentially tested at the 0.025 
(two-sided) level of significance (associated with a potential adjustment via Hochberg’s 
procedure). Subject numbers are restricted by feasibility considerations (availability of 
subjects) but that recruitment could be greater if subjects are available (up to 16 subjects). 
11.2. 
Statistical and Analytical Plans 
11.2.1. 
General Considerations 
All trial data are to be displayed in the data listings. 
Statistical analysis of this trial will be the responsibility of the Sponsor or its designee.    
Additional details regarding analyses will be included in separate statistical analysis plan 
(SAP). 


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11.2.2. 
Subject Disposition 
All subjects who discontinue from the trial will be identified, and the extent of their 
participation in the trial 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. Data will be presented by treatment group as appropriate, 
where treatment is defined for subjects within a specific period.  Formal statistical tests 
(where performed) will be 2-sided at the alpha=0.05 level of significance, except where 
otherwise noted to adjust for multiplicity for the primary endpoint family. 
71 
11.2.4.2. Analysis Populations 
Approximately 12 subjects will be randomized and will receive either IMP (elamipretide or 
placebo) in the first treatment period, followed by the alternative treatment in the second 
treatment period, according to the randomly assigned treatment sequence.   
Statistical analysis will be performed in the following populations: 
Safety Population – Includes all trial subjects who receive at least 1 dose of IMP according to 
treatment received within a period. 
Intention-to-Treat (ITT) Population – Includes all trial subjects who receive at least 1 dose of 
IMP, according to the treatment sequence group to which they were randomized.  
Per-Protocol (PP) Population – Includes all ITT subjects without major protocol 
violations/deviations. The list of major protocol violations/deviations will be identified and 
specified prior to final database lock for the trial that would lead to exclusion for the PP 
analysis. 


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Pharmacokinetic (PK) Population – Includes all trial subjects who have at least 1 PK sample 
taken during their participation.  
The details of all analyses will be described in the Statistical Analysis Plan to be finalized 
before unblinding.    
11.2.5. 
Efficacy Analyses  
Efficacy analyses will be conducted on the ITT population. All tests of treatment effects will 
be conducted at a 2-sided alpha level of 0.05. 
The distance walked (meters) during the 6MWT and Total Fatigue score on the BTHS-SA 
constitute the family of primary endpoints. A family-wise alpha level of 0.05 will be 
maintained for the primary endpoint family, using Hochberg’s procedure. If both primary 
endpoints are significantly different from placebo at the 0.05 (two-sided) level of significance 
(in favor of treatment), then both will be considered statistically significant. Otherwise the 
endpoint with the smaller p-value of the two will be considered statistically significant, if 
statistically significant at the 0.025 (two-sided) level of significance.  
Analyses of continuous endpoints at the end of each treatment period will be conducted 
utilizing a mixed model repeated measures (MMRM) approach. Subject will be considered as 
a random effect.  Additional details regarding the model and underlying assumptions will be 
specified in the SAP. 
Secondary and exploratory efficacy endpoints will be assessed in a similar manner as the 
primary efficacy endpoints.   
No adjustments for multiplicity will be provided for secondary or exploratory endpoints.   
11.2.5.1. Handling of Missing Data 
A significant amount of missing data are not anticipated, given characteristics of the subject 
population from which subjects will be enrolled. In addition, the mixed model repeated 
measures approach is valid under a missing at random (MAR) missingness mechanism.  
72 
Nevertheless, depending on the extent of missing data, additional sensitivity analyses may be 
considered.  
11.2.6. 
Pharmacokinetic (PK) Analysis 
Elamipretide and metabolite plasma concentration data will be collected in all subjects and 
will be used in a non-linear mixed effects model to assess the characteristics of elamipretide 
and metabolite PK in the PK population.  


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The PK model will be generated and validated using data reported from historical, thorough 
PK studies. Where sufficient data allows, covariates will include age, race, renal function (as 
described by eGFR), intercurrent conditions and concomitant medications.  
Plasma samples will be analyzed for elamipretide and metabolites using a validated liquid 
chromatography/ tandem mass spectrometry assay.   
Additional details and all model assumptions, validation and data analysis will be detailed in 
the PK Analysis Plan prior to database lock.  
11.2.7. 
Safety Analyses  
Safety data analysis will be conducted on all subjects in the Safety Population with treatment 
group determined by treatment received in a particular period (i.e., subjects dosing in both 
periods will be counted in both treatment groups).  
11.2.7.1. Adverse Events 
The number and percentage of subjects experiencing 1 or more AEs will be summarized by 
treatment group, relationship to IMP, and severity. AEs will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) terminology.  AEs will be summarized by 
system organ class (SOC), preferred term (PT), and treatment group. 
All reported AEs will be listed, but only treatment-emergent adverse events (TEAEs) will be 
summarized. 
The incidence of all TEAEs, drug relationship with TEAEs, and severity of TEAE 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 (within a treatment group). If a 
subject has the same AE 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 event will be presented. If severity is missing, subjects 
will be included as missing (for severity). If drug relationship is missing, subjects will be 
included in related tables (e.g., considered related).  
11.2.7.2. 
Deaths and Other Serious Adverse 
Events Listings will be provided for the following: x 
Deaths x SAEs 
x AEs leading to discontinuation of IMP 
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11.2.7.3. Clinical Laboratory Evaluations  
Summary tables for laboratory parameters (including hematology, chemistry, and urinalysis) 
will include descriptive statistics of change relative to baseline where appropriate, and data 
listings of clinically significant abnormalities. 
Subjects with laboratory data outside the normal range will be listed with abnormal values 
flagged.  
Shift tables (e.g., tables that show the number of subjects who are low, normal, or high at 
baseline versus each post-baseline scheduled assessment) will be produced. 
The number and percentage of subjects with urinalysis results outside the normal range will 
be presented by endpoint and visit for each treatment group. Shift tables for urinalysis will 
show the number of subjects who are normal/abnormal at baseline and normal/abnormal at 
the end of trial. 
11.2.7.4. 
Vital Signs 
Vital signs data will be summarized by changes from baseline values at each treatment group 
using descriptive statistics. 
Shift tables for heart rate and blood pressure (e.g., tables that show the number of subjects 
who are low, normal, or high at baseline versus each post-baseline scheduled assessment) will 
be produced.  
11.2.7.5. Electrocardiogram 
ECG data will be summarized by changes from baseline values at each treatment group using 
descriptive statistics. 
Electrocardiogram results (normal versus abnormal) and an assessment of the clinical 
significance of any abnormalities, in the opinion of the Investigator, will be listed for 
individual subjects.  Intervals of PR, RR, QRS, QT, and QTcB will also be listed.  
Similar data will be reported for ambulatory arrhythmias.  
11.2.7.6. Other Safety Parameters 
Any other safety data captured on the eCRF will be listed. 


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12. 
INFORMED CONSENT, ETHICAL REVIEW, AND 
REGULATORY CONSIDERATIONS 
12.1. 
Informed Consent 
The Investigator is responsible for ensuring that the subject understands the potential risks 
and benefits of participating in the trial, including answering any questions the subject may 
have throughout the trial and sharing in a timely manner any new information that may be 
relevant to the subject willingness to continue his or her participation in the trial.  
The ICF will be used to explain the potential risks and benefits of trial participation to the 
subject in simple terms before the subject is entered into the trial, and to document that the 
subject is satisfied with his or her understanding of the risks and benefits of participating in 
the trial and desires to participate in the trial. 
The Investigator is responsible for ensuring that informed consent is given by each subject or 
legal representative.  This includes obtaining the appropriate signatures and dates on the ICF 
prior to the performance of any protocol procedures and prior to the administration of 
investigational product.  
As used in this protocol, the term “informed consent” includes all consent and assent given 
by subject or their legal representatives. 
12.2. 
Ethical Review 
The Sponsor or its representatives must approve all ICFs before they are used at investigative 
trial 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 trial may begin at the investigative trial center.  The EC will review the protocol as 
required.  
The trial center’s EC should be provided with the following: x 
The current IB and updates during the course of the trial  
x ICF 
x Relevant curricula vitae 
12.3. 
Regulatory Considerations 
This trial will be conducted in accordance with:  
1) Consensus ethics principles derived from international ethics guidelines, including the 
CIOMS International Ethical Guidelines 
2) The ICH GCP Guideline [E6] 
3) Applicable laws and regulations  


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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.  
75 
An identification code assigned to each subject will be used in lieu of the subject’s name to 
protect the subject’s identity when reporting AEs and/or other trial-related data.  
12.3.1. 
Protocol Approval  
The Sponsor’s responsible medical officer will approve the protocol, confirming that, to the 
best of their knowledge, the protocol accurately describes the planned design and conduct of 
the trial. 
12.3.2. 
Final Report Approval 
The Sponsor’s responsible medical officer will approve the final clinical trial report for this 
trial, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the trial.  
12.3.3. 
Trial Monitoring 
The Investigators and institution(s) will permit trial-related monitoring of the CRF data by 
Stealth BioTherapeutics, Inc., or their assignee by providing direct access to source data 
and/or documents.  The trial monitor will verify the eCRFs 100% against the source 
documentation.  Deviations from the protocol with regard to subject enrollment or trial 
conduct will also be noted in the source documentation, in the eCRF and a complementary 
database.  A Sponsor representative will visit the trial center to initiate the trial, prior to the 
first treatment of the first subject, and at agreed times throughout the trial, including at the 
end of the trial.  Drug dispensing and clinical drug supply records will be 100% verified at 
the trial center by the trial monitor.  It is understood that all subject specific information is 
confidential and no documentation that can link trial information to the specific subject will 
be collected or retained by the Sponsor.  
12.3.4. 
Retention of Records 
All trial 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 trial or notification from 
the Sponsor that the data can be destroyed, whichever comes first.  
12.3.5. 
Disclosure of Information 
Information concerning the investigational medication and patent application processes, 
scientific data or other pertinent information is confidential and remains the property of 


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Stealth BioTherapeutics, Inc.  The Investigator may use this information for the purposes of 
the trial only.  It is understood by the Investigator that Stealth BioTherapeutics, Inc., will use 
information developed in this clinical trial in connection with the development of the 
investigational medication and therefore may disclose it as required to other clinical 
Investigators and to regulatory agencies.  In order to allow the use of the information derived 
from this clinical trial, the Investigator understands that he/she has an obligation to provide 
complete test results and all data developed during this trial to the Sponsor.  
76 
The Investigator may not submit for publication or presentation the results of this trial 
without first receiving written authorization from Stealth BioTherapeutics, Inc. Stealth  
BioTherapeutics, Inc., agrees that before it publishes any results of the trial, it shall provide 
the Investigator with at least 30 days for review of the pre-publication manuscript prior to the 
submission of the manuscript to the publisher. 


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 13. 
REFERENCES 
Adès LC, Gedeon AK, Wilson MJ, et al. Barth syndrome: clinical features and confirmation 
of gene localisation to distal Xq28. Am J Med Genet 1993;45:327–334.  
Chicco AJ, Sparagna GC. Role of cardiolipin alterations in mitochondrial dysfunction and 
disease. American Journal of Physiology-Cell Physiology. 2007 Jan 1;292(1):C33-44.  
Clarke SL, Bowron A, Gonzalez IL, Groves SJ, Newbury-Ecob R, Clayton N, Martin RP, 
TsaiGoodman B, Garratt V, Ashworth M, Bowen VM. Barth syndrome. Orphanet journal of 
rare diseases. 2013 Feb 12;8(1):1.  
Fry M, Green DE. Cardiolipin requirement for electron transfer in complex I and III of the 
mitochondrial respiratory chain. Journal of Biological Chemistry. 1981 Feb 25;256(4):1874-
80.  
Hoch FL. Cardiolipins and biomembrane function. BiochimBiophysActa. 1992; 1113(1):71– 
133. 
Jefferies JL. Barth syndrome. InAmerican Journal of Medical Genetics Part C: Seminars in 
Medical Genetics 2013 Aug 1 (Vol. 163, No. 3, pp. 198-205).  
Min K, Smuder AJ, Kwon OS, Kavazis AN, Szeto HH, Powers SK. Mitochondrial-targeted 
antioxidants protect skeletal muscle against immobilization-induced muscle atrophy. Journal 
of Applied Physiology. 2011 Nov 1;111(5):1459-66.   
Paradies G, Paradies V, De Benedictis V, Ruggiero FM, Petrosillo G. Functional role of 
cardiolipin 
in 
mitochondrial 
bioenergetics. 
Biochimica 
et 
Biophysica 
Acta 
(BBA)Bioenergetics. 2014 Apr 30;1837(4):408-17.  
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. Critical care medicine. 2011 Jul 1;39(7):1749-59.   
Saric A, Andreau K, Armand AS, Møller IM, Petit PX. Barth Syndrome: From Mitochondrial 
Dysfunctions Associated with Aberrant Production of Reactive Oxygen Species to Pluripotent 
Stem Cell Studies. Frontiers in genetics. 2015;6.  
Sandlers Y, Mercier K, Pathmasiri W, Carlson J, McRitchie S, Sumner S, Vernon HJ. 
Metabolomics Reveals New Mechanisms for Pathogenesis in Barth Syndrome and Introduces 
Novel Roles for Cardiolipin in Cellular Function. PloS one. 2016 Mar 25;11(3):e0151802.  
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 


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energetics and skeletal muscle performance in aged mice. Aging cell. 2013 Oct 1;12(5):763-
71. 
Soustek MS, Falk DJ, Mah CS, Toth MJ, Schlame M, Lewin AS, Byrne BJ. Characterization 
of a transgenic short hairpin RNA-induced murine model of Tafazzin deficiency. Human gene 
therapy. 2010 Dec 13;22(7):865-71.  
78 
Talbert EE, Smuder AJ, Min K, Kwon OS, Szeto HH, Powers SK. Immobilization-induced 
activation of key proteolytic systems in skeletal muscles is prevented by a mitochondria-
targeted antioxidant. Journal of applied physiology. 2013 Aug 15;115(4):529-38.   
Vreken P, Valianpour F, Nijtmans LG, Grivell LA, Plecko B, Wanders RJ, et al. Defective 
remodeling of cardiolipin and phosphatidylglycerol in Barth syndrome. BiochemBiophys Res 
Comm. 2000; 279: 378– 382.  
Zorov DB, Filburn CR, Klotz LO, Zweier JL, Sollott SJ. Reactive oxygen species (Ros-
Induced) Ros release a new phenomenon accompanying induction of the mitochondrial 
permeability transition in cardiac myocytes. The Journal of experimental medicine. 2000 Oct 
2;192(7):100114. 
Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial ROS-induced ROS release: an update and 
review. Biochimica et Biophysica Acta (BBA)-Bioenergetics. 2006 Jun 30;1757(5):509-17.  


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14. 
ATTACHMENTS 


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Attachment 1   
Part 1 and Part 2 Schedule of Assessments (Trial Center Visits) 
Part 1  
Screening a 
Treatment Period  
 
Treatment Period 1b 
Day -28 to Day 
-1 (min. approx. 
7 days) 
Visit 1 
Pre-dose  
(Baseline) Visitc 
(Day 1) 
Days 
2-5 Visitsd 
Visit 5 
Week 12 Visit 
(Day 85 ± 7) 
Washout  
Periode  
(28 days +7) 
 
Treatment Period 2b 
 
Visit 6 
Pre-dose Visitc 
(Day 1) 
Days 
2-5 Visitsd 
Visit 10 
Week 12 Visit 
(Day 85 ± 7) 
Part 1  
Follow-up  
Periode  
(28 days +7) 
Visit 11A 
Part 1 End-of- 
Trial/ Early D/C  
Visite  
(Day 113 +7) 
Informed Consent 
X 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
Randomizationf 
 
X 
 
 
 
 
Review of  
Inclusion/Exclusion Criteriaf 
X  
X  
 
 
 
 
Relevant Medical Historyf 
X 
X 
 
 
 
 
Concomitant  
Medication/Procedure  
Review 
X  
X  
 
X  
 
X  
Review AEs 
 
X  
X  
X  
X  
X  
Physical Examg 
X 
X 
 
X 
 
X 
Vital Signsh 
X 
X 
 
X 
 
X 
12-Lead ECGi 
X 
X 
 
X 
 
X 
Blood Chemistry &  
Hematologyj 
X  
X  
 
X  
 
X  
Urinalysisj 
X 
X 
 
X 
 
X 
Blood Spotj 
X  
X  
 
X  
 
X  
Plasma and Urine  
Biomarkersj 
X  
X  
 
X  
 
X  
Plasma and Urine  
Metabolomic Profile 
 
X  
 
X  
 
X  
2-D and 3-D Echos 
X 
X 
 
X 
 
X 


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AVIVO™ MPM Systemk 
X 
X 
 
X 
 
 
C-SSRS “Lifetime Recent” 
X 
 
 
 
 
 
C-SSRS “Since Last Visit” 
 
X 
 
X 
 
X 
PROMIS Short Form  
Fatiguel 
X  
X  
 
X  
 
X  
BTHS-SAm 
          X-------------------------Daily------------------------X  
 
PGI Scalesn 
X 
X 
 
X 
 
X 
CGI Scales 
X 
X 
 
X 
 
X 
CaGI Scaleso 
X 
X 
 
X 
 
X 
EQ-5Dp 
X 
X 
 
X 
 
X 
6MWTq 
X 
X 
 
X 
 
X 
5XSSTq 
X 
X 
 
X 
 
X 
HHDq 
X  
X  
 
X  
 
X  
SWAYq 
X 
X 
 
X 
 
X 
Daily IMP Injectionr 
 
          X---------------Daily--------------X 
 
 
a. 
The ICF must be signed prior to any trial related procedures are performed.  If applicable, informed consent in writing from parent(s) 
or legally-acceptable representative(s) and, informed assent from subject (if age appropriate according to local  
81 
requirements) should be provided.  
b. All study center visits should occur at approximately (±2 hours) the same time and after at least 3 hours of fasting. Days and Weeks 
are relative to the Pre-dose Visit of the respective Treatment Period. 
c. 
Screening assessments that were completed within 24 hours of the Baseline Visit, do not need to be recompleted. Pre-dose 
assessments must be completed within 24 hours prior to receiving IMP. 
d. Subjects may be evaluated at the trial center daily for up to the first 5 days of each Treatment Period. The decision to have a subject 
return for the Days 2 through 5 Visits for both Treatment Period 1 and Treatment Period 2 should be made and documented prior to 
the Baseline Visit. 
e. 
The Washout Period will only occur after Treatment Period 1. The Part 1 Follow-Up Period and the Part 1 End-of-Trial Visit will 
only occur after Treatment Period 2 and if the subject is not continuing into Part 2. 
f. 
Only to be completed at the Baseline Visit. 
g. Height will be measured during all physical examinations, and used in the trial to calculate BMI.  Physical examination will include: 
general appearance, skin, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, chest, heart, abdomen, extremities, 
and nervous system, and weight. 
h. Vital signs will include HR, RR, and BP after sitting for 5 min, and temperature. 
i. 
All scheduled ECGs must be performed after the subject has rested quietly for at least 10 min in the supine position. 


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j. 
See Attachment 4 for laboratory tests.  Additional blood samples, at the Treatment Period 1 Baseline Visit, Treatment Period 2 Week 
12 Visit, and (if applicable) the Part 1 Early Discontinuation Visit, will be collected and stored for assessing the immunogenicity 
potential of the IMP. 
k. Starting at the Screening Visit, subjects will be provided with an AVIVO™ MPM System which will be applied, as instructed in the 
product manual, at trial center visits by the Investigator (or designee). The Investigator (or designee) will educate the subject on 
appropriate application and use of the AVIVO™ MPM System. Subjects will be instructed and reminded to apply and wear a new 
AVIVO™ MPM System at approximately Week 11, immediately prior to the Treatment Period 1 Week 12 Visit and Treatment 
Period 2 Week 12 Visit.  Subjects will be instructed to wear each AVIVO™ MPM System for approximately 7 consecutive days after 
each application.  Subjects will return all AVIVO™ MPM Systems by the completion of his/her participation in the trial. 
l. 
For subjects ≥ 18 years of age at the Screening Visit, the PROMIS Adult Short Form Fatigue should be completed. Subjects 12-17 
years of age at the Screening Visit, the PROMIS Pediatric Short Form Fatigue should be completed for the duration of the trial. 
m. The age appropriate BTHS-SA should be completed daily by the subject in a diary starting at the Screening Visit and continued until 
the Treatment Period 2 Week 12 Visit. For subjects ≥ 16 years of age at the Screening Visit, the BTHS-SA Adult should be 
completed. Subjects 12-15 years of age at the Screening Visit, the BTHS-SA Adolescent should be completed for the duration of the 
trial. 
n. For subjects ≥ 16 years of age at the Screening Visit, the PGI Adult should be completed. Subjects 12-15 years of age at the 
Screening Visit, the PGI Adolescent should be completed for the duration of the trial. 
o. If applicable. For subjects ≥ 16 years of age at the Screening Visit, the CaGI Adult should be completed. Subjects 12-15 years of age 
at the Screening Visit, the CaGI Adolescent should be completed for the duration of the trial. 
p. For subjects ≥ 16 years of age at the Screening Visit, the EQ-5D-5L should be completed. Subjects 12-15 years of age at the 
Screening Visit, the EQ-5D-Y should be completed for the duration of the trial. 
q. The 6MWT (Attachment 14), the 5XSST (Attachment 15), and HHD should be performed after all other trial procedures (except for 
IMP administration). The 5XSST should be performed after the 6MWT and after at least 5 minutes rest (should not be more than 30 
minutes). Handheld dynamometry should be performed after completion of the 5XSST and at least 5 minutes rest (should not be 
more than 30 minutes). The SWAY Application Balance Assessments should be performed after completion of the HHD and at least 
5 minutes rest (should not be more than 30 minutes). The Investigator (or designee) conducting the 6MWT, 5XSST, HHD, and 
SWAY Application Balance Assessments should not be the same Investigator (or designee) completing the safety assessments for a 
particular subject. 
r. 
At Treatment Period 1 and Treatment Period 2 Pre-dose Visits, all other trial procedures must be completed prior to administering 
IMP. Subjects should be instructed to administer the IMP on the day of Treatment Period 1 Week 12 and Treatment Period 2 Week 
12 Visit, prior to returning to the trial center. The location (injection in the abdomen [rotating around the four abdominal quadrants] 
or thigh, provided that it is at least 5 cm from the previous day’s location of administration]) and time of the IMP administration (at 
approximately the same time each day [e.g. early morning, noon, early afternoon, or evening]) will be recorded daily in a diary. 
82 
Part 2 (begins on the day after the  
Treatment Period 2 Week 12 Visit of 
Part 1) 
Treatment Perioda 
Part 2 Follow-Up Period 
Part 2 Treatment Period Visit 
Visit 11B 
(Week 12  
Visit) 
Visits 12-20n 
(Week 24, 36, 48,  
72, 96, 120, 144,  
168, 192 Visits) 
Phone Call (or other 
method)  
(Weeks 60, 84, 108,  
132, 156, 180) 
Visit 21 
(Week 196)  
Part 2 End-of-Trial or 
Early D/C Visit 
Window 
± 1 week 
± 2 weeks 
± 2 weeks 
+ 7 days 
Concomitant Medication/Procedure 
Review 
X  
X  
X  
X  


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Review AEs 
X 
X 
X 
X 
Physical Examb 
X 
X 
 
X 
Vital Signsc 
X 
X 
 
X 
12-Lead ECGd 
X 
X 
 
X 
Blood Chemistry & Hematologye 
X 
X 
 
X 
Urinalysise 
X 
X 
 
X 
Blood Spote 
X 
X 
 
X 
Plasma and Urine Biomarkerse 
X 
X 
 
X 
Plasma and Urine Metabolomic Profile 
X 
X 
 
X 
2-D and 3-D Echos 
X 
X 
 
X 
C-SSRS “Since Last Visit” 
X 
X 
 
X 
PROMIS Short Form Fatiguef 
X 
X 
 
X 
BTHS-SAg 
X 
X 
 
X 
PGI Scalesh 
X 
X 
 
X 
CGI Scales 
X 
X 
 
X 
CaGI Scalesi 
X 
X 
 
X 
EQ-5Dj 
X 
X 
 
X 
6MWTk 
X 
X 
 
X 
5XSSTk 
X 
X 
 
X 
HHDk 
X 
X 
 
X 
SWAYk 
X 
X 
 
X 
PK Samplesl 
X 
 
 
Daily IMP Injectionm 
X-------------------------Daily-------------------------X 
 


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Page 663 of 713 
a. 
All study center visits should occur at approximately (±2 hours) the same time and after at least 3 hours of fasting. Days and Weeks 
are relative to the Pre-dose Visit of the respective Treatment Period. 
b. Height will only be measured during all physical examinations, and used in the trial to calculate BMI.  Physical examination will 
include: general appearance, skin, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, chest, heart, abdomen, 
extremities, and nervous system, and weight. 
c. 
Vital signs will include HR, RR, and BP after sitting for 5 min, and temperature. 
d. All scheduled ECGs must be performed after the subject has rested quietly for at least 10 min in the supine position. 
e. 
See Attachment 4 for laboratory tests. Additional blood samples, at the Part 2 Early Discontinuation Visit (if applicable), will be 
collected and stored for assessing the immunogenicity potential of the IMP. 
f. 
For subjects ≥ 18 years of age at the Screening Visit, the PROMIS Adult Short Form Fatigue should be completed. Subjects 12-17 
years of age at the Screening Visit, the PROMIS Pediatric Short Form Fatigue should be completed for the duration of the trial. 
g. The age appropriate BTHS-SA should be completed only at clinical site visits. For subjects ≥ 16 years of age at the Screening Visit, 
the BTHS-SA Adult should be completed. Subjects 12-15 years of age at the Screening Visit, the BTHS-SA Adolescent should be 
completed for the duration of the trial. 
h. For subjects ≥ 16 years of age at the Screening Visit, the PGI Adult should be completed. Subjects 12-15 years of age at the 
Screening Visit, the PGI Adolescent should be completed for the duration of the trial. 
i. 
If applicable. For subjects ≥ 16 years of age at the Screening Visit, the CaGI Adult should be completed. Subjects 12-15 years of age 
at the Screening Visit, the CaGI Adolescent should be completed for the duration of the trial. 
j. 
For subjects ≥ 16 years of age at the Screening Visit, the EQ-5D-5L should be completed. Subjects 12-15 years of age at the 
Screening Visit, the EQ-5D-Y should be completed for the duration of the trial. 
k. The 6MWT (Attachment 14), the 5XSST (Attachment 15), and HHD should be performed after all other trial procedures (except 
83 
for IMP administration). The 5XSST should be performed after the 6MWT and after at least 5 minutes rest (should not be more than 
30 minutes). Handheld dynamometry should be performed after completion of the 5XSST and at least 5 minutes rest (should not be 
more than 30 minutes). The SWAY Application Balance Assessments should be performed after completion of the HHD and at least 
5 minutes rest (should not be more than 30 minutes). The Investigator (or designee) conducting the 6MWT, 5XSST, HHD, and 
SWAY Application Balance Assessments should not be the same Investigator (or designee) completing the safety assessments for a 
particular subject. 
l. 
PK Schedule: Pre-dose (-30 min); 0.5h (± 5 min); 1h (± 10 min); 2h (± 15 min); 4h (± 15 min). All PK sampling should be 
conducted at the defined time points at a single clinical site visit. The clinical site visit at which the PK sampling should occur 
should be the earliest clinical site visit possible in Part 2 (at or after the Week 12 Visit in Part 2). On the day of the Visit that the PK 
samples are collected, subjects should be instructed to administer the IMP at the trial center. To reduce trial procedure burden, PK 
sampling may be completed during a scheduled clinical site visits in Part 2 or on an independent clinical site visit.  
Additionally, to reduce the need for multiple venipunctures, in the opinion of the Investigator, a venous catheter may be used for PK 
sample collection. 
m. Daily IMP injections should begin the day after the Part 1 Treatment Period 2 Week 12 Visit. On the day of the Visit that the PK 
samples are collected, subjects should be instructed to administer the IMP at the trial center. Injections should be in the abdomen 
(rotating around the four abdominal quadrants) or thigh, provided that it is at least 5 cm from the previous day’s location of 
administration at approximately the same time each day (e.g. early morning, noon, early afternoon, or evening).  
n. The Part 2 Treatment Period will end with the Part 2 EOT Visit.  This will occur after completion of the Week 192 Visit, or anytime 
between the Week 144 – 192 Visits during Part 2 when the subject and Investigator determine that the subject will enroll in another 
SBT follow-on clinical trial in Barth syndrome or EAP.  Subjects enrolling in another SBT follow-on clinical trial in Barth syndrome 
or EAP must complete all scheduled assessments for the EOT visit prior to enrolling in the subsequent SBT program. 
  


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CONFIDENTIAL 
Page 664 of 713 
84 
Attachment 2 
Part 1 Schedule of Visiting Nurse Visit Assessmentsa 
Treatment Period 1 
Visit 2 Week 1 
(Day 8 ± 1) 
Visit 3 Week 4 (Day 
29 ± 2) 
Visit 4 Week 8 (Day 
57 ± 2) 
Treatment Period 2 
Visit 7 Week 1 
(Day 8 ± 1) 
Visit 8 Week 4 (Day 
29 ± 2) 
Visit 9 Week 8 (Day 
57 ± 2) 
Confirm IMP storage conditions 
X  
X  
X  
IMP administrationb 
X  
X  
X  
Injection site assessmentc 
X  
X  
X  
Review AEs 
X  
X  
X  
Vital signsd 
X  
X  
X  
Clinical chemistry & hematologye 
X  
X  
X  
Plasma and urine biomarkerse 
X  
X  
X  
Reminder of new AVIVO™ MPM Systemf 
 
 
X  
PROMIS Short Form Fatigueg 
X  
X  
X  
BTHS-SAh 
X--------------------------Daily----------------------------X  
PGI Scalesi 
X  
X  
X  
CaGI Scalesj 
X  
X  
X  
EQ-5Dk 
X  
X  
X  
Review IMP compliancel 
X  
X  
X  
a. 
Given the challenges of scheduling Visiting Nurse Visits to subject’s homes (or other Investigator agreed upon location) (e.g. remote 
geographic locations, subject scheduling conflicts, extreme weather or other natural disasters etc.), in consultation and agreement 
with the Sponsor and Investigator, these visits may be postponed, changed or cancelled. The decision on the schedule of Visiting 
Nursing Visits for both Treatment Period 1 and Treatment Period 2 should be made and documented prior to the Baseline Visit. 
b. 
Visiting Nurse may administer IMP at all home (or other Investigator agreed upon location) visits. 
c. 
Injection sites will be assessed using the “Table for Grading the Severity of Site Reactions to Injections” (Attachment 16). 
Completed forms will be sent to the study center for review. 
d. 
Vital signs will include HR, RR, and BP after sitting for 5 min, and temperature. 
e. 
See Attachment 4 for clinical laboratory tests. 
f. 
Subjects will be reminded to apply and wear a new AVIVO™ MPM System for approximately 7 consecutive days immediately 
prior to the Treatment Period 1 Week 12 Visit and Treatment Period 2 Week 12 Visit. 
g. 
For subjects ≥ 18 years of age at the Screening Visit, the PROMIS Adult Short Form Fatigue should be completed. Subjects 12-17 
years of age at the Screening Visit, the PROMIS Pediatric Short Form Fatigue should be completed for the duration of the trial. 
h. 
The age appropriate BTHS-SA should be completed daily by the subject in a diary starting at the Screening Visit and continued until 
the Treatment Period 2 Week 12 Visit. For subjects ≥ 16 years of age at the Screening Visit, the BTHS-SA Adult should be 
completed. Subjects 12-15 years of age at the Screening Visit, the BTHS-SA Adolescent should be completed for the duration of the 
trial. 
i. 
For subjects ≥ 16 years of age at the Screening Visit, the PGI Adult should be completed. Subjects 12-15 years of age at the 
Screening Visit, the PGI Adolescent should be completed for the duration of the trial. 
j. 
If applicable. For subjects ≥ 16 years of age at the Screening Visit, the CaGI Adult should be completed. Subjects 12-15 years of age 
at the Screening Visit, the CaGI Adolescent should be completed for the duration of the trial. 


Elamipretide (MTP-131 for SC Injection) 
SPIBA-201 Version 4.1 
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CONFIDENTIAL 
Page 665 of 713 
k. 
For subjects ≥ 16 years of age at the Screening Visit, the EQ-5D-5L should be completed. Subjects 12-15 years of age at the 
Screening Visit, the EQ-5D-Y should be completed for the duration of the trial. 
l. 
The Visiting Nurse will assess compliance with IMP administration and may re-train the subject or caregiver on proper 
administration technique, as appropriate. 
85 
Attachment 3 
Trial Schematics 
Part 1 
 
Part 2  
 
Screening  
Visit  
Pre-dose  
( Baseline)  
Visit  
Screening  
Elamipretide 40mg SC daily fo r 12 weeks  
Placebo SC da ily fo r 12 weeks  
LUJ  
Days  2-5 
Visiting Nurse Visits  
( Weeks 1, 4, and 8)  
Treatment  Period  1 
Week 12  
Visit  
Washout  
Elamipretide 40mg SC daily for 12 weeks  
Placebo SC daily  fo r 12 weeks  
Pre-dose  
Visit  
LUJ  
Days  2-5 
Visiting Nurse Visits  
Weeks 1, 4, and 8)  
( 
Treatment Period 2  
Week 12  
Site Visit  
Fo llow-Up  
Visit*  
Follow-Up*  
*only applicable  if  subject and/or Investigator decide not to continue subject into Part 2  
180 ( phone call ) 
Part 2 End-of-Trial/ 
Elamipretide 40 mg SC daily  
I  
12 weeks  
:   12 weeks  
12 weeks  
28 days  
I  
I  
I  
I  
1---- 
•  
:   
I  
I  
,  _________
..
Treatment Period  2   
Week 12 Visit (Part 1)  
Week 12 Visit  
repeat for  
( 
Week 24, 36,  
48 Visits)  
Weeks 60, 84,  
,  1 
108 
32 , 156  
Part 2 Treatment Period  
Week 72, 96, 120,  
144 , 168,192  Visits  
Early  DIC  Visit  
Part 2 Follow-Up Period  


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SPIBA-201 Version 4.1 
23 April 2021 
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CONFIDENTIAL 
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86 


 
Page 667 of 713 
Elamipretide (MTP-131 for SC Injection) 
SPIBA-201 Version 4.1 
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Attachment 4 
Clinical Laboratory Tests 
Haematology: 
Serum Clinical Chemistry: 
Haemoglobin 
Sodium 
Haematocrit 
Potassium 
Erythrocyte count (RBC) 
Total bilirubin 
Leukocytes (WBC) 
Direct bilirubin 
Neutrophils (ANC, 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 
Blood Spot  
Calcium 
MLCL: L4-CL Ratio 
Glucose (non-fasting) 
 
Albumin 
Biomarkers 
Chloride 
Serum GDF-15 
Triglycerides 
Serum FGF-21 
HDL 
Serum glutathione/reduced glutathione 
LDL 
Urine 8-hydroxy-2-deoxyguanosine  
NT-proBNP 
Urine 8-isoprostane  
hs-Troponin I 
Urine and plasma metabolomics (urine at site visits 
only) 
 
Urine 3-methylgutaconic acid  
Urinalysis: 
Immunogenicity (at Treatment Period 1 Baseline Visit, 
Treatment Period 2 Week 12 Visit, and [if applicable]  
Part 1 or Part 2 Early Discontinuation Visits only) 
Specific Gravity 
Exploratory biomarkers – to be determined by Sponsor  
(i.e. glial fibrillary acidic protein [GFAP] and Brain- 
Derived Neurotrophic [BDNF], ST2, Galectin-3 
[GAL3], cystatin C and neutrophil gelatinase-associated 
lipocalin [NGAL]) 
pH 
Protein 
Glucose 
Ketones 


 
Page 668 of 713 
 
Blood 
 
Leukocyte esterase 
Stealth BioTherapeutics, Inc.  
CONFIDENTIAL 
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Elamipretide (MTP-131 for SC Injection) 
SPIBA-201 Version 4.1 
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Page 669 of 713 
Attachment 5 Columbia-Suicide Severity Rating Scale (C-SSRS) “Lifetime Recent” 
Stealth BioTherapeutics, Inc.  
CONFIDENTIAL 
88 


 
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Elamipretide (MTP-131 for SC Injection) 
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Attachment 6 Columbia-Suicide Severity Rating Scale (C-SSRS) “Since Last Visit” 
Stealth BioTherapeutics, Inc.  
CONFIDENTIAL 


 
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92 


 
Obtained from Clireo DMS 2018-03-19 7:09:44 PM (4:00 UTC) (6) Effective Date:3/19/2018 
Page 675 of 713 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS)  
Since Last Visit - Clinical  
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. 
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 
□ 


 
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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 t 
and 5 being the most severe).  
Most Severe Ideation:   
 _____  
Type # (1-5)  
o the most severe type of ideation (i.e., 1-5 from above, with 1 being the least severe  
_________________________________________________ 
 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 wanti 
(1) Easily able to control thoughts 
(2) Can control thoughts with little difficulty  
(3) Can control thoughts with some difficulty  
ng to die if you want to? 
(4) Can control thoughts with a lot of difficulty 
(5) Unable to control thoughts 
(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 end/stop the pain 
(5) Completely to end or stop the pain (you couldn’t go 
on living with the pain or  how you were feeling) (0) 
Does not apply 
____ 
© 2008 Research Foundation for Mental Hygiene, Inc. 
C-SSRS—Since Last Visit - Clinical (Version 1/14/09)  
  Page 1 of 2 
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last 
Visit 


 
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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 □ 
□ 
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 or Self-Interrupted 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 or 
self- 
interrupted 
______ 
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 
□   □ 
Total # of 
preparatory 
acts 
______ 
Suicide: 
Death by suicide occurred since last assessment. 
Yes    No □ 
□ 
 
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 
______ 


 
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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 
______ 
© 2008 Research Foundation for Mental Hygiene, Inc. 
C-SSRS—Since Last Visit - Clinical (Version 1/14/09)  
  Page 2 of 2 


 
Page 679 of 713 
Elamipretide (MTP-131 for SC Injection) 
 
SPIBA-201 Version 4.1 
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Attachment  
PROMIS Short Form Fatigue 
 
Stealth BioTherapeutics, Inc.  
CONFIDENTIAL 


 
Page 680 of 713 
96 
PROMISTM Pediatric Item Bank v.1.0 - Fatigue - Short Form 10a 
Pediatric Fatigue - Short Form  
Please respond to each item by marking one box per row. 
In the past 7 days……. 
 
Never 
Almost Never 
Sometimes 
Often 
Almost Always 
Being tired made it hard for me to play or 
go out with my friends as much as I'd like. 
 
0 
 
1 
 
2 
 
3 
 
4 
I felt weak. 
 
0 
 
1 
 
2 
 
3 
 
4 
I got tired easily. 
 
0 
 
1 
 
2 
 
3 
 
4 
Being tired made it hard for me to keep up 
with my schoolwork. 
 
0 
 
1 
 
2 
 
3 
 
4 
I had trouble finishing things because I was 
too tired. 
 
0 
 
1 
 
2 
 
3 
 
4 
I had trouble starting things because I was 
too tired. 
 
0 
 
1 
 
2 
 
3 
 
4 
I was so tired it was hard for me to pay 
attention. 
 
0 
 
1 
 
2 
 
3 
 
4 
I was too tired to do sports or exercise. 
 
0 
 
1 
 
2 
 
3 
 
4 
I was too tired to do things outside. 
 
0 
 
1 
 
2 
 
3 
 
4 
I was too tired to enjoy the things I like to 
do. 
 
0 
 
1 
 
2 
 
3 
 
4 
97 
TM 
 
© 2009-2012 PROMIS 
 Health Organization and PROMIS Cooperative Group 
Obtained from Clireo DMS 2018-03-19 7:09:44 PM (4:00 UTC) (6) Effective Date:3/19/2018 
PROMIS Item Bank v1.0 – Fatigue – Short Form 8a  
Fatigue – Short Form 8a 
Please respond to each question or statement by marking one box per row.  
During the past 7 days… 
 
Not at all 
A little bit 
Somewhat 
Quite a bit Very much 


 
Page 681 of 713 
HI7 
1  
I feel fatigued .............................................  
 
1 
 
 
2 
 
 
3 
 
 
4 
 
 
5 
 
 
 
 
 
 
 
AN3 
2  
I have trouble starting things because I am 
tired............................................................. 
 
1 
 
2 
 
3 
 
4 
 
5 
 
In the past 7 days… 
 
 
 
 
 
FATEXP41 
3  
How run-down did you feel on average? ... 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
FATEXP40  
4  
How fatigued were you on average?......... 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
FATEXP35 
5  
How much were you bothered by your 
fatigue on average?..................................... 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
FATIMP49 
6  
To what degree did your fatigue interfere 
with your physical functioning?................. 
 
1 
 
2 
 
3 
 
4 
 
5 
 
In the past 7 days… 
Never 
Rarely 
Sometimes 
Often 
Always 
FATIMP3 
7  
How often did you have to push yourself 
to get things done because of your 
fatigue?...................................................... 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
FATIMP16 
8  
How often did you have trouble finishing 
things because of your fatigue?.................. 
 
1 
 
2 
 
3 
 
4 
 
5 
 
Investigator Format  © 2008-2012 PROMIS Health Organization and PROMIS Cooperative Group  
Page 1 of 1  
Obtained from Clireo DMS 2018-03-19 7:09:44 PM (4:00 UTC) (6) Effective Date:3/19/2018 
Elamipretide (MTP-131 for SC Injection) 
 
SPIBA-201 Version 4.1 
23 April 2021 
 


 
Page 682 of 713 
 
Attachment  
BarTH Syndrome Symptom Assessment (BTHS-SA) 
 
Stealth BioTherapeutics, Inc.  
CONFIDENTIAL 
99 
BarTH Syndrome Symptom Assessment (BTHS-SA) – Adolescent version 


 
Page 683 of 713 
Instructions: The following questions ask about Barth Syndrome.  Please select the response 
that best describes your experience with Barth Syndrome over the past 24 hours. Please select 
only one answer for each question.  Please answer all of the questions and do not skip any.  
There are no right or wrong answers to any of the questions. 
Please indicate (with a check mark ) responses to the questions below. 
1. Please rate your worst feeling of 
No 
Mild  
Moderate  
Severe  
Very severe  
tiredness at rest in the past 24 hours. 
tiredness at  
tiredness 
tiredness 
tiredness 
tiredness 
all 
 
 
 
 
 
 
2. Please rate your worst feeling of 
No 
Mild  
Moderate  
Severe  
Very severe  
tiredness during activities in the past 24 
tiredness at  
tiredness tiredness tiredness tiredness 
hours. 
all 
 
 
 
 
 
 
3. Please rate your worst feeling of No muscle Mild muscle Moderate Severe Very severe muscle weakness at 
rest in the past 24 weakness weakness muscle muscle muscle hours. at all weakness weakness weakness 
 
 
 
 
 
 
4. Please rate your worst feeling of No muscle Mild muscle Moderate Severe Very severe muscle weakness during 
activities in weakness weakness muscle muscle muscle 
the past 24 hours. 
at all 
weakness 
weakness 
weakness 
 
 
 
 
 
 
5. Please rate your worst feeling of No muscle Mild muscle Moderate Severe Very severe muscle pain at rest in 
the past 24 pain at all pain muscle pain muscle pain muscle pain hours. 
 
 
 
 
 
 
6. Please rate your worst feeling of No muscle Mild muscle Moderate Severe Very severe muscle pain due to 
activities in the past pain at all pain muscle pain muscle pain muscle pain 
24 hours. 
 
 
 
 
 
 
7. Please rate your worst feeling of 
No feeling  
Mild feeling  
Moderate  
Severe  Very 
severe early fullness when eating in the past 
of early  of early  feeling of  feeling of  feeling of  
24 hours. 
fullness at fullness 
early  
early  
early fullness all
 fullness 
fullness 
 
 
 
 
 
 
8. Please rate your worst difficulty 
No difficulty  
Mild  
Moderate  
Severe  Very severe 
eating (for example, chewing and/or eating at all 
difficulty  difficulty  difficulty  difficulty swallowing) in 
the past 24 hours. eating 
eating 
eating 
eating 
 
 
 
 
 
 
9. Please rate your worst feeling of 
No 
Mild  
Moderate  
Severe  Very severe headache 
in the past 24 hours. 
headache at 
headache headache headache headache 
all 
 
 
 
 
 
 
GQ7666A BTHS-SA-Adolescent 5-point version v2_0  
18 Nov 2016  
Obtained from Clireo DMS 2018-03-19 7:09:44 PM (4:00 UTC) (6) Effective Date:3/19/2018 
BarTH Syndrome Symptom Assessment (BTHS-SA) – Adult version 
Instructions: The following questions ask about Barth Syndrome.  Please select the response 
that best describes your experience with Barth Syndrome over the past 24 hours. Please select 
only one answer for each question.  Please answer all of the questions and do not skip any.  There 
are no right or wrong answers to any of the questions. 
Please indicate (with a check mark ) responses to the questions below. 


 
Page 684 of 713 
1. Please rate your worst feeling of 
No tiredness  
Mild  
Moderate  
Severe  Very severe 
tiredness at rest in the past 24 hours. at all 
tiredness tiredness tiredness tiredness 
 
 
 
 
 
 
2. Please rate your worst feeling of No tiredness Mild Moderate Severe Very severe tiredness during activities in 
the past at all tiredness tiredness tiredness tiredness 
24 hours. 
 
 
 
 
 
 
3. Please rate your worst feeling of 
No muscle  
Mild muscle  
Moderate  
Severe  Very 
severe muscle weakness at rest in the past 
weakness at  
weakness muscle  muscle  muscle  
24 hours. 
all 
weakness 
weakness 
weakness 
 
 
 
 
 
 
4. Please rate your worst feeling of No muscle Mild muscle Moderate Severe Very severe muscle weakness during 
activities in weakness at weakness muscle muscle muscle 
the past 24 hours. 
all 
weakness 
weakness 
weakness 
 
 
 
 
 
 
5. Please rate your worst feeling of No muscle Mild muscle Moderate Severe Very severe muscle pain at rest in the 
past 24 pain at all pain muscle pain muscle pain muscle pain hours. 
 
 
 
 
 
 
6. Please rate your worst feeling of 
No muscle  
Mild muscle  
Moderate  
Severe  Very 
severe muscle pain due to activities in the 
pain at all pain 
muscle pain 
muscle pain
 
muscle pain past 24 hours. 
 
 
 
 
 
 
7. Please rate your worst feeling of No Mild Moderate Severe Very severe dizziness/lightheadedness in the past 
dizziness/ dizziness/ dizziness/ dizziness/ dizziness/ 
24 hours. 
lightheaded 
lightheaded 
lightheaded 
lightheaded
 
lightheaded ness at all 
ness 
ness 
ness 
ness 
 
 
 
 
 
 
8. Please rate your worst feeling of No Mild Moderate Severe Very severe shortness of breath in the past 24 
shortness of shortness of shortness of shortness of shortness of hours. breath at all breath breath breath breath 
 
 
 
 
 
 
GQ7666A BTHS-SA-Adult 5-point version v2_0  
18 Nov 2016  
Obtained from Clireo DMS 2018-03-19 7:09:44 PM (4:00 UTC) (6) Effective Date:3/19/2018 
Elamipretide (MTP-131 for SC Injection) 
 
SPIBA-201 Version 4.1 
23 April 2021 
 


 
Page 685 of 713 
 
Attachment  
Patient Global Impression (PGI) Scales 
 
Stealth BioTherapeutics, Inc.  
CONFIDENTIAL 
102 


 
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Page 686 of 713 
Patient Global Impression of Symptoms (Patient age 12-15)  
Date Completed: ________________________  
The following questions ask you about your Barth Syndrome symptoms OVER THE 
PAST WEEK.  
1. How bad have your Barth Syndrome symptoms been over the past week? 
 No Symptoms 
 Mild Symptoms 
 Moderate Symptoms 
 Severe Symptoms 
 Very Severe Symptoms 
2. How bad has your feeling of tiredness at rest been over the past week? 
 No Tiredness 
 Mild Tiredness 
 Moderate Tiredness 
 Severe Tiredness 
 Very Severe Tiredness 
3. How bad has your feeling of tiredness during activities been over the past week? 
 No Tiredness 
 Mild Tiredness 
 Moderate Tiredness 
 Severe Tiredness 
 Very Severe Tiredness 
4. How bad has your feeling of muscle weakness at rest been over the past week? 
 No Muscle Weakness 
 Mild Muscle Weakness 
 Moderate Muscle Weakness 
 Severe Muscle Weakness 
 Very Severe Muscle Weakness 
5. How bad has your feeling of muscle weakness during activities been over the 
past week? 
 No Muscle Weakness 
 Mild Muscle Weakness 


 
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Page 687 of 713 
 Moderate Muscle Weakness 
 Severe Muscle Weakness 
 Very Severe Muscle Weakness 
6. How bad has your feeling of muscle pain at rest been over the past week? 
 No Muscle Pain 
 Mild Muscle Pain 
 Moderate Muscle Pain 
 Severe Muscle Pain 
 Very Severe Muscle Pain 
7. How bad has your feeling of muscle pain due to activities been over the past 
week? 
 No Muscle Pain 
 Mild Muscle Pain 
 Moderate Muscle Pain 
 Severe Muscle Pain 
 Very Severe Muscle Pain 
8. How bad has your feeling of early fullness when eating been over the past week? 
 No Early Fullness 
 Mild Early Fullness 
 Moderate Early Fullness 
 Severe Early Fullness 
 Very Severe Early Fullness 
9. How bad has your feeling of difficulty eating (for example, chewing and/or 
swallowing) been over the past week? 
 No Difficulty Eating 
 Mild Difficulty Eating 
 Moderate Difficulty Eating 
 Severe Difficulty Eating 
 Very Severe Difficulty Eating 
10. How bad has your feeling of headache been over the past week? 
 No Headache 
 Mild Headache 
 Moderate Headache 
 Severe Headache 


 
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Page 688 of 713 
 Very Severe Headache 
Patient Global Impression of Symptoms (Patient age >= 16)  
Date Completed: ________________________  
The following questions ask you about your Barth Syndrome symptoms OVER THE 
PAST WEEK.  
1. How bad have your Barth Syndrome symptoms been over the past week? 
 No Symptoms 
 Mild Symptoms 
 Moderate Symptoms 
 Severe Symptoms 
 Very Severe Symptoms 
2. How bad has your feeling of tiredness at rest been over the past week? 
 No Tiredness 
 Mild Tiredness 
 Moderate Tiredness 
 Severe Tiredness 
 Very Severe Tiredness 
3. How bad has your feeling of tiredness during activities been over the past week? 
 No Tiredness 
 Mild Tiredness 
 Moderate Tiredness 
 Severe Tiredness 
 Very Severe Tiredness 
4. How bad has your feeling of muscle weakness at rest been over the past week? 
 No Muscle Weakness 
 Mild Muscle Weakness 
 Moderate Muscle Weakness 
 Severe Muscle Weakness 
 Very Severe Muscle Weakness 
5. How bad has your feeling of muscle weakness during activities been over the 
past week? 
 No Muscle Weakness 


 
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Page 689 of 713 
 Mild Muscle Weakness 
 Moderate Muscle Weakness 
 Severe Muscle Weakness 
 Very Severe Muscle Weakness 
6. How bad has your feeling of muscle pain at rest been over the past week? 
 No Muscle Pain 
 Mild Muscle Pain 
 Moderate Muscle Pain 
 Severe Muscle Pain 
 Very Severe Muscle Pain 
7. How bad has your feeling of muscle pain due to activities been over the past 
week? 
 No Muscle Pain 
 Mild Muscle Pain 
 Moderate Muscle Pain 
 Severe Muscle Pain 
 Very Severe Muscle Pain 
8. How bad has your feeling of dizziness/lightheadedness been over the past week? 
 No Dizziness/Lightheadedness 
 Mild Dizziness/Lightheadedness 
 Moderate Dizziness/Lightheadedness 
 Severe Dizziness/Lightheadedness 
 Very Severe Dizziness/Lightheadedness 
9. How bad has your feeling of shortness of breath been over the past week? 
 No Shortness of Breath 
 Mild Shortness of Breath 
 Moderate Shortness of Breath 
 Severe Shortness of Breath 
 Very Severe Shortness of Breath 


TREATMENT PERIOD 1  
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Page 690 of 713 
Patient Global Impression of Change (Patient age 12-15)  
To be administered at Week 12 of Treatment Period 1.  
Date Completed: ________________________  
Please think about how your Barth Syndrome symptoms have changed from the time just 
before you started the study medication in Treatment Period 1 to today. The following 
questions ask you about how your symptoms have changed SINCE THE TIME JUST 
BEFORE YOU STARTED THE STUDY MEDICATION IN TREATMENT PERIOD 1 TO TODAY.  
1. Please choose the response below that best describes how your Barth Syndrome 
symptoms have changed since the time just before you started the study 
medication in Treatment Period 1 to today. My Barth Syndrome symptoms are: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
2. Please choose the response below that best describes how your feeling of 
tiredness at rest has changed since the time just before you started the study 
medication in Treatment Period 1 to today. My tiredness at rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
3. Please choose the response below that best describes how your feeling of 
tiredness during activities has changed since the time just before you started the 
study medication in Treatment Period 1 to today. My tiredness during activities is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 


TREATMENT PERIOD 1  
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Page 691 of 713 
 Moderately Worse 
 Very much Worse 
4. Please choose the response below that best describes how your feeling of muscle 
weakness at rest has changed since the time just before you started the study 
medication in Treatment Period 1 to today. My muscle weakness at rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
5. Please choose the response below that best describes how your feeling of muscle 
weakness during activities has changed since the time just before you started the 
study medication in Treatment Period 1 to today. My muscle weakness during 
activities is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
6. Please choose the response below that best describes how your feeling of muscle 
pain at rest has changed since the time just before you started the study 
medication in Treatment Period 1 to today. My muscle pain at rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
7. Please choose the response below that best describes how your feeling of muscle 
pain during activities has changed since the time just before you started the study 
medication in Treatment Period 1 to today. My muscle pain during activities is: 
 Very much Better 


TREATMENT PERIOD 1  
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Page 692 of 713 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
8. Please choose the response below that best describes how your feeling of early 
fullness when eating has changed since the time just before you started the study 
medication in Treatment Period 1 to today. My feeling of early fullness when 
eating is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
9. Please choose the response below that best describes how your feeling of 
difficulty eating (for example, chewing and/or swallowing) has changed since the 
time just before you started the study medication in Treatment Period 1 to today. 
My feeling of difficulty eating is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
10. Please choose the response below that best describes how your feeling of 
headache has changed since the time just before you started the study medication 
in Treatment Period 1 to today. My feeling of headache is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 


TREATMENT PERIOD 1  
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Page 693 of 713 
 Very much Worse 
Patient Global Impression of Change (Patient age >= 16)  
To be administered at Week 12 of Treatment Period 1.  
Date Completed: ________________________  
Please think about how your Barth Syndrome symptoms have changed from the time just 
before you started the study medication in Treatment Period 1 to today. The following 
questions ask you about how your symptoms have changed SINCE THE TIME JUST 
BEFORE YOU STARTED THE STUDY MEDICATION IN TREATMENT PERIOD 1 TO TODAY.  
1. Please choose the response below that best describes how your Barth Syndrome 
symptoms have changed since the time just before you started the study 
medication in Treatment Period 1 to today. My Barth Syndrome symptoms are: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
2. Please choose the response below that best describes how your feeling of 
tiredness at rest has changed since the time just before you started the study 
medication in Treatment Period 1 to today. My tiredness at rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
3. Please choose the response below that best describes how your feeling of 
tiredness during activities has changed since the time just before you started the 
study medication in Treatment Period 1 to today. My tiredness during activities is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 


TREATMENT PERIOD 1  
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Page 694 of 713 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
4. Please choose the response below that best describes how your feeling of muscle 
weakness at rest has changed since the time just before you started the study 
medication in Treatment Period 1 to today. My muscle weakness at rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
5. Please choose the response below that best describes how your feeling of muscle 
weakness during activities has changed since the time just before you started the 
study medication in Treatment Period 1 to today. My muscle weakness during 
activities is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
6. Please choose the response below that best describes how your feeling of muscle 
pain at rest has changed since the time just before you started the study 
medication in Treatment Period 1 to today. My muscle pain at rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
7. Please choose the response below that best describes how your feeling of muscle 
pain during activities has changed since the time just before you started the study 
medication in Treatment Period 1 to today. My muscle pain during activities is: 


TREATMENT PERIOD 1  
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 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
8. Please choose the response below that best describes how your feeling of 
dizziness/lightheadedness has changed since the time just before you started the 
study medication in Treatment Period 1 to today. My feeling of 
dizziness/lightheadedness is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
9. Please choose the response below that best describes how your feeling of 
shortness of breath has changed since the time just before you started the study 
medication in Treatment Period 1 to today. My feeling of shortness of breath is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 


TREATMENT PERIOD 2  
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Page 696 of 713 
Patient Global Impression of Change (Patient age 12-15)  
To be administered at Week 12 of Treatment Period 2.  
Date Completed: ________________________  
Please think about how your Barth Syndrome symptoms have changed from the time just 
before you started the study medication in Treatment Period 2 to today. The following 
questions ask you about how your symptoms have changed SINCE THE TIME JUST 
BEFORE YOU STARTED THE STUDY MEDICATION IN TREATMENT PERIOD 2 TO TODAY.  
1. Please choose the response below that best describes how your Barth Syndrome 
symptoms have changed since the time just before you started the study 
medication in Treatment Period 2 to today. My Barth Syndrome symptoms are: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
2. Please choose the response below that best describes how your feeling of 
tiredness at rest has changed since the time just before you started the study 
medication in Treatment Period 2 to today. My tiredness at rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
3. Please choose the response below that best describes how your feeling of 
tiredness during activities has changed since the time just before you started the 
study medication in Treatment Period 2 to today. My tiredness during activities is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 


TREATMENT PERIOD 2  
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Page 697 of 713 
 Moderately Worse 
 Very much Worse 
4. Please choose the response below that best describes how your feeling of muscle 
weakness at rest has changed since the time just before you started the study 
medication in Treatment Period 2 to today. My muscle weakness at rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
5. Please choose the response below that best describes how your feeling of muscle 
weakness during activities has changed since the time just before you started the 
study medication in Treatment Period 2 to today. My muscle weakness during 
activities is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
6. Please choose the response below that best describes how your feeling of muscle 
pain at rest has changed since the time just before you started the study 
medication in Treatment Period 2 to today. My muscle pain at rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
7. Please choose the response below that best describes how your feeling of muscle 
pain during activities has changed since the time just before you started the study 
medication in Treatment Period 2 to today. My muscle pain during activities is: 
 Very much Better 


TREATMENT PERIOD 2  
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 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
8. Please choose the response below that best describes how your feeling of early 
fullness when eating has changed since the time just before you started the study 
medication in Treatment Period 2 to today. My feeling of early fullness when 
eating is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
9. Please choose the response below that best describes how your feeling of 
difficulty eating (for example, chewing and/or swallowing) has changed since the 
time just before you started the study medication in Treatment Period 2 to today. 
My feeling of difficulty eating is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
10. Please choose the response below that best describes how your feeling of 
headache has changed since the time just before you started the study medication 
in Treatment Period 2 to today. My feeling of headache is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 


TREATMENT PERIOD 2  
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Page 699 of 713 
 Very much Worse 
Patient Global Impression of Change (Patient age >= 16)  
To be administered at Week 12 of Treatment Period 2.  
Date Completed: ________________________  
Please think about how your Barth Syndrome symptoms have changed from the time just 
before you started the study medication in Treatment Period 2 to today. The following 
questions ask you about how your symptoms have changed SINCE THE TIME JUST 
BEFORE YOU STARTED THE STUDY MEDICATION IN TREATMENT PERIOD 2 TO TODAY.  
1. Please choose the response below that best describes how your Barth Syndrome 
symptoms have changed since the time just before you started the study 
medication in Treatment Period 2 to today. My Barth Syndrome symptoms are: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
2. Please choose the response below that best describes how your feeling of 
tiredness at rest has changed since the time just before you started the study 
medication in Treatment Period 2 to today. My tiredness at rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
3. Please choose the response below that best describes how your feeling of 
tiredness during activities has changed since the time just before you started the 
study medication in Treatment Period 2 to today. My tiredness during activities is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 


TREATMENT PERIOD 2  
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 A Little Worse 
 Moderately Worse 
 Very much Worse 
4. Please choose the response below that best describes how your feeling of muscle 
weakness at rest has changed since the time just before you started the study 
medication in Treatment Period 2 to today. My muscle weakness at rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
5. Please choose the response below that best describes how your feeling of muscle 
weakness during activities has changed since the time just before you started the 
study medication in Treatment Period 2 to today. My muscle weakness during 
activities is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
6. Please choose the response below that best describes how your feeling of muscle 
pain at rest has changed since the time just before you started the study 
medication in Treatment Period 2 to today. My muscle pain at rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
7. Please choose the response below that best describes how your feeling of muscle 
pain during activities has changed since the time just before you started the study 
medication in Treatment Period 2 to today. My muscle pain during activities is: 


TREATMENT PERIOD 2  
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 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
8. Please choose the response below that best describes how your feeling of 
dizziness/lightheadedness has changed since the time just before you started the 
study medication in Treatment Period 2 to today. My feeling of 
dizziness/lightheadedness is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
9. Please choose the response below that best describes how your feeling of 
shortness of breath has changed since the time just before you started the study 
medication in Treatment Period 2 to today. My feeling of shortness of breath is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 


 
Page 702 of 713 
Elamipretide (MTP-131 for SC Injection) 
SPIBA-201 Version 4.1 
23 April 2021 
 
Attachment Clinician Global Impression (CGI) Scales 
Stealth BioTherapeutics, Inc.  
CONFIDENTIAL 
119 


 
Page 703 of 713 
Clinician Global Impression of Symptoms (all ages)  
Date Completed: ________________________  
 
1. Overall, how severe are the patient’s Barth Syndrome symptoms today? 
 No Symptoms 
 Mild Symptoms 
 Moderate Symptoms 
 Severe Symptoms 
 Very Severe Symptoms 
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Page 704 of 713 
TREATMENT PERIOD 1  
Clinician Global Impression of Change (All ages)  
To be administered at Week 12 of Treatment Period 1.  
Date Completed: ________________________  
Please think about how the patient’s Barth Syndrome symptoms have changed from the 
time just before he/she started the study medication in Treatment Period 1 to today. The 
following questions ask you about how the patient’s symptoms have changed SINCE THE 
TIME JUST BEFORE HE/SHE STARTED THE STUDY MEDICATION IN TREATMENT PERIOD 
1 TO TODAY.  
1. Please choose the response below that best describes how the patient’s Barth 
Syndrome symptoms have changed since the time just before he/she started the 
study medication in Treatment Period 1 to today. The patient’s Barth Syndrome 
symptoms are: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
Obtained from Clireo DMS 2018-03-19 7:09:44 PM (4:00 UTC) (6) Effective Date:3/19/2018 


 
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Page 705 of 713 
TREATMENT PERIOD 2  
Clinician Global Impression of Change (All ages)  
To be administered at Week 12 of Treatment Period 2.  
Date Completed: ________________________  
Please think about how the patient’s Barth Syndrome symptoms have changed from the 
time just before he/she started the study medication in Treatment Period 2 to today. The 
following questions ask you about how the patient’s symptoms have changed SINCE THE 
TIME JUST BEFORE HE/SHE STARTED THE STUDY MEDICATION IN TREATMENT PERIOD 
2 TO TODAY.  
1. Please choose the response below that best describes how the patient’s Barth 
Syndrome symptoms have changed since the time just before he/she started the 
study medication in Treatment Period 2 to today. The patient’s Barth Syndrome 
symptoms are: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
Elamipretide (MTP-131 for SC Injection) 
SPIBA-201 Version 4.1 
23 April 2021 
 


 
Page 706 of 713 
Attachment  Caregiver Global Impression (CaGI) Scales 
Stealth BioTherapeutics, Inc.  
CONFIDENTIAL 
123 
Caregiver Global Impression of Symptoms (Patient age 12-15)  


 
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Page 707 of 713 
Date Completed: ________________________  
The following questions ask you about your child’s Barth Syndrome symptoms OVER THE 
PAST WEEK. Please base your responses on what you have observed or what your child 
has told you about their symptoms in the past week.  
1. How bad have your child’s Barth Syndrome symptoms been over the past week? 
 No Symptoms 
 Mild Symptoms 
 Moderate Symptoms 
 Severe Symptoms 
 Very Severe Symptoms 
2. How bad has your child’s feeling of tiredness at rest been over the past week? 
 No Tiredness 
 Mild Tiredness 
 Moderate Tiredness 
 Severe Tiredness 
 Very Severe Tiredness 
3. How bad has your child’s feeling of tiredness during activities been over the past 
week? 
 No Tiredness 
 Mild Tiredness 
 Moderate Tiredness 
 Severe Tiredness 
 Very Severe Tiredness 
4. How bad has your child’s feeling of muscle weakness at rest been over the past 
week? 
 No Muscle Weakness 
 Mild Muscle Weakness 
 Moderate Muscle Weakness 
 Severe Muscle Weakness 
 Very Severe Muscle Weakness 
5. How bad has your child’s feeling of muscle weakness during activities been over the 
past week? 
 No Muscle Weakness 
 Mild Muscle Weakness 
 Moderate Muscle Weakness 
 Severe Muscle Weakness 


 
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Page 708 of 713 
Very Severe Muscle Weakness 
6. How bad has your child’s feeling of muscle pain at rest been over the past week? 
 No Muscle Pain 
 Mild Muscle Pain 
 Moderate Muscle Pain 
 Severe Muscle Pain 
 Very Severe Muscle Pain 
7. How bad has your child’s feeling of muscle pain due to activities been over the 
past week? 
 No Muscle Pain 
 Mild Muscle Pain 
 Moderate Muscle Pain 
 Severe Muscle Pain 
 Very Severe Muscle Pain 
8. How bad has your child’s feeling of early fullness when eating been over the past 
week? 
 No Early Fullness 
 Mild Early Fullness 
 Moderate Early Fullness 
 Severe Early Fullness 
 Very Severe Early Fullness 
9. How bad has your child’s feeling of difficulty eating (for example, chewing and/or 
swallowing) been over the past week? 
 No Difficulty Eating 
 Mild Difficulty Eating 
 Moderate Difficulty Eating 
 Severe Difficulty Eating 
 Very Severe Difficulty Eating 
10. How bad has your child’s feeling of headache been over the past week? 
 No Headache 
 Mild Headache 
 Moderate Headache 
 Severe Headache 


 
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Page 709 of 713 
 Very Severe Headache 
Caregiver Global Impression of Symptoms (Patient age >= 16)  
Date Completed: ________________________  
The following questions ask you about the individual with Barth Syndrome that you care 
for and the symptoms that he/she has had OVER THE PAST WEEK. Please base your 
responses on what you have observed or what the individual with Barth Syndrome has 
told you about his/her symptoms in the past week.  
1. How bad have his/her Barth Syndrome symptoms been over the past week? 
 No Symptoms 
 Mild Symptoms 
 Moderate Symptoms 
 Severe Symptoms 
 Very Severe Symptoms 
2. How bad has his/her feeling of tiredness at rest been over the past week? 
 No Tiredness 
 Mild Tiredness 
 Moderate Tiredness 
 Severe Tiredness 
 Very Severe Tiredness 
3. How bad has his/her feeling of tiredness during activities been over the past 
week? 
 No Tiredness 
 Mild Tiredness 
 Moderate Tiredness 
 Severe Tiredness 
 Very Severe Tiredness 
4. How bad has his/her feeling of muscle weakness at rest been over the past week? 
 No Muscle Weakness 
 Mild Muscle Weakness 
 Moderate Muscle Weakness 
 Severe Muscle Weakness 
 Very Severe Muscle Weakness 


 
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5. How bad has his/her feeling of muscle weakness during activities been over the 
past week? 
 No Muscle Weakness 
 Mild Muscle Weakness 
 Moderate Muscle Weakness 
 Severe Muscle Weakness 
Very Severe Muscle Weakness 
6. How bad has his/her feeling of muscle pain at rest been over the past week? 
 No Muscle Pain 
 Mild Muscle Pain 
 Moderate Muscle Pain 
 Severe Muscle Pain 
 Very Severe Muscle Pain 
7. How bad has his/her feeling of muscle pain due to activities been over the past 
week? 
 No Muscle Pain 
 Mild Muscle Pain 
 Moderate Muscle Pain 
 Severe Muscle Pain 
 Very Severe Muscle Pain 
8. How bad has his/her feeling of dizziness/lightheadedness been over the past 
week? 
 No Dizziness/Lightheadedness 
 Mild Dizziness/Lightheadedness 
 Moderate Dizziness/Lightheadedness 
 Severe Dizziness/Lightheadedness 
 Very Severe Dizziness/Lightheadedness 
9. How bad has his/her feeling of shortness of breath been over the past week? 
 No Shortness of Breath 
 Mild Shortness of Breath 
 Moderate Shortness of Breath 
 Severe Shortness of Breath 
 Very Severe Shortness of Breath 


TREATMENT PERIOD 1  
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Caregiver Global Impression of Change (Patient age 12-15)  
To be administered at Week 12 of Treatment Period 1.  
Date Completed: ________________________  
Please think about how your child’s Barth Syndrome symptoms have changed from the 
time just before he/she started the study medication in Treatment Period 1 to today. The  
following questions ask you about how your child’s symptoms have changed SINCE THE 
TIME JUST BEFORE HE/SHE STARTED THE STUDY MEDICATION IN TREATMENT 
PERIOD 1 TO TODAY. Please base your responses on what you have observed or what 
your child has told you about their symptoms.  
1. Please choose the response below that best describes how your child’s Barth 
Syndrome symptoms have changed since the time just before he/she started the 
study medication in Treatment Period 1 to today. My child’s Barth Syndrome 
symptoms are: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
2. Please choose the response below that best describes how your child’s feeling of 
tiredness at rest has changed since the time just before he/she started the study 
medication in Treatment Period 1 to today. My child’s tiredness at rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
3. Please choose the response below that best describes how your child’s feeling of 
tiredness during activities has changed since the time just before he/she started 
the study medication in Treatment Period 1 to today. My child’s tiredness during 
activities is: 
 Very much Better 
 Moderately Better 


TREATMENT PERIOD 1  
 
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Page 712 of 713 
 A Little Better 
 No Change 
 A Little Worse 
Moderately Worse 
 Very much Worse 
4. Please choose the response below that best describes how your child’s feeling of 
muscle weakness at rest has changed since the time just before he/she started the 
study medication in Treatment Period 1 to today. My child’s muscle weakness at 
rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
5. Please choose the response below that best describes how your child’s feeling of 
muscle weakness during activities has changed since the time just before he/she 
started the study medication in Treatment Period 1 to today. My child’s muscle 
weakness during activities is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
6. Please choose the response below that best describes how your child’s feeling of 
muscle pain at rest has changed since the time just before he/she started the study 
medication in Treatment Period 1 to today. My child’s muscle pain at rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 


TREATMENT PERIOD 1  
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Page 713 of 713 
 Very much Worse 
7. Please choose the response below that best describes how your child’s feeling of 
muscle pain during activities has changed since the time just before he/she started 
the study medication in Treatment Period 1 to today. My child’s muscle pain 
during activities is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
8. Please choose the response below that best describes how your child’s feeling of 
early fullness when eating has changed since the time just before he/she started 
the study medication in Treatment Period 1 to today. My child’s feeling of early 
fullness when eating is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
9. Please choose the response below that best describes how your child’s feeling of 
difficulty eating (for example, chewing and/or swallowing) has changed since the 
time just before he/she started the study medication in Treatment Period 1 to 
today. 
My child’s feeling of difficulty eating is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 


TREATMENT PERIOD 1  
 
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Page 714 of 713 
10. Please choose the response below that best describes how your child’s feeling 
ofheadache has changed since the time just before he/she started the study 
medication in Treatment Period 1 to today. My child’s feeling of headache is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 


TREATMENT PERIOD 1  
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Page 715 of 713 
Caregiver Global Impression of Change (Patient age >= 16)  
To be administered at Week 12 of Treatment Period 1.  
Date Completed: ________________________  
Please think about the individual that you care for and how his/her Barth Syndrome 
symptoms have changed from the time just before he/she started the study medication in 
Treatment Period 1 to today. The following questions ask you about how his/her 
symptoms have changed SINCE THE TIME JUST BEFORE HE/SHE STARTED THE STUDY 
MEDICATION IN TREATMENT PERIOD 1 TO TODAY. Please base your responses on what 
you have observed or what the individual with Barth Syndrome has told you about 
his/her symptoms.  
1. Please choose the response below that best describes how his/her Barth 
Syndrome symptoms have changed since the time just before he/she started the 
study medication in Treatment Period 1 to today. His/her Barth Syndrome 
symptoms are: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
2. Please choose the response below that best describes how his/her feeling of 
tiredness at rest has changed since the time just before he/she started the study 
medication in Treatment Period 1 to today. His/her tiredness at rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
3. Please choose the response below that best describes how his/her feeling of 
tiredness during activities has changed since the time just before he/she started 
the study medication in Treatment Period 1 to today. His/her tiredness during 
activities is: 
 Very much Better 


TREATMENT PERIOD 1  
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 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
4. Please choose the response below that best describes how his/her feeling of 
muscle weakness at rest has changed since the time just before he/she started the 
study medication in Treatment Period 1 to today. His/her muscle weakness at rest 
is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
5. Please choose the response below that best describes how his/her feeling of 
muscle weakness during activities has changed since the time just before he/she 
started the study medication in Treatment Period 1 to today. His/her muscle 
weakness during activities is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
6. Please choose the response below that best describes how his/her feeling of 
muscle pain at rest has changed since the time just before he/she started the study 
medication in Treatment Period 1 to today. His/her muscle pain at rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 


TREATMENT PERIOD 1  
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 Very much Worse 
7. Please choose the response below that best describes how his/her feeling of 
muscle pain during activities has changed since the time just before he/she started 
the study medication in Treatment Period 1 to today. His/her muscle pain during 
activities is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
8. Please choose the response below that best describes how his/her feeling of 
dizziness/lightheadedness has changed since the time just before he/she started 
the study medication in Treatment Period 1 to today. His/her 
dizziness/lightheadedness is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
9. Please choose the response below that best describes how his/her feeling of 
shortness of breath has changed since the time just before he/she started the 
study medication in Treatment Period 1 to today. His/her feeling of shortness of 
breath is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 


TREATMENT PERIOD 2  
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Caregiver Global Impression of Change (Patient age 12-15)  
To be administered at Week 12 of Treatment Period 2.  
Date Completed: ________________________  
Please think about how your child’s Barth Syndrome symptoms have changed from the 
time just before he/she started the study medication in Treatment Period 2 to today. The  
following questions ask you about how your child’s symptoms have changed SINCE THE 
TIME JUST BEFORE HE/SHE STARTED THE STUDY MEDICATION IN TREATMENT 
PERIOD 2 TO TODAY. Please base your responses on what you have observed or what 
your child has told you about their symptoms.  
1. Please choose the response below that best describes how your child’s Barth 
Syndrome symptoms have changed since the time just before he/she started the 
study medication in Treatment Period 2 to today. My child’s Barth Syndrome 
symptoms are: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
2. Please choose the response below that best describes how your child’s feeling of 
tiredness at rest has changed since the time just before he/she started the study 
medication in Treatment Period 2 to today. My child’s tiredness at rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
3. Please choose the response below that best describes how your child’s feeling of 
tiredness during activities has changed since the time just before he/she started 
the study medication in Treatment Period 2 to today. My child’s tiredness during 
activities is: 
 Very much Better 
 Moderately Better 


TREATMENT PERIOD 2  
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 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
4. Please choose the response below that best describes how your child’s feeling of 
muscle weakness at rest has changed since the time just before he/she started the 
study medication in Treatment Period 2 to today. My child’s muscle weakness at 
rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
5. Please choose the response below that best describes how your child’s feeling of 
muscle weakness during activities has changed since the time just before he/she 
started the study medication in Treatment Period 2 to today. My child’s muscle 
weakness during activities is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
6. Please choose the response below that best describes how your child’s feeling of 
muscle pain at rest has changed since the time just before he/she started the study 
medication in Treatment Period 2 to today. My child’s muscle pain at rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 


TREATMENT PERIOD 2  
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7. Please choose the response below that best describes how your child’s feeling of 
muscle pain during activities has changed since the time just before he/she started 
the study medication in Treatment Period 2 to today. My child’s muscle pain 
during activities is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
8. Please choose the response below that best describes how your child’s feeling of 
early fullness when eating has changed since the time just before he/she started 
the study medication in Treatment Period 2 to today. My child’s feeling of early 
fullness when eating is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
9. Please choose the response below that best describes how your child’s feeling of 
difficulty eating (for example, chewing and/or swallowing) has changed since the 
time just before he/she started the study medication in Treatment Period 2 to 
today. 
My child’s feeling of difficulty eating is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
10. Please choose the response below that best describes how your child’s feeling 
ofheadache has changed since the time just before he/she started the study 
medication in Treatment Period 2 to today. My child’s feeling of headache is: 
 Very much Better 


TREATMENT PERIOD 2  
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Page 721 of 713 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
Caregiver Global Impression of Change (Patient age >= 16)  
To be administered at Week 12 of Treatment Period 2.  
Date Completed: ________________________  
Please think about the individual that you care for and how his/her Barth Syndrome 
symptoms have changed from the time just before he/she started the study medication in 
Treatment Period 2 to today. The following questions ask you about how his/her 
symptoms have changed SINCE THE TIME JUST BEFORE HE/SHE STARTED THE STUDY 
MEDICATION IN TREATMENT PERIOD 2 TO TODAY. Please base your responses on what 
you have observed or what the individual with Barth Syndrome has told you about 
his/her symptoms.  
1. Please choose the response below that best describes how his/her Barth 
Syndrome symptoms have changed since the time just before he/she started the 
study medication in Treatment Period 2 to today. His/her Barth Syndrome 
symptoms are: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
2. Please choose the response below that best describes how his/her feeling of 
tiredness at rest has changed since the time just before he/she started the study 
medication in Treatment Period 2 to today. His/her tiredness at rest is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 


TREATMENT PERIOD 2  
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Page 722 of 713 
 Very much Worse 
3. Please choose the response below that best describes how his/her feeling of 
tiredness during activities has changed since the time just before he/she started 
the study medication in Treatment Period 2 to today. His/her tiredness during 
activities is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
4. Please choose the response below that best describes how his/her feeling of 
muscle weakness at rest has changed since the time just before he/she started the 
study medication in Treatment Period 2 to today. His/her muscle weakness at rest 
is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
5. Please choose the response below that best describes how his/her feeling of 
muscle weakness during activities has changed since the time just before he/she 
started the study medication in Treatment Period 2 to today. His/her muscle 
weakness during activities is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
6. Please choose the response below that best describes how his/her feeling of 
muscle pain at rest has changed since the time just before he/she started the study 
medication in Treatment Period 2 to today. His/her muscle pain at rest is: 


TREATMENT PERIOD 2  
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Page 723 of 713 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
7. Please choose the response below that best describes how his/her feeling of 
muscle pain during activities has changed since the time just before he/she started 
the study medication in Treatment Period 2 to today. His/her muscle pain during 
activities is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
8. Please choose the response below that best describes how his/her feeling of 
dizziness/lightheadedness has changed since the time just before he/she started 
the study medication in Treatment Period 2 to today. His/her 
dizziness/lightheadedness is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 
 A Little Worse 
 Moderately Worse 
 Very much Worse 
9. Please choose the response below that best describes how his/her feeling of 
shortness of breath has changed since the time just before he/she started the 
study medication in Treatment Period 2 to today. His/her feeling of shortness of 
breath is: 
 Very much Better 
 Moderately Better 
 A Little Better 
 No Change 


TREATMENT PERIOD 2  
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Page 724 of 713 
 A Little Worse 
 Moderately Worse 
 Very much Worse 


 
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Elamipretide (MTP-131 for SC Injection) 
 
SPIBA-201 Version 4.1 
23 April 2021 
 


 
Page 726 of 713 
 
Attachment 1 
EQ-5D  
 
Stealth BioTherapeutics, Inc.  
CONFIDENTIAL 
140 


 
Page 727 of 713 
 
Health Questionnaire 
English version for the USA 
USA (English) © 2012 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
Obtained from Clireo DMS 2018-03-19 7:09:44 PM (4:00 UTC) (6) Effective Date:3/19/2018 
EQ-5D-Y 


 
Page 728 of 713 
Describing your health TODAY 
Please check the ONE box that best describes your health TODAY. 
Mobility (walking around) 
 
I have no problems walking around 
 
 
I have some problems walking around 
 
 
I have a lot of problems walking around 
 
Taking care of myself 
I have no problems taking a bath or shower by myself or getting dressed 
by myself 
 
I have some problems taking a bath or shower by myself or getting  
 
dressed by myself 
 
I have a lot of problems taking a bath or shower by myself or getting  
 
dressed by myself 
 
Doing usual activities (for example, going to school, hobbies, sports, playing, 
doing things with family or friends) 
I have no problems doing my usual activities 
I have some problems doing my usual activities 
I have a lot of problems doing my usual activities 
Having pain or discomfort 
I have no pain or discomfort 
I have some pain or discomfort 
I have a lot of pain or discomfort 
Feeling worried, sad, or unhappy 
I am not worried, sad, or unhappy 
I am a little worried, sad, or unhappy 
I am very worried, sad, or unhappy 
2 
USA (English) © 2012 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
Obtained from Clireo DMS 2018-03-19 7:09:44 PM (4:00 UTC) (6) Effective Date:3/19/2018 
The best health  
 
How good is your health TODAY 
you can imagine 


 
Page 729 of 713 
100 
95 
90 
85 
80 
75 
70 
65 
• 
We would like to know how good or bad your health is TODAY.60 
• 
This line is numbered from 0 to 100.55 
• 
100 means the best health you can imagine.50 
0 means the worst health you can imagine.45 
• 
Please mark an X on the line to show how good or bad your40 health is 
TODAY. 
35 
30 
25 
20 
15 
10 
5 
0 
The worst health you 
can imagine 
3 
USA (English) © 2012 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 


 
Page 730 of 713 
Obtained from Clireo DMS 2018-03-19 7:09:44 PM (4:00 UTC) (6) Effective Date:3/19/2018 
 
Health Questionnaire 
English version for the USA 
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group  


 
Page 731 of 713 
Obtained from Clireo DMS 2018-03-19 7:09:44 PM (4:00 UTC) (6) Effective Date:3/19/2018 
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 

2  
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group  
Obtained from Clireo DMS 2018-03-19 7:09:44 PM (4:00 UTC) (6) Effective Date:3/19/2018 
The best health you 
can imagine 


 
Page 732 of 713 
x We would like to know how good or bad your health is TODAY. x This 
scale is numbered from 0 to 100. 
x 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
x Mark an X on the scale to indicate how your health is TODAY. 
x Now, please write the number you marked on the scale in the box below. 
 
YOUR HEALTH TODAY = 
 
The worst health 
you can imagine 
3  
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group  
Obtained from Clireo DMS 2018-03-19 7:09:44 PM (4:00 UTC) (6) Effective Date:3/19/2018 
Elamipretide (MTP-131 for SC Injection) 
SPIBA-201 Version 4.1 
23 April 2021 
 


 
Page 733 of 713 
Attachment 1 
SWAY Application Balance Assessments   
1. Access the portal via either: 
a. Computer: login to my.swaybalance.com utilizing email address and password. 
b. iPhone: Ensure the application is downloaded on the iPhone (app can be locatedin the 
Sway Balance app in the app store) 
2. Enter patient profile. Information required: 
a. First name: site number 
b. Last name: subject number 
c. Height: in feet/inches. 
d. Weight: in lbs. 
e. Birth date: 
f. Gender: 
g. Group: SPIBA-201 
h. Protocol: Sports 
3. Prior to providing subject the phone, ensure the phone is in airplane mode (to 
ensuretesting is not disrupted), with WiFi enabled (if possible, to allow automatic 
syncing to portal). Ensure case is removed from phone. 
4. At the Screening visit: Choose Baseline (as opposed to create event). At 
subsequentvisits, choose Create Event. 
5. Ask the subject to follow the screen’s directions on 10 second stand positions, duringtest 
intervals. 
“During testing, please hold the phone with both hands against your chest (region of 
sternum). The phone will make a sound to let you know a section of the test has been 
completed.” (Screen of phone will be against sternum of subject) 
a. Stand with feet together with eyes closed. 
b. Stand in tandem stance with right foot in front with eyes closed. 
c. Stand in tandem stance with left foot in front with eyes closed. 
d. Stand on right leg with EYES OPEN 
e. Stand on left leg with EYES OPEN 
f. 5 motion reaction tests 
At the Screening Visit: Have subject complete at least 2 additional trials following 1st trial 
At subsequent visits, subject will only complete 1 trial. 
Stealth BioTherapeutics, Inc.  
CONFIDENTIAL 
147 
Elamipretide (MTP-131 for SC Injection) 


 
Page 734 of 713 
 
SPIBA-201 Version 4.1 
23 April 2021 
 
 
Attachment 1 
6-Minute Walk Test (6MWT) 
Performed based on American Thoracic Society Guidelines for the 6-Minute Walk Test (March 
2002). To be completed following strength testing. 
1. Testing Guidelines 
a. 10 minute rest period will be given prior to the test 
b. Subjects should wear comfortable clothes and appropriate shoes for walking 
c. Subject may not touch the wall while walking 
2. Set up 
a. Test will be performed indoors, along a long, flat, straight, enclosed corridor with a 
hard surface. The walking course will be 30 m (100 feet) in length. 
b. Turn around points will be marked with a cone. A starting line (to mark thebeginning 
and end of each 60-m lap) will be marked on the floor using brightly colored tape. 
c. Area will be within easy access of medical assistance. 
d. One lap is the distance from one cone to the other  and back (60 meters) 
3. Conducting the Test 
a. Subject will sit in a chair for 10 minutes. During this time tester should obtain the 
following baseline measurements: heart rate, blood pressure and SPO2. 
b. Following the 10 minute rest period, subject will stand and tester will obtain 
baselinedyspnea and fatigue utilizing the Borg Scale using the following statements: 
i. 
“Please grade your level of shortness of breath using this scale.” 
ii. 
“Please grade your level of fatigue using this scale.” 
c. Tester will assemble stopwatch, timer, clipboard, Borg Scale and worksheet and move to 
starting point with subject. 
d. Tester will give the subject the following instruction regarding the test: 
i. 
“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 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.” 
e. Tester will then demonstrate walking one lap and turning around the cone briskly. 
f. Next tester will state: 
i. 
“Are you ready to do that? I will keep track of the number of laps you 
complete. Remember that the object is to walk as far as possible for 6 minutes, 
don’t run or jog.” 
g. Tester will start timer as soon as subject starts to walk. 
h. Tester should remain 1-2 meters behind the start line with the stopwatch, 
worksheet,timing the test. 
i. Tester should not talk to anyone during the walk, use an even tone of voice when using 
the standard phrases of encouragement. 


 
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Stealth BioTherapeutics, Inc.  
CONFIDENTIAL 
148 
Elamipretide (MTP-131 for SC Injection) 
 
SPIBA-201 Version 4.1 
23 April 2021 
 
j. Tester will place a line on the worksheet each time subject returns to starting line. 
k. If the subject stops during the walking test and needs a rest tester should say: 
i. 
“You can lean against the wall if you would like; then continue to walk 
whenever you feel able.” 
ii. 
Do not stop the timer. If the subject stops before the 6 minutes are up and 
refuses to continue (or you decide that they should not continue), bring the 
chair over to the subject to sit on, discontinue the walk, note on the worksheet 
the distance, time stopped and reason for stopping prematurely. 
l. After the first minute, tester should tell the subject the following (in even tones): 
 
i. 
“You are doing well. You have 5 minutes to go.” 
m. After the second minute, tester should tell the subject: 
 
i. 
“Keep up the good work. You have 4 minutes to go.” 
n. After 3 minutes, tester should tell the subject: 
 
i. 
“You are doing well. You are halfway done.” 
o. After 4 minutes, tester should tell the subject: 
 
i. 
“Keep up the good work. You have only 2 minutes left.” 
p. After 5 minutes, tester should tell the subject: 
 
i. 
“You are doing well. You have only 1 minute to go.” 
q. When the timer is 15 seconds from completion tester should say: 
i. 
“In a moment I am going to tell you to stop. When I do, just stop right where 
you are and I will come to you.” 
r. When the 6 minutes is up the tester should say: 
i. 
“Stop!” 
ii. 
Tester should walk to the subject (consider bringing chair if they look 
exhausted). Mark spot subject stopped with tape. 
s. Tester should record Dyspnea using Borg scale. 
i. 
Remind subject of breathing number that they chose before the exercise and 
ask the subject to grade their breathing level again (please grade your level of 
shortness of breath using this scale). 
t. Tester should record Fatigue using the Borg Scale. 
i. 
Remind subject of fatigue number that they chose before the exercise and ask 
the subject to grade their breathing level again (please grade your level of 
fatigue using this scale). 
u. Tester should record heart rate and SPO2 using pulse oximeter. 
v. Tester should ask subject: 
 
i. 
“What, if anything, kept you from walking farther?” 
w. Tester should record number of laps based on number of tick marks on worksheet. 
x. Tester should record additional distance covered (the number of meters in the final partial 
lap) using distance wheel. Calculate the total distance covered, rounding to the nearest 
meter and record it on the worksheet. 
y. Congratulate the subject on good effort and offer a drink of water. 


 
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Stealth BioTherapeutics, Inc.  
CONFIDENTIAL 
149 
Elamipretide (MTP-131 for SC Injection) 
 
SPIBA-201 Version 4.0 
23 April 2021 
 
Attachment 1 
Five Times Sit-to-Stand Test (5XSST) Description: 
Assesses functional lower extremity strength, transitional movements, balance, and fall risk.  
Equipment: 
Stopwatch; standard height chair with straight back (16 inches high).  
Therapist Instructions: 
Have the subject sit with their back against the back of the chair. Count each stand aloud so 
that the subject remains oriented. Stop the test when the subject achieves the standing 
position on the 5th repetition.   
Subject Instructions: 
“Please stand up straight as quickly as you can 5 times, without stopping in between. Keep 
your arms folded across your chest. I’ll be timing you with a stopwatch. Ready, begin.”  


 
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Stealth BioTherapeutics, Inc.  
CONFIDENTIAL 
150 


 
 
Elamipretide (MTP-131 for SC Injection) 
SPIBA-201 Version 4.0 
23 April 2021 
 
Attachment 1 
Table for Grading the Severity of Site Reactions to Injections 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-  
THREATENING 
Injection Site Pain or Tenderness Pain or tenderness 
causing no or minimal 
limitation of use of limb 
Pain or tenderness causing 
greater 
than 
minimal 
limitation of use of limb 
Pain or tenderness 
causing inability to 
perform usual social 
& functional activities 
Pain or tenderness causing  
inability to perform basic selfcare 
function OR 
Hospitalization indicated 
Injection Site Erythema or 
Redness 
2.5 to < 5 cm in diameter 
OR 6.25 to < 25 cm2 
surface 
area 
AND 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities 
≥ 5 to < 10 cm in diameter OR 
≥ 25 to < 100 cm2 surface area 
OR Symptoms 
causing 
greater 
than 
minimal interference with 
usual social & functional 
activities 
≥ 10 cm in diameter OR ≥  
100 cm2 surface area OR 
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR 
Drainage 
OR 
Symptoms 
causing inability to perform 
usual social & functional 
activities 
Potentially lifethreatening 
consequences 
(e.g., 
abscess, 
exfoliative 
dermatitis, 
necrosis 
involving dermis or deeper 
tissue) 
Injection Site Induration or 
Swelling 
Same as for Injection Site 
Erythema or Redness 
Same as for Injection Site 
Erythema or Redness 
Same as for Injection Site 
Erythema or Redness 
Same as for Injection Site 
Erythema or Redness 
Injection Site Pruritus 
Itching localized to the 
injection 
site 
that 
is 
relieved spontaneously or 
in < 48 hours of treatment 
Itching 
beyond 
the 
injection site that is not 
generalized OR Itching 
localized to the injection 
site requiring ≥ 48 hours 
treatment 
Generalized itching 
causing inability to 
perform usual social 
& functional activities 
NA 
Adapted from Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2, November 2014. 


 
 
Stealth BioTherapeutics, Inc.  
CONFIDENTIAL 
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Page 712 of 713 


 
 
Elamipretide (MTP-131 for SC Injection) 
SPIBA-201 Version 4.0 
23 April 2021 
 
Attachment 1 
Sample Telephone Call (or other forms of communication) Script 
This page provides a sample script for the phone call (or other forms of communication) that 
will be made to the subject occur approximately every 12 weeks (after the Part 2 Week 12 
Visit) between clinical site visits after the subject is enrolled in Part 2 to ensure the safe and 
compliant use of the study drug and to appropriately collect the safety events with use of the 
study drug.   
The sample script below is provided to assist clinical sites with conducting safety telephone 
calls (or other forms of communication). Additional questions are permitted to ensure 
completeness of answers.  
During each safety telephone call (or other forms of communication), the following script 
should be followed:   
Script 
Hello, my name is ______________, and I'm calling from (name of facility and/or  
Investigator’s name office). I am calling since it has been about 3 months since we last spoke 
about your experience using elamipretide, the study drug in the Part 2 of the trial that 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).  


 
 
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CONFIDENTIAL 
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