Clinical trial NCT02788747
Conditions: Heart Failure
Sponsor: Stealth BioTherapeutics Inc.
Start date: 2016-06-01; Completion date: 2017-10-01
Enrollment: 71 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a randomized, double-blinded, placebo-controlled, multiple-dose study in subjects with stable heart failure (HF) with reduced ejection fraction (HFrEF).

Detailed description:
This was a randomized, double-blinded, placebo-controlled, multiple-dose study in subjects with stable heart failure (HF) with reduced ejection fraction (HFrEF). After completing the Screening period, a total of 71 subjects were randomized, in a 1:1:1 ratio, to receive either placebo, 4 mg elamipretide, or 40 mg elamipretide once daily for 28 consecutive days.

Each treatment group went through 3 distinct periods: Screening, Treatment, and Follow up.

Arms: arm 1: 4 mg elamipretide once daily for 28 consecutive days arm 2: 40 mg elamipretide once daily for 28 consecutive days arm 3: Placebo once daily for 28 consecutive days
Interventions: intervention 1: 4 mg elamipretide intervention 2: 40 mg elamipretide intervention 3: Placebo
Intervention descriptions: intervention 1: Subcutaneous injection of 4 mg elamipretide administered once daily for 28 consecutive days intervention 2: Subcutaneous injection of 40 mg elamipretide administered once daily for 28 consecutive days intervention 3: Subcutaneous injection of placebo administered once daily for 28 consecutive days

Protocol documents:
Prot_000.pdf: 
 
 
 
A Phase 2 Randomized, Double-Blinded, Placebo-Controlled Study to Evaluate the Effects of Multiple 
Subcutaneous Injections of Elamipretide on Left Ventricular Function in Subjects with Stable Heart 
Failure with Reduced Ejection Fraction 
NCT02788747 
21st March 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CLINICAL STUDY PROTOCOL 
A Phase 2 Randomized, Double-Blinded, Placebo-Controlled Study to 
Evaluate the Effects of Multiple Subcutaneous Injections of Elamipretide on 
Left Ventricular Function in Subjects with Stable Heart Failure with Reduced 
Ejection Fraction 
 
Study Phase: 
Phase 2 
Study Number: 
SPIHF-201 
Document Version: 
Version 8.0 
Final Approval Date:  
21st March 2017 
EudraCT Number: 
2014-005724-10 
Sponsor: 
Stealth BioTherapeutics Inc. 
275 Grove Street, Suite 3-107 
Newton, MA 02466 
Unites States of America 
Sponsor Clinical Lead: 
        James Carr, PharmD 
 
 
Confidentiality Statement 
The information contained in this document is confidential and is the property of Stealth 
BioTherapeutics Inc.  No part of it may be transmitted, reproduced, published, or used by 
anyone without the written permission of Stealth BioTherapeutics Inc.  
 
 
 


PROTOCOL APPROVAL 
 
 
Protocol Title: 
A Phase 2 Randomized, Double-Blinded, Placebo-
Controlled Study to Evaluate the Effects of Multiple 
Subcutaneous Injections of Elamipretide on Left 
Ventricular Function in Subjects with Stable Heart 
Failure with Reduced Ejection Fraction 
Protocol Number: 
SPIHF-201 
Protocol Version: 
8.0 
Protocol Date: 
21st March 2017 
 
 
 
 
 
James Carr, PharmD 
Vice President, Clinical Development 
 
 
 
Date 


INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for elamipretide (MTP-131).  I have read 
the SPIHF-201 protocol and agree to conduct the study as outlined.  I confirm that I will conduct 
the study in accordance with ICH GCP guidelines.  I will also ensure that sub-Investigator(s) and 
other relevant members of my staff have access to copies of this protocol, and the ICH GCP 
guidelines to enable them to work in accordance with the provisions of these documents.  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) 
 
 


1. 
SYNOPSIS 
Name of Sponsor/Company:  Stealth BioTherapeutics Inc. 
Investigational Product:  Elamipretide (MTP-131) 
Title of Study:  A Phase 2 Randomized, Double-Blinded, Placebo-Controlled Study to 
Evaluate the Effects of Multiple Subcutaneous Injections of Elamipretide on Left Ventricular 
Function in Subjects with Stable Heart Failure with Reduced Ejection Fraction 
Study Center(s): This study will be conducted in up to 20 centers in Europe 
Objectives:  
Primary: 
To evaluate the effects of multiple subcutaneous (SC) doses of elamipretide on left ventricular 
end systolic volume (LV ESV) assessed by cardiac Magnetic Resonance Imaging (MRI) 
Secondary: 
• To evaluate the safety and tolerability of multiple SC doses of elamipretide 
• To evaluate the effects of multiple SC doses of elamipretide on LV systolic and 
diastolic function, LV volumes, LV global longitudinal strain, left atrial (LA) volume, 
LV mass, mitral and tricuspid regurgitation severity, and right ventricular (RV) 
function. 
Exploratory: 
To evaluate the effects of multiple SC doses of elamipretide on: 
• 6-minute walking distance 
• Quality of Life 
• N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels 
Methodology:   
This is a randomized, double-blinded, placebo-controlled, multiple dose study in subjects with 
stable heart failure with reduced ejection fraction (HFrEF).  After completing the screening 
period, approximately 70 subjects will be randomized, in a 1:1:1 ratio, to receive either 
placebo, 4 mg elamipretide, or 40 mg elamipretide once daily for 28 consecutive days.   
Each treatment group will go through 3 distinct periods: Screening, Treatment and Follow-up. 
Study procedures, their timing, and additional details for the three study periods are found in 
the Study Schedule in Attachment 1 and are detailed in the protocol. Details regarding the 
clinical laboratory tests to be performed are found in Attachment 2 and are detailed in the 
protocol. 
Number of Subjects: Around 70 subjects will be randomized 


Inclusion Criteria: 
A subject must meet all of the following criteria prior to Day 1 to be eligible for inclusion in 
the study: 
1. Willing and able to provide signed informed consent form (ICF) prior to participation 
in any study-related procedures. 
2. Age ≥40 and <80 years. 
3. A known history of chronic ischemic or non-ischemic cardiomyopathy of at least 6 
months duration from the time of the initial diagnosis or signs and symptoms 
consistent with heart failure. 
4. Receiving heart failure (HF) treatment, including, but not limited to, angiotensin 
converting enzyme inhibitors (ACEI) and/or angiotensin receptor blockers (ARB), and 
an evidence-based beta blocker for the treatment of HF. Subjects who cannot tolerate 
ACEI or ARB due to reduced renal function or hypotension are eligible. Subjects may 
be receiving aldosterone antagonists, but this is not a requirement for the study. 
5. HF is considered to be stable in the judgment of the Investigator AND doses of HF 
treatment have been stable for at least 1 month prior to the Screening Visit. 
6. In normal sinus rhythm (electrocardiogram documented) at Screening and Day 1 and 
no history of atrial fibrillation in the past 12 months 
7. No hospitalization related to HF within 1 month prior to the Screening Visit.  
8. Left Ventricular Ejection Fraction (LVEF) ≤ 40% by 2-D echocardiography at 
Screening. 
9. At least 3 viable segments (hyperenhancement ≤ 25%) by a qualifying delayed 
gadolinium-enhanced cardiac MRI examination at Screening (confirmed by 
independent core lab). 
10. Willing to adhere to the study requirements for the length of the trial. 
11. Women of childbearing potential must agree to use 1 of the following methods of birth 
control from the date they sign the ICF until two months after the last dose of study 
medication: 
a. Abstinence, when it is in line with the preferred and usual lifestyle of the 
subject.  Subject agrees to use an acceptable method of contraception should 
they become sexually active. 
b. Maintenance of monogamous relationship with a male partner who has been 
surgically sterilized by vasectomy (the vasectomy procedure must have been 
conducted at least 60 days prior to the Screening Visit or confirmed via sperm 
analysis). 
c. Barrier method (e.g., condom or occlusive cap) with spermicidal 
foam/gel/film/cream AND either hormonal contraception (oral, implanted, or 
injectable) or an intrauterine device or system. 


Note: Non-childbearing potential is defined as surgical sterilization (e.g., bilateral 
oophorectomy, hysterectomy, or tubal ligation) or postmenopausal (defined as 
permanent cessation of menstruation for at least 12 consecutive months prior to the 
Screening Visit). 
Exclusion Criteria: 
A subject who meets any of the following criteria at Screening will be excluded from the 
study: 
1. History of any concurrent medical condition which, in the opinion of the Investigator, 
significantly increases the potential risks associated with administration of study 
medication or any other aspect of study participation. 
2. Any contraindication to MRI scanning as assessed by local MRI safety questionnaire, 
which may include: 
a. History of intra-orbital metal fragments which have not been removed 
b. Severe claustrophobia 
c. Non-MRI safe cochlear implant(s) or intracranial aneurysm clips 
d. Extensive tattoos located on the torso that contain metallic inks 
e. Other non-removable implanted metallic or electronic devices that have not 
been determined to be MRI safe 
f. Inability to lie flat 
3. Inadequate echocardiogram image quality (defined as poor sound transmission and/or 
< 10 endocardial segments seen). 
4. LVEDD indexed to Body Surface Area is > 45 mm/m2 assessed by 2-D 
echocardiography. 
5. Coronary or peripheral revascularization procedures, valvular procedures, OR any 
major surgical procedure within 3 months prior to the Screening Visit. 
6. Acute coronary syndrome, stroke or transient ischemic attack (TIA) within 3 months 
prior to the Screening Visit. 
7. Obstructive or restrictive cardiomyopathy, infiltrative diseases of the myocardium 
(e.g., amyloid, sarcoid, etc.) myocarditis, or reductions in LV function thought to be 
secondary primarily to valvular heart disease, prior cardiac valve surgery or known 
aortic stenosis. 
8. The presence or anticipated placement of any pacemaker, implantable cardioverter 
defibrillator (ICD), or cardiac resynchronization therapy (CRT) devices during the 
ensuing 6-week study period. 
9. Presence of second degree or advanced heart block. 


10. Uncontrolled hypertension defined as a systolic blood pressure > 160 mmHg or a 
diastolic blood pressure > 110 mmHg on at least two consecutive readings. 
11. Presence of any left ventricular thrombus, pericardial disease, uncorrected thyroid 
disease or a dyskinetic left ventricular aneurysm. 
12. History of cancer that causes symptoms, disabilities, or is likely to lead to 
hospitalization or treatment in the next 12 months. 
13. Currently receiving treatment with chemotherapeutic agents or immunosuppressant 
agents or has received prior radiation therapy to the chest. 
14. Liver enzymes (alanine aminotransferase [ALT] AND/OR aspartate aminotransferase 
[AST]) elevation > 3 times the upper limit of normal (ULN). 
15. Total bilirubin > 1.5 times ULN in the absence of Gilbert’s Syndrome. 
16. Bleeding diathesis or any known blood dyscrasia. 
17. Anemia, defined as hemoglobin < 9 g/dL or planned blood transfusions in the next 6 
weeks. 
18. Estimated glomerular filtration rate (eGFR) < 30 mL/min, using the Modification of 
Diet in Renal Disease (MDRD) Study 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) 
19. History of hepatitis B, hepatitis C or Human Immunodeficiency Virus (HIV) infection, 
or diagnosis of immunodeficiency. 
20. Known active drug or alcohol abuse within 1 year of the Screening Visit.  Alcohol 
abuse is defined as 15 or more drinks for men per week or 8 or more for women. 
21. Recipient of any investigational drugs, stem cell or gene therapies, or devices OR 
participation in another clinical trial, within 3 months prior to the Screening Visit. 
22. Any significant acute or chronic medical or psychiatric illness that, in the judgment of 
the Investigator, could compromise the subject’s safety, limit subject’s ability to 
complete the study, and/or compromise the objectives of the study. 
23. Female subjects who are pregnant, planning to become pregnant, or lactating. 
24. Currently requiring any changes in doses of cardiovascular medication (including 
diuretics) in order to control worsening of HF symptoms. 
25. Known allergy to gadolinium. 
26. Currently receiving treatment with therapeutic doses of anticoagulants. Antiplatelet 
therapy used to prevent cardiovascular disease (primary prevention) or to treat chronic 
disease (secondary prevention) is permitted, as well as vitamin K antagonists.   
27. Currently receiving treatment with sacubitril/valsartan or trimetazidine.  


Investigational product, dosage and mode of administration: Elamipretide (MTP-131) will 
be supplied as 40 mg/1 mL of sterile solution for subcutaneous injection.  The doses of 
elamipretide will be 4 mg or 40 mg administered as a once daily SC injection.   
Planned Study Duration:  
Screening Period: Up to 28 days 
Treatment Period: At least 28 days 
Follow-up Period: 14 days 
Reference therapy, dosage and mode of administration: 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 as active drug. 
Criteria for evaluation: 
Primary Endpoints 
Change from baseline in left ventricular end systolic volume (LV ESV) assessed by cardiac 
MRI 
Secondary Endpoints 
• Adverse events (AEs) 
• Changes from baseline in vital signs 
• Changes from baseline in electrocardiograms (ECGs) 
• Changes from baseline in clinical laboratory evaluations 
• Changes from baseline in the following parameters assessed by cardiac MRI: 
o LV EF 
o LV end diastolic volume (EDV) 
• Changes from baseline in the following parameters assessed by echocardiography: 
o E/A (ratio between early and late mitral inflow velocity),  
o E/e’ (Ratio between early mitral inflow velocity and mitral annular early 
diastolic velocity) 
o LV EDV, LV ESV and biplane EF  
o LV global longitudinal strain 
o LA volume 
o LV mass 
o Mitral regurgitation severity 
o Tricuspid regurgitation severity 


o RV fractional area change 
o RV systolic pressure (RVSP) 
Exploratory Endpoints 
• Changes from baseline in: 
o Distance walked (meters) on the 6-minute walk test (6MWT) 
o Kansas City Cardiomyopathy Questionnaire (KCCQ) score 
o Levels of N-terminal pro-brain natriuretic peptide (NT-pro-BNP)  
o Change in Borg dyspnea scale 
Statistical methods: 
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. 
Each active dose will be tested against placebo. 
For primary and secondary efficacy endpoints, the change from baseline in all continuous 
endpoints will be summarized using descriptive statistics (mean, median, standard deviation, 
minimum, maximum) by treatment group.  Additional analyses will be performed according to 
the Statistical Analysis Plan (SAP). 
Safety data analysis will be conducted on all subjects in the Safety Population. The number 
and percentage of subjects experiencing one or more treatment emergent AEs will be 
summarized by treatment group, relationship to study medication, and severity. Listings of 
subjects who experience withdrawal due to an AE, serious AEs, suspected unexpected serious 
adverse reactions, and/or death will be presented. Laboratory parameters will be summarized 
using descriptive statistics, by post-dosing shifts relative to baseline where appropriate, and 
data listings of clinically significant abnormalities. Vital signs and ECG data will be 
summarized by changes from baseline values using descriptive statistics. 
Sample Size: 
The initial sample size of 45 patients was based on the assumption that a sample size of 15 
subjects per treatment group provided 90% power to detect an 8 milliliter (mL) difference 
between treatment groups in LV ESV, as measured by MRI, assuming a standard deviation of 
6.5 mL. 
A revised estimate of the standard deviation, based on a review of blinded LV ESV data from 
the first 11 subjects who completed treatment, suggests it may ultimately be as high as 9.4 mL.  
Accordingly, the sample size is being increased to around 22 subjects per treatment group, 
which provides 80% power to detect the aforementioned 8 mL difference between treatment 
groups. If necessary, the standard deviation will be reassessed in blinded fashion and the 
sample size modified accordingly. 


2. 
TABLE OF CONTENTS 
PROTOCOL APPROVAL ........................................................................................................................................... 3 
INVESTIGATOR’S AGREEMENT ............................................................................................................................... 4 
1. 
SYNOPSIS....................................................................................................................................................... 5 
2. 
TABLE OF CONTENTS ................................................................................................................................... 11 
3. 
ABBREVIATIONS AND DEFINITIONS ............................................................................................................. 14 
4. 
INTRODUCTION ........................................................................................................................................... 16 
4.1. 
HEART FAILURE............................................................................................................................................... 16 
4.2. 
ELAMIPRETIDE RISK/BENEFIT ASSESSMENT .......................................................................................................... 17 
4.2.1. 
Potential Benefits .............................................................................................................................. 17 
4.2.2. 
Potential Risks ................................................................................................................................... 17 
4.2.2.1. 
Safety findings – Nonclinical studies ............................................................................................................. 17 
4.2.2.2. 
Human safety ................................................................................................................................................ 18 
4.2.3. 
Conclusions ........................................................................................................................................ 18 
5. 
OBJECTIVES ................................................................................................................................................. 19 
5.1. 
PRIMARY OBJECTIVE ........................................................................................................................................ 19 
5.2. 
SECONDARY OBJECTIVE .................................................................................................................................... 19 
5.3. 
EXPLORATORY OBJECTIVES ................................................................................................................................ 19 
6. 
INVESTIGATIONAL PLAN .............................................................................................................................. 20 
6.1. 
STUDY DESIGN ................................................................................................................................................ 20 
6.2. 
STUDY SCHEDULE ............................................................................................................................................ 20 
6.2.1. 
Screening Period: Day -28 to Day -1 .................................................................................................. 20 
6.2.2. 
Treatment Period: Study Visits .......................................................................................................... 21 
6.2.2.1. 
Day 1 (Baseline) ............................................................................................................................................ 21 
6.2.2.2. 
Week 1 (Day 8 + 3 days) ................................................................................................................................ 22 
6.2.2.3. 
Week 2 (Day 15 ± 3 days) .............................................................................................................................. 22 
6.2.2.4. 
Week 4 (Day 29 + 3 days)/Early Discontinuation Visit .................................................................................. 23 
6.2.3. 
Follow-up Period ................................................................................................................................ 23 
6.2.3.1. 
Week 6 (Day 43 ± 3 days) .............................................................................................................................. 23 
6.3. 
STUDY ASSESSMENTS ....................................................................................................................................... 24 
6.3.1. 
Relevant Medical History and Cardiovascular Physical Examination ................................................ 24 
6.3.2. 
Kansas City Cardiomyopathy Questionnaire (KCCQ) ......................................................................... 24 
6.3.3. 
Vital signs .......................................................................................................................................... 24 
6.3.4. 
Electrocardiograms (ECGs) ................................................................................................................ 24 
6.3.5. 
Echocardiogram ................................................................................................................................ 24 
6.3.6. 
Cardiac MRI ....................................................................................................................................... 25 
6.3.7. 
Borg Dyspnea Scale ........................................................................................................................... 25 
6.3.8. 
6-Minute Walk Test (6MWT) ............................................................................................................. 25 
6.3.9. 
Clinical Laboratory Testing ................................................................................................................ 25 
6.3.9.1. 
Blood chemistries.......................................................................................................................................... 25 
6.3.9.2. 
Hematology ................................................................................................................................................... 25 
6.3.9.3. 
Urinalysis ....................................................................................................................................................... 25 


6.3.9.4. 
Pregnancy tests ............................................................................................................................................. 26 
6.3.9.5. 
Samples for elamipretide and metabolite plasma levels .............................................................................. 26 
6.3.9.6. 
Exploratory biomarkers ................................................................................................................................. 26 
6.3.10. 
Injection Site Reaction (ISR) Assessments .......................................................................................... 26 
7. 
STUDY POPULATION .................................................................................................................................... 27 
7.1. 
INCLUSION CRITERIA ........................................................................................................................................ 27 
7.2. 
EXCLUSION CRITERIA ........................................................................................................................................ 28 
7.3. 
PROHIBITED MEDICATIONS ............................................................................................................................... 30 
7.4. 
DISCONTINUATIONS ......................................................................................................................................... 30 
7.4.1. 
Discontinuation of Subjects ............................................................................................................... 30 
7.4.2. 
Discontinuation of Study Sites ........................................................................................................... 31 
7.4.3. 
Discontinuation of the Study ............................................................................................................. 31 
8. 
TREATMENT ................................................................................................................................................ 32 
8.1. 
TREATMENTS ADMINISTERED ............................................................................................................................ 32 
8.2. 
MATERIALS AND SUPPLIES ................................................................................................................................ 32 
8.2.1. 
Elamipretide ...................................................................................................................................... 32 
8.2.2. 
Placebo .............................................................................................................................................. 32 
8.3. 
TREATMENT LOGISTICS AND ACCOUNTABILITY ...................................................................................................... 33 
8.4. 
METHOD OF ASSIGNMENT TO TREATMENT AND RANDOMIZATION ............................................................................ 33 
8.5. 
RATIONALE FOR SELECTION OF DOSES IN THE STUDY .............................................................................................. 33 
8.6. 
CONTINUED ACCESS TO INVESTIGATIONAL MEDICINAL PRODUCT .............................................................................. 34 
8.7. 
BLINDING AND UNBLINDING PROCEDURES ........................................................................................................... 34 
8.8. 
TREATMENT COMPLIANCE ................................................................................................................................ 34 
9. 
EFFICACY AND SAFETY EVALUATIONS AND APPROPRIATENESS OF MEASUREMENTS.................................. 35 
9.1. 
EFFICACY MEASURES ....................................................................................................................................... 35 
9.1.1. 
Primary efficacy measure .................................................................................................................. 35 
9.1.2. 
Secondary efficacy measure .............................................................................................................. 35 
9.1.3. 
Exploratory efficacy measures ........................................................................................................... 35 
9.2. 
SAFETY EVALUATIONS ...................................................................................................................................... 35 
9.2.1. 
Adverse Events................................................................................................................................... 36 
9.3. 
PRE-TREATMENT EVENTS ................................................................................................................................. 36 
9.4. 
BASELINE MEDICAL CONDITIONS ........................................................................................................................ 37 
9.5. 
ABNORMAL LABORATORY AND OTHER ABNORMAL INVESTIGATIONAL FINDINGS .......................................................... 37 
9.6. 
SERIOUS ADVERSE EVENTS ................................................................................................................................ 37 
9.6.1. 
Events that Do Not Meet the Definition of a Serious Adverse Event ................................................. 38 
9.7. 
RECORDING OF ADVERSE EVENTS ....................................................................................................................... 38 
9.7.1. 
Investigator Assessments .................................................................................................................. 39 
9.7.1.1. 
Severity/Intensity .......................................................................................................................................... 39 
9.7.1.2. 
Relationship to the Investigational Medicinal Product (IMP) ....................................................................... 39 
9.7.2. 
Adverse Event Reporting Period ........................................................................................................ 39 
9.8. 
SERIOUS ADVERSE EVENT EXPEDITED REPORTING .................................................................................................. 40 
9.8.1. 
Pregnancy and Contraception ........................................................................................................... 41 
9.8.2. 
Responsibilities to Regulatory Authorities, Investigators and Ethics Committees ............................. 42 
9.9. 
APPROPRIATENESS OF MEASUREMENTS ............................................................................................................... 42 


10. 
DATA QUALITY ASSURANCE .................................................................................................................... 43 
10.1. 
DATA CAPTURE SYSTEM ................................................................................................................................... 43 
11. 
SAMPLE SIZE AND STATISTICAL METHODS .............................................................................................. 44 
11.1. 
DETERMINATION OF SAMPLE SIZE ...................................................................................................................... 44 
11.2. 
STATISTICAL AND ANALYTICAL PLANS .................................................................................................................. 44 
11.2.1. 
General Considerations ..................................................................................................................... 44 
11.2.2. 
Subject Disposition ............................................................................................................................ 44 
11.2.3. 
Subject Characteristics ...................................................................................................................... 44 
11.2.4. 
Endpoints and Methodology ............................................................................................................. 44 
11.2.4.1. 
General Considerations ................................................................................................................................. 44 
11.2.4.2. 
Analysis Populations ..................................................................................................................................... 45 
11.2.5. 
Efficacy Analyses ............................................................................................................................... 45 
11.2.6. 
Safety Analyses .................................................................................................................................. 45 
11.2.6.1. 
Adverse Events .............................................................................................................................................. 45 
11.2.6.2. 
Deaths and Other Serious Adverse Events .................................................................................................... 46 
11.2.6.3. 
Clinical Laboratory Evaluations ..................................................................................................................... 46 
11.2.6.4. 
Vital Signs ...................................................................................................................................................... 46 
11.2.6.5. 
Electrocardiogram ......................................................................................................................................... 46 
11.2.6.6. 
Other Safety Parameters............................................................................................................................... 46 
12. 
INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY CONSIDERATIONS ...................................... 47 
12.1. 
INFORMED CONSENT ....................................................................................................................................... 47 
12.2. 
ETHICAL REVIEW ............................................................................................................................................. 47 
12.3. 
REGULATORY CONSIDERATIONS ......................................................................................................................... 47 
12.3.1. 
Protocol Approval .............................................................................................................................. 48 
12.3.2. 
Final Report Approval ........................................................................................................................ 48 
12.3.3. 
Study Monitoring ............................................................................................................................... 48 
12.3.4. 
Retention of Records ......................................................................................................................... 48 
12.3.5. 
Disclosure of Information .................................................................................................................. 48 
13. 
REFERENCES ............................................................................................................................................ 50 
14. 
ATTACHMENTS ........................................................................................................................................ 51 
 


3. 
ABBREVIATIONS AND DEFINITIONS 
Term 
Definition 
6MWT 
Six-minute walk test 
ACEI 
Angiotensin converting enzyme inhibitors  
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ARB 
Angiotensin receptor blockers 
AST 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
AUC 
Area under the plasma concentration versus time curve 
AUC0-τ 
Area under the plasma concentration vs time curve from time 0 to end of the dosing 
interval  
BMI 
Body mass index 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
Maximum plasma concentration 
CRT 
Cardiac resynchronization therapy 
E/A 
Ratio between early and late mitral inflow velocity 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
Electronic data capture 
EDV 
end-diastolic volume 
E/e’ 
Ratio of mitral peak velocity of early filling (E) to early diastolic mitral annular 
velocity (e’) 
EF 
ejection fraction 
eGFR 
estimated glomerular filtration rate 
ESV 
end-systolic volume 
GCP 
Good Clinical Practice 
HF 
heart failure 
HFrEF 
heart failure with reduced ejection fraction 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICD 
implantable cardioverter defibrillator 
ICF 
informed consent form 


Term 
Definition 
ICH 
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
ISR 
Injection Site Reaction 
IV 
intravenous 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LA 
left atrial 
LV 
left ventricular 
LVEDD 
left ventricular end-diastolic dimension 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
milliliter 
MRI 
magnetic resonance imaging 
MTP-131 
elamipretide or Bendavia™ 
NT-pro-BNP  
N-terminal pro-brain natriuretic peptide 
PK 
pharmacokinetic(s) 
PT 
preferred term 
RV 
right ventricular 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
 
 
 


4. 
INTRODUCTION 
This study will be conducted in strict accordance with the Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, ICH GCP 
guideline, and all applicable laws and regulations. For detailed information on the study 
medication and the nonclinical and clinical studies conducted to date, please refer to the most 
recent edition of the MTP-131 Investigator’s Brochure (IB). 
4.1. 
Heart Failure 
It is estimated that approximately 1-2% of the adult population in developed countries has Heart 
Failure (HF) and the prevalence is rising to ≥ 10% among persons 70 years of age or older (1). 
HF incidence is continuously increasing. The overall worldwide economic cost of HF in 2012 
was estimated at 108 billion US dollars per annum (2). 
Chronic systolic HF is a multisystem disease. Although initiated by a reduction in cardiac 
function, chronic HF is characterized by systemic responses induced by declines in cardiac 
function, particularly regarding neurohormonal activation (renin-angiotensin-aldosterone system 
and the sympathetic nervous system). Besides the negative effect on the myocardium, these 
systemic responses negatively impact the blood vessels, kidneys, muscles, bone marrow, lungs 
and liver (3, 4). Exercise intolerance is widely recognized as a defining symptom in individuals 
with chronic HF, limiting physical activity and impairing quality of life. This attenuated exercise 
capacity has been traditionally attributed to the “central” limitations associated with a 
malfunctioning cardiac pump. In addition, many non-cardiac factors may contribute substantially 
to exercise intolerance: changes in peripheral vascular function, skeletal muscle physiology, 
pulmonary gas exchange, neurohormonal and reflex autonomic activity, and renal sodium 
handling (5). 
Despite the significant improvement in symptoms and survival observed with pharmacologic 
blockade of the renin-angiotensin and beta adrenergic systems, such drug therapy generally has 
had limited impact on exercise capacity. 
This has led to the concept that multi-targeted mechanistic approaches to HF are required to 
successfully translate experimental interventions into protection against the clinical 
manifestations of the disease state, as well as beneficially impact its associated major adverse 
events, including recurrent hospitalization and death. Such a broad-based approach must include 
therapies that simultaneously impact multiple affected organ systems and cellular mechanisms 
including the: 
• Heart: Limited cardiac output 
• Mitochondria: Limited energetics 
• Skeletal Muscle: Limited bulk and strength 
• Endothelium: Limited vascular function 
• Lungs: Limited gas exchange 
• Kidneys: Abnormal salt and volume regulation 


Elamipretide, with its multi-organ beneficial actions on function and metabolism in vitro and in 
animal models, is a promising candidate for targeting the complex interplay of factors that 
ultimately result in the syndrome of clinical HF. The potential of elamipretide to treat the 
multiple organs systems and organelles that contribute to the HF state represents an important 
opportunity to address a critical and unmet clinical need. 
4.2. 
Elamipretide Risk/Benefit Assessment 
4.2.1. 
Potential Benefits 
In animal models of HF, elamipretide has been shown to beneficially impact the major potential 
therapeutic targets for HF.  In canine studies of severe well established HF both a single infusion 
and 3 months of daily elamipretide injections improved left ventricular (LV) ejection fraction, 
LV end diastolic pressure, and rate of rise of LV pressure (dP/dtmax), without changes in heart 
rate or mean aortic pressure.  In different murine models of heart failure, elamipretide 
ameliorated cardiac hypertrophy and enlargement, systolic and diastolic dysfunction, and 
myocardial fibrosis. 
In a Phase 1 trial (SPIHF-101) evaluating single ascending IV doses of elamipretide in 24 
patients with moderate chronic HF receiving concomitant standard of care pharmacologic 
therapy for chronic HF, echocardiography was used to assess effects on cardiac function. An 
independent analysis by Duke Clinical Research Institute suggested that the highest dose of 
elamipretide (0.25 mg/kg/hr administered intravenously over 4 hours) significantly improved 
mean left ventricular (LV) end systolic volume (absolute change from baseline -11.1 mL versus 
1.5 mL for placebo; mean difference = -12.6 mL; p=.0157) and mean LV end diastolic volume 
(absolute change from baseline -17.9 mL versus 2.9 mL for placebo; mean difference = -20.8 
mL; p=.002) at the end of the infusion. These changes occurred in the absence of any heart rate 
or blood pressure change.  These findings, after a single dose of elamipretide, are suggestive of a 
beneficial effect and require further investigation with repeat dosing. 
4.2.2. 
Potential Risks 
4.2.2.1. 
Safety findings – Nonclinical studies 
Toxicology studies in rats and dogs showed that elamipretide has an acceptable profile that 
permits clinical investigations in humans for the proposed duration of the study.  
In rats and dogs, no safety issues relevant to either IV infusion or SC administration at 
therapeutic doses were identified during the nonclinical evaluation of elamipretide.  Elamipretide 
did not cause end-organ toxicity at any dosage tested in either rats or dogs.  Systemic toxicity at 
high doses was manifested primarily by acute and transient clinical signs, which may have been 
mediated by histaminergic-like reactions.  Effects were associated with maximum elamipretide 
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 increase in heart rate, which is thought 
to be consistent with histaminergic-like reactions.  In all studies, the severity of the effects was 
proportional to Cmax for elamipretide; thus, the safety margin is estimated based on Cmax, and not 
area under the plasma-concentration-time curve (AUC).  The plasma elamipretide threshold 


concentration for clinically-relevant adverse effects appears to be ~20,000 ng/mL in both rats 
and dogs, which is more than 10-fold higher than the maximum anticipated human exposures.  
Local injection site reactions evident upon SC administration varied with species, dose and dose 
concentration.  In rats, it was determined that 40 mg/day and 40 mg/mL, respectively, were well 
tolerated. 
Elamipretide was negative for genotoxicity in the full battery of tests and caused no significant 
hemolysis or inhibition of receptor binding.  Elamipretide was not associated with adverse 
effects on fertility or embryo-fetal development.   
No formal immunotoxicity studies have been performed. As a tetrapeptide the immunogenic 
potential of the drug is expected to be low.  
4.2.2.2. 
Human safety 
The safety profile of multiple SC doses of elamipretide has not yet been evaluated in HF 
patients.  Single elamipretide doses up to 1 mg/kg administered IV over 4 hours were safe and 
well-tolerated in 24 patients with stable CHF in a Phase 1 trial.  No SAEs or deaths were 
recorded.  A total of four TEAEs were reported in three elamipretide-treated subjects: worsening 
renal failure, dyspnea, tachycardia, and low hemoglobin.  These events were assessed by the 
investigator to be of mild or moderate in severity and unrelated to study medication.  
In 7 completed single-dose IV trials in healthy subjects, the most commonly reported treatment 
emergent adverse events (TEAEs) in subjects dosed with MTP 131 were headache, nausea, and 
hyponatremia.  Across the 3 trials evaluating single IV doses of elamipretide in cardio-renal 
patient populations (i.e., chronic HF, acute kidney injury, and acute coronary syndrome), single 
IV doses of elamipretide were generally safe and well tolerated with no notable differences 
between the elamipretide and placebo treatment groups in the frequency or severity of adverse 
events.   
Both single-dose SC administration and multiple-dose SC administration for seven days were 
well tolerated in healthy adult subjects.  No deaths or drug-related SAEs occurred, and no 
subjects withdrew from the study for drug-related reasons.  The most commonly reported TEAE 
in the elamipretide treatment group was mild injection site pruritus, reported with similar 
frequency after single and multiple doses.   
4.2.3. 
Conclusions 
In summary, based on the clinical and non-clinical study data, acceptable safety risks are 
expected for the proposed current study. Visiting Nurses will visit subjects daily to administer 
study medication and therefore subjects will have an opportunity to report any safety concerns on 
a daily basis. Hence the benefit:risk ratio of this study is considered favorable. 
 
 


5. 
OBJECTIVES 
5.1. 
Primary Objective 
To evaluate the effects of multiple subcutaneous (SC) doses of elamipretide on left ventricular 
end systolic volume (LV ESV) assessed by cardiac Magnetic Resonance Imaging (MRI). 
5.2. 
Secondary Objective 
• To evaluate the safety and tolerability of multiple SC doses of elamipretide 
• To evaluate the effects of multiple SC doses of elamipretide on LV systolic and diastolic 
function, LV volumes, LV global longitudinal strain, left atrial (LA) volume, LV mass, 
mitral and tricuspid regurgitation severity, and right ventricular (RV) function. 
5.3. 
Exploratory Objectives 
To evaluate the effects of multiple SC doses of elamipretide on: 
• 6-minute walking distance 
• Quality of life 
• NT-pro-BNP levels 
• Borg dyspnea scale 
 
 


6. 
INVESTIGATIONAL PLAN 
6.1. 
Study Design 
This is a randomized, double-blinded, placebo-controlled, multiple dose Phase 2 study in 
subjects with stable heart failure with reduced ejection fraction (HFrEF).  Subjects will go 
through three distinct periods during the study: 
Screening Period:  The Screening Period will begin with the signature of the informed consent 
form (ICF) and will last up to 28 days.  During the Screening Period, subjects will undergo 
screening procedures as described in the Study Schedule (see Attachment 1) to determine their 
eligibility for the study.  Screening procedures may be completed over more than 1 day during 
the Screening Period, so long as all procedures are completed within the Screening Period.  
Subjects who meet all study requirements, including all inclusion and none of the exclusion 
criteria, as well as confirmation by an independent MRI core lab of at least 3 viable LV segments 
(hyperenhancement ≤ 25%) may enter the Treatment Period.   
Treatment Period:  The Treatment Period will begin on the day of the Baseline Visit, which will 
be defined as Study Day 1.  At the Baseline Visit, subjects will undergo Baseline procedures as 
described in the Study Schedule (see Attachment 1).  Subjects who continue to meet eligibility 
criteria will enter the Treatment Period.  Subjects will be administered study medication by 
subcutaneous (SC) injection at the Study Center on Days 1 through 3 and will receive instruction 
on scheduling daily visits with a Visiting Nurse to inject study medication SC on a daily basis 
(except for study visit days) for the remainder of the Treatment Period. The subject will return to 
the study center for assessments and administration of study medication at the Weeks 1 and 2 
Visits.  Subjects will receive the last dose of study medication on the day prior to the Week 4 
Visit, when the Treatment Period will conclude. 
Follow-Up Period:  The Follow-Up Period will begin after completion of the Week 4 Visit and 
will last for 14 days.  Subjects will return to the Study Center for a visit at Week 6 for final 
safety and efficacy assessments, as described in the Study Schedule (see Attachment 1). 
6.2. 
Study Schedule 
Study procedures and their timing are summarized in the Study Schedule (Attachment 1). A list 
of all clinical laboratory tests to be performed is found in Attachment 2. 
6.2.1. 
Screening Period: Day -28 to Day -1  
• Informed Consent Form will be reviewed and signed 
• Demographics will be recorded (age, gender, ethnicity, race) 
• All inclusion and exclusion criteria will be reviewed 
A three-step screening procedure will be performed: 
STEP 1: 
• Relevant medical history will be taken, including a detailed treatment history 
 
• Documentation of concomitant medication (including supplements and vitamins) 


• Cardiovascular physical examination including height (as described in Section 6.3.1)  
• 12-lead resting Electrocardiogram (ECG)  
• Vital signs will be recorded (as described in Section 6.3.3): temperature, heart rate, 
respiration rate and blood pressure, recorded in the sitting position after at least 10 
minutes rest 
• 2-D echocardiography will be used to assess LVEF and LVEDD indexed to Body 
Surface Area (BSA).   
STEP 2: 
If the subject qualifies for the study after Step 1, the following assessments will be conducted: 
• Blood drawn for local clinical laboratory testing as outlined in Attachment 2 
• Women of child-bearing potential will have a serum pregnancy test performed 
• Urine will be sampled for analysis 
STEP 3: 
If the subject qualifies for the study after both Step 1 and Step 2, the subject will undergo a 
delayed gadolinium-enhanced cardiac MRI evaluation to evaluate eligibility and to determine the 
number of viable LV segments. At the discretion of the Investigator, local clinical laboratory 
testing may be repeated prior to the MRI if there is concern of changes to subject eligibility. The 
images will be sent to the cardiac MRI core lab for an assessment of suitability for study entry. 
6.2.2. 
Treatment Period: Study Visits  
6.2.2.1. 
Day 1 (Baseline)  
Subjects who have been deemed eligible during the Screening Period will return for 
randomization and the following procedures will be performed: 
Before Study Medication Injection 
• All inclusion and exclusion criteria will be reviewed 
• Review of the relevant medical history since the Screening Visit 
• Documentation of AEs that are related to a study procedure and/or meet seriousness 
criteria that occurred since the signing of the informed consent form as outlined in 
Section 9.7.2.  
• Documentation of concomitant medication (including supplements and vitamins) 
• Cardiovascular physical examination (as described in Section 6.3.1) 
• 12-lead resting ECG (as described in Section 6.3.4) 
• Vital signs (as described in Section 6.3.3) 
• Blood drawn for clinical laboratory testing and NT-pro-BNP as outlined in Attachment 2 
• Urine will be sampled for analysis (as described in Section 6.3.9.3) 


• Women of child-bearing potential will have a urine pregnancy test performed 
• 2-D and 3-D echocardiography  
• 6-Minute Walk Test (as described in Section 6.3.7 and as outlined in Attachment 3) 
• Kansas City Cardiomyopathy Questionnaire (KCCQ) (as described in Section 6.3.2 and 
as outlined in Attachment 4) 
• Borg dyspnea scale 
• Blood drawn for plasma analysis of elamipretide and metabolites (pre-dose) (as described 
in Section 6.3.9.5) 
• Study medication injection 
After Study Medication Injection 
• Injection site reaction (ISR) assessments (as described in Section 6.3.10) 
• Blood drawn for plasma analysis of elamipretide and metabolites (45 minutes post-
injection ±15 minutes) (as described in Section 6.3.9.5) 
6.2.2.2. 
Week 1 (Day 8 + 3 days) 
The following evaluations will be performed: 
• Documentation of concomitant medications (including supplements and vitamins) 
• Documentation of AEs 
• Cardiovascular physical examination 
• Vital signs 
• 12-lead resting ECG 
• Blood drawn for clinical laboratory and NT-pro-BNP  
• Blood drawn for plasma analysis of elamipretide and metabolites (pre-dose and 45 
minutes post-injection ±15 minutes) 
• Study medication injection 
• ISR assessments 
• Cardiac MRI approximately 1 to 6 hours post-injection 
• Please note that on days 1 through 3 patients have to return to the site for the 
administration of the IMP as well as the assessment of injection site reactions 
6.2.2.3. 
Week 2 (Day 15 ± 3 days) 
The following evaluations will be performed: 
• Documentation of concomitant medications (including supplements and vitamins) 
• Documentation of AEs 


• Cardiovascular physical examination 
• Vital signs  
• 12-lead resting ECG  
• Blood drawn for clinical laboratory testing and NT-pro-BNP  
• Blood drawn for plasma analysis of elamipretide and metabolites (pre-dose and 45 
minutes post-injection ±15 minutes) 
• Study medication injection 
• ISR assessments 
6.2.2.4. 
Week 4 (Day 29 + 3 days)/Early Discontinuation Visit 
The following evaluations will be performed: 
• Documentation of concomitant medication (including supplements and vitamins) 
• Documentation of AEs 
• Cardiovascular physical examination  
• 12-lead ECG 
• Vital signs will be recorded  
• Blood drawn for clinical laboratory testing and NT-pro-BNP  
• Blood drawn for plasma analysis of elamipretide and metabolites  
• Urine will be sampled for analysis 
• Women of child-bearing potential will have a urine pregnancy test performed 
• 2-D and 3-D echocardiography 
• Cardiac MRI  
• KCCQ 
• Borg dyspnea scale 
• 6-Minute Walk Test  
6.2.3. 
Follow-up Period 
6.2.3.1. 
Week 6 (Day 43 ± 3 days) 
The following evaluations will be performed: 
• Documentation of concomitant medication (including supplements and vitamins) 
• Documentation of AEs 
• Cardiovascular physical examination  
• Vital signs  


• 12-lead resting ECG  
• Blood drawn for clinical laboratory testing and NT-pro-BNP levels  
• Blood drawn for plasma analysis of elamipretide and metabolites 
• 2-D and 3-D echocardiography 
• Subject will conclude the study 
6.3. 
Study Assessments  
The following section describes study assessments occurring during the study. Study assessments 
and procedures are presented by study visit in Attachment 1. Details regarding clinical laboratory 
tests are found in Attachment 2. 
6.3.1. 
Relevant Medical History and Cardiovascular Physical Examination 
At the Screening Visit, a relevant medical history (including medication and procedure history, 
smoking history, heart failure etiology, and concomitant medication) will be taken.  
At the Day 1 visit, a review of the relevant medical history (including concomitant medication 
and procedures) since the Screening visit will be taken. 
At all visits, a cardiovascular physical examination including lung auscultation and weight will 
be performed. Height will only be measured at the Screening Visit. 
6.3.2. 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
KCCQ will be performed according to the standardized questionnaire at the Day 1 and Week 4 
visits. The KCCQ instructions are provided in Attachment 4. 
6.3.3. 
Vital signs 
During all site study visits, the vital signs measurements will include temperature, heart rate, 
respiration rate and blood pressure, recorded in the sitting position after at least 10 minutes rest. 
At Day 1 these vital signs measurements will be performed as part of the study eligibility 
confirmation.   
6.3.4. 
Electrocardiograms (ECGs) 
A 12-lead resting ECG will be obtained in the supine position at all study visits.  
ECG intervals (PR, QRS, QT, QTc), heart rate and ECG findings will be recorded for each 
subject. Based on signs or symptoms, additional 12-lead ECGs may be performed. 
6.3.5. 
Echocardiogram 
At the Screening Visit, a 2-D echocardiographic screening evaluation of LVEF and LV end-
diastolic dimension (LVEDD) will be performed. 
At Day 1, Week 4, and Week 6 visits, both 2-D and a 3-D echocardiograms will be performed to 
assess parameters of LV systolic and diastolic function, global longitudinal strain, LA volume, 
LV mass, mitral and tricuspid regurgitation severity, and RV function.  


Detailed specifications of the echocardiogram procedures and image assessments are presented 
in the Study Echocardiography Manual. 
6.3.6. 
Cardiac MRI 
At the Screening Visit, subjects who qualify after initial Step 1 screening evaluations will 
undergo a delayed gadolinium-enhanced cardiac MRI.  The screening evaluation of the number 
of viable segments will be performed by an independent cardiac MRI core lab that will decide if 
subjects are eligible for inclusion.  At the Week 1 and Week 4 visits, subjects will undergo a 
cardiac MRI examination, to evaluate LV cardiac volumes and function.  At the Week 1 visit, the 
cardiac MRI examination will occur at approximately 1 to 6 hours post-dose. 
Detailed specifications of the MRI procedures and image assessments are presented in the Study 
MRI Manual. 
6.3.7. 
Borg Dyspnea Scale 
Borg dyspnea scale will be assessed at Day 1 (baseline) and Week 4 visits. The instructions are 
provided in Attachment 7 
6.3.8. 
6-Minute Walk Test (6MWT) 
At the Day 1 and Week 4 visits, the distance walked (in meters) during the 6MWT will be 
recorded.  The Day 1 6MWT should be completed prior to study medication administration. The 
6MWT instructions are provided in Attachment 3. 
 
6.3.9. 
Clinical Laboratory Testing 
Sample collection, processing and handling details are provided in the Laboratory Manual.  
6.3.9.1. 
Blood chemistries 
The following blood chemistries will be carried out at all study visits: sodium, potassium, 
chloride, bicarbonate, blood urea nitrogen (BUN), creatinine (and eGFR calculated with the 
MDRD Study equation), total bilirubin, alkaline phosphatase, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), calcium, albumin, total protein, hsTroponin I, venous blood 
glucose, and triglycerides. 
6.3.9.2. 
Hematology 
The following parameters will be determined on all study visits: hemoglobin, hematocrit, 
erythrocyte count (RBC), leukocytes (WBC), segmented neutrophils, lymphocytes, monocytes, 
eosinophils, basophils and platelets.  
6.3.9.3. 
Urinalysis 
Urinalysis will be sampled at the Screening Visit, Day 1, and Week 4 and will include: urine 
specific gravity, pH, protein, microalbuminuria, glucose, ketones, blood, sodium, chloride, and 
creatinine. 


6.3.9.4. 
Pregnancy tests 
Women of child-bearing potential will have a serum pregnancy test performed at the Screening 
Visit.  Women of child-bearing potential will have a urine pregnancy test on Day 1 and Week 4.   
The results of the Day 1 pre-dose pregnancy test must be evaluated before randomization to 
ensure eligibility. 
6.3.9.5. 
Samples for elamipretide and metabolite plasma levels 
Blood samples for PK determinations of elamipretide and metabolites (M1, M2) concentrations 
will be collected before administration of study medication and at 45 minutes ±15 minutes post-
dose at the Day 1, Week 1 and Week 2 visits, and at any time point at the Week 4 and Week 6 
visits.  
Please refer to the Laboratory Manual and the Pharmacy Manual for specific details of sample 
handling, preparation, and shipping instructions. 
6.3.9.6. 
Exploratory biomarkers 
Blood samples for determination of NT-pro-BNP will be collected on all study visits from Day 1 
through Week 6 prior to administration of study medication. 
6.3.10. 
Injection Site Reaction (ISR) Assessments  
During the 4-week treatment period, injection site reactions will be assessed on a daily basis to 
better characterize subcutaneous administration. Two assessments will occur after each injection:  
1. Subjects will complete the ISR self-assessment questionnaire (see Attachment 5) at 
approximately 15 minutes post-injection. The questionnaire assesses how bothered the 
patient was following study medication injection. The responses to the ISR self-
assessment questionnaires will be reviewed by the Investigator (or designee) at each on-
site visit. Any injection site reaction reported by the subject and determined to be 
clinically significant by the Investigator, regardless of whether it is captured as part of 
this assessment, should be reported as an AE. 
2. At each home visit, the Visiting Nurse will assess the current day’s injection site. At 
Days 1 through 3, Week 1 and Week 2 visits, the Investigator (or designee) will assess 
the current day’s injection site. The assessment will evaluate erythema, pain, swelling, 
and pruritus at approximately 15 minutes post-injection.  If any reaction is apparent, the 
injection site will also be evaluated at 30 minutes post-injection.  
Injection site reactions determined to be adverse events by the Investigator should be graded 
according to the guidelines detailed in Attachment 6. 
 
 
 


7. 
STUDY POPULATION 
The inclusion and exclusion criteria for participation in this study are provided below.  All 
screening procedures must be completed during the Screening period, but may be performed on 
different days.  Screening procedures cannot be repeated, and subjects cannot be re-screened 
without the Sponsor’s approval.  If a subject is re-screened, they will maintain their original 
screening number. Subjects may only be enrolled into the study one time. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
7.1. 
Inclusion Criteria 
A subject must meet all of the following criteria prior to Study Day 1 to be eligible for inclusion 
in the study: 
1. Willing and able to provide signed informed consent form (ICF) prior to participation in 
any study-related procedures. 
2. Age ≥40 and <80 years. 
3. A known history of chronic ischemic or non-ischemic cardiomyopathy of at least 6 
months duration from the time of the initial diagnosis or signs and symptoms consistent 
with heart failure.. 
4. Receiving heart failure (HF) treatment, including, but not limited to, angiotensin 
converting enzyme inhibitors (ACEI) and/or angiotensin receptor blockers (ARB), and an 
evidence-based beta blocker for the treatment of HF. Subjects who cannot tolerate ACEI 
or ARB due to reduced renal function or hypotension are eligible. Subjects may be 
receiving aldosterone antagonists, but this is not a requirement for the study. 
5. HF is considered to be stable in the judgment of the Investigator AND doses of HF 
treatment have been stable for at least 1 month prior to the Screening Visit. 
6. In normal sinus rhythm (electrocardiogram documented) at Screening and Day 1 and no 
history of atrial fibrillation in the past 12 months 
7. No hospitalization related to HF within 1 month prior to the Screening Visit.  
8. Left Ventricular Ejection Fraction (LVEF) ≤ 40% by 2-D echocardiography at Screening. 
9. At least 3 viable segments (hyperenhancement ≤ 25%) by a qualifying delayed 
gadolinium-enhanced cardiac MRI examination at Screening (confirmed by independent 
core lab). 
10. Willing to adhere to the study requirements for the length of the trial. 
11. Women of childbearing potential must agree to use 1 of the following methods of birth 
control from the date they sign the ICF until two months after the last dose of study 
medication: 
a. Abstinence, when it is in line with the preferred and usual lifestyle of the subject.  
Subject agrees to use an acceptable method of contraception should they become 
sexually active. 


b. Maintenance of monogamous relationship with a male partner who has been 
surgically sterilized by vasectomy (the vasectomy procedure must have been 
conducted at least 60 days prior to the Screening Visit or confirmed via sperm 
analysis). 
c. Barrier method (e.g., condom or occlusive cap) with spermicidal 
foam/gel/film/cream AND either hormonal contraception (oral, implanted, or 
injectable) or an intrauterine device or system. 
d. Note: Non-childbearing potential is defined as surgical sterilization (e.g., bilateral 
oophorectomy, hysterectomy, or tubal ligation) or postmenopausal (defined as 
permanent cessation of menstruation for at least 12 consecutive months prior to 
the Screening Visit). 
7.2. 
Exclusion Criteria 
A subject who meets any of the following criteria at Screening will be excluded from the study: 
1. History of any concurrent medical condition which, in the opinion of the Investigator, 
significantly increases the potential risks associated with administration of study 
medication or any other aspect of study participation. 
2. Any contraindication to MRI scanning as assessed by local MRI safety questionnaire, 
which may include: 
a. History of intra-orbital metal fragments which have not been removed 
b. Severe claustrophobia 
c. Non-MRI safe cochlear implant(s) or intracranial aneurysm clips 
d. Extensive tattoos located on the torso that contain metallic inks 
e. Other non-removable implanted metallic or electronic devices that have not been 
determined to be MRI safe 
f. Inability to lie flat 
3. Inadequate echocardiogram image quality (defined as poor sound transmission and/or < 
10 endocardial segments seen). 
4. LVEDD indexed to Body Surface Area is > 45 mm/m2 assessed by 2-D 
echocardiography. 
5. Coronary or peripheral revascularization procedures, valvular procedures, OR any major 
surgical procedure within 3 months prior to the Screening Visit. 
6. Acute coronary syndrome, stroke or transient ischemic attack (TIA) within 3 months 
prior to the Screening Visit. 
7. Obstructive or restrictive cardiomyopathy, infiltrative diseases of the myocardium (e.g., 
amyloid, sarcoid, etc.) myocarditis, or reductions in LV function thought to be secondary 
primarily to valvular heart disease, prior cardiac valve surgery or known aortic stenosis. 


8. The presence or anticipated placement of any pacemaker, implantable cardioverter 
defibrillator (ICD), or cardiac resynchronization therapy (CRT) devices during the 
ensuing 6-week study period. 
9. Presence of second degree or advanced heart block. 
10. Uncontrolled hypertension defined as a systolic blood pressure > 160 mmHg or a 
diastolic blood pressure > 110 mmHg on at least two consecutive readings. 
11. Presence of any left ventricular thrombus, pericardial disease, uncorrected thyroid disease 
or a dyskinetic left ventricular aneurysm. 
12. History of cancer that causes symptoms, disabilities, or is likely to lead to hospitalization 
or treatment in the next 12 months. 
13. Currently receiving treatment with chemotherapeutic agents or immunosuppressant 
agents or has received prior radiation therapy to the chest. 
14. Liver enzymes (alanine aminotransferase [ALT] AND/OR aspartate aminotransferase 
[AST]) elevation > 3 times the upper limit of normal (ULN). 
15. Total bilirubin > 1.5 times ULN in the absence of Gilbert’s Syndrome. 
16. Bleeding diathesis or any known blood dyscrasia. 
17. Anemia, defined as hemoglobin < 9 g/dL or planned blood transfusions in the next 6 
weeks. 
18. Estimated glomerular filtration rate (eGFR) < 30 mL/min, using the Modification of Diet 
in Renal Disease (MDRD) Study equation: 
a. 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) 
19. History of hepatitis B, hepatitis C or Human Immunodeficiency Virus (HIV) infection, or 
diagnosis of immunodeficiency. 
20. Known active drug or alcohol abuse within 1 year of the Screening Visit.  Alcohol abuse 
is defined as 15 or more drinks for men per week or 8 or more for women. 
21. Recipient of any investigational drugs, stem cell or gene therapies, or devices OR 
participation in another clinical trial, within 3 months prior to the Screening Visit. 
22. Any significant acute or chronic medical or psychiatric illness that, in the judgment of the 
Investigator, could compromise the subject’s safety, limit subject’s ability to complete 
the study, and/or compromise the objectives of the study. 
23. Female subjects who are pregnant, planning to become pregnant, or lactating. 
24. Currently requiring any changes in doses of cardiovascular medication (including 
diuretics) in order to control worsening of HF symptoms. 
25. Known allergy to gadolinium. 


26. Currently receiving treatment with therapeutic doses of anticoagulants. Antiplatelet 
therapy used to prevent cardiovascular disease (primary prevention) or to treat chronic 
disease (secondary prevention) is permitted, as well as vitamin K antagonists.   
27. Currently receiving treatment with sacubitril/valsartan or trimetazidine. 
7.3. 
Prohibited Medications 
The use of any other investigational drug except elamipretide is prohibited during the conduct of 
the current trial. 
The use of therapeutic doses of anticoagulants (not including antiplatelet therapy used to prevent 
cardiovascular disease [primary prevention] or to treat chronic disease [secondary prevention]), 
sacubitril/valsartan, trimetazidine, chemotherapeutic or immunosuppressant medications is 
prohibited in this study.  No additional medications are prohibited per protocol.  All concomitant 
medications will be recorded in the source data and the Electronic Case Report Form (eCRF). 
Changes in dosages of current therapeutic agents during the conduct of the study will be 
discouraged, unless required to treat an Adverse Event. 
7.4. 
Discontinuations 
7.4.1. 
Discontinuation of Subjects 
Subjects may be discontinued for the following reasons: 
• Investigator Decision 
o The Investigator decides that the subject should be discontinued from the study 
for any reason. 
• Subject Decision  
o The subject or the subject’s designee, (e.g., parents or legal guardian), requests to 
be withdrawn from the study.   
▪ Subjects who withdraw should be explicitly asked about the contribution 
of possible adverse events 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 site should document and sign the reason for the subject’s failure to 
withdraw consent in writing.  
o The subject is lost to follow-up after a reasonable number of attempts to contact 
the subject (including documented phone calls and/or emails, and a certified 
letter) have been completed. 
• Sponsor Decision 
o The Sponsor or its designee stops the study or stops the subject’s participation in 
the study for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP guidelines. 


• Adverse Event  
o If the Investigator decides that the subject should be withdrawn because of an AE 
or a clinically significant laboratory value, the investigational product is to be 
discontinued and appropriate measures are to be taken.  The Sponsor or its 
designee is to be alerted immediately.   
Any subject withdrawing from the study will be asked to complete the Early Discontinuation 
visit assessments (see Attachment 1).   
7.4.2. 
Discontinuation of Study Sites 
Study site (research center) participation may be discontinued if the Sponsor or its designee, the 
Investigator, or the Ethics Committee (EC) of the study site judges it necessary for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and GCP 
guidelines. 
7.4.3. 
Discontinuation of the Study 
The study will be discontinued if the Sponsor or its designee judges it necessary for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and GCP 
guidelines. 
 
 


8. 
TREATMENT 
8.1. 
Treatments Administered 
Approximately 70 subjects will receive study medication administered as a single daily 
subcutaneous (SC) injection containing either 4 mg elamipretide, 40 mg elamipretide, or placebo 
for 4 consecutive weeks.  Study medication will be administered daily to the subject in the 
abdomen (rotating clockwise around the four abdominal quadrants) by either the clinical site 
staff or a Visiting Nurse. Subjects will be instructed to take their background heart failure 
medication at approximately the same time every day during the 4 week treatment period.   At 
the Day 1 visit, study medication injection will occur after completion of several baseline 
procedures (see Section 6.2.2.1). A few assessments will be completed after study medication 
injection on Day 1. Study medication injection and evaluation on Days 2 through 3 will occur at 
the study site. Starting on Day 4, subjects will be instructed to schedule the daily Visiting Nurse 
visits at approximately the same relative time each day.  If, in the opinion of the Visiting Nurse 
or the clinical site staff, it is more appropriate to administer the medication in another body area 
judged appropriate for a SC injection, he/she may do so at his/her discretion, provided that it is at 
least 5 cm from the previous day’s location of administration.  At each home visit, in addition to 
the subject completing the ISR self-assessment questionnaire, the Visiting Nurse will assess the 
current day’s injection site. At Days 1 through 3, Week 1 and Week 2 visits, the Investigator (or 
designee) will assess the current day’s injection site. The assessment will evaluate erythema, 
pain, swelling, and pruritus at the injection site at approximately 15 minutes post-injection.  If 
any reaction is apparent, the injection site will also be evaluated at 30 minutes post-injection.  
Injection site reactions determined to be adverse events by the Investigator should be graded 
according to the guidelines detailed in Attachment 6. 
8.2. 
Materials and Supplies 
Study medication (elamipretide and placebo) will be dispensed, stored, and administered 
according to the Pharmacy Manual. 
8.2.1. 
Elamipretide 
Elamipretide (MTP-131) drug product will be provided as a sterile solution for administration by 
SC injection.  Each single-use vial is filled with one milliliter of drug product containing the 
equivalent of 40 mg elamipretide, added as MTP-131 acetate, in an isotonic, unpreserved, clear, 
colorless solution.   
8.2.2. 
Placebo 
The placebo for this trial will be provided as a sterile solution in matching sterile glass vials and 
is composed of the excipients used to manufacture the investigational drug elamipretide without 
the active drug substance.  The placebo will be handled and administered identically as active 
drug.  Subjects randomized to placebo will receive an injection containing either 1 mL or 0.1 mL 
of sterile solution to match the two volumes administered in the active arm. 


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 study medication.  These records should contain the 
dates, quantity, and study medication: 
• Received at site 
• Administered to each subject, 
• Dispensed to each subject, 
• Returned from each subject, and 
• Disposed of at the site or returned to the Sponsor or designee 
The clinical monitor responsible for the study site will provide written approval for the 
destruction or return of unused study medication vials following reconciliation of all clinical 
supplies. 
8.4. 
Method of Assignment to Treatment and Randomization 
At Day 1, after eligibility criteria have been confirmed, a treatment kit number will be assigned 
to each subject on the basis of a centralized computer-generated randomization schedule. 
Subjects will be randomized into 1 of 3 treatment groups in a 1:1:1 fashion to receive either 
elamipretide 4 mg, elamipretide 40 mg, or placebo, so that a target of at least 22 subjects will be 
randomized to the elamipretide 4 mg dose group, 22 subjects will be randomized to the 
elamipretide 40 mg dose group, and 22 subjects will be randomized to the placebo treatment 
group.  Treatment kits for placebo will specify injection volumes of either 0.1 or 1 mL in order to 
maintain the blind. 
8.5. 
Rationale for Selection of Doses in the Study 
The doses and route of administration (i.e., 4 mg in 0.1 mL and 40 mg in 1.0 mL via SC 
injection) for the current study have previously been tested in a clinical trial involving healthy 
subjects.  Single IV doses ranging from 0.02 mg/kg to 1 mg/kg have been tested in subjects with 
stable HF.  The doses for the current study were chosen based on the systemic exposure profile, 
as well as the safety observed in previous clinical trials.  
The plasma elamipretide threshold concentration for clinically-relevant adverse effects appears 
to be ~20,000 ng/mL in both rats and dogs, which is more than 10-fold higher than the maximum 
anticipated human exposures.  In healthy human adults, 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.   
In a completed Phase 1 trial (SPISC-101), elamipretide given SC to healthy volunteers at doses 
up to 40 mg in 1 mL once daily for seven consecutive days was well tolerated, with no systemic 
safety issues.  Local injection site reactions were limited to transient, local erythema and 
occasional pruritus or swelling, which resolved quickly without sequelae and without 
intervention.   


Elamipretide demonstrated an acceptable safety and tolerability profile with single IV infusions 
of up to 1 mg/kg administered over 4 hours in subjects with stable HF in a completed Phase 1 
trial (SPIHF-101).   
8.6. 
Continued Access to Investigational Medicinal Product 
Elamipretide will not be made available to study subjects after the conclusion of the study. 
8.7. 
Blinding and Unblinding Procedures 
The Sponsor, study 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 assignment   
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 reason, and the 
date and time of the unblinding must be included in source documentation. The name of the 
individual who broke the blind must be included in the site’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, site, Sponsor) will have premature access to the 
subjects’ treatment assignments. As described above, specific Sponsor personnel will be 
unblinded during the trial and will have access to study data in an unblinded fashion before the 
data lock. 
8.8. 
Treatment Compliance 
During the treatment period, study medication will be administered by clinical site staff or 
Visiting Nurse.  Injection times and locations will be recorded. 
 


9. 
EFFICACY AND SAFETY EVALUATIONS AND 
APPROPRIATENESS OF MEASUREMENTS 
Study procedures and their timing are summarized in Attachment 1 and in Attachment 2. 
9.1. 
Efficacy Measures  
9.1.1. 
Primary efficacy measure 
• LV ESV assessed by MRI 
9.1.2. 
Secondary efficacy measure 
• LVEF and LV EDV assessed by MRI 
• The following parameters by echocardiography: 
o E/A (ratio between early and late mitral inflow velocity),  
o E/e' (Ratio between early mitral inflow velocity and mitral annular early diastolic 
velocity) 
o LV EDV, LV ESV and biplane EF  
o LV global longitudinal strain 
o LA volume 
o LV mass 
o Mitral regurgitation severity 
o Tricuspid regurgitation severity 
o RV fractional area change 
o RV systolic pressure (RVSP) 
9.1.3. 
Exploratory efficacy measures 
• Distance walked (meters) during 6MWT. 
• Levels of NT-pro-BNP 
• KCCQ score  
• Borg dyspnea scale 
9.2. 
Safety Evaluations 
The safety and tolerability end-points will be assessed by: 
• AEs  
• Changes from baseline in vital signs 
• Changes from baseline in electrocardiograms (ECGs) 
• Changes from baseline in clinical laboratory evaluations 


Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Sponsor or its designee to any event that seems unusual, even if this event may 
be considered an unanticipated benefit to the subject. 
The Investigator is responsible for the appropriate medical care of subjects during the study. 
The Investigator remains responsible for following, through an appropriate health care option, of 
AEs that are serious, considered related to the study treatment or the study, or that caused the 
subject to discontinue before completing the study.  The subject should be followed until the 
event is resolved or explained. 
The safety profile of elamipretide will be assessed through the recording, reporting, and 
analyzing of AEs, clinical evaluations, and laboratory tests. 
Comprehensive assessment of any apparent toxicity experienced by study subjects will be 
performed throughout the course of the study, from the time of the subject’s signature of 
informed consent.  Study site personnel will report any AE, whether observed by the Investigator 
or reported by the subject.  The reporting period for AEs is described in Section 9.7.2. 
9.2.1. 
Adverse Events 
An AE is defined as any untoward medical occurrence in the form of signs, symptoms, abnormal 
laboratory findings, or diseases that emerge or worsen relative to baseline during administration 
of an investigational medicinal product (IMP), regardless of causal relationship. 
Adverse Events may include the following: 
• Suspected adverse drug reactions: side effects known or suspected to be caused by the 
study medication. 
• Other medical experiences, regardless of their relationship with the study medication, 
such as injury, surgery, accidents, extensions of symptoms or apparently unrelated 
illnesses, and significant abnormalities in clinical laboratory values, psychological 
testing, or physical examination findings. 
• Events occurring as a result of protocol interventions (pre- or post-IMP administration) 
• Reactions from study medication overdose, abuse, withdrawal, sensitivity, or toxicity.  
The Sponsor has standards for reporting AEs that are to be followed regardless of 
applicable regulatory requirements that may be less stringent.  
9.3. 
Pre-Treatment Events 
Untoward events and/or incidental diagnoses that occur prior to study medication administration 
are by definition, unrelated to the study medication. 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 study procedure and/or meets 
seriousness criteria, it will be recorded as an AE on the AE eCRF, processed, and followed 
accordingly. 


9.4. 
Baseline Medical Conditions 
Those medical conditions related to the disease under study whose changes during the study are 
consistent with natural disease progression, or which are attributable to a lack of clinical efficacy 
of the study medication, are NOT considered as AEs and should not be recorded as such in the 
eCRF.  These are handled in the efficacy assessments and should be documented on the medical 
history page of the eCRF. 
Baseline medical conditions, not in the therapeutic area of interest/investigation, that worsen in 
severity or frequency during the study should be recorded and reported as AEs. 
9.5. 
Abnormal Laboratory and Other Abnormal Investigational 
Findings 
Abnormal laboratory findings and other objective measurements should NOT be routinely 
captured and reported as AEs.  However, abnormal laboratory findings or other objective 
measurements should be reported on the AE pages of the eCRF that: 
• meet the criteria for a SAE 
• result in discontinuation of the IMP 
• require medical intervention or 
• are judged by the Investigator to be clinically significant changes from baseline 
When reporting an abnormal laboratory finding on the AE pages of the eCRF, if available, a 
clinical diagnosis should be recorded rather than the abnormal value itself  (for example, 
“anemia” or “decreased red blood cell count” rather than “hemoglobin = 10.5 g/dL”). 
9.6. 
Serious Adverse Events 
A serious adverse event (SAE) is any AE from this study that: 
• Results in death.  In case of a death, the cause of death is used as the AE term, and the 
fatality is considered as the OUTCOME. 
• Is life-threatening. The term “life-threatening” refers to a SAE in which the subject is at 
risk of death at the time of the event; it does not refer to an event that hypothetically 
might cause death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is otherwise considered medically important. 
Important medical events may be considered as SAEs when, based upon medical judgment, they 
may jeopardize the subject or may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 


Examples of such events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
For the purposes of reporting, any suspected transmission of an infectious agent via an IMP is 
also considered an SAE and all such cases should be reported in an expedited manner as 
described in Section 9.8. 
9.6.1. 
Events that Do Not Meet the Definition of a Serious Adverse Event 
Elective hospitalizations to simplify study treatment or study procedures (e.g., an overnight stay) 
are not considered as SAEs. However, all events leading to unplanned hospitalizations (not 
documented prior to ICF signing) or unplanned prolongation of an elective hospitalization (e.g., 
undesirable effects of any administered treatment) must be documented and reported as SAEs. 
9.7. 
Recording of Adverse Events 
Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be recorded on an ongoing basis in the appropriate section of the 
electronic Case Report Form (eCRF).  Among these AEs, all serious AEs must be additionally 
documented and reported using the study specific SAE Report Form.  
It is important that each AE report include a description of the event along with the duration 
(onset and resolution dates), severity, relationship to study medication, potential causal factors, 
treatment given or other action taken (including dose modification or discontinuation of the 
IMP), and the outcome. 
As the quality and precision of acquired AE data are critical, Investigators should use the AE 
definitions provided and should observe the following guidelines when completing the AE pages 
of the eCRF: 
• Whenever possible, recognized medical terms should be used to describe AEs rather than 
lay terms (for example, “influenza” rather than “flu”), and abbreviations should be 
avoided. 
• Adverse events should be described using a specific clinical diagnosis, if available, rather 
than a list of signs or symptoms (for example, “congestive heart failure” rather than 
“dyspnea, rales, and cyanosis”).  However, signs and symptoms that are not associated 
with an identified disease or syndrome, or for which an overall diagnosis is not yet 
available, should be reported as individual AEs. 
• Provisional diagnoses (e.g., “suspected myocardial infarction”) are acceptable, but should 
be followed up with a definitive diagnosis if later available. Similarly, a fatal event with 
an unknown cause should be recorded as “death of unknown cause.” 
• In cases of surgical or diagnostic procedures, the condition or illness leading to the 
procedure is considered the AE rather than the procedure itself. 
Adverse events occurring secondary to other events (e.g., sequelae or complications) should be 
identified by the primary cause. A primary AE, if clearly identifiable, generally represents the 
most accurate clinical term to record in the eCRF. 


9.7.1. 
Investigator Assessments 
9.7.1.1. 
Severity/Intensity 
Investigators must assess the severity/intensity of AEs according to the following qualitative 
toxicity scale: 
Mild: 
The subject is aware of the event or symptom, but the event or symptom is 
easily tolerated. 
Moderate: 
The subject experiences sufficient discomfort to interfere with or reduce 
his or her usual level of activity. 
Severe: 
Significant impairment of functioning: the subject is unable to carry out 
usual activities. 
Adverse events relating to injection reactions should be graded according to the guidelines 
detailed in Attachment 6. 
9.7.1.2. 
Relationship to the Investigational Medicinal Product (IMP) 
Investigators must systematically assess the causal relationship of AEs to the study medication 
using the following definitions (the decisive factor being the temporal relationship between the 
AE and administration of the study medication):  
Probable: 
A causal relationship is clinically/biologically highly plausible, there is a 
plausible time sequence between onset of the AE and administration of the 
study medication, and there is a reasonable response on withdrawal. 
Possible: 
A causal relationship is clinically/biologically plausible and there is a 
plausible time sequence between onset of the AE and administration of the 
study medication. 
Unlikely: 
A causal relationship is improbable and another documented cause of the 
AE is most plausible. 
Unrelated: 
A causal relationship can be excluded and another documented cause of 
the AE is most plausible. 
9.7.2. 
Adverse Event Reporting Period 
The AE reporting period begins when the subject signs the ICF and continues through the 
clinical study’s post treatment follow-up period, defined as 14 days after last administration of 
study medication.   
Note that AEs that occur between the time subject signs the ICF and the time the subject is dosed 
with study medication will be summarized in the medical history eCRF and not as an AE unless 
the event is assessed by the Investigator as related to a study procedure and/or meets the 
definition of an SAE.  New protocol related AEs (caused by any intervention required by the 
protocol) and updates on all AEs ongoing or with an unknown outcome must be recorded until 
the last subject visit required by the protocol.  A last batch of queries will be sent after last study 
visit if remaining ongoing/unknown outcomes of reported AEs are pending.  After the last batch 


of queries with all collected data have been fully processed, CRFs and database will no longer be 
updated.   
However, SAEs and medically relevant ongoing/unknown outcome AEs will be followed-up 
until resolution or stabilization by the Sponsors Pharmacovigilance department.  Beyond this 
defined reporting period, any new SAE spontaneously reported to the Sponsor by the 
Investigator would be collected and processed.  Additional information on SAE, obtained after 
database lock, will reside solely in the safety database. 
Within the study, all subjects who took at least 1 dose of IMP, whether they completed the 
treatment period or not, should enter the 14-day period as defined above. 
If a subject is documented as lost-to follow-up, ongoing/unknown outcome AEs will not be 
followed-up. 
For screening failure subjects, new AEs and updates must be recorded in the CRFs until the date 
the subject was determined to be a screen failure.  Beyond that date, only SAEs and medically 
relevant AEs will be followed-up by the Sponsor’s Pharmacovigilance group and all data will be 
housed within the safety database. 
9.8. 
Serious Adverse Event Expedited Reporting 
In the event an SAE occurs during the reporting period, the Investigator must immediately 
(within a maximum of 24 hours after becoming aware of the event) inform the Sponsor as 
detailed in the Clinical Trial Pharmacovigilance Procedural Manual. 
For any SAE, the following minimum information is required as initial notification: 
• Investigator/Reporter with full contact information 
• Subject identification details (study number, site number, subject number) 
• Study medication administration details (dose and dates) 
• Event verbatim terms, a brief description of signs/symptoms/diagnosis and the date of 
onset 
• Seriousness criteria(ion) met 
• Relationship of the event to the study medication (eg, the causality according to the 
Investigator) 
Reporting procedures and timelines are the same for any new follow-up information on a 
previously reported SAE. 
All SAE reports must be completed as described in the eCRF completion guidelines and 
submitted through the Electronic Data Capture (EDC) system of the clinical database.  Other 
relevant information from the clinical database (including demographic data, medical history, 
concomitant medication and study medication dosing information) will automatically be sent via 
the EDC system when the SAE form is submitted. 
The names, addresses, telephone and fax numbers for SAE back-up reporting (paper), are 
included in the Safety Reporting Plan.   


The Investigator/Reporter must respond to any request for follow-up information (e.g., additional 
information, outcome and final evaluation, specific records where needed) or to any question the 
Sponsor may have on the AE within the same timelines as described for initial reports. This is 
necessary to permit a prompt assessment of the event by the Sponsor and (as applicable) to allow 
the Company to meet strict regulatory timelines associated with expedited safety reporting 
obligations. 
9.8.1. 
Pregnancy and Contraception 
Any pregnancies must be reported to the Investigator in the two months after the last dose of 
study medication.  In addition, women of childbearing potential must agree to use 1 of the 
following methods of birth control from the date they sign the ICF until two months after the last 
dose of study medication: 
• Abstinence, when it is in line with the preferred and usual lifestyle of the subject.  Subject 
agrees to use an acceptable method of contraception should they become sexually active. 
• Maintenance of a monogamous relationship with a male partner who has been surgically 
sterilized by vasectomy (the vasectomy procedure must have been conducted at least 60 
days prior to the Screening Visit or confirmed via sperm analysis). 
• Barrier method (e.g., condom or occlusive cap) with spermicidal foam/gel/film/cream 
AND either hormonal contraception (oral, implanted, or injectable) or an intrauterine 
device or system. 
Non-childbearing potential is defined as surgical sterilization (e.g., bilateral oophorectomy, 
hysterectomy, or tubal ligation) or postmenopausal (defined as permanent cessation of 
menstruation for at least 12 consecutive months prior to the Screening Visit). 
For male subjects with female partners of child-bearing potential, highly effective methods of 
contraception must be adhered to prior to entry into the study and for at least 2 months after the 
last dose of study medication. 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 last dose of study medication. Sperm or egg donation by patients is not permitted from 
the start of treatment until 2 months after the study medication was administered. 
Only pregnancies considered by the Investigator as related to study treatment (e.g., resulting 
from an interaction between study medication and a contraceptive medication) are considered 
AEs unto themselves.  However, all pregnancies with an estimated conception date that occurred 
during the AE reporting period, as defined in Section 9.7.2, must be recorded in the AE section 
of the eCRF.  For this study, this applies to pregnancies in female subjects and in female partners 
of male subjects. 
The Investigator must notify the Sponsor in an expedited manner of any pregnancy using the 
Pregnancy Form and the back-up reporting procedure as described in the Clinical Trial 
Pharmacovigilance Procedural Manual.  Investigators must actively follow up, document, and 
report on the outcome of all pregnancies.   


The Investigator must notify the Sponsor of these outcomes using Section II of the Pregnancy 
Form and submit the information using the back-up reporting procedure.  Any abnormal outcome 
must be reported in an expedited manner as described in Section 9.8, while normal outcomes 
must be reported within 45 days from delivery. 
In the case of an abnormal outcome, whereby the mother sustains an event, the SAE Report 
Form is required and will be submitted as described above. 
9.8.2. 
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 site-specific requirements related to the 
reporting of SAEs involving subjects to the EC that approved the study. 
In accordance with International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) GCP guidelines, the Sponsor will inform 
the Investigator of findings that could adversely affect the safety of subjects, impact the conduct 
of the study, or alter the EC’s approval/favorable opinion to continue the study.  In particular, 
and in line with respective regulations, the Sponsor will inform the Investigator of AEs that are 
both serious and unexpected and are considered to be related to the administered product 
(SUSARs).  The Investigator should place copies of the safety reports in the Investigator site file.  
Country-specific 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 and will maintain records of these notifications.  
When direct reporting by the Sponsor is not clearly defined by country- or site- specific 
regulations, the Investigator will be responsible for promptly notifying the concerned IEC of any 
safety reports provided by the Sponsor and or filing copies of all related correspondence in the 
site file. 
For studies 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 related guidances. 
9.9. 
Appropriateness of Measurements  
 
The measures used to assess safety in this study are consistent with those widely used and 
generally recognized as reliable, accurate, and relevant. 
 
 


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


11. 
SAMPLE SIZE AND STATISTICAL METHODS 
11.1. 
Determination of Sample Size 
The initial sample size of 45 patients was based on the assumption that a sample size of 15 
subjects per treatment group provided 90% power to detect an 8 milliliter (mL) difference 
between treatment groups in LV ESV, as measured by MRI, assuming a standard deviation of 
6.5 mL. 
A revised estimate of the standard deviation, based on a review of blinded LV ESV data from the 
first 11 subjects who completed treatment, suggests it may ultimately be as high as 9.4 mL.  
Accordingly, the sample size is being increased to around 22 subjects per treatment group, which 
provides 80% power to detect the aforementioned 8 mL difference between treatment groups. If 
necessary, the standard deviation will be reassessed in blinded fashion and the sample size 
modified accordingly. 
11.2. 
Statistical and Analytical Plans 
11.2.1. 
General Considerations 
All study data are to be displayed in the data listings.  
Statistical analysis of this study will be the responsibility of the Sponsor or its designee.   
Additional details regarding analyses will be included in separate statistical analysis plan (SAP). 
11.2.2. 
Subject Disposition 
All subjects who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported.  If known, a reason for their discontinuation will be 
given. 
11.2.3. 
Subject Characteristics 
Subject’s age, sex, weight, height, body mass index (BMI), and other demographic 
characteristics will be recorded and summarized by treatment group. 
Relevant 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. Each active 
dose will be tested against placebo.  Formal statistical tests (where performed) will be 2-sided 
and tested at the alpha=0.05 level of significance. 


11.2.4.2. Analysis Populations 
Approximately 70 adult subjects (age ≥40 and ≤80 years) will be randomized and will receive 
elamipretide or placebo according to the randomly assigned treatment sequence.  
Statistical analysis will be performed in the following populations: 
Per-Protocol Population – Includes subjects who meet minimal eligibility criteria, have sufficient 
information to determine the subject’s outcome, and have no confounding factors that interfere 
with the assessment of that outcome. The Per-Protocol Population is further defined in the SAP.  
Safety Population – Includes all study subjects who receive any amount of study medication 
according to treatment received. 
Below only an outline of the data analyses are given. The details of all analyses will be described 
in the Statistical Analysis Plan to be finalized before unblinding.   
11.2.5. 
Efficacy Analyses  
For primary and secondary efficacy endpoints, the change from baseline in all continuous 
endpoints will be summarized using descriptive statistics (mean, median, standard deviation, 
minimum, maximum) by treatment group. Categorical variables will be described using 
frequencies and percentages by treatment group. 
Efficacy analyses will be conducted on the Per-Protocol population. All test of treatment effects 
will be conducted at a 2-sided alpha level of 0.05. 
Additionally, change in LV ESV measurements of all three treatment groups together will be 
analyzed by mixed model repeated measures (MMRM), in order to study trends in the treatment 
effects over 4 weeks, with the primary time point of interest being at Week 4.  Additional details 
of the model, as well as adjustments for multiplicity (if needed) will be specified in the Statistical 
Analysis Plan. 
Secondary and exploratory endpoints will be analyzed analogously. 
11.2.6. 
Safety Analyses 
Safety data analysis will be conducted on all subjects in the Safety Population. 
11.2.6.1. Adverse Events 
The number and percentage of subjects experiencing 1 or more AEs will be summarized by 
treatment group, relationship to study medication, 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. If a subject has the same AE on multiple 
occasions, the highest severity (severe > moderate > mild) or drug relationship (probable > 
possibly related > unlikely related > unrelated) recorded for the event will be presented. If 


severity is missing, subjects will be included as missing (for severity). If drug relationship is 
missing, subjects will be included in related tables (e.g., considered related). 
11.2.6.2. Deaths and Other Serious Adverse Events 
Listings will be provided for the following: 
• Deaths 
• SAEs 
• SUSARs 
• AEs leading to discontinuation of study medication 
11.2.6.3. 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 assessments) 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 
study. 
11.2.6.4. 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. 
11.2.6.5. 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, QRS, QT, and QTc will also be listed. 
11.2.6.6. Other Safety Parameters 
Any other safety data captured on the eCRF will be listed. 
 


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


An identification code assigned to each subject will be used in lieu of the subject’s name to 
protect the subject’s identity when reporting AEs and/or other study-related data.  
12.3.1. 
Protocol Approval 
The Sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of their knowledge, the protocol accurately describes the planned design and conduct of the 
study. 
12.3.2. 
Final Report Approval 
The Sponsor’s responsible medical officer will approve the final clinical study report for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study. 
12.3.3. 
Study Monitoring 
The Investigators and institution(s) will permit study-related monitoring of the CRF data by 
Stealth BioTherapeutics Inc., or their assignee by providing direct access to source data and/or 
documents.  The study monitor will verify the eCRFs against the source documentation.  
Deviations from the protocol with regard to subject enrollment or study conduct will also be 
noted in the source documentation, in the eCRF and a complementary database.  A Sponsor 
representative will visit the site to initiate the study, prior to the first treatment of the first 
subject, and at agreed times throughout the study, including at the end of the study.  Medication 
dispensing and clinical drug supply records will be verified at the study site by the study 
monitor.  It is understood that all subject specific information is confidential and no 
documentation that can link study information to the specific subject will be collected or retained 
by the Sponsor. 
12.3.4. 
Retention of Records 
All study related material including source documents, eCRFs, Central Authority, and EC 
correspondence and analyses and any other documentation required by applicable laws and 
regulations will be maintained for 15 years after completion of the study or notification from the 
Sponsor that the data can be destroyed, whichever comes first. 
12.3.5. 
Disclosure of Information 
Information concerning the investigational medication and patent application processes, 
scientific data or other pertinent information is confidential and remains the property of Stealth 
BioTherapeutics Inc.  The Investigator may use this information for the purposes of the study 
only.  It is understood by the Investigator that Stealth BioTherapeutics Inc., will use information 
developed in this clinical study in connection with the development of the investigational 
medication and therefore may disclose it as required to other clinical Investigators and to 
regulatory agencies.  In order to allow the use of the information derived from this clinical study, 
the Investigator understands that he/she has an obligation to provide complete test results and all 
data developed during this study to the Sponsor. 
The Investigator may not submit for publication or presentation the results of this study without 
first receiving written authorization from Stealth BioTherapeutics Inc. Stealth BioTherapeutics 


Inc., agrees that before it publishes any results of the study, it shall provide the Investigator with 
at least 30 days for review of the pre-publication manuscript prior to the submission of the 
manuscript to the publisher. 
 
 


13. 
REFERENCES 
1. Mosterd A. et al., Clinical epidemiology of heart failure. Heart 2007; 93: p. 1137-1146. 
2. Cook C. et al, The annual global economic burden of heart failure. Int J Cardiol 2014; 171(3): 
p. 368-76.  
3. Shah A.M. et al., In search of new therapeutic targets and strategies for heart failure: recent 
advances in basic science. Lancet 2011; 378 (9792): p. 704-712. 
4. McMurray J.J., Clinical practice. Systolic heart failure. N Engl J Med 2010; 362 (3): p. 228-
238. 
5. Hunt S.A. et al., 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for 
the Diagnosis and Management of Heart Failure in Adults: a report of the American College of 
Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: 
developed in collaboration with the International Society for Heart and Lung Transplantation. 
Circulation 2009; 119 (14): p. e391-e479. 
 
 


14. 
ATTACHMENTS 
 
 


Attachment 1  
Schedule of Assessments  
 
Screening Period 
Treatment Period 
Follow-Up 
Period 
 
Days -28 to -1  
(Screening Visit) 
Day 1a  
(Baseline) 
Week 1 
(Day 8 + 3) 
Week 2 
(Day 15 ± 3) 
Week 4/EDb 
(Day 29 + 3) 
Week 6 
(Day 43 ± 3)  
Informed Consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Review of Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
Relevant Medical Historyc 
X 
X 
 
 
 
 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
Review AEs 
 
X 
X 
X 
X 
X 
Cardiovascular Physical Examinationd 
X 
X 
X 
X 
X 
X 
Vital Signse 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
X 
X 
X 
X 
Blood Chemistry & Hematology 
X 
X 
X 
X 
X 
X 
PK Samplesf 
 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
 
X 
 
Pregnancy Testg 
X 
X 
 
 
X 
 
Echocardiographyh 
X 
X 
 
 
X 
X 
Cardiac MRIi 
X 
 
X 
 
X 
 
KCCQ 
 
X 
 
 
X 
 
NT-pro-BNP 
 
X 
X 
X 
X 
X 
6-Minute Walk Test 
 
X 
 
 
X 
 
Borg dyspnea scale 
 
X 
 
 
X 
 
Study Medication Dispensing 
 
X 
X 
X 
 
 
Study Medication Injectionj 
 
X-----------------------------------------------------------------X 
 
ISR Self-Assessment Questionnaire 
 
X-----------------------------------------------------------------X 
 
Visiting Nurse/Investigator ISR Assessmentk 
 
X-----------------------------------------------------------------X 
 


a All Day 1 assessments should be performed prior to administering the first dose of study medication except the ISR assessments (as described in Section 6.3.9) and blood 
drawn for plasma analysis of elamipretide and metabolites (45 minutes post-injection ±15 minutes) (as described in Section 6.3.8.5) which should be completed after study 
medication administration. 
b If a subject discontinues study medication early, the subject will have an Early Discontinuation Visit and will be asked to complete the Week 4 assessments. 
c At the Screening Visit, a relevant medical history will be taken. Relevant medical history will be updated at the Day 1 visit. 
d Cardiovascular physical examination including lung auscultation and weight. Height will only be measured at the Screening Visit. 
e Vital signs measurements will include temperature, heart rate, respiration rate and blood pressure, recorded in the sitting position after at least 10 minutes rest.  
f Blood samples for PK determinations of elamipretide and metabolites concentrations will be collected before administration of study medication and at 45 minutes  (±15 
minutes) post-dose at the Day 1, Week 1, and Week 2 visits, and at any time point at the Week 4 and 6 visit. 
g Serum pregnancy test will be done for women of childbearing potential at the Screening visit.  Urine pregnancy test will be done for women of childbearing potential on 
Day 1 and Week 4. The results of the Day 1 pre-dose pregnancy test must be evaluated before randomization to ensure eligibility.  
h At the Screening Visit, only a 2-D echocardiography will be performed and it will be performed prior to Step 2 (blood draw, urinalysis) and Step 3 (cardiac MRI) screening 
procedures. Both 2-D and 3-D echocardiography will be performed at the Day 1, Week 4 and Week 6 visits. 
i At the Screening visit, subjects will undergo delayed gadolinium-enhanced cardiac MRI prior to study medication injection. At the Week 1 visit, subjects will undergo 
cardiac MRI approximately 1 to 6 hours following injection of study medication. 
j At Day 1, study medication injection will occur after the completion of baseline procedures (as noted in footnote a).  Study medication will be administered daily by a 
Visiting Nurse, except on Study Visits, at Days 1 through 3 and during the Week 1 and Week 2 visits. The last dose of study medication will be administered on the day prior 
to the Week 4 visit. 
k At each home visit, the Visiting Nurse will assess the current day’s injection site. At Days 1 through 3, Week 1 and Week 2 visits, the Investigator (or designee) will assess 
the current day’s injection site. The assessment will evaluate erythema, pain, swelling, and pruritus at the injection site at approximately 15 minutes post-injection.  If any 
reaction is apparent, the injection site will also be evaluated at 30 minutes post-injection.  
 
 


 
Attachment 2  
Clinical Laboratory Tests 
Hematology: 
Clinical Chemistry: 
Hemoglobin 
Serum: 
Hematocrit 
Sodium 
Erythrocyte count (RBC) 
Potassium 
Leukocytes (WBC) 
Total bilirubin 
Neutrophils, segmented 
Alkaline phosphatase 
Lymphocytes 
Alanine aminotransferase (ALT) 
Monocytes 
Aspartate aminotransferase (AST) 
Eosinophils 
Blood urea nitrogen (BUN) 
Basophils 
Creatinine 
Platelets 
Calcium 
 
Glucose (non-fasting) 
Urinalysis: 
Albumin 
Specific gravity 
Chloride 
pH 
Bicarbonate 
Protein 
Total protein 
Glucose 
Triglycerides 
Ketones 
eGFR calculated with the MDRD study equation 
Blood 
hsTroponin I  
Sodium 
 
Chloride 
Exploratory HF Biomarker 
Creatinine 
NT-pro-BNP 
Microalbuminuria 
 
 
 
 


 
Attachment 3  
Six Minute Walk Test 
Key Considerations:  
• 
Consistency in administering the test is very important  
• 
At least 30 minutes rest should be allowed between successive tests if applicable.  
• 
If two successive tests are conducted results of both tests are recorded with the best result 
used to determine functionality.  
• 
A health professional trained in CPR with the ability to run the test must be present or 
immediately available during the conduct of the 6MWT.  
 
Required Equipment:  
• 
Walking Track or Area - The walking track or area must be the same for all tests and all 
patients  
o The track may be a continuous track (oval or rectangular) or a point-to-point area 
(stop- turn around-go back).  
o Turns in the walking course should be minimized when possible  
o The track or area should be flat with no blind turns, traffic or obstacles.  
o The walking length should be 98.4 ft. (30m) and should be marked in 3 foot or 1 
meter increments.  
• 
Stethoscope, vital sign equipment, pulse oximeter  
• 
Stop watch  
• 
Portable oxygen delivery system  
• 
Chairs at the starting position and along the walking course for the patient to rest if needed 
 
Before the 6MWT:  
• 
Confirm the patient has signed the ICF and the Principal Investigator has approved the 
subject’s participation in the 6MWT.  
• 
Instruct the patient to dress comfortably, wear appropriate footwear and to avoid eating for at 
least two hours before the test (where possible or appropriate).  
• 
Any prescribed inhaled bronchodilator medication should be taken within one hour of testing 
or when the patient arrives for testing. All medications must be recorded as specified in the 
protocol.  
• 
The patient should rest comfortably for at least 15 minutes before beginning the test.  
• 
A comfortable ambient temperature and humidity should be maintained for all tests.  
• 
Record: 
o Blood pressure  
o Heart rate  
o Respiratory rate 
o Oxygen saturation  
 
Instructions to the Patient:  
The instructions should be placed on a laminated card and read out loud to the patient. Instructions 
should be clear and consistent for every test conducted.  
• 
Describe the walking track or area to the patient.  
• 
Explain the objective of the test.  
• 
Provide instructions on what to do and what not to do during the test.  
• 
Emphasize the need for the patient to report any untoward effects.  
 


 
Sample instructions:  
“You are now going to do a six-minute walking test. The object of this test is to walk as quickly as 
you can for six minutes around the track (or up and down the corridor etc… depending on the track 
set up) so that you cover as much ground as possible. You may slow down if necessary. If you stop, I 
want you to continue to walk again as soon as possible. You will be kept informed of the time and 
you will be encouraged to do your best. Your goal is to walk as far as possible in six minutes.  
Please do not talk during the test unless you have a problem or if I ask you a question. You must let 
me know if you have any chest pain or dizziness. When the six minutes is up I will ask you to stop 
where you are. Do you have any questions?”  
 
Begin the Test by instructing the patient to start walking and start the stop watch.  
 
During the Test:  
• 
Monitor the patient for untoward signs and symptoms.  
• 
Use standard encouragements during the test.  
o At minute one: “Five minutes remaining. Do your best!”  
o At minute two: “Four minutes remaining. You're doing well - keep it up!”  
o At minute three: “Half way point. Three minutes remaining. Do your best!”  
o At minute four: “Two minutes remaining. You're doing well - keep it up!”  
o At minute five: “One minute remaining. Do your best!”  
 
At the End of the 6MWT:  
• 
Put a marker on the distance walked and record the value.  
• 
Have the patient sit down or if the patient prefers, allow the patient to stand.  
*Note: The measurements taken before and after the test should be taken with the patient in the 
same position.  
• 
Immediately record oxygen saturation (SpO2%), heart rate, and blood pressure on the 
recording sheet.  
• 
Record respiratory rate 
• 
Measure the distance remaining on the walking course with a tape measure and add up the 
total distance.  
• 
The patient should remain in a clinical area for at least 15 minutes following an 
uncomplicated test.  
 
Clinical Notes:  
Normally the clinician does not walk with the patient during the test to avoid the problem of setting 
the walking pace. The pulse oximeter should be applied immediately if the patient chooses to rest and 
at completion of the six-minute walking period. Any delay may result in readings being recorded that 
are not representative of maximum exercise response.  
 
In some instances, the clinician may choose to walk with the patient for the entire test (e.g., if 
continuous oximetry is desired). If this is the case the clinician should try to walk slightly behind the 
patient to avoid setting the walking pace. Alternatively, if the oximeter is small and lightweight, it 
may be attached to the patient and checked throughout the test without interfering with walking pace.  
 
If the Patient Stops During the Six Minutes: 
• 
Allow the patient to sit in a chair if they wish.  
• 
Measure the SpO2% and heart rate.  


 
• 
Ask the patient why they stopped and record the reason stated.  
• 
Record the time the patient stopped (but keep the stop watch running).  
• 
Encourage the patient to begin walking as soon as he/she is feeling better and offer 
encouragement every 15 seconds if necessary.  
• 
Monitor the patient for untoward signs and symptoms.  
 
Stop the Test in the Event of Any of the Following: 
• 
Chest pain suspicious for angina.  
• 
Evolving mental confusion or lack of coordination.  
• 
Evolving light-headedness.  
• 
Intolerable dyspnea.  
• 
Leg cramps or extreme leg muscle fatigue.  
• 
Persistent SpO2 < 85%.  
• 
Any other clinically warranted reason.  
 
References: 
ATS Statement: Guidelines for the 6MWT Am J Respir Crit Care Med 2002; 166: 111-117.  
Olsson et al Eur Heart Journal 2005; 26: 778-793.  
Miyamoto et al Am J Respir Care 2000; 161: 487-492. 
 
 


 
Attachment 4  
Kansas City Cardiomyopathy Questionnaire (KCCQ)  
The following questions refer to your heart failure and how it may affect your life. Please read and complete the following questions. There are no 
right or wrong answers. Please mark the answer that best applies to you. 
 
1. Heart failure affects different people in different ways. Some feel shortness of breath while others feel fatigue. Please indicate how much 
you are limited by heart failure (shortness of breath or fatigue) in your ability to do the following activities over the past 2 weeks. 
 
Place an X in one box on each line 
Activity 
Extremely 
Limited 
Quite a bit 
Limited 
Moderately 
Limited 
Slightly 
Limited 
Not at all 
Limited 
Limited for other reasons or 
did not do the activity 
Dressing yourself 
□ 
□ 
□ 
□ 
□ 
□ 
Showering/Bathing 
□ 
□ 
□ 
□ 
□ 
□ 
Walking 1 block on level ground 
□ 
□ 
□ 
□ 
□ 
□ 
Doing yardwork, housework or 
carrying groceries 
□ 
□ 
□ 
□ 
□ 
□ 
Climbing a flight of stairs without 
stopping 
□ 
□ 
□ 
□ 
□ 
□ 
Hurrying or jogging (as if to catch 
a bus) 
□ 
□ 
□ 
□ 
□ 
□ 
 
2. Compared with 2 weeks ago, have your symptoms of heart failure (shortness of breath, fatigue or ankle swelling) changed? My 
symptoms of heart failure have become . . . 
 
Much worse 
Slightly worse 
Not changed 
Slightly better 
Much better 
I’ve had no symptoms over the last 2 weeks 
□ 
□ 
□ 
□ 
□ 
□ 
 
3. Over the past 2 weeks, how many times did you have swelling in your feet, ankles or legs when you woke up in the morning? 
 
Every morning 
3 or more times a week, but not every day 
1-2 times a week 
Less than once a week 
Never over the past 2 weeks 
□ 
□ 
□ 
□ 
□ 
 
4. Over the past 2 weeks, how much has swelling in your feet, ankles or legs bothered you? It has been . . . 
 
Extremely 
bothersome 
Quite a bit 
bothersome 
Moderately 
bothersome 
Slightly 
bothersome 
Not at all 
bothersome 
I’ve had no 
swelling 
□ 
□ 
□ 
□ 
□ 
□ 
 


 
5. Over the past 2 weeks, on average, how many times has fatigue limited your ability to do what you want? 
 
All of the 
time 
Several times 
per day 
At least once a 
day 
3 or more times per week 
but not every day 
1-2 times per 
week 
Less than once 
a week  
Never over the past 
2 weeks  
□ 
□ 
□ 
□ 
□ 
□ 
□ 
 
6. Over the past 2 weeks, how much has your fatigue bothered you? It has been . . . 
 
Extremely 
bothersome 
Quite a bit 
bothersome 
Moderately 
bothersome 
Slightly bothersome 
Not at all 
bothersome 
I’ve had no fatigue 
□ 
□ 
□ 
□ 
□ 
□ 
 
7. Over the past 2 weeks, on average, how many times has shortness of breath limited your ability to do what you wanted? 
 
All of the 
time 
Several times 
per day 
At least once a 
day 
3 or more times per week 
but not every day 
1-2 times per 
week 
Less than once 
a week  
Never over the past 
2 weeks  
□ 
□ 
□ 
□ 
□ 
□ 
□ 
 
8. Over the past 2 weeks, how much has your shortness of breath bothered you? It has been . . . 
 
Extremely 
bothersome 
Quite a bit 
bothersome 
Moderately 
bothersome 
Slightly bothersome 
Not at all 
bothersome 
I’ve had no shortness of 
breath 
□ 
□ 
□ 
□ 
□ 
□ 
 
9. Over the past 2 weeks, on average, how many times have you been forced to sleep sitting up in a chair or with at least 3 pillows to prop 
you up because of shortness of breath? 
 
Every night 
3 or more times a week, but 
not every day 
1-2 times a week 
Less than once a week 
Never over the past 2 weeks 
□ 
□ 
□ 
□ 
□ 
 
10. Heart failure symptoms can worsen for a number of reasons. How sure are you that you know what to do, or whom to call, if your heart 
failure gets worse? 
 
Not at all sure 
Not very sure 
Somewhat sure 
Mostly sure 
Completely sure  
□ 
□ 
□ 
□ 
□ 
 
11. How well do you understand what things you are able to do to keep your heart failure symptoms from getting worse? (for example, 
weighing yourself, eating a low salt diet, etc.) 
 


 
Do not understand at all 
Do not understand very well 
Somewhat understand 
Mostly understand  
Completely understand  
□ 
□ 
□ 
□ 
□ 
 
12. Over the past 2 weeks, how much has your heart failure limited your enjoyment of life? 
 
It has extremely limited 
my enjoyment of life 
It has limited my enjoyment 
of life quite a bit 
It has moderately limited 
my enjoyment of life 
It has slightly limited 
my enjoyment of life 
It has not limited my 
enjoyment of life at all 
□ 
□ 
□ 
□ 
□ 
 
13. If you had to spend the rest of your life with your heart failure the way it is right now, how would you feel about this? 
 
Not at all satisfied 
Mostly dissatisfied 
Somewhat satisfied 
Mostly satisfied 
Completely satisfied 
□ 
□ 
□ 
□ 
□ 
 
14. Over the past 2 weeks, how often have you felt discouraged or down in the dumps because of your heart failure? 
 
I felt that way all of the time I felt that way most of the time I occasionally felt that way I rarely felt that way I never felt that way 
□ 
□ 
□ 
□ 
□ 
 
15. How much does your heart failure affect your lifestyle? Please indicate how your heart failure may have limited your participation in the 
following activities over the past 2 weeks. 
Please place an X in one box on each line 
 
Severely 
Limited 
Limited 
quite a bit 
Moderately 
limited 
Slightly 
limited 
Did not 
limit at all 
Does not apply or did 
not do for other reasons 
Hobbies, recreational activities 
□ 
□ 
□ 
□ 
□ 
□ 
Working or doing household chores 
□ 
□ 
□ 
□ 
□ 
□ 
Visiting family or friends 
out of your home 
□ 
□ 
□ 
□ 
□ 
□ 
Intimate relationships with loved ones 
□ 
□ 
□ 
□ 
□ 
□ 
 
 
 


 
 
Attachment 5  
Injection Site Reaction (ISR) Self-Assessment Questionnairea  
Please answer each question below by checking the box that best represents your opinion (Check only one box per question).  Select 
“Not at all” if you did not experience the injection site reaction. 
1. During and/or after the injection of today’s dose of study medication, how bothered were you by the following potential pain 
and skin reactions at the injection site:   
 
Not at all 
A little 
Moderately 
Very 
Extremely 
a.  pain? 
 
 
 
 
 
b.   burning sensation? 
 
 
 
 
 
c.    cold sensation? 
 
 
 
 
 
d.   itching? 
 
 
 
 
 
e. redness? 
 
 
 
 
 
f.   swelling? 
 
 
 
 
 
g.  bruising? 
 
 
 
 
 
a Adapted from the Self-Injection Assessment Questionnaire © 2011 Keininger and Coteur; licensee BioMed Central Ltd. 
 
THANK YOU FOR COMPLETING THIS QUESTIONNAIRE 


 
 
Attachment 6  
Table for Grading the Severity of Site Reactions to Injections and Infusions (Adults) 
 
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 self-
care 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 life- 
threatening 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. 
 
 
 
 
 
 
 
 


 
 
Attachment 7  
Modified Borg Dyspnoea Scale 
Subject Instructions for Modified Borg Dyspnoea Scale 
“This is a scale that asks you to rate the difficulty of your breathing, in this case after you have lain flat for up to ten minutes – or if you cannot 
manage that how breathless you imagine you would be if you tried to lie flat. 
 
It starts at number 0 where your breathing is causing you no difficulty at all and progresses through to number 10 where your breathing 
difficulty is maximal. How much difficulty is your breathing causing you right now?” 
  0 
 Nothing at all 
  0.5 
 Very, very slight (just noticeable) 
  1 
 Very slight 
  2 
 Slight 
  3 
 Moderate 
  4 
Somewhat severe 
  5 
Severe  
 
  6 
  7 
 Very severe 
  8 
  9  
 Very, very severe (almost maximal) 
10 
 Maximal 
 

SAP_001.pdf: 
  
 
  
 
 
A Phase 2 Randomized, Double-Blinded, Placebo-Controlled Study to Evaluate the Effects of 
Multiple Subcutaneous Injections of Elamipretide on Left Ventricular Function in Subjects with 
Stable Heart Failure with Reduced Ejection Fraction 
NCT02788747 
04 DECEMBER 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


  
 
STATISTICAL ANALYSIS PLAN  
  
 
  
 
Trial Sponsor:   
Stealth BioTherapeutics, Inc.  
Protocol Number:  
SPIHF-201 IND Number:  N/A EUDRACT 
Number:  2014-005724-10 Investigational Drug:  
Elamipretide (MTP-131)  
 
Indication:  
Heart Failure with reduced Ejection  
Fraction (HFrEF)  
Dosage Form/Strength: Elamipretide (MTP-131) 40 mg/1 mL of 
sterile solution for subcutaneous injection 
with doses of 4 mg or 40 mg 
administered once daily  
  
  
Protocol Title: A Phase 2 Randomized, Double-Blinded, Placebo-Controlled Study to  
Evaluate the Effects of Multiple Subcutaneous Injections of Elamipretide on Left Ventricular 
Function in Subjects with Stable Heart Failure with Reduced Ejection Fraction  
  
  
  
  
  
___________________________________________________________________________________  
The information in this document is confidential and is proprietary to Stealth Biotherapeutics. It is understood that 
information in this document shall not be disclosed to any third party, in any form, without prior written consent 
of an authorized officer of Stealth Biotherapeutics. 
Version 1.0  
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Statistical Analysis Plan   
Protocol No. SPIHF-201  
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CHANGE LOG FOR CHANGES MADE AFTER THE INITIAL APPROVAL  
Revision 
Date*  
Section(s) 
Modified  
Brief Description of Revision(s) or 
Reason(s) for Revision  
Modifications Reviewed and 
Approved by**  
Sponsor, Everest  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
* Update the Last Revision Dates on the cover page and the document header.  
** Provide person’s initial and last name.  
  
TABLE OF CONTENTS  
1.  INTRODUCTION ................................................................................................................................... 8 
2.  STUDY OBJECTIVES ............................................................................................................................ 9 
2.1  Primary Objective .......................................................................................................................... 9 
2.2  Secondary Objectives ..................................................................................................................... 9 
2.3  Exploratory Objectives ................................................................................................................ 10 
3.  STUDY DESIGN .................................................................................................................................. 10 
3.1 Study Design ................................................................................................................................. 10 
3.2 Randomization .............................................................................................................................. 11 
3.3 Hypothesis Testing ........................................................................................................................ 12 
3.4 Interim Analysis ............................................................................................................................ 12 
3.5 Sample Size ................................................................................................................................... 12 
3.6  Schedule of Assessments and Study Procedures ......................................................................... 12 
4.  DATA AND ANALYTICAL QUALITY ASSURANCE ..................................................................... 16 
5.  ANALYSIS POPULATIONS ............................................................................................................... 16 
5.1 Safety Population .......................................................................................................................... 16 
5.2 Intent-to-Treat (ITT) Population ................................................................................................... 16 
5.3  Per-Protocol (PP) Population ....................................................................................................... 16 
6. SPECIFICATION OF ENDPOINTS AND VARIABLES ..................................................................... 16 
6.1 Demographic and Baseline Characteristics ................................................................................... 16 


  
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6.2  Efficacy ........................................................................................................................................ 17 
6.2.1 Study Day and Visit Window Definitions ....................................................................... 17 
6.2.2 Primary Efficacy Variables .............................................................................................. 18 
6.2.3  Secondary Efficacy Variables ......................................................................................... 18 
6.2.4  Exploratory Efficacy Variables ....................................................................................... 19 
6.2.5  Plasma Concentration ..................................................................................................... 19 
6.3  Safety ........................................................................................................................................... 20 
6.3.1 Study Day and Visit Window Definitions ....................................................................... 20 
6.3.2 Extent of Exposure to Study Medication ......................................................................... 21 
6.3.3 Adverse Events ................................................................................................................ 21 
6.3.4 Laboratory Data ............................................................................................................... 23 
6.3.5 Vital Signs ....................................................................................................................... 25 
6.3.6 Electrocardiogram (ECG) ................................................................................................ 25 
6.3.7 Physical Examination ...................................................................................................... 25 
6.3.8 Pregnancy Test ................................................................................................................. 25 
6.3.9  Concomitant Medications/Treatments ............................................................................ 25 
7.  STATISTICAL ANALYSIS ................................................................................................................. 27 
7.1  General Data Handling Rules and Definitions ............................................................................. 27 
7.2 Subject Disposition ....................................................................................................................... 28 
7.3 Demographic and Baseline Characteristics ................................................................................... 28 
7.4  Efficacy Analyses ........................................................................................................................ 28 
7.4.1 Primary Efficacy .............................................................................................................. 28 
7.4.2 Secondary Efficacy .......................................................................................................... 29 
7.4.3 Exploratory Efficacy ........................................................................................................ 30 
7.4.4  Efficacy Subgroup Analyses ........................................................................................... 31 
7.5  Plasma Concentration Analyses ................................................................................................... 31 
7.6  Safety Analyses ............................................................................................................................ 32 
7.6.1 Extent of Exposure to Study Medication ......................................................................... 32 
7.6.2 Adverse Events ................................................................................................................ 32 
7.6.3 Deaths .............................................................................................................................. 33 
7.6.4 Clinical Laboratory Evaluations ...................................................................................... 33 
7.6.5 Vital Signs ....................................................................................................................... 34 
7.6.6 Electrocardiogram (ECG) ................................................................................................ 34 
7.6.7 Physical Examination ...................................................................................................... 34 
7.6.8  Concomitant Medications/Treatments ............................................................................ 34 
8.  ANALYSES PERFORMED BEFORE DATABASE CLOSURE ........................................................ 35 
9.  CHANGES FROM METHODS PLANNED IN THE PROTOCOL .................................................... 35 
10. STATISTICAL SOFTWARE ............................................................................................................... 35 
11. REFERENCES ..................................................................................................................................... 35 
APPENDIX 1 DATA HANDLING RULES .............................................................................................. 35 
APPENDIX 2 SAS CODE FOR STATISTICAL ANALYSES ................................................................. 36 


  
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APPENDIX 3  REFERENCE RANGES AND CLINICALLY RELEVANT CHANGES FROM 
BASELINE FOR MARKED LABORATORY ABNORMALITIES ........................................................ 37 
APPENDIX 4  MOCKUP TABLES, LISTINGS, AND GRAPHS (TLGS) .............................................. 38 
 
6-minute walk test  
AE  
Adverse event  
ATP  
Adenosine triphosphate  
ATPmax  
Maximal ATP synthetic mitochondrial energy coupling 
AUC  
Area under the plasma concentration versus time curve  
BMI  
Body mass index  
BP  
Blood pressure  
BSA  
Body surface area  
BUN  
Blood urea nitrogen  
CK  
Creatine kinase  
ECG  
Electrocardiogram  
eCRF  
electronic Case Report Form  
EF  
Ejection fraction  
DBP  
Diastolic blood pressure  
HFrEF  
Heart failure with reduced ejection fraction  
Hgb  
Hemoglobin  
IMP  
Investigational medicinal product  
ITT  
Intent-to-treat  
IV  
Intravenous  
IWRS  
Interactive web-based response system  
KCCQ  
Kansas City Cardiomyopathy Questionnaire  
LA  
Left atria  
LV  
Left ventricle  
LV EDV  
Left ventricular end diastolic volume  
LVEF  
Left ventricular ejection fraction  


  
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GLOSSARY OF ABBREVIATIONS  
 
LV ESV  
Left ventricular end systolic volume  
Mb  
Myoglobin  
Abbreviation  
Term  
6 MWT  


  
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MedDRA  
Medical Dictionary for Regulatory Activities  
 
MRI  
Magnetic resonance imaging  
 
MRS  
Magnetic resonance spectroscopy  
 
MTP-131  
Elamipretide  
 
NAD  
Nicotine adenine dinucleotide  
 
NT-pro-BNP  
N-terminal pro-brain natriuretic peptide  
 
PCr  
Phosphocreatine  
 
31P  
Phosphorus-31  
 
P/O  
Mitochondrial coupling  
 
PT  
Preferred term  
 
RBC  
Erythrocyte count  
 
RV  
Right ventricle  
 
RVSP  
Right ventricular systolic pressure  
 
SAE  
Serious adverse event  
 
SAP  
Statistical analysis plan  
 
SBP  
Systolic blood pressure  
 
SC  
Subcutaneous  
 
SOC  
System organ class  
 
TEAE  
Treatment-emergent adverse event  
 
US  
United States  
 
WBC  
Leukocytes  
 
WHO-DD  
World Health Organization Drug Dictionary  
 
1. INTRODUCTION  
This Statistical Analysis Plan (SAP) outlines the planned statistical methods for the display, 
summary and analysis of data collected within the scope of Stealth BioTherapeutics, Inc. 
protocol SPIHF-201 version 8.0 dated 21 March 2017. The analysis of the data should allow 


  
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changes in the plan to the extent that deviations from the original plan would provide a more 
reliable and valid analysis of the data. As such, deviations from this SAP must be substantiated 
by a sound statistical rationale and described in the clinical study report (CSR).  
The SAP should be read in conjunction with the study protocol and the electronic Case Report 
Forms (eCRFs). This version of the SAP has been developed using the final version of the 
protocol mentioned above and the final version of the annotated eCRFs dated 16 June 2016.   
The SAP details the analysis of the data collected in the study and the presentation of the results 
of the analyses. The table, listing, and figure (TLF) shells are displayed in a companion 
document which provides information on the layout of the data displays. Analysis dataset 
specifications will be developed to detail the programming specifications and mapping rules 
needed to create the analysis datasets and the TLFs.  
All statistical analyses will be performed using SAS® version 9.3, or higher. Adverse events will 
be coded using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA 
19.1 or newer).  
This study is a Phase 2, randomized, double-blind, placebo-controlled, multiple dose study, 
conducted in up to 20 centers in Europe, enrolling 66 subjects with previous evidence of stable 
heart failure with reduced ejection fraction (HFrEF) to evaluate the effects of multiple 
subcutaneous (SC) doses of elamipretide on left ventricular end systolic volume (LV ESV).   
2. STUDY OBJECTIVES  
2.1 
Primary Objective  
To evaluate the effects of multiple SC doses of elamipretide on LV ESV assessed by cardiac 
Magnetic Resonance Imaging (MRI).  
2.2 
Secondary Objectives  
• 
To evaluate the safety and tolerability of multiple SC doses of elamipretide.    
• 
To evaluate the effects of multiple SC doses of elamipretide on left ventricular (LV) 
systolic and diastolic function to include: LV volumes, LV global longitudinal strain, left 
atrial (LA) volume, LV mass, extent of mitral and tricuspid regurgitation severity, and 
right ventricular (RV) function (original and indexed to BSA).  


  
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2.3 
Exploratory Objectives  
To evaluate the effects of multiple SC doses of elamipretide on:  
• 
6-minute walking distance  
• 
Quality of life using the KCCQ  
• 
N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels  
3. STUDY DESIGN  
3.1 
Study Design  
This is a randomized, double-blinded, placebo-controlled, multiple dose Phase 2 study in 
subjects with HFrEF.  The objectives are to evaluate the effects of multiple SC doses of 
elamipretide on LV ESV, LV systolic and diastolic function, LV volumes, LV global 
longitudinal strain, LA volume, LV mass, mitral and tricuspid regurgitation severity, and RV 
function in subjects with stable heart failure with reduced ejection fraction.  After completing the 
screening period, approximately 66 subjects will be randomized, in a 1:1:1 ratio, to receive either 
placebo, 4 mg elamipretide, or 40 mg elamipretide once daily for 28 consecutive days.  
Efficacy will be assessed with the following measurements:  
• 
LV ESV assessed by MRI  
• 
Left ventricular ejection fraction (LVEF) and left ventricular end diastolic volume (LV 
EDV) assessed by MRI  
• 
The following parameters by echocardiography:  
o E/A (ratio between early and late mitral inflow velocity),  
o E/e' (Ratio between early mitral inflow velocity and mitral annular early diastolic 
velocity)  
o LV EDV, LV ESV and biplane ejection fraction (EF)  
o LV global longitudinal strain  
o LA volume o LV mass  
o Mitral regurgitation severity o Tricuspid regurgitation severity o RV fractional 
area change o RV systolic pressure (RVSP)  
• 
Distance walked (meters) on the 6-minute walk test (6MWT)  


  
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• 
Kansas City Cardiomyopathy Questionnaire (KCCQ) score  
• 
Levels of NT-pro-BNP  
Subjects will be screened for reduced EF, defined as LVEF ≤ 40%, by 2-D echocardiography.  
There are 3 study treatment groups randomized in equal ratio:  
• 
Elamipretide (MTP-131) 40 mg of 40 mg/1 mL of sterile solution, administered as a once 
daily SC injection for 28 consecutive days.  
• 
Elamipretide (MTP-131) 4 mg of 40 mg/1 mL of sterile solution, administered as a once 
daily SC injection for 28 consecutive days.  
• 
Placebo (excipients used to manufacture the investigational drug but without the active 
drug substance) administered as a once daily SC injection for 28 consecutive days.  
3.2 
Randomization  
Randomization will be used in this study to avoid bias in the assignment of study treatments to 
subjects, to increase the likelihood that known and unknown subject attributes (e.g., 
demographics and baseline characteristics) are balanced across treatment groups, and to enhance 
the possible validity of statistical comparisons across treatment groups. Blinded treatment will be 
used to reduce potential bias during data collection and evaluation of endpoints. Only those 
subjects who meet protocol-specified criteria for stable heart failure with reduced ejection 
fraction will be randomized to study treatment.   
At Day 1, after the eligibility criteria have been confirmed, a treatment kit number will be 
assigned to each subject on the basis of a centralized computer-generated randomization 
schedule administered by IWRS. Subjects will be randomized into 1 of 3 treatment groups in a 
1:1:1 fashion to receive either elamipretide 4 mg, elamipretide 40 mg, or placebo, so that a target 
of 22 subjects will be randomized to the elamipretide 4 mg dose group, 22 subjects will be 
randomized to the elamipretide 40 mg dose group, and 22 subjects will be randomized to the 
placebo treatment group. Treatment kits for placebo will specify injection volumes of either 0.1 
or 1 mL in order to maintain the blind. This will be accomplished by administering a 
randomization schedule in randomized blocks of 6 with a ratio of 2:2:1:1 (elamipretide 4 mg [0.1 
mL], elamipretide 40 mg [1 mL], placebo [0.1 mL] or placebo [1 mL]).  This design maintains 
the 1:1:1 ratio of elamipretide 4 mg, elamipretide 40 mg, and placebo in addition to ensuring the 
complete blind to study treatment.  


  
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3.3 
Hypothesis Testing  
Primary hypothesis:  
Null hypothesis H0: There is no difference between the elamipretide 40 mg and placebo 
treatment groups in change in LV ESV at Week 4 from baseline.   
Alternative hypothesis Ha: There is a difference between the elamipretide 40 mg and placebo 
treatment groups in change in LV ESV at Week 4 from baseline.   
The elamipretide 4 mg treatment will also be compared to placebo as a secondary hypothesis.    
3.4 
Interim Analysis  
No formal interim analyses are planned for this study.  
3.5 
Sample Size  
The target sample size of 22 subjects per treatment group provides 80% power to detect an 8 mL 
difference between treatment groups in LV ESV, as measured by MRI, assuming a standard 
deviation of 9.4 mL.  
3.6 
Schedule of Assessments and Study Procedures  


  
 
Statistical Analysis Plan  
Protocol No.: SPIHF-201  
 
  
Last Revision Date: 04 DECEMBER 2017  
  
  
Screening Period  
Treatment Period  
Follow-Up Period  
  
Days -28 to -1  
(Screening Visit)  
Day 1a  
(Baseline)  
Week 1  
(Day 8 + 3)  
Week 2  
(Day 15 ± 3)  
Week 4/EDb 
(Day 29 + 3)  
Week 6  
(Day 43 ± 3)   
Informed Consent  
X  
  
  
  
  
  
Demographics  
X  
  
  
  
  
  
Randomization  
  
X  
  
  
  
  
Review of Inclusion/Exclusion Criteria  
X  
X  
  
  
  
  
Relevant Medical Historyc  
X  
X  
  
  
  
  
Concomitant Medication Review  
X  
X  
X  
X  
X  
X  
Review AEs  
  
X  
X  
X  
X  
X  
Cardiovascular Physical Examinationd  
X  
X  
X  
X  
X  
X  
Vital Signse  
X  
X  
X  
X  
X  
X  
12-Lead ECG  
X  
X  
X  
X  
X  
X  
Blood Chemistry & Hematology  
X  
X  
X  
X  
X  
X  
PK Samplesf  
  
X  
X  
X  
X  
X  
Urinalysis  
X  
X  
  
  
X  
  
Pregnancy Testg  
X  
X  
  
  
X  
  
Echocardiographyh  
X  
X  
  
  
X  
X  
Cardiac MRIi  
X  
  
X  
  
X  
  
KCCQ  
  
X  
  
  
X  
  
NT-pro-BNP  
  
X  
X  
X  
X  
X  
6-Minute Walk Test  
  
X  
  
  
X  
  
Study Medication Dispensing  
  
X  
X  
X  
  
  
Study Medication Injectionj  
  
X-----------------------------------------------------------------X  
  
ISR Self-Assessment Questionnaire  
  
X-----------------------------------------------------------------X  
  
Visiting Nurse/Investigator ISR Assessmentk  
  
X-----------------------------------------------------------------X  
  


  
 
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a All Day 1 assessments should be performed prior to administering the first dose of study medication except the ISR assessments (as described in Section 6.3.9) 
and blood drawn for plasma analysis of elamipretide and metabolites (45 minutes post-injection ±15 minutes) (as described in Section 6.3.8.5) which should be 
completed after study medication administration. b If a subject discontinues study medication early, the subject will have an Early Discontinuation Visit and will 
be asked to complete the Week 4 assessments. c At the Screening Visit, a relevant medical history will be taken. Relevant medical history will be updated at the 
Day 1 visit. d Cardiovascular physical examination including lung auscultation and weight. Height will only be measured at the Screening Visit. e Vital signs 
measurements will include temperature, heart rate, respiration rate and blood pressure, recorded in the sitting position after at least 10 minutes rest.   
f 
Blood samples for PK determinations of elamipretide and metabolites concentrations will be collected before administration of study medication and at 
45 minutes  (±15 minutes) post-dose at the Day 1, Week 1, and Week 2 visits, and at any time point at the Week 4 and 6 visit.  
g 
Serum pregnancy test will be done for women of childbearing potential at the Screening visit.  Urine pregnancy test will be done for women of 
childbearing potential on Day 1 and Week 4. The results of the Day 1 pre-dose pregnancy test must be evaluated before randomization to ensure eligibility.   
h 
At the Screening Visit, only a 2-D echocardiography will be performed and it will be performed prior to Step 2 (blood draw, urinalysis) and Step 3 
(cardiac MRI) screening procedures. Both 2-D and 3-D echocardiography will be performed at the Day 1, Week 4 and Week 6 visits.  
i 
At the Screening visit, subjects will undergo delayed gadolinium-enhanced cardiac MRI prior to study medication injection. At the Week 1 visit, 
subjects will undergo cardiac MRI approximately 1 to 6 hours following injection of study medication.  
j 
At Day 1, study medication injection will occur after the completion of baseline procedures (as noted in footnote a).  Study medication will be 
administered daily by a Visiting Nurse, except on Study Visits, at Days 1 through 3 and during the Week 1 and Week 2 visits. The last dose of study medication 
will be administered on the day prior to the Week 4 visit.  
k 
At each home visit, the Visiting Nurse will assess the current day’s injection site. At Days 1 through 3, Week 1 and Week 2 visits, the Investigator (or 
designee) will assess the current day’s injection site. The assessment will evaluate erythema, pain, swelling, and pruritus at the injection site at approximately 15 
minutes post-injection.  If any reaction is apparent, the injection site will also be evaluated at 30 minutes post-injection.   
  


  
 
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4. DATA AND ANALYTICAL QUALITY ASSURANCE  
The overall quality assurance procedures for the study data, statistical programming and analyses 
are described in the Everest’s Standard Operating Procedures. Detailed data management 
procedures are documented in the Data Management Plan, Data Validation Check Specifications, 
and Data Review Plan. Detailed statistical and programming quality control and quality assurance 
procedures are documented in the Statistical Analysis and Programming QC/QA Plan.   
5. ANALYSIS POPULATIONS  
5.1 
Safety Population  
Safety population includes all subjects receiving at least one dose of the investigational medicinal 
product (IMP). Safety analyses will be conducted on the safety population according to the 
treatment received.   
5.2 Intent-to-Treat (ITT) Population  
The Intent-To-Treat Population (ITT) will consist of all subjects who were randomized and receive 
at least 1 dose of IMP. The ITT population will be the primary analysis for efficacy assessments. 
Efficacy analyses will be conducted on the ITT Population according to the treatment group to 
which the subjects were randomized.  
5.3 Per-Protocol (PP) Population  
The Per-Protocol Population (PP) will consist of all randomized subjects receiving at least one 
dose of the IMP without major protocol violations/deviations. The list of major protocol 
violations/deviations will be identified by the Sponsor prior to final database lock for the study that 
would lead to exclusion from the PP analysis. The PP population will be a sensitivity analysis to 
the ITT analysis for efficacy assessments.  If there are no major deviations which exclude data 
from the PP population, the PP analysis will not be reported.    
6. SPECIFICATION OF ENDPOINTS AND VARIABLES  
6.1 
Demographic and Baseline Characteristics  
Demographic variables consist of the following:  
• 
Age in years (continuous) derived as the integer of (informed consent date – date of birth +  
1)/365.25  
• 
Gender  


  
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• 
Race  
• 
Ethnicity  
Baseline characteristics consist of the following:  
• 
Weight (kg)   
• 
Height (cm)   
• 
BMI (kg/m²) derived as   
• 
weight in kg divided by (height in m)²   
• 
Vital signs (heart rate, systolic blood pressure, diastolic blood pressure, and temperature 
[oral or tympanic])  
• 
Physical cardiovascular examination (any clinically significant abnormalities (yes, no))  
• 
Medical and surgical history   
• 
Prior medications  
6.2 
Efficacy  
The effect of multiple SC doses of elamipretide on left ventricular end systolic volume is assessed 
using the change in LVESV between Baseline and Week 4.    
6.2.1 
Study Day and Visit Window Definitions  
The date the subject is randomized and is expected to receive the first dose of study medication 
will be used as the Study Day 1.   
Study day will be calculated as follows:  
Before study day 1: Study Day = date of assessment – date of study day 1.  
On or after study day 1: Study Day = date of assessment – date of study day 1 + 1.  
The last study date is the last visit date of any scheduled, unscheduled or early discontinuation 
visits. The last Study Day is calculated as:  
Last Study Day = last study date – date of study day 1 + 1.  
The target study days are summarized in Table 1 below:  
 
Table 1. Visit Windows for Efficacy Assessments  
 


  
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Scheduled  
Visit Number  
Visit (label)  
Time  
Interval  
(day)  
Target Time 
Point (day)  
0  
Screening  
-28 to -1  
-28 to -1  
1  
Baseline/Day 1  
1  
1  
2  
Week 1  
1 (postdose)  
to 11  
8  
3  
Week 2  
12 to 22  
15  
4  
Week 4  
23 to 36  
29  
5  
Week 6  
≥37  
43  
  
The baseline assessment is defined as the last assessment prior to the first dose of study 
medication. In some cases, these baseline measurements are obtained at the screening visit.   
If multiple assessments fall in the same visit window, the non-missing assessment closest to target 
time point will be selected for analysis.  Data obtained during unscheduled visits will be allocated 
to the scheduled visit corresponding to the visit window they fall in.  If an unscheduled visit is 
closer to the target time point than the scheduled visit, a blinded review will be done at the end of 
the study to determine which visit to use.  The choice will depend on how far off the scheduled 
visit occurred and what data was collected at each of the visits.  
6.2.2 
Primary Efficacy Variables  
The primary efficacy endpoint is change in LV ESV assessed by MRI at Week 4 from baseline.  
6.2.3 
Secondary Efficacy Variables  
Secondary efficacy endpoints are changes from baseline for the following measures:  
• 
LVEF and LV EDV assessed by MRI  
• 
The following parameters by echocardiography:  
o E/A (ratio between early and late mitral inflow velocity),  
o E/e' (Ratio between early mitral inflow velocity and mitral annular early diastolic 
velocity) o LV EDV, LV ESV and biplane ejection fraction (EF)  


  
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o LV global longitudinal strain  
o LA volume  
o LV mass  
o Mitral regurgitation severity o Tricuspid regurgitation severity o RV fractional area 
change o RV systolic pressure (RVSP)  
Change from baseline for the above MRI measures will be assessed at Week 1 (approximately 1 to 
6 hours following injection of study medication) and at Week 4, and for the echocardiography 
measures at Weeks 4 and 6.  
The measures of volume, LV ESV, LV EDV, LA volume, LV mass, RV ESV, RV EDV, and RV 
myocardial mass, will be indexed to body surface area (BSA) by dividing the measures by BSA.  
All analyses will be done on the indexed values.  Listings will include both indexed and 
nonindexed values.    
6.2.4 
Exploratory Efficacy Variables  
Exploratory efficacy endpoints are changes from screening for the following measures:  
• 
Distance walked (meters) during 6MWT  
• 
Levels of NT-pro-BNP  
• 
KCCQ score  
Change from baseline for the Distance walked measure will be assessed at Week 4, the levels of 
NT-pro-BNP measure at Weeks 1, 2, 4, and 6, and as an AUC for visits Baseline, Weeks 1, 2, 4, 
and 6, and for the KCCQ measure at Week 4.  
6.2.5 
Plasma Concentration  
Blood samples for PK determinations of elamipretide and metabolites (M1, M2) concentrations 
will be collected before administration of study medication and at 45 minutes ±15 minutes 
postdose at the Day 1, Week 1 and Week 2 visits, and at any time point at the Week 4 and Week 6 
visits.  
Plasma samples will be analyzed for MTP-131 concentrations using a validated liquid 
chromatography/ tandem mass spectrometry assay.   


  
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6.3 
Safety  
The safety profile of elamipretide will be assessed through the recording, reporting, and analyzing 
of AEs, clinical evaluations, and laboratory tests. Safety variables include the following:  
• 
Adverse events and serious adverse events  
• 
Local laboratory measurements – clinical chemistry and hematology with specific attention 
to Na+ and K+  
• 
Urinalysis  
• 
Vital signs  
• 
Electrocardiogram (ECG)  
• 
Physical examination  
• 
Pregnancy   
• 
Concomitant medications/treatments  
• 
Injection site reaction (ISR)  
6.3.1 
Study Day and Visit Window Definitions  
The term “Safety analysis period” is from the first dose of study medication to 30 days after the 
last dose of study drug.   
Study day is defined as in Section 6.2.1.   
The date at the first dose of study medication is used as Study Day 1. The target study days are 
summarized in Table 2 below:  
 
Table 2. Visit Windows for Safety Assessments   
Scheduled Visit 
Number  
Visit (label)  
Time Interval (day)  
Target Time Point 
(day)  
0  
Screening  
-28 to -1  
-28 to -1  
1  
Baseline/Day 1  
1  
1  
2  
Week 1  
1 (postdose) to 11  
8  
3  
Week 2  
12 to 18  
15  
4  
Week 4  
23 to 36  
29  
5  
Week 6  
>37  
43  
  


  
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Data obtained during unscheduled visits will be allocated to the scheduled visit corresponding to 
the visit window they fall in. If multiple assessments fall in the same visit window, the nonmissing 
assessment closest to target time point will be selected for analysis.  
Baseline values for clinical laboratory tests, vital signs and ECGs will be defined as the last 
evaluation performed prior to the first dose of study medication.  
6.3.2 
Extent of Exposure to Study Medication  
Elamipretide 4 mg or 40 mg, or Placebo (excipients used to manufacture the investigational drug 
but without the active drug substance) will be administered as a once daily SC injection for 28 
consecutive days.  
The study medication exposure variables include:  
• 
Study treatment exposure (days) = Treatment end date - treatment start date – number of 
days of missed doses + 1  
• 
Study treatment compliance (%) = Average over total time of exposure (Treatment start 
date to treatment end date):  
For each day:  
 
100 × Day X Total Volume ExpectedDay X Total Volume Injected   
  
  
The average calculation should include all days from the treatment start date to the treament end 
date, including days with missed doses.  
6.3.3 
Adverse Events  
The AE reporting period begins when the subject signs the ICF and continues through the clinical 
study’s post treatment follow-up period, defined as 14 days after last administration of study 
medication.  Within the study, all subjects who took at least 1 dose of IMP, whether they 
completed the treatment period or not, should enter the 14-day period as defined above.  If a 
subject is documented as lost-to follow-up, ongoing/unknown outcome AEs will not be 
followedup.  
Adverse events will be collected and coded using the latest version of the Medical Dictionary for  


  
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Regulatory Activities (MedDRA 19.1 or newer). An adverse event is considered 
treatmentemergent if the date of onset is on or after the date of first dose of study medication, or 
worsening during the treatment period (intensity/severity changed to worsen grades). All reported 
AEs will be listed, but only treatment-emergent adverse events (TEAEs) will be summarized. All 
adverse events are assessed by investigators on intensity, relationship to study drug, and 
seriousness according to the definitions in protocol Sections 9.7.1.1 and 9.7.1.2.  
Intensity:   
AEs will be rated as Mild, Moderate or Severe.  
Relationship to study  
AEs will be qualified as either related (unlikely, probably or 
drug:   
possibly related) or non-related (unrelated) to study drug. Seriousness:   
AEs 
will be categorized as serious or non-serious  
  
Adverse Events Counting Rules:  
1. A subject with more than one different adverse event in a particular system organ class 
(SOC) will be counted only once in the total of subjects experiencing adverse events in that 
particular SOC.   
2. A subject having experienced the same event (AE preferred term) more than once during 
the study will be counted only once in the number of subjects with that event.   
3. A subject having experienced the same event (AE preferred term) more than once during 
the study with a different intensity or seriousness, it will be counted only once with the 
worst grade and seriousness respectively.   
4. A subject having experienced the same event (AE preferred term) more than once during 
the study with a different causal relationship to the study drug, it will be counted only once 
by considering the most-related documented degree of relationship.  
Events with Irregular Start or End Dates:   
Partial dates may be imputed when appropriate. Imputed dates will be used to determine Study 
Day.  
If a partial date is reported for the start of an adverse event, a complete date will be estimated by 
the following algorithm:  
1. Only the year is reported: If the subject started receiving study medication in the previous 
year, then January 1 will be used as the starting date of the event. If the subject started 
receiving study medication in the year reported, then the date of the first dose of study 
medication will be used as the start of the event.   
2. The month and year is reported: If the subject started receiving study medication prior to 
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of the event. If the subject started receiving study medication during the month and year 
reported, then the date of the first dose of study medication will be used as the start of the 
event.   
If a partial date is reported for the end of an adverse event and the adverse event is not continuing, 
a complete date will be estimated by the following algorithm:   
1. Only the year is reported: If the subject started receiving study drug in the previous year, 
then the date of final study contact with the subject will be used as the end of the adverse 
event. If the subject started receiving study medication in the year reported, then the earlier 
of December 31 or the date of final study contact with the subject will be used as the end of 
the adverse event.   
2. The month and year reported: The earlier of the last date of the month or the date of final 
contact with the subject will be used as the end of the adverse event.   
The above rules are subject to logical sense (for example, imputed start date should be on or prior 
to imputed end date and vice-versa).  
6.3.4 
Laboratory Data  
Clinical laboratory tests on hematology, chemistry, urinalysis, and HF biomarkers will be 
performed according to the schedule in Section 3.6. Investigators will assess whether there are any 
clinically significant abnormalities and record the abnormality on medical and surgical history or 
adverse event forms. The lists of laboratory parameters collected are as follows:  
Hematology:   
• 
Hemoglobin  
• 
Hematocrit   
• 
Erythrocyte count (RBC)  
• 
Leukocytes (WBC)   
• 
Neutrophils, segmented   
• 
Lymphocytes   
• 
Monocytes   
• 
Eosinophils   
• 
Basophils   
• 
Platelets  
Clinical Chemistry (Serum Concentrations of):  
• 
Sodium  
• 
Potassium  


  
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• 
Total bilirubin  
• 
Alkaline phosphatase (ALP)  
• 
Alanine aminotransferase (ALT)  
• 
Aspartate aminotransferase (AST)  
• 
Blood urea nitrogen (BUN)  
• 
Creatinine  
• 
Calcium  
• 
Glucose, nonfasting   
• 
Albumin  
• 
Chloride  
• 
Bicarbonate  
• 
Total Protein  
• 
Triglycerides  
• 
eGFR calculated with the MDRD study equation  
• 
hsTroponin I Urinalysis:   
• 
Specific gravity   
• 
pH   
• 
Protein  
• 
Glucose  
• 
Ketones  
• 
Blood   
• 
Sodium  
• 
Chloride  
• 
Creatinine  
• 
Microalbuminuria HF Biomarker:  
• 
NT-pro-BNP  
Conversion to the International System of Units  
All laboratory data will be stored in the database with the units in which they are originally 
reported. Laboratory data in summary tables and subject data listings will be presented in the 
International System of Units (SI units; Système International d’Unités). Laboratory data not 
reported in SI units will be converted to SI units before further processing or data analysis.   
Abnormal Values  
Based upon laboratory normal ranges, laboratory test results will be categorized according to the 
normal range as low, normal and high. Subjects with laboratory data outside the normal range will 
be listed with abnormal values flagged.  


  
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6.3.5 
Vital Signs  
Vital signs include heart rate (beats per minute [BPM]), respiration rate, systolic and diastolic 
blood pressure (mmHg) and oral or tympanic temperature (oC). Vital signs will be collected at 
each scheduled visit.  
Baseline values are those measured at last evaluation prior to the first dose of study medication.  
Change from baseline to time point t, denoted Changet, will be calculated as:  
Changet = Valuet – ValueBaseline.  
6.3.6 
Electrocardiogram (ECG)  
Baseline ECGs will be defined as the last evaluation performed prior to the first dose of study 
medication. Electrocardiogram results (normal versus abnormal), intervals of HR, PR, QRS, QT, 
and RR in msec are reported on eCRF at screening, Day 1 (Baseline), Week 1, Week 2, Week 4, 
and Week 6.  The Fridericia corrected QT interval (QTcF) will be calculated as: QTcF = 
QT/(RR)⅓.    
6.3.7 
Physical Examination  
A cardiovascular physical examination, including lung auscultation and weight, will be measured 
at screening, Day 1 (Baseline), Week 1, Week 2, Week 4, and Week 6.  Height will only be 
measured at the Screening Visit.  
The results of the physical examination with any clinical significant abnormalities (yes/no) are 
reported on the eCRF.   
6.3.8 
Pregnancy Test  
All pregnancies with an estimated conception date that occurred during the AE reporting period, as 
defined in Section 6.3.3, must be recorded in the AE section of the eCRF. For this study, this 
applies to pregnancies in female subjects and in female partners of male subjects.  
6.3.9 
Concomitant Medications/Treatments  
Prior and concomitant medications will be recorded at Screening and during the study. Prior 
medication is defined as any medication taken before the first dose of the IMP. Concomitant 


  
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medication is defined as any medication taken during the study between the date of the first dose 
of IMP and the last study date of the subject. Any medications started after the last study date of 
the subject will not be considered concomitant medications.  
All relevant information, including reason for use, dose, frequency and route, will be recorded for 
any medication administered or received prior and during the study.  
Summaries of all concomitant therapies taken during the course of the study will be presented in 
tabular form using Anatomical Therapeutic Chemical 3 classification codes and preferred drug 
name via the World Health Organization Drug Dictionary (WHO-DD) with latest version to be 
specified in the Clinical Study Report.   
All medications will be summarized by treatment group and sorted alphabetically by medication 
class and medication subclass. For the summary tables, if a subject has taken a concomitant 
medication more than once, the subject will be counted only once in the total.  
The concomitant medication listing will be reviewed as part of the identification of protocol 
deviations to identify subjects who took medications which may affect the efficacy of the study 
drug.  Medications of interest include beta blockers, ACE or ARBS, Spironolactone, diuretics 
(specifically furosemide), and oral long acting nitrates.    
Medications with Incomplete Dates:   
For medications with incomplete dates, imputation will be used to convert to a complete date. 
Imputed dates will be used to determine Study Day.  
Partial medication start dates will be imputed as follows:   
1. Only the year is reported: If the subject started to receive study drug in the year reported, 
then the date of the first dose of study drug will be used as the starting date of the 
medication. Otherwise, January 1 will be used as the start of the medication.  
2. The month and year is reported: If the subject started to receive study drug during the 
month and year reported, then the date of first dose of study drug will be used as the 
starting date of the medication. Otherwise, the first day of the month will be used as the 
start of the medication.  
Partial medication end dates will be imputed for non-ongoing medications as follows:   


  
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1. Only the year is reported: If the subject stopped to receive study drug in the year reported, 
then the date of the last dose of study drug will be used as the end date of the medication. 
Otherwise, December 31 will be used as the end of the medication.   
2. The month and year is reported: If the subject stopped to receive study drug during the 
month and year reported, then the date of last dose of study drug will be used as the end 
date of the medication. Otherwise, the last day of the month will be used as the end of the 
medication.  
The above rules are subject to logical sense (for example, imputed start date should be on or prior 
to imputed end date and vice-versa).  
7. STATISTICAL ANALYSIS  
7.1 
General Data Handling Rules and Definitions  
All data collected on case report forms will be provided in listings, except data collected only for 
confirmation of study entry criteria and for study administrative purposes. If any randomized 
subject is found to not have valid documented informed consent, the subject’s data will be 
excluded from the report, except as necessary to document the error.   
Except where specified all continuous variables will be summarized with descriptive statistics (the 
number of non-missing values, mean, standard deviation, median, minimum and maximum) and 
all categorical variables will be summarized with frequency counts and percentages, by treatment 
group. Unless otherwise specified, the mean and median will be displayed to one more decimal 
place than the original data, and standard deviation and standard error of the mean should be 
displayed to two more decimal place than the original data. All percentages for frequencies will be 
rounded to 1 decimal place.   
When statistical hypothesis testing is performed, the treatment comparison will be two-sided and 
tested at an alpha=0.05 level of significance. Although, this provides for experiment-wise alpha at 
the strict 0.05 level, for the primary endpoint (LV ESV), significant results on LV EF would also 
be considered positive.  In addition, if both endpoints are statistically significant at the 0.10 level 
of statistical significance, the study will similarly be considered positive.  This effectively 
implements a Hochberg’s adjustment for a primary endpoint family (of LV ESV and LV EF) at the 
0.10 family-wise alpha-level.        


  
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Missing data will be maintained as missing unless specified otherwise. For variables where 
missing data is imputed, the analysis dataset will contain one variable with the imputed value and 
the original variable with missing maintained as missing.   
7.2 
Subject Disposition  
Subject disposition summaries will include the number of subjects randomized and the numbers 
included in the Safety, ITT, and Per-Protocol populations by treatment group for all subjects. The 
number and percentage of subjects who complete or discontinue from the study will be 
summarized by reason for discontinuation for each treatment group.  
The frequency distribution of the extent of subject participation in the study (last study date – 
randomization date – number of days of missed doses + 1) will be provided by treatment group for 
all randomized subjects.   
7.3 
Demographic and Baseline Characteristics  
Subject’s age, gender, race, ethnicity, weight, height, BMI, and baseline characteristics, vital signs, 
cardiovascular physical examination results (any clinically significant abnormalities (yes, no)), and 
ischemic/non-ischemic status will be summarized by treatment group and for all subjects in the 
Safety, ITT, and Per-Protocol populations. The medical and surgical history will be listed.  
7.4 
Efficacy Analyses  
Efficacy analyses will be conducted on the ITT population, along with the Per-Protocol population 
for sensitivity; according to the treatment the subjects were assigned.  
Since imaging may be performed after a clinic visit there will be an allowable 5 day window from 
the clinic visit.  Any imaging that is collected more than 5 days after the clinic visit will not be 
included in the analysis.  
7.4.1 
Primary Efficacy  
The primary efficacy endpoint is change in LV ESV assessed by MRI at Week 4 from baseline.  
Actual values and change from baseline values will be summarized by treatment group in the ITT 
and Per-Protocol populations. Mean change in LV ESV measurements of all three treatment 
groups together will be analyzed using a mixed-effect model for repeated measures (MMRM), in 
order to study trends in the treatment effects over 4 weeks, with the primary time point of interest 


  
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being at Week 4.  The model will include treatment (4 mg elamipretide, 40 mg elamipretide, 
placebo), visit (week numbers), treatment-by-visit interaction, and ischemic/non-ischemic as fixed 
effects, baseline LV ESV and baseline LV ESV by visit interaction as covariates, and subject as a 
random effect. An unstructured covariance matrix will be used to model the covariance of 
withinpatient results.  The Kenward Roger method will be used to compute the denominator 
degrees of freedom.  All LV ESV data at Week 1 and Week 4 will be included in the MMRM 
model. All pairwise comparisons among treatment groups for change from baseline in LV ESV 
and the corresponding 2-sided 95% confidence interval (CI) will be calculated based on the 
MMRM model for each visit.  In addition a linear contrasts (at each visit) will be constructed to 
test for trend over dose levels, such that differences in contrast coefficients are proportional to 
differences in dose level (0 mg, 4 mg and 40 mg).      
The primary comparison for the primary analysis involves the comparison of 40 mg elamipretide 
vs. placebo at Week 4.  This provides for experiment-wise alpha at the strict 0.05 alpha-level for 
this comparison, only.    
Nevertheless, a failure of the primary comparison for the primary endpoint will not automatically 
be considered a “failed study” for internal decision making, where the decision will necessarily be 
made based on the totality of the data.  Accordingly, nominal significance on key secondary 
endpoints (such as LV EF) or even strong trends in a preponderance of endpoints with key 
secondary endpoints significant at a slightly inflated alpha-level of, say, 0.10, may be considered 
sufficient for progression of the compound in this indication, despite an outcome not generally 
considered to represent “substantial evidence of effectiveness”.           
The normality and homogeneity of variances assumptions will be checked graphically by residual 
plot. If these model assumptions fail despite data transformation (e.g. log) a non-parametric 
approach (e.g. Kruskal-Wallis test) may be used.    
7.4.2 
Secondary Efficacy  
Secondary analyses to address the secondary objective will include comparisons in change from 
baseline between treatment groups for the following endpoints. The MRI endpoints will be 
analyzed in the same manner as the primary efficacy measures. The model will include the same 
terms as for the primary analysis, but will include the baseline (pre-treatment) assessment of the 
same endpoint. The echocardiography endpoints (except those endpoints noted below) will be 
analyzed with the same MMRM model as the primary endpoint, with the exception that Week 4 


  
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and Week 6 (two week post-treatment follow-up visit) will be included in the model (instead of 
Week 1 and Week 4). The model will include the same terms as for the primary analysis, but will 
include the baseline (pre-treatment) assessment of the same endpoint.  Due to the high degree of 
measurement error associated with echocardiography measurements, only descriptive statistics will 
be produced for select echocardiography parameters as described below.   
Secondary Endpoints Assessed by MRI:  
o 
LVEF  o LV EDV  o LVSV  
o 
LVCO  
o 
LV myocardial mass  o RV ESV o RV EDV  
o 
RVEF  
  
Secondary Endpoints Assessed by Echocardiography:  
o 
E/A (ratio between early and late mitral inflow velocity),  
o 
E/e' (Ratio between early mitral inflow velocity and mitral annular early diastolic 
velocity)  
o 
LA volume o LV GLS  
The following secondary endpoints assessed by echocardiography with descriptive statistics only:  
o 
LV EDV o LV ESV  o LVEF (biplane)  
o 
LV mass  
o 
Mitral regurgitation severity  
o 
Tricuspid regurgitation severity o RV fractional area change o RV systolic 
pressure (RVSP)  
7.4.3 
Exploratory Efficacy  
Exploratory analyses to address the exploratory objective will include comparisons in change from 
baseline between treatment groups for the following endpoints. hsTroponin and the log of NT-
proBNP levels will be analyzed in the same manner as the primary efficacy measures, with a 
MMRM model.  The distance walked (meters) during 6MWT and the KCCQ score only have one 
postbaseline assessment so they will not be analyzed as repeated measures.  Instead, the change 


  
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from baseline of these two endpoints will be analyzed with an ANCOVA model.  The model terms 
will include terms for treatment, baseline (pre-treatment) value, and ischemic/non-ischemic. 
Treatment difference estimates using least square means along with the 95% confidence intervals 
for the estimates will be presented for scheduled visits. The difference in mean change from 
baseline between the elamipretide treatment groups and placebo will be tested at a 2-sided 
significance level of 0.05.  
• 
Distance walked (meters) during 6MWT  
• 
Levels of NT-pro-BNP (log transformed)  
• 
KCCQ score  
Additionally, the LV myocardial mass, LV stroke volume, LV cardiac output, RV end systolic 
volume, RV end diastolic volume, RV myocardial mass, and the RV ejection fraction, assessed by 
MRI, will be analyzed in the same manner as the primary efficacy measures, including 
comparisons in change from baseline between treatment groups.    
7.4.4 
Efficacy Subgroup Analyses  
The primary efficacy endpoint, change in LV ESV assessed by MRI at Week 4 from baseline, will 
be summarized by treatment group for subgroups of subjects with baseline ischemic/non-ischemic 
status, high versus low baseline hsTroponin,  subgroups of baseline NT-pro-BNP levels.  The 
values of the endpoint for the subgroups will also be plotted by treatment group over time for  
Screening, Week 1, and Week 4.  The analyses and plots will be done using the ITT population.    
7.5 
Plasma Concentration Analyses  
Plasma concentration analyses will be conducted on the Safety population. Plasma samples will be 
analyzed for elamipretide, M1, and M2 concentrations.  No formal statistical analyses will be 
performed.  
Individual concentration time data for elamipretide will be listed, sorted by subject, and 
summarized for each nominal time point (as determined by nominal hour).   
The plasma concentration data for elamipretide, M1, and M2 at each time point will be listed and 
summarized for the safety population. Descriptive statistics will include the number of 
observations (n), mean, standard deviation, coefficient of variation, median, minimum, maximum, 
geometric mean, and geometric coefficient of variation.  


  
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The plasma concentration-time profiles for individual and mean (+/-SD) plasma concentrations of 
elamipretide, M1, and M2 will be presented on both linear/linear and semi-logarithmic (log/linear) 
scales. For individual profiles, three figures will be presented with all individual profiles, one each 
for elamipretide, M1, and M2, superimposed on a same profile panel. For the mean linear-linear 
and semi-logarithmic profiles, three figures will be created with the mean concentrations of 
elamipretide, M1, and M2 at each nominal time-point for all subjects displayed.  
7.6 
Safety Analyses  
Except where otherwise specified, safety analyses will be performed using the safety population. 
Safety measurements will include AEs, clinical laboratory tests (i.e. serum chemistry, hematology, 
urinalysis, and hsTroponin), ECGs, physical exams and vital signs. All safety data will be 
summarized by treatment group. Baseline values for clinical laboratory tests, vital signs and ECGs 
will be defined as the last evaluation performed prior to administration of study drug.  
7.6.1 
Extent of Exposure to Study Medication  
The following study medication exposure variables as listed in Section 6.3.2 will be summarized 
by treatment groups.  
• 
Study treatment exposure (days)  
• 
Study treatment compliance (%)  
Study medication dosing information will be listed by subject.  
7.6.2 
Adverse Events  
All AEs will be coded to system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA version 19.1 or newer) coding dictionary (version 
to be specified in the clinical study report). All reported AEs will be listed, but only 
treatmentemergent adverse events (TEAEs) will be summarized.  
Frequency and percentage of subjects experiencing a specific adverse event will be tabulated by 
system organ class, preferred term, and treatment group. Summary tables will be provided for 
adverse events by maximum intensity, relationship to study drug, serious adverse events, and 
adverse events causing discontinuation of study medication.  
The incidence of all TEAEs, drug relationship with TEAEs, and severity of TEAE will be 
summarized by treatment group and all subjects in the safety population with frequencies and 


  
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percentages. In the summary tables, subjects may be counted under multiple SOCs and PTs, but 
for each SOC and PT, subjects are only counted once. If a subject has the same AE on multiple 
occasions, the highest intensity (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 Grade 3 (for severity). If drug relationship is missing, 
subjects will be included in related tables (i.e., considered related). Summary tables will be sorted 
by SOC, and then PT.   
The following summaries will be presented for TEAEs:   
1. Summary of Adverse Events by Treatment Group;  
2. Incidence of Adverse Events by System Organ Class and Preferred Term;  
3. Incidence of Serious Adverse Events by System Organ Class and Preferred Term;   
4. Incidence of Adverse Events by System Organ Class, Preferred Term and Intensity;   
5. Incidence of Study Drug Related Adverse Events by System Organ Class, Preferred Term 
and Intensity;   
6. Incidence of Adverse Events by System Organ Class, Preferred Term and Relationship to 
Study Drug;   
7. Incidence of Adverse Events Leading to Discontinuation of Study Drug by System Organ 
Class and Preferred Term  
7.6.3 
Deaths  
Summary of deaths will be provided as a listing, displaying treatment group, date of death, study 
day of death and reason for death.   
7.6.4 
Clinical Laboratory Evaluations  
Summary tables for laboratory parameters (including hematology, chemistry, urinalysis, and 
hsTroponin) will include descriptive statistics for values and change from baseline for all 
continuous variables for each treatment group. Subjects with laboratory data outside the normal 
range will be listed with abnormal values flagged.  
Shift tables (i.e., tables that show the number of subjects who are low, normal, or high at baseline 
versus each post-baseline scheduled assessment, Section 3.6) will be produced.  
The number and percentage of subjects with urinalysis results outside the normal range will be 
presented by parameter and time point for each treatment group. Shift tables for urinalysis will 


  
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show the number of subjects who are normal/abnormal at baseline and normal/abnormal at the end 
of study.  
Laboratory test reference ranges, flags for values outside of the normal ranges, as well as 
investigators assessment of these values as non-clinically or clinically significant are all displayed 
in subject data listings by treatment group and measurement time point for all subjects from the 
safety population.  
7.6.5 
Vital Signs  
Vital sign changes from baseline tables will be summarized by treatment group and visit time 
point. Listing of vital signs will be provided for all subjects in the safety population.  
7.6.6 
Electrocardiogram (ECG)  
ECG changes from baseline tables will be summarized by treatment group and visit time point, and 
a subgroup table for low and high QRS interval duration. ECG 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 HR, PR, QRS, QT, and QTc will 
also be listed.  Patients who have either an increase of >60 msec between baseline and end of 
treatment in their QT or an absolute QT value >500 msec at any point in time during the study will 
be listed separately.  
7.6.7 
Physical Examination  
The number and percentage of subjects experiencing clinically significant abnormalities (yes, no, 
not done) in the cardiovascular physical examination will be tabulated at every visit by treatment 
group and for all subjects combined. The number and percentage of subjects experiencing 
clinically significant abnormalities (yes, no, not done), and the weight, height, and BMI, in the 
physical measurements will be summarized at every visit by treatment group and for all subjects 
combined. Physical examinations results will be presented in individual subject data listings.   
7.6.8 
Concomitant Medications/Treatments  
The number and percentage of subjects have reported concomitant therapies during the course of 
the study will be tabulated by using Anatomical Therapeutic Chemical 3 classification codes and 
preferred drug name via the World Health Organization Drug Dictionary (WHO-DD) in latest 
version (version 3Q2016 WHODRUG DDE in addition to WHODRUG HD, or later), with version 
to be specified in the Clinical Study Report.   


  
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All medications will be summarized by treatment group and sorted alphabetically by medication 
class and medication subclass. For the summary tables, if a subject has taken a concomitant 
medication more than once, the subject will be counted only once in the total.  
All prior and concomitant medication data will be presented in individual subject data listings.  
8. ANALYSES PERFORMED BEFORE DATABASE CLOSURE  
No interim analyses are planned for this study.  
9. CHANGES FROM METHODS PLANNED IN THE PROTOCOL   
Any changes to methods planned in this statistical analysis plan will be documented in a revision 
to this statistical plan prior to database lock, or identified in the clinical study report.  
10. STATISTICAL SOFTWARE  
The statistical software to be used for generation of the tables, listings, and figures is SAS® 
version 9.3 or higher.  
11. REFERENCES  
  
  
APPENDIX 1  
DATA HANDLING RULES  
Category  
Description  
Data Handling Rules  
Demographics  Age at informed 
consent  
Age = integer ((date of informed consent signed – date of 
birth+1)/365.25)  
For some sites (Italy and U.K.) only month and year of birth 
are collected, and day of birth is imputed as the 1st of the 
month.   
For some sites (Netherlands) only year of birth is collected, and 
day and month of birth are imputed as the 1st of January. This 
same imputation rule will apply for all missing day of birth to 
the 1st of the month, and month of birth to January.  
Baseline  
Baseline assessment  
Baseline assessment is defined as last assessment prior to first 
dose of study medication.  
Timing  
Study Day 1  
Date subject is randomized and expected to receive the first 
dose of study medication.  


  
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Timing  
Study Day   
Before study day 1: study day = date of assessment – date of 
study day 1.  
On or after study day 1: study day = date of assessment – date 
of study day 1 + 1.  
Timing  
Day 1 and Hour 0  
The date and time at first dose of study medication.  
Timing  
Time from first dose of 
study medication  
The time from first dose of study medication = time of 
assessment – time of first dose of study medication.  
  
Outcome 
measures/Vita 
l Signs/Lab  
Change from baseline  
Changet = Value t – ValueBaseline.  
  
Exposure  
Extent of study drug 
exposure  
Extent of exposure to study medication (days) = Treatment end 
date – treatment start date  – number of days of missed doses + 
1.  
  
APPENDIX 2  
SAS CODE FOR STATISTICAL ANALYSES  
The following table presents the SAS code for the statistical analyses. This section will be finalized 
after examining the existing data and prior to the final signoff of this SAP.  
  
Test  
Table/Figure  
SAS Codes   
MMRM with  
baseline value as 
covariate  
Primary and secondary 
MRI and exploratory 
endpoints-  requiring 
MMRM  
proc mixed;    
  class treatment timepoint patient;   
model cfb = treatment baseline timepoint  
baseline*timepoint treatment*timepoint ischemic / residual 
ddfm=kenwardroger;  ** cfb is change from baseline **;   
repeated timepoint / type=un subject=patient;   lsmeans 
treatment*timepoint / pdiff cl;   run;  
ANCOVA with  
baseline value as 
covariate  
Secondary and  
Exploratory endpoints 
requiring ANCOVA  
proc glm;   class 
treatment;  
  model cfb = treatment baseline baseline_MRI ischemic;  
**cfb is change from baseline;   
lsmeans treatment  / cl pdiff;   run;  


  
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Linear trend test  
for MMRM 
models  
Primary, and 
secondary MRI, and 
exploratory endpoints-  
requiring MMRM  
proc mixed;  
  class treatment timepoint patient;   model cfb = 
treatment baseline timepoint baseline*timepoint 
treatment*timepoint ischemic;  
  **A contrast 'linear trend test' will involve the following 
coefficients to test treatment effects at each visit -0.470757  
-0.342368 0.8131249;   
** coefficients calculated from SAS PROC IML; ** in 
order of placebo, 4, 40; If treatment=3 is placebo, code 
treatment as 0 so placebo will go first. Coefficients are 
applied to estimates of treatment effect for each 
treatment group at each visit, which will consist of main 
effect and interaction terms, specific for the visit under 
consideration. run;  
Linear trend test 
for ANCOVA 
models  
Secondary and  
Exploratory endpoints 
requiring ANCOVA  
proc glm;   class 
treatment;  
  model cfb = treatment baseline baseline_MRI ischemic;   
contrast 'linear trend test' treatment -0.470757 -0.342368  
0.8131249;   
** coefficients calculated from SAS PROC IML; ** in 
order of placebo, 4, 40; If treatment=3 is placebo, code 
treatment as 0 so placebo will go first. run;  
APPENDIX 3  
REFERENCE RANGES AND CLINICALLY RELEVANT CHANGES 
FROM BASELINE FOR MARKED LABORATORY ABNORMALITIES  
Not applicable.  
 


  
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APPENDIX 4  
MOCKUP TABLES, LISTINGS, AND GRAPHS (TLGS)  
Mockup tables, listings, and graphs are presented in a separate document.  
  


  
  
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SPECIFICATION OF END OF TEXT STANDARD  
OUTPUT TABLES, LISTINGS, AND FIGURES   
(TLFs)  
  
  
  
Trial Sponsor:   
Stealth BioTherapeutics, Inc.  
  
Protocol Number:  
SPIHF-201 IND Number:  N/A EUDRACT Number:  2014-005724-10  
Investigational Drug:  
Elamipretide™ (MTP-131)  
Indication:  
Heart Failure with reduced Ejection Fraction 
(HFrEF)  
Dosage Form/Strength: Elamipretide™ (MTP-131) 40 mg/1 mL of 
sterile solution for subcutaneous injection 
with doses of 4 mg or 40 mg administered 
as a once daily SC injection  
  
  
Protocol Title: A Phase 2 Randomized, Double-Blinded, Placebo-Controlled Study to  
Evaluate the Effects of Multiple Subcutaneous Injections of Elamipretide on Left Ventricular 
Function in Subjects with Stable Heart Failure with Reduced Ejection Fraction  
  
  
_____________________________________________________________________________________  
The information in this document is confidential and is proprietary to Stealth Biotherapeutics. It is understood that 
information in this document shall not be disclosed to any third party, in any form, without prior written consent of an 
authorized officer of Stealth Biotherapeutics.  
  
  
  
  
CHANGE LOG FOR CHANGES MADE AFTER THE INITIAL APPROVAL  
  


  
  
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Revision  
Date**  
  
Section(s)  
Modified  
  
Brief Description of Revision(s) or 
Reason(s) for Revision  
Modifications Reviewed and 
Approved by*  
Sponsor, Everest  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
*   Provide person’s initial and last name. ** Update the Last Revision Dates 
on the cover page and the document header.  
  
  
  
 


  
  
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General Instructions for End-of-Text TFLs  
  
Following are the specifications for end-of-text standard tables, figures and listings (TFLs).  
  
Header  
The following header should appear at the very top of each page of a table, a figure, or a listing (TFL):  
  
Stealth Protocol SPIBioTherapeuticsHF-201  
, 
Inc. ElamipretidePage n of N 
TM (MTP-131 for SC Injection)  
  
Footer  
The following footer should appear at the bottom of each page of a TFL generated in SAS:  
  
Program: /sasdir/pgname.sas   
  
  
  
  
Version 2014-01-25 13:37     
  
where: PGNAME = SAS program name. Version will be replaced by “Draft” or “Final”.  
  
Title  
At least three (3) lines should be reserved for the whole title. The first line is for the TFL number (i.e., title 
index #); the second line is for the actual title (title); and the third line is reserved for the analysis population 
descriptor (population). All titles should be centered, as shown in the following example:  
  
Table 1.1  
Demographics  
Safety Population  
  
Footnotes  
In general, a footnote serves as a brief explanation/clarification/definition/concept of a flag symbol or a 
character, an abbreviation, a terminology, etc., that appears in, or related directly to the displayed content of 
a TFL. Detailed/technical elaboration of, for example, a mathematical/statistical formula, a statistical 
term/test, or an algorithm for deriving a parameter value, should be addressed in the text of the statistical 
analysis plan (SAP).  
All footnotes should follow immediately after a horizontal solid line. There should be one and only one space 
between the last footnote and the footer.   
When an abbreviation (e.g., TEAE, SAE, etc.) appears for the first time in the entire set of TFLs for a study, 
a footnote should be provided at least once;  it is up to the Study Biostatistician, Scientist, and Study 
Programmer to decide whether there is a need to repeat the same footnote for the rest of TFLs (if 
applicable).   
Each line of a complete footnote should end with a period. When a footnote needs more than 1 line, one (1) 
period is needed.  


  
  
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Footnotes should be in the format shown in the following example:    
<abbreviations> <notes>  
[a]  
[b]  
[c]  
Source: Listings 2.1.1, 2.1.2, 2.3  
  
Page Layout   
All output should be in landscape orientation.   
All efforts should be made to present all treatment groups in one page.  
The Scientist and Study Biostatistician will pre-determine the order for the display of the treatment groups.   
  
Page Format  
There should be a solid line at the top of the tables and listings just below the title.  
There should be a solid line just below the column headings that runs completely across the width of the 
tables and listings.  
There should be a solid line at the bottom of the tables and listings just above the footnote(s) on every page.  
  
Font  
The default font to be used in the actual study tables/listings should be Courier New 8 point which is 
approximately equivalent to the acceptable font size of Times New Roman 9-10 in accordance with the 
FDA’s guidance on Electronic Common Technical Document Specification.   
  
Descriptive Statistics  
By default, descriptive statistics in this template covers: n, mean, median, standard deviation (SD), 
minimum (min), and maximum (max). Unless otherwise specified in the actual table shells, the mean and 
median should be displayed to one more decimal place than the original data, and standard deviation and 
standard error of the mean should be displayed to two more decimal place than the original data.  
  
Rounding for Percentage  
All percentages will be rounded to 1 decimal place in all TFLs.  P-values 
will be presented with 4 decimal places.  
  
Alignment of Decimals  
It is recommended that all the decimal places be aligned in summary tables, as shown in the following 
example:  
  


  
  
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Decimal Align 
n  
xxx  
Mean  
xx.xx  
SD  
xx.xxx  
Median  
xx.xx  
Min, Max  
xx.x, xx.x  
  
When numbers with decimal points are included in brackets (e.g., percentages), the brackets should be 
aligned to the right and then padded to allow for all possible percentages and then the left brackets will also 
be aligned. For example:  
  
Brackets Align  
(99.9%) (xx.x%)  
( 9.9%) ( x.x%)  
   
It is recommended that all column entries in a summary tables and listings are aligned to the center.  
Columns for text fields are all left justified. Columns with whole numbers are all right justified. For 
graphs, the lines are distinguishable and that the symbols for each line are appropriate. Legend is 
consistent across output for treatment names and abbreviations.  
   
Use of N Versus n  
N = total number of subjects in the defined analysis set.  n 
= total number of subjects in the specific category.  
If N is specified in the column heading then any reference to the number of subjects in the body should be 
small n, as shown in the following example:  
  
Demographic Parameter  
Treatment  
Group A  
(N = xxx)  
Treatment  
Group B  
(N = xxx)  
Total  
(N = xxx)  
  
Age (years) n  
Mean SD  
Median  
Min, Max  
 xx 
xx.x 
x.xx 
xx.x 
xx, xx  
 xx 
xx.x 
x.xx 
xx.x 
xx, xx  
 xx 
xx.x 
x.xx 
xx.x 
xx, xx  
  
A Note for Subject Data Listings  
Observed Dates/AE Severity/Relationship to investigational product are used in subject data listings.  
Observed values or raw assessment scores are used in data listings along with their derived values used in 
analyses, e.g., raw assessment scores and derived total scores.  
  
  
TABLE OF CONTENTS FOR TABLES, FIGURES AND LISTINGS  


  
  
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1. 
SUBJECT DISPOSITION ............................................................................................................. 19 
Table 1.1 ........................................................................................................................................ 19  
Subject Disposition  
All Randomized Subjects  
Table 1.2 ........................................................................................................................................ 20  
Extent of Participation in the Study  
All Randomized Subjects  
2. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ....................................................... 21  
Table 2.1a ....................................................................................................................................... 21  
Demographic and Non-Imaging Baseline Characteristics  
Safety Population  
Table 2.1b ...................................................................................................................................... 25  
Baseline Characteristics from MRI  
Safety Population  
Table 2.1c ....................................................................................................................................... 27  
Baseline Characteristics from Echocardiography Safety 
Population  
Table 2.2a ....................................................................................................................................... 29  
Demographic and Non-Imaging Baseline Characteristics ITT 
Population  
Table 2.2b ...................................................................................................................................... 29  
Baseline Characteristics from MRI ITT 
Population  
Table 2.2c ....................................................................................................................................... 29  
Baseline Characteristics from Echocardiography ITT 
Population  
Table 2.3a ....................................................................................................................................... 29  
Demographic and Non-Imaging Baseline Characteristics  
Per-Protocol Population  
Table 2.3b ...................................................................................................................................... 29  
Baseline Characteristics from MRI  
Per-Protocol Population  
Table 2.3c ....................................................................................................................................... 29  
Baseline Characteristics from Echocardiography Per-Protocol 
Population  
3. 
EFFICACY ANALYSIS ............................................................................................................... 30  
3.1  
EFFICACY ANALYSIS ............................................................................................................... 31  
Table 3.1 ........................................................................................................................................ 31  
Summary of Change From Baseline in Left Ventricular End Systolic Volume (LV ESV),  
Assessed by MRI  
ITT Population  
Table 3.2 ........................................................................................................................................ 32 


  
  
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Summary of Change From Baseline in Left Ventricular End Systolic Volume (LV ESV),  
Assessed by MRI  
Per-Protocol Population  
Table 3.3 ........................................................................................................................................ 32  
Summary of Change From Baseline in Left Ventricular Ejection Fraction (LVEF), Assessed by 
MRI  
ITT Population  
Table 3.4 ........................................................................................................................................ 33  
Summary of Change From Baseline in Left Ventricular Ejection Fraction (LVEF), Assessed by 
MRI  
Per-Protocol Population  
Table 3.5 ........................................................................................................................................ 33  
Summary of Change From Baseline in Left Ventricular End Diastolic Volume (LV EDV),  
Assessed by MRI ITT 
Population  
Table 3.6 ........................................................................................................................................ 33  
Summary of Change From Baseline in Left Ventricular End Diastolic Volume (LV EDV),  
Assessed by MRI  
Per-Protocol Population  
Table 3.7 ........................................................................................................................................ 33  
Summary of Change From Baseline in Left Ventricular Stroke Volume (LVSV), Assessed by 
MRI  
ITT Population  
Table 3.8 ........................................................................................................................................ 34  
Summary of Change From Baseline in Left Ventricular Stroke Volume (LVSV), Assessed by 
MRI  
Per-Protocol Population  
Table 3.9 ........................................................................................................................................ 34  
Summary of Change From Baseline in Left Ventricular Cardiac Output (LVCO), Assessed by 
MRI  
ITT Population  
Table 3.10 ...................................................................................................................................... 34  
Summary of Change From Baseline in Left Ventricular Cardiac Output (LVCO), Assessed by 
MRI  
Per-Protocol Population  
Table 3.11 ...................................................................................................................................... 34  
Summary of Change From Baseline in Left Ventricular Myocardial Mass (LV Mass),  
Assessed by MRI ITT 
Population  
Table 3.12 ...................................................................................................................................... 35  
Summary of Change From Baseline in Left Ventricular Myocardial Mass (LV Mass),  
Assessed by MRI  


  
  
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Per-Protocol Population  
Table 3.13 ...................................................................................................................................... 35 
Summary of Change From Baseline in Right Ventricular End Systolic Volume (RV ESV),  
Assessed by MRI ITT 
Population  
Table 3.14 ...................................................................................................................................... 35  
Summary of Change From Baseline in Right Ventricular End Systolic Volume (RV ESV),  
Assessed by MRI  
Per-Protocol Population  
Table 3.15 ...................................................................................................................................... 35  
Summary of Change From Baseline in Right Ventricular End Diastolic Volume (RV EDV),  
Assessed by MRI ITT 
Population  
Table 3.16 ...................................................................................................................................... 35  
Summary of Change From Baseline in Right Ventricular End Diastolic Volume (RV EDV),  
Assessed by MRI  
Per-Protocol Population  
Table 3.17 ...................................................................................................................................... 36  
Summary of Change From Baseline in Right Ventricular Ejection Fraction (RVEF),  
Assessed by MRI ITT 
Population  
Table 3.18 ...................................................................................................................................... 36  
Summary of Change From Baseline in Right Ventricular Ejection Fraction (RVEF),  
Assessed by MRI  
Per-Protocol Population  
Table 3.19 ...................................................................................................................................... 36  
Summary of Change From Baseline in E/A (Ratio Between Early And Late Mitral Inflow  
Velocity), Assessed by Echocardiography ITT 
Population  
Table 3.20 ...................................................................................................................................... 36  
Summary of Change From Baseline in E/A (Ratio Between Early And Late Mitral Inflow  
Velocity), Assessed by Echocardiography  
Per-Protocol Population  
Table 3.21 ...................................................................................................................................... 37  
Summary of Change From Baseline in E/e' (Ratio Between Early Mitral Inflow Velocity and 
Mitral Annular Early Diastolic Velocity), Assessed by Echocardiography ITT Population  
Table 3.22 ...................................................................................................................................... 37  
Summary of Change From Baseline in E/e' (Ratio Between Early Mitral Inflow Velocity and  
Mitral Annular Early Diastolic Velocity), Assessed by Echocardiography  
Per-Protocol Population  
Table 3.23 ...................................................................................................................................... 37  


  
  
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Summary of Change From Baseline in Left Atrial Volume, Assessed by Echocardiography ITT 
Population  
Table 3.24 ...................................................................................................................................... 37  
Summary of Change From Baseline in Left Atrial Volume, Assessed by Echocardiography Per-
Protocol Population  
Table 3.25 ...................................................................................................................................... 38 
Summary of Change From Baseline in Left Ventricular Global Longitudinal Strain,  
Assessed by Echocardiography ITT 
Population  
Table 3.26 ...................................................................................................................................... 38  
Summary of Change From Baseline in Left Ventricular Global Longitudinal Strain,  
Assessed by Echocardiography  
Per-Protocol Population  
Table 3.27 ...................................................................................................................................... 39  
Summary of Change From Baseline in Left Ventricular End Diastolic Volume (LV EDV),  
Assessed by Echocardiography ITT 
Population  
Table 3.28 ...................................................................................................................................... 40  
Summary of Change From Baseline in Left Ventricular End Diastolic Volume (LV EDV),  
Assessed by Echocardiography  
Per-Protocol Population  
Table 3.29 ...................................................................................................................................... 40  
Summary of Change From Baseline in Left Ventricular End Systolic Volume (LV ESV),  
Assessed by Echocardiography ITT 
Population  
Table 3.30 ...................................................................................................................................... 40  
Summary of Change From Baseline in Left Ventricular End Systolic Volume (LV ESV),  
Assessed by Echocardiography  
Per-Protocol Population  
Table 3.31 ...................................................................................................................................... 40  
Summary of Change From Baseline in Biplane Ejection Fraction (EF), Assessed by  
Echocardiography ITT 
Population  
Table 3.32 ...................................................................................................................................... 41  
Summary of Change From Baseline in Biplane Ejection Fraction (EF), Assessed by  
Echocardiography  
Per-Protocol Population  
Table 3.33 ...................................................................................................................................... 41  
Summary of Change From Baseline in Left Ventricular Mass, Assessed by  
Echocardiography ITT 
Population  
Table 3.34 ...................................................................................................................................... 41  


  
  
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Summary of Change From Baseline in Left Ventricular Mass, Assessed by  
Echocardiography  
Per-Protocol Population  
Table 3.35 ...................................................................................................................................... 41  
Summary of Change From Baseline in Mitral Regurgitation Severity, Assessed by  
Echocardiography  
ITT Population  
Table 3.36 ...................................................................................................................................... 41 
Summary of Change From Baseline in Mitral Regurgitation Severity, Assessed by  
Echocardiography  
Per-Protocol Population  
Table 3.37 ...................................................................................................................................... 41  
Summary of Change From Baseline in Tricuspid Regurgitation Severity, Assessed by  
Echocardiography ITT 
Population  
Table 3.38 ...................................................................................................................................... 42  
Summary of Change From Baseline in Tricuspid Regurgitation Severity, Assessed by 
Echocardiography  
Per-Protocol Population  
Table 3.39 ...................................................................................................................................... 42  
Summary of Change From Baseline in Right Ventricular Fractional Area Change, Assessed 
by Echocardiography ITT Population  
Table 3.40 ...................................................................................................................................... 42  
Summary of Change From Baseline in Right Ventricular Fractional Area Change, Assessed 
by Echocardiography Per-Protocol Population  
Table 3.41 ...................................................................................................................................... 42  
Summary of Change From Baseline in Right Ventricular Systolic Pressure (RVSP),  
Assessed by Echocardiography ITT 
Population  
Table 3.42 ...................................................................................................................................... 42  
Summary of Change From Baseline in Right Ventricular Systolic Pressure (RVSP),  
Assessed by Echocardiography  
Per-Protocol Population  
Table 3.43 ...................................................................................................................................... 42  
Summary of Change From Baseline in Distance Walked (meters) During 6-minute Walking  
Test (6MWT)  
ITT Population  
Table 3.44 ...................................................................................................................................... 43  
Summary of Change From Baseline in Distance Walked (meters) During 6-minute Walking Test 
(6MWT)  
Per-Protocol Population  
Table 3.45 ...................................................................................................................................... 43  


  
  
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Summary of Change From Baseline in Levels of NT-pro-BNP ITT 
Population  
Table 3.46 ...................................................................................................................................... 44  
Summary of Change From Baseline in Levels of NT-pro-BNP  
Per-Protocol Population  
Table 3.47 ...................................................................................................................................... 44  
Summary of Change From Baseline in Levels of hsTroponin  
ITT Population  
Table 3.48 ...................................................................................................................................... 44 
Summary of Change From Baseline in Levels of hsTroponin  
Per-Protocol Population  
Table 3.49 ...................................................................................................................................... 45  
Summary of Change From Baseline in Kansas City Cardiomyopathy Questionnaire 
(KCCQ) Overall Summary Score ITT Population  
Table 3.50 ...................................................................................................................................... 45  
Summary of Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ)  
Overall Summary Score  
Per-Protocol Population  
4. 
PLASMA CONCENTRATION ANALYSIS ................................................................................ 46  
Table 4.1 ........................................................................................................................................ 46  
Summary of Plasma Concentrations of Elamipretide and Metabolites (M1, M2)  by Time  
Point  
Safety Population  
5. 
EXTENT OF EXPOSURE TO STUDY MEDICATION ............................................................. 48  
Table 5.1 ........................................................................................................................................ 48  
Extent of Exposure to Study Medication by Treatment Group Safety 
Population  
6. 
ADVERSE EVENTS ..................................................................................................................... 49  
Table 6.1 ........................................................................................................................................ 49  
Overall Summary of Treatment-Emergent Adverse Events by Treatment Group Safety 
Population  
Table 6.2 ........................................................................................................................................ 50  
Incidence of Treatment-Emergent Adverse Events by System Organ Class and Preferred  
Term  
Safety Population  
Table 6.3 ........................................................................................................................................ 51  
Incidence of Treatment-Emergent Serious Adverse Events by System Organ Class and  
Preferred Term  
Safety Population  
Table 6.4 ........................................................................................................................................ 52  
Incidence of Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, 
and Intensity Safety Population  


  
  
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Statistical Analysis Plan   
Protocol No. SPIHF-201  
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Table 6.5 ........................................................................................................................................ 53  
Incidence of Study Treatment Related Adverse Events by System Organ Class, Preferred Term, 
and Intensity  
Safety Population  
Table 6.6 ........................................................................................................................................ 54  
Incidence of Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and 
Relationship to Study Drug  
Safety Population  
Table 6.7 ........................................................................................................................................ 55 
Incidence of Treatment-Emergent Adverse Events Leading to Discontinuation of Study  
Drug by System Organ Class and Preferred Term  
Safety Population  
Table 6.8 ........................................................................................................................................ 56  
Deaths  
Safety Population  
7.  
CLINICAL LABORATORY EVALUATIONS ........................................................................... 57  
Table 7.1a ....................................................................................................................................... 57  
Change From Baseline in Hematology Parameters by Visit  
Safety Population  
Table 7.1b ...................................................................................................................................... 59  
Shift Table of Hematology Parameters From Baseline to Post Baseline Visits Safety 
Population  
Table 7.2a ....................................................................................................................................... 60  
Change From Baseline in Blood Chemistry Parameters by Visit  
Safety Population  
Table 7.2b ...................................................................................................................................... 60  
Shift Table of Blood Chemistry Parameters From Baseline to Post Baseline Visits Safety 
Population  
Table 7.3a ....................................................................................................................................... 60  
Change From Baseline in Urinalysis Parameters by Visit Safety 
Population  
Table 7.3b ...................................................................................................................................... 60  
Shift Table of Urinalysis Parameters From Baseline to Post Baseline Visits Safety 
Population  
Table 7. 4a ...................................................................................................................................... 61  
Change From Baseline in Levels of hsTroponin by Visit Safety 
Population  
8. 
ELECTROCARDIOGRAM EVALUATIONS ............................................................................. 62  
Table 8.1 ........................................................................................................................................ 62  
Change From Baseline in Electrocardiogram (ECG) Parameters by Visit Safety 
Population  


  
  
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Protocol No. SPIHF-201  
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9. 
VITAL SIGNS ............................................................................................................................... 64 
Table 9.1 ........................................................................................................................................ 64  
Change From Baseline in Vital Signs  
Safety Population  
10. 
PHYSICAL EXAMINATION ....................................................................................................... 66  
Table 10.1 ...................................................................................................................................... 66  
Cardiovascular Physical Examination Results by Visit  
Safety Population  
Table 10.2 ...................................................................................................................................... 67  
Physical Measurement Results by Visit  
Safety Population  
11. 
CONCOMITANT MEDICATIONS/TREATMENTS .................................................................. 70 
Table 11.1 ...................................................................................................................................... 70  
Concomitant Medications by ATC and Preferred Drug Name Safety 
Population  
LISTINGS ................................................................................................................................................... 71  
LISTINGS – SUBJECT DISPOSITION, DEMOGRAPHICS, AND BASELINE  
CHARACTERISTICS ................................................................................................................... 71  
Listing 1.1 ...................................................................................................................................... 72  
Study Completion or Early Discontinuation Status  
All Randomized Subjects  
Listing 1.2 ...................................................................................................................................... 73  
Violations of Inclusion/Exclusion Criteria  
All Subjects  
Listing 1.3 ...................................................................................................................................... 74  
Randomization Status  
All Subjects  
Listing 1.4 ...................................................................................................................................... 75  
Demographic Information  
All Randomized Subjects  
Listing 1.5 ...................................................................................................................................... 76  
Medical and Surgical History  
All Randomized Subjects  
LISTINGS – EFFICACY ........................................................................................................................... 77  
Listing 2.1 ...................................................................................................................................... 77  
Cardiac MRI Assessments – Actual and Change from Baseline Values ITT 
Population  
Listing 2.2 ...................................................................................................................................... 79  
Echocardiography Assessments– Actual and Change from Baseline Values ITT 
Population  
Listing 2.3 ...................................................................................................................................... 81  


  
  
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Statistical Analysis Plan   
Protocol No. SPIHF-201  
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Exploratory Assessments – Actual and Change from Baseline Values ITT 
Population  
Listing 2.4.1 ................................................................................................................................... 82  
Six-Minute Walk Test – Part I ITT 
Population  
Listing 2.4.2 ................................................................................................................................... 83  
Six-Minute Walk Test – Part II ITT 
Population  
Listing 2.5.1 ................................................................................................................................... 84  
Kansas City Cardiomyopathy Questionnaire – Page 1 ITT 
Population  
Listing 2.5.2 ................................................................................................................................... 85  
Kansas City Cardiomyopathy Questionnaire – Page 2  
ITT Population  
Listing 2.5.3 ................................................................................................................................... 86 
Kansas City Cardiomyopathy Questionnaire – Page 3 ITT 
Population  
Listing 2.5.4 ................................................................................................................................... 87  
Kansas City Cardiomyopathy Questionnaire – Page 4 ITT 
Population  
Listing 2.5.5 ................................................................................................................................... 88  
Kansas City Cardiomyopathy Questionnaire – Summary Scores ITT 
Population  
LISTINGS – STUDY DRUG AND PRIOR/CONCOMITANT MEDICATIONS .................................... 89  
Listing 3.1 ...................................................................................................................................... 89  
Study Drug Injection Records  
Safety Population  
Listing 3.2 ...................................................................................................................................... 90  
Prior and Concomitant Medications by Subject Safety 
Population  
LISTINGS – PLASMA CONCENTRATION ............................................................................................ 91  
Listing 4.1 ...................................................................................................................................... 91  
Plasma Concentrations of Elamipretide and Metabolites (M1, M2) Safety 
Population  
LISTINGS – ADVERSE EVENTS ............................................................................................................ 92  
Listing 5.1 ...................................................................................................................................... 92  
Adverse Events  
Safety Population  
Listing 5.2 ...................................................................................................................................... 93  
Serious Adverse Events Safety 
Population  
Listing 5.3 ...................................................................................................................................... 94  


  
  
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Statistical Analysis Plan   
Protocol No. SPIHF-201  
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Adverse Events Leading to Discontinuation of Study Drug Safety 
Population  
LISTINGS – LABORATORY DATA ....................................................................................................... 95  
Listing 6.1 ...................................................................................................................................... 95  
Hematology Results by Subject and Visit  
Safety Population  
Listing 6.2 ...................................................................................................................................... 96  
Blood Chemistry Results by Subject and Visit  
Safety Population  
Listing 6.3 ...................................................................................................................................... 96  
Urinalysis Results by Subject and Visit  
Safety Population  
Listing 6.4 ...................................................................................................................................... 96  
Levels of hsTroponin by Subject and Visit Safety 
Population  
LISTINGS – OTHER SAFETY DATA ..................................................................................................... 97 
Listing 7.1 ...................................................................................................................................... 97 
Vital Signs by Subject and Visit  
Safety Population  
Listing 7.2a .................................................................................................................................... 98  
Electrocardiogram (ECG) by Subject and Visit  
Safety Population  
Listing 7.2b .................................................................................................................................... 98  
Electrocardiogram (ECG) by Subject and Visit with QRS Duration of <= 110 msec Safety 
Population  
Listing 7.2c .................................................................................................................................... 98  
Electrocardiogram (ECG) by Subject and Visit with QRS Duration of >110 msec Safety 
Population  
Listing 7.3 ...................................................................................................................................... 99  
Electrocardiogram (ECG) by Subject and Visit  
Subjects with Either an Increase of >60 msec Between Baseline and End of Treatment in  
Their QT or QTcF or an Absolute QT or QTcF value >500 msec at Any Point in Time During 
the Study  
Safety Population  
Listing 7.4 .................................................................................................................................... 100  
Cardiovascular Physical Examination and Physical Measurements by Subject and Visit Safety 
Population  
Listing 7.5 .................................................................................................................................... 101  
Injection Site Reaction (Nurse/Investigator Assessment)  
Safety Population  
Listing 7.6 .................................................................................................................................... 102  


  
  
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Statistical Analysis Plan   
Protocol No. SPIHF-201  
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Injection Site Reaction Self-Assessment Questionnaire Safety 
Population  
Listing 7.7 .................................................................................................................................... 103  
Comments  
All Subjects  
FIGURES .................................................................................................................................................. 104  
Figure 1a ...................................................................................................................................... 104  
Change From Baseline in Left Ventricular End Systolic Volume (LV ESV), Assessed by 
MRI, for Elamipretide 4 mg Group (By Subject) ITT Population  
Figure 1b ...................................................................................................................................... 105  
Change From Baseline in Left Ventricular End Systolic Volume (LV ESV), Assessed by  
MRI, for Elamipretide 4 mg Group (By Subject)  
Per-Protocol Population  
Figure 1c ...................................................................................................................................... 105  
Change From Baseline in Left Ventricular End Systolic Volume (LV ESV), Assessed by  
MRI, for Elamipretide 40 mg Group (By Subject)  
ITT Population  
Figure 1d ...................................................................................................................................... 105 
Change From Baseline in Left Ventricular End Systolic Volume (LV ESV), Assessed by  
MRI, for Elamipretide 40 mg Group (By Subject)  
Per-Protocol Population  
Figure 1e ...................................................................................................................................... 105  
Change From Baseline in Left Ventricular End Systolic Volume (LV ESV), Assessed by  
MRI, for Placebo Group (By Subject) ITT 
Population  
Figure 1f ....................................................................................................................................... 105  
Change From Baseline in Left Ventricular End Systolic Volume (LV ESV), Assessed by MRI, 
for Placebo Group (By Subject)  
Per-Protocol Population  
Figure 1g ...................................................................................................................................... 105  
LS Mean Change From Baseline in Left Ventricular End Systolic Volume (LV ESV),  
Assessed by MRI, (By Treatment Group) ITT 
Population  
Figure 1h ...................................................................................................................................... 105  
LS Mean Change From Baseline in Left Ventricular End Systolic Volume (LV ESV), Assessed 
by MRI, (By Treatment Group)  
Per-Protocol Population  
 


  
  
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Protocol No. SPIHF-201  
Last Revision Date: 04 DECEMBER 2017   
Figure 2a to Figure 2h (LVEF assessed by MRI) ........................................................................ 106 
Figure 3a to Figure 2h (LV EDV assessed by MRI) .................................................................... 106 
Figure 4a to Figure 4h (LVSV assessed by MRI) ........................................................................ 106  
Figure 5a to Figure 5h (LVCO assessed by MRI) ....................................................................... 106  
Figure 6a to Figure 6h (LV Myocardial Mass assessed by MRI) ................................................ 106 
Figure 7a to Figure 7h (RV ESV assessed by MRI) .................................................................... 106 
Figure 8a to Figure 8h (RV EDV assessed by MRI) ................................................................... 106  
Figure 9a to Figure 9h (RVEF assessed by MRI) ........................................................................ 106 
Figure 10a to Figure 10h (E/A assessed by Echocardiography) .................................................. 106  
Figure 11a to Figure 11h (E/e’ assessed by Echocardiography) .................................................. 106 
Figure 12a to Figure 12h (LA Volume assessed by Echocardiography) ..................................... 106 
Figure 13a to Figure 13h (LV GLS assessed by Echocardiography) ........................................... 106 
Figure 14a to Figure 14f (LV EDV assessed by Echocardiography) ........................................... 106  
Figure 15a to Figure 15f (LV ESV assessed by Echocardiography) ........................................... 106  
Figure 16a to Figure 16f (LVEF Biplane assessed by Echocardiography) .................................. 106 
Figure 17a to Figure 17f (LV Mass assessed by Echocardiography) .......................................... 106 
Figure 18a to Figure 18f (Mitral Regurgitation Severity assessed by Echocardiography) .......... 106 
Figure 19a to Figure 19f (Tricuspid Regurgitation Severity assessed by Echocardiography) ..... 106 
Figure 20a to Figure 20f (RV fractional area change assessed by Echocardiography) ............... 106  
Figure 21a to Figure 21f (RV systolic pressure assessed by Echocardiography) ........................ 106 
Figure 22a to Figure 22h (6MWT) .............................................................................................. 106  
Figure 23a to Figure 23f (NT-pro-BNP) ...................................................................................... 106 
Figure 24a to Figure 24h (Log10 NT-pro-BNP) .......................................................................... 107  
Figure 25a to Figure 25h (hs Troponin) ....................................................................................... 107  
Figure 26a to Figure 26h (KCCQ) ............................................................................................... 107  
Figure 27a .................................................................................................................................... 108  
Mean Plasma Concentration-Time Profile of Elamipretide (Linear Scale)  
Safety Population  
Figure 27b .................................................................................................................................... 109  
Mean Plasma Concentration-Time Profile of Elamipretide Metabolite M1 (Linear Scale) Safety 
Population  
Figure 27c .................................................................................................................................... 109  
Mean Plasma Concentration-Time Profile of Elamipretide Metabolite M2 (Linear Scale) Safety 
Population  
Figure 27d .................................................................................................................................... 110  
Log Mean Plasma Concentration-Time Profile of Elamipretide (Semi-logarithmic Scale) Safety 
Population  
Figure 27e .................................................................................................................................... 110  
Log Mean Plasma Concentration-Time Profile of Elamipretide Metabolite M1 
(Semilogarithmic Scale) Safety Population  
Figure 27f ..................................................................................................................................... 110 


  
  
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Statistical Analysis Plan   
Protocol No. SPIHF-201  
Last Revision Date: 04 DECEMBER 2017   
Log Mean Plasma Concentration-Time Profile of Elamipretide Metabolite M2 
(Semilogarithmic Scale) Safety Population  
Figure 27g .................................................................................................................................... 111  
Individual Plasma Concentration-Time Profile of Elamipretide (Linear Scale) Safety 
Population  
Figure 27h .................................................................................................................................... 111  
Individual Plasma Concentration-Time Profile of Elamipretide Metabolite M1 (Linear  
Scale)  
Safety Population  
Figure 27i ..................................................................................................................................... 111  
Individual Plasma Concentration-Time Profile of Elamipretide Metabolite M2 (Linear  
Scale)  
Safety Population  
Figure 27j ..................................................................................................................................... 111  
Individual Plasma Concentration-Time Profile of Elamipretide (Semi-logarithmic Scale) Safety 
Population  
Figure 27k .................................................................................................................................... 112  
Individual Plasma Concentration-Time Profile of Elamipretide Metabolite M1 
(Semilogarithmic Scale) Safety Population  
Figure 27l ..................................................................................................................................... 112  
Individual Plasma Concentration-Time Profile of Elamipretide Metabolite M2 
(Semilogarithmic Scale) Safety Population  
Figure 28a .................................................................................................................................... 112  
QTc for Subjects with a QTc value >500 msec at Any Point in Time During the Study (By  
Subject)  
Safety Population  


Stealth BioTherapeutics,Inc.  
  
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1. SUBJECT DISPOSITION   
  
Table 1.1  
Subject Disposition  
All Randomized Subjects  
  
  
Elamipretide 4 mg  
Elamipretide 40 mg  
Placebo  
All Subjects  
 
(N=xx)  
(N=xx)  
(N=xx)  
(N=xx)  
  
n (%)  
n (%)  
n (%)  
n (%)  
Subjects Randomized   
Safety Population [a]  
ITT Population [b]  
Per-Protocol Population [c]  
Not Treated  
  
xx 
xx  
 
xx 
xx   
( xx.x%)  
( xx.x%)  
 
( xx.x%)  
( xx.x%)  
 
xx 
xx  
 
xx 
xx   
( xx.x%)  
( xx.x%)  
 
( xx.x%)  
( xx.x%)  
 
xx 
xx  
 
xx 
xx   
( xx.x%)  
( xx.x%)  
 
( xx.x%)  
( xx.x%)  
 
xx 
xx  
 
xx 
xx   
( xx.x%)  
( xx.x%)  
 
( xx.x%)  
( xx.x%)  
 
Completed Study  
Early Discontinuation from the Study  
Primary Reason for Discontinuation Adverse 
Event  
Subject Withdrawal of Consent  
Sponsor Decision  
Investigator Decision  
Pregnancy  
Subject Lost to Follow-up  
xx 
xx  
 
xx 
xx 
xx 
xx 
xx 
xx  
( xx.x%)  
( xx.x%)  
 
( xx.x%)  
( xx.x%)  
( xx.x%)  
( xx.x%)  
( xx.x%)  
( xx.x%)  
xx 
xx  
 
xx 
xx 
xx 
xx 
xx 
xx  
( xx.x%)  
( xx.x%)  
 
( xx.x%)  
( xx.x%)  
( xx.x%)  
( xx.x%)  
( xx.x%)  
( xx.x%)  
xx 
xx  
 
xx 
xx 
xx 
xx 
xx 
xx  
( xx.x%)  
( xx.x%)  
 
( xx.x%)  
( xx.x%)  
( xx.x%)  
( xx.x%)  
( xx.x%)  
( xx.x%)  
xx 
xx  
 
xx 
xx 
xx 
xx 
xx 
xx  
( xx.x%)  
( xx.x%)  
 
( xx.x%)  
( xx.x%)  
( xx.x%)  
( xx.x%)  
( xx.x%)  
( xx.x%)  
% = 100*n/N, where n = number of subjects in the specific row category and N = number of subjects in the column category.  
[a] 
Safety Population = all subjects who received at least 1 dose of the investigational medicinal product (IMP), summarized 
according to the treatment received.  
[b] 
ITT Population = all subjects who were randomized and receive at least 1 dose of IMP, summarized according to the treatment 
group to which the subjects were randomized  
[c] 
Per-Protocol Population = all randomized subjects receiving at least one dose of the IMP without major protocol 
violations/deviations, summarized according to the treatment group to which the subjects were randomized. Source: Listing 1.1  
  
  
  
  
Table 1.2  
Extent of Participation in the Study 
All Randomized Subjects  


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Elamipretide 4 mg 
(N=xx)  
Elamipretide 40 mg 
(N=xx)  
Placebo 
(N=xx)  
All Subjects 
(N=xx)  
  
Extent of Participation in the study [a]  
 Treatment Period  
  n  
  1-5 days   
  6-10 days   
  11-15 days   
  16-20 days   
  21-25 days   
  26-28 days   
   >28 days  
  
 
  
xx  xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
 
  
  
xx  xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%)  
 
  
  
xx  xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
 
  
  
xx  xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%)  
 
  Mean    
SD  
  Median  
  Min, Max  
xx.x  
xx.xx 
xx.x xx, 
xx  
xx.x  
xx.xx 
xx.x xx, 
xx  
xx.x  
xx.xx 
xx.x xx, 
xx  
xx.x  
xx.xx 
xx.x xx, 
xx  
  
 Follow-up Period  
  n  
  1-5 days after last dose  
  6-10 days after last dose  
  11-14 days after last dose  
   >14 days after last dose   
 xx  xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
 
 xx  xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%)  
 
 xx  xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
 
 xx  xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%)  
 
[a] Extent of Participation in the Study = Treatment Period:  last treatment date – randomization date + 1.  Follow-up Period:  last 
study date – last treatment date + 1.    
  
Source: Listing 1.1  
  
  
  


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2. DEMOGRAPHIC AND BASELINE CHARACTERISTICS  
Table 2.1a  
Demographic and Non-Imaging Baseline Characteristics Safety 
Population  
  
  
Elamipretide 4 mg Elamipretide 40 mg  
Placebo  
All Subjects  
 
(N=xx)  
(N=xx)  
(N=xx)  
(N=xx)  


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Age (years)  
n  Mean   
SD  
Median  
Min, Max   
Age (years)  
n  
< 65  
≥ 65   
Gender  
n  
Male  
Female  
Race  
n  
White  
Black or African American  
Asian  
American Indian or Alaska Native  
Native Hawaiian or other Pacific Islander  
Other  
Unknown   
Ethnicity  
n  
Hispanic or Latino  
Not Hispanic or Latino  
Not reported  
Unknown  
 
Baseline Weight (kg)  
n  Mean   SD  
Median  
Min, Max  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
  xx xx 
(xx.x%) 
xx 
(xx.x%)  
  xx xx 
(xx.x%) 
xx 
(xx.x%)  
  xx xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%)  
  xx xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%)  
  xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx xx 
(xx.x%) 
xx 
(xx.x%)  
 xx xx 
(xx.x%) 
xx 
(xx.x%)  
 xx xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%)  
 xx xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%)  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx xx 
(xx.x%) 
xx 
(xx.x%)  
 xx xx 
(xx.x%) 
xx 
(xx.x%)  
 xx xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%)  
 xx xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%)  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx xx 
(xx.x%) 
xx 
(xx.x%)  
 xx xx 
(xx.x%) 
xx 
(xx.x%)  
 xx xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%)  
 xx xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%)  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
  
Elamipretide 4 mg Elamipretide 40 mg  
Placebo  
All Subjects  
 
(N=xx)  
(N=xx)  
(N=xx)  
(N=xx)  


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Baseline Height (cm)  
n  Mean   SD  
Median  
Min, Max  
 
Body Mass Index (kg/m2)  
Baseline  
n  Mean   
SD  
Median  
Min, Max  
  
2)  
Body Surface Area (m 
n Mean  SD  
Median  
Min, Max  
  
Non-Imaging Efficacy Assessments  
  
Baseline Distance Walked (meters) During 6-minute  
Walking Test  
n  Mean   SD  
Median  
Min, Max  
  
Baseline Levels of Log10 [NT-pro-BNP (ng/mL)]  
n  Mean   SD  
Median  
Min, Max  
  
Baseline Levels of NT-pro-BNP (ng/mL)  
n  
Geometric Mean (CV%)   
Mean   
SD  
Median  
Min, Max  
 
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 
 
  
xx xx.x  
xx.xx 
xx.x 
xx, xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx xx.x 
(xx.xx) 
xx.x  xx.xx 
xx.x xx, xx  
 
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 
 
  
xx xx.x  
xx.xx 
xx.x 
xx, xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx xx.x 
(xx.xx) 
xx.x  xx.xx 
xx.x xx, xx  
 
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 
 
  
xx xx.x  
xx.xx 
xx.x 
xx, xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx xx.x 
(xx.xx) 
xx.x  xx.xx 
xx.x xx, xx  
 
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 
 
  
xx 
xx.x  
xx.xx 
xx.x 
xx, xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx xx.x 
(xx.xx) 
xx.x  xx.xx 
xx.x xx, xx  
 


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Baseline eGFR (ml/min)  
n  
< 60  
≥ 60  
Mean   SD  
Median  
Min, Max  
  
Baseline Kansas City Cardiomyopathy Questionnaire  
(KCCQ) Overall Summary Score  
n  
  
Min, Max  
  
Vital Signs  
  
Baseline Heart Rate (bpm)  
n  Mean   SD  
Median  
Min, Max  
 
Baseline Respiration Rate (breaths/min)  
n  Mean   SD  
Median  
Min, Max  
 
Baseline Systolic Blood Pressure (mmHg)  
n  Mean   SD  
Median  
Min, Max  
 
Baseline Diastolic Blood Pressure (mmHg)  
n  Mean   SD  
Median  
Min, Max  
xx xx 
(xx.x%) 
xx 
(xx.x%) 
xx.x  
xx.xx 
xx.x xx, 
xx  
  
xx xx.x  
xx.xx 
xx.x 
xx, xx  
 
 
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
xx xx 
(xx.x%) 
xx 
(xx.x%) 
xx.x  
xx.xx 
xx.x xx, 
xx  
  
xx xx.x  
xx.xx 
xx.x 
xx, xx  
 
 
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
xx xx 
(xx.x%) 
xx 
(xx.x%) 
xx.x  
xx.xx 
xx.x xx, 
xx  
  
xx xx.x  
xx.xx 
xx.x 
xx, xx  
 
 
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
xx xx 
(xx.x%) 
xx 
(xx.x%) 
xx.x  
xx.xx 
xx.x xx, 
xx  
  
xx 
xx.x  
xx.xx 
xx.x 
xx, xx  
 
 
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  


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E lamipretide 4 mg   
N=xx ) 
( 
  
E lamipretide  4 0   mg   
) 
( N=xx   
Placebo   
( 
) 
N=xx   
All Subjects   
N=xx 
( 
)   


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Baseline value is the last available measure prior to treatment.  
  
SD = Standard deviation. Age is age at informed consent. n represents the number of subjects contributing 
to summary statistics. Percentages are based on n for each characteristic.  
  
 Source: Listings 1.4, 2.3, 7.1, 7.4.  
  
  
  
  
Table 2.1b  
Baseline Characteristics from MRI Safety 
Population  
  
  
Elamipretide 4 mg Elamipretide 40 mg  
Placebo  
All Subjects  
 
(N=xx)  
(N=xx)  
(N=xx)  
(N=xx)  
  
Elamipretide 4 mg 
(N=xx)  
Elamipretide 40 mg 
(N=xx)  
Placebo (N=xx)  
All Subjects 
(N=xx)  
 
oC)  
Baseline Temperature (Oral or Tympanic) (  
n  Mean   SD  
 Median  
 Min, Max  
  
 xx 
xx.x  
xx.xx 
xx.x 
xx, xx   
 xx 
xx.x  
xx.xx 
xx.x 
xx, xx   
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx   
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx   
Baseline Cardiovascular Physical Examination with  
Clinically Significant Abnormalities  
n  Yes  
 No  
  
 
xx xx 
(xx.x%) xx 
(xx.x%)   
 
xx xx 
(xx.x%) xx 
(xx.x%)   
 
xx xx 
(xx.x%) 
xx 
(xx.x%)   
 
xx xx 
(xx.x%) 
xx 
(xx.x%)   


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Baseline Left Ventricular End Systolic Volume (LV 
ESV) (mL) [a]  
n  Mean   SD  
Median  
Min, Max  
  
Baseline Left Ventricular Ejection Fraction  
(LVEF) (%)  
n  Mean   
SD  
Median  
Min, Max  
  
Baseline Left Ventricular End Diastolic Volume  
(LV EDV) (mL) [a]  
n  Mean   SD  
Median  
Min, Max  
  
  
Percent Scarring of LV Mass (%)  
n  Mean   SD  
Median  
Min, Max  
 
Ischemic/Non-ischemic Status [b]  
n  
Ischemic  
Non-ischemic  
 
 
 
 
 
xx xx.x  
xx.xx 
xx.x 
xx, xx  
 
 
xx 
xx.x  
xx.xx 
xx.x 
xx, xx  
 
 
xx xx.x  
xx.xx 
xx.x 
xx, xx  
 
 
xx 
xx.x  
xx.xx 
xx.x 
xx, xx  
 
 
xx xx.x  
xx.xx 
xx.x 
xx, xx  
 
 xx 
xx.x  
xx.xx 
xx.x 
xx, xx  
 
 
xx 
xx.x  
xx.xx 
xx.x 
xx, xx  
 
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx xx 
(xx.x%) 
xx 
(xx.x%)  
 
xx xx 
(xx.x%) xx 
(xx.x%)  
 
  
Elamipretide 4 mg Elamipretide 40 mg  
Placebo  
All Subjects  
 
(N=xx)  
(N=xx)  
(N=xx)  
(N=xx)  
Baseline value is the last available measure prior to treatment.  
  


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SD = Standard deviation. n represents the number of subjects contributing to summary statistics. 
Percentages are based on n for each characteristic.  
[a] Value indexed by body surface area [BSA].  
[b] Ischemic status as determined by scar pattern.  
  
 Source: Listings 2.1.  
  
  
  
  
 


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Table 2.1c  
Baseline Characteristics from Echocardiography Safety 
Population  
  
  
Elamipretide 4 mg Elamipretide 40 mg  
Placebo  
All Subjects  
 
(N=xx)  
(N=xx)  
(N=xx)  
(N=xx)  


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Baseline E/A (Ratio Between Early And Late Mitral
Inflow Velocity)  
n  Mean   SD  
Median  
Min, Max  
  
Baseline E/e' (Ratio Between Early Mitral Inflow 
Velocity And Mitral Annular Early Diastolic  
Velocity)  
n  Mean   
SD  
Median  
Min, Max  
  
Baseline Left Ventricular Ejection Fraction  
(LVEF) Biplane (%)  
n  Mean   SD  
Median  
Min, Max  
  
Baseline Left Ventricular Global Longitudinal  
Strain (%)  
n  Mean   
SD  
Median  
Min, Max  
  
Baseline Left Atrial Volume (mL) [a]  
n  Mean   SD  
Median  
Min, Max  
  
Baseline Left Ventricular Mass (g) [a]  
 
 
 
 
xx xx.x  
xx.xx 
xx.x 
xx, xx  
 
 
xx 
xx.x  
xx.xx 
xx.x 
xx, xx 
 
 
xx xx.x  
xx.xx 
xx.x 
xx, xx  
 
 
xx 
xx.x  
xx.xx 
xx.x 
xx, xx 
 
 
xx xx.x  
xx.xx 
xx.x 
xx, xx  
 
 
xx 
xx.x  
xx.xx 
xx.x 
xx, xx 
 
 
xx xx.x  
xx.xx 
xx.x 
xx, xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, xx  
 
 
xx 
xx.x  
xx.xx 
xx.x 
xx, xx 
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 
 


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Baseline value is the last available measure prior to treatment.  
  
SD = Standard deviation. Age is 
age at informed consent.  
n represents the number of subjects contributing to summary statistics. Percentages are based on n for each characteristic.  
[a] Value indexed by body surface area [BSA].  
  
 Source: Listings 2.2.  
  
  
  
  
Table 2.2a  
  
Elamipretide 4 mg 
(N=xx)  
Elamipretide 40 mg 
(N=xx)  
Placebo (N=xx)  
All Subjects 
(N=xx)  
 n  Mean   
SD  
 Median  
 Min, Max  
xx xx.x  
xx.xx 
xx.x 
xx, xx  
xx xx.x  
xx.xx 
xx.x 
xx, xx  
xx xx.x  
xx.xx 
xx.x 
xx, xx  
xx xx.x  
xx.xx 
xx.x 
xx, xx  
  
Baseline Mitral Regurgitation Severity (cm2)  
n  Mean   SD  
 Median  
 Min, Max  
 xx 
xx.x  
xx.xx 
xx.x 
xx, xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
  
Baseline Tricuspid Regurgitation Severity (cm2)   
n  Mean   SD  
 Median  
 Min, Max   
 xx 
xx.x  
xx.xx 
xx.x 
xx, xx   
 xx 
xx.x  
xx.xx 
xx.x 
xx, xx   
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx   
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx   
Baseline Right Ventricular Fractional Area Change  
(%)  n  
Mean   
SD  
 Median  
 Min, Max   
 
xx xx.x  
xx.xx 
xx.x 
xx, xx  
 
 
xx xx.x  
xx.xx 
xx.x 
xx, xx  
 
 
xx xx.x  
xx.xx 
xx.x 
xx, xx  
 
 
xx xx.x  
xx.xx 
xx.x 
xx, xx  
 
Baseline Right Ventricular Systolic Pressure  
(RVSP) (mmHg)  
n  Mean   SD  
 Median  
 Min, Max   
 
xx xx.x  
xx.xx 
xx.x 
xx, xx  
 
 
xx xx.x  
xx.xx 
xx.x 
xx, xx  
 
 
xx xx.x  
xx.xx 
xx.x 
xx, xx  
 
 
xx xx.x  
xx.xx 
xx.x 
xx, xx  
 


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Demographic and Non-Imaging Baseline Characteristics ITT 
Population  
  
Table 2.2b  
Baseline Characteristics from MRI  
ITT Population  
  
Table 2.2c  
Baseline Characteristics from Echocardiography  
ITT Population  
  
  
Table 2.3a  
Demographic and Non-Imaging Baseline Characteristics Per-Protocol 
Population  
  
Table 2.3b  
Baseline Characteristics from MRI  
Per-Protocol Population  
  
Table 2.3c  
Baseline Characteristics from Echocardiography  
Per-Protocol Population  
  
  
  
3. EFFICACY ANALYSIS  
  
  
 


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3.1  
EFFICACY ANALYSIS   
  
Linear  
Difference Between Trend  
Difference Between Difference Between Elamipretide 40 mg Test LV ESV 
Elamipretide Elamipretide  
Elamipretide 4 mg  
Elamipretide 40 mg and Elamipretide 4 P- 
(mL)  
4 mg  
40 mg  Placebo  
and Placebo (95%  
and Placebo (95%  
mg (95% CI), P- 
value Time 
Point [a]  
(N=xx)  (N=xx)  (N=xx)  CI), P-value [b]  
CI), P-value [b]  
value [b]  
[c]  
Baseline  
n  
xx  
  
xx  
  
  
  
   
Mean  
xx.x     
xx.x     
  
  
  
 SD  
xx.xx    
xx.xx    
  
  
   
Median xx.x  
  
xx.x  
  
  
  
  
  
Min,  
xx, xx  
  
xx, xx  
  
  
  
  
Max  
  
  
  
  
  
  
  
  
 Week 1  
n  
xx  
  
xx  
  
  
  
  
 Mean  
xx.x     
xx.x     
  
  
   
SD  
xx.xx    
xx.xx    
  
  
   
Median xx.x 
  
xx.x  
  
  
  
  
  
Min,  
xx, xx  
  
xx, xx  
  
  
  
  
Max  
  
  
  
  
  
  
  
  
 Change  
  
  
  
 from Baseline to Week 1  
[d]  
n  
xx  
  
xx  
  
Mean  
xx.x   
  
xx.x   
xx.x (xx.x, xx.x)x.xxxx  
  
xx.x (xx.x, xx.x)x.xxxx  
  xx.x 
(xx.x, xx.x)x.xxxx    x.xxxx  
 SD xx.xx  xx.xx      Median xx.x  xx.x      
  
Min,  
xx, xx  
  
xx, xx  
  
  
  
  
Max  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 Week 4  
n  
xx  
  
xx  
  
  
  
  
 Mean  
xx.x     
xx.x     
  
  
   
SD  
xx.xx    
xx.xx    
  
  
   
Median xx.x 
  
xx.x  
  
  
  
  
  
Min,  
xx, xx  
  
xx, xx  
  
  
  
  
Max  
  
  
  
  
  
  
  
  
 Change  
n  
xx  
  
xx  
  
  
  
  
Table 3.1  
Summary of Change From Baseline in Left Ventricular End Systolic Volume (LV ESV), Assessed by MRI ITT 
Population  
 


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Time Point  
LV ESV 
(mL) [a]  
Elamipretide  
4 mg  
(N=xx)  
Elamipretide  
40 mg Placebo (N=xx) 
(N=xx)  
Difference Between 
Elamipretide 4 mg and 
Placebo (95% CI), P-
value [b]  
Difference Between 
Elamipretide 40 mg 
and Placebo (95% CI), 
P-value [b]  
Difference Between 
Elamipretide 40 mg 
and Elamipretide 4 
mg (95% CI), Pvalue 
[b]  
Linear 
Trend  
Test 
Pvalue 
[c]  
from 
Baseline 
to Week 4  
[d]  
  
  
  
  
Mean  
SD  
Median 
Min, Max  
xx.x   
xx.xx 
xx.x xx, 
xx  
 
xx.x   
 
xx.xx   xx.x  
 
xx, xx  
xx.x (xx.x, xx.x)   
x.xxxx  
  
  
  
xx.x (xx.x, xx.x)   
x.xxxx  
  
  
  
xx.x (xx.x, xx.x)   
x.xxxx  
  
  
  
x.xxxx  
  
  
  
ITT Population = all subjects who were randomized and receive at least 1 dose of IMP, according to the treatment group to which the 
subjects were randomized.  
Baseline value is the last available measure prior to treatment.  
[a] Value indexed by body surface area [BSA].   
[b] 95% confidence interval is based on the t-distribution and Lsmean of between treatment group difference from a mixed model 
repeated measures for the change from baseline which includes treatment group, treatment-by-visit interaction, and ischemic/non-
ischemic as factors and the baseline value and baseline value-by-visit interaction as continuous covariates.  P-value corresponds 
to a 2-sided significance level of the between treatment group difference from the mixed model repeated measures. [c] Linear trend 
test.   
[d] Change from Baseline at time point t: Changet = Value t – ValueBaseline. Source: 
Listings 2.1  
  
Table 3.2  
Summary of Change From Baseline in Left Ventricular End Systolic Volume (LV ESV), Assessed by MRI  
Per-Protocol Population  
  
[Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations,  
according to the treatment group to which the subjects were randomized.]  
  
Table 3.3  
Summary of Change From Baseline in Left Ventricular Ejection Fraction (LVEF), Assessed by MRI  
ITT Population  
  


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[Change 2nd column header to:  LVEF]  
[Remove footnote for indexing to BSA]  
  
Table 3.4  
Summary of Change From Baseline in Left Ventricular Ejection Fraction (LVEF), Assessed by MRI  
Per-Protocol Population  
  
[Change 2nd column header to:  LVEF]  
[Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations,  
according to the treatment group to which the subjects were randomized.]   
[Remove footnote for indexing to BSA]  
  
Table 3.5  
Summary of Change From Baseline in Left Ventricular End Diastolic Volume (LV EDV), Assessed by MRI  
ITT Population  
  
[Change 2nd column header to:  LV EDV]  
  
Table 3.6  
Summary of Change From Baseline in Left Ventricular End Diastolic Volume (LV EDV), Assessed by MRI  
Per-Protocol Population  
  
[Change 2nd column header to:  LV EDV]  
[Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations, 
according to the treatment group to which the subjects were randomized.]  
  
Table 3.7  
Summary of Change From Baseline in Left Ventricular Stroke Volume (LVSV), Assessed by MRI  
ITT Population  


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[Change 2nd column header to:  LVSV]   
[Remove footnote for indexing to BSA]  
  
Table 3.8  
Summary of Change From Baseline in Left Ventricular Stroke Volume (LVSV), Assessed by MRI  
Per-Protocol Population  
  
[Change 2nd column header to:  LVSV]   
[Remove footnote for indexing to BSA]  
[Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations, 
according to the treatment group to which the subjects were randomized.]  
  
Table 3.9  
Summary of Change From Baseline in Left Ventricular Cardiac Output (LVCO), Assessed by MRI  
ITT Population  
  
[Change 2nd column header to:  LVCO]   
[Remove footnote for indexing to BSA]  
  
Table 3.10  
Summary of Change From Baseline in Left Ventricular Cardiac Output (LVCO), Assessed by MRI  
Per-Protocol Population  
  
[Change 2nd column header to:  LVCO]   
[Remove footnote for indexing to BSA]  
[Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations, 
according to the treatment group to which the subjects were randomized.]  


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Table 3.11  
Summary of Change From Baseline in Left Ventricular Myocardial Mass (LV Mass), Assessed by MRI  
ITT Population  
  
[Change 2nd column header to:  LV Mass]  
  
Table 3.12  
Summary of Change From Baseline in Left Ventricular Myocardial Mass (LV Mass), Assessed by MRI  
Per-Protocol Population  
  
[Change 2nd column header to:  LV Mass]  
[Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations, 
according to the treatment group to which the subjects were randomized.]  
  
Table 3.13  
Summary of Change From Baseline in Right Ventricular End Systolic Volume (RV ESV), Assessed by MRI  
ITT Population  
  
[Change 2nd column header to:  RV ESV]  
  
Table 3.14  
Summary of Change From Baseline in Right Ventricular End Systolic Volume (RV ESV), Assessed by MRI  
Per-Protocol Population  
  
[Change 2nd column header to:  RV ESV]  
[Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations, 
according to the treatment group to which the subjects were randomized.]  
  


Stealth BioTherapeutics,Inc.  
  
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Table 3.15  
Summary of Change From Baseline in Right Ventricular End Diastolic Volume (RV EDV), Assessed by MRI  
ITT Population  
  
[Change 2nd column header to:  RV EDV]  
  
Table 3.16  
Summary of Change From Baseline in Right Ventricular End Diastolic Volume (RV EDV), Assessed by MRI  
Per-Protocol Population  
  
[Change 2nd column header to:  RV EDV]  
[Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations, 
according to the treatment group to which the subjects were randomized.]  
  
Table 3.17  
Summary of Change From Baseline in Right Ventricular Ejection Fraction (RVEF), Assessed by MRI  
ITT Population  
  
[Change 2nd column header to:  RVEF]   
[Remove footnote for indexing to BSA]  
  
Table 3.18  
Summary of Change From Baseline in Right Ventricular Ejection Fraction (RVEF), Assessed by MRI  
Per-Protocol Population  
  
[Change 2nd column header to:  RVEF]   
[Remove footnote for indexing to BSA]  
[Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations, 
according to the treatment group to which the subjects were randomized.]  


Stealth BioTherapeutics,Inc.  
  
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Table 3.19  
Summary of Change From Baseline in E/A (Ratio Between Early And Late Mitral Inflow Velocity), Assessed by Echocardiography  
ITT Population  
  
[Change 2nd column header to:  E/A, Change Timepoints to Weeks 4 and 6, Change footnote to Listing 2.2]  
[Remove footnote for indexing to BSA]  
  
Table 3.20  
Summary of Change From Baseline in E/A (Ratio Between Early And Late Mitral Inflow Velocity), Assessed by Echocardiography  
Per-Protocol Population  
  
[Change 2nd column header to:  E/A, Change Timepoints to Weeks 4 and 6, Change footnote to Listing 2.2]  
[Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations,  
according to the treatment group to which the subjects were randomized.] [Remove 
footnote for indexing to BSA]  
  
Table 3.21  
Summary of Change From Baseline in E/e' (Ratio Between Early Mitral Inflow Velocity and Mitral Annular Early Diastolic Velocity), Assessed by Echocardiography 
ITT Population  
  
[Change 2nd column header to:  E/e', Change Timepoints to Weeks 4 and 6, Change footnote to Listing 2.2]  
[Remove footnote for indexing to BSA]  
  
Table 3.22  
Summary of Change From Baseline in E/e' (Ratio Between Early Mitral Inflow Velocity and Mitral Annular Early Diastolic Velocity), Assessed by Echocardiography Per-
Protocol Population  
  
[Change 2nd column header to:  E/e', Change Timepoints to Weeks 4 and 6, Change footnote to Listing 2.2]  


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[Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations,  
according to the treatment group to which the subjects were randomized.]  
[Remove footnote for indexing to BSA]  
  
Table 3.23  
Summary of Change From Baseline in Left Atrial Volume, Assessed by Echocardiography  
ITT Population  
  
[Change 2nd column header to:  LAV, Change Timepoints to Weeks 4 and 6, Change footnote to Listing 2.2]  
  
Table 3.24  
Summary of Change From Baseline in Left Atrial Volume, Assessed by Echocardiography  
Per-Protocol Population  
  
[Change 2nd column header to:  LAV, Change Timepoints to Weeks 4 and 6, Change footnote to Listing 2.2]  
[Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations, 
according to the treatment group to which the subjects were randomized.]  
  
Table 3.25  
Summary of Change From Baseline in Left Ventricular Global Longitudinal Strain, Assessed by Echocardiography  
ITT Population  
  
[Change 2nd column header to:  LV GLS, Change Timepoints to Weeks 4 and 6, Change footnote to Listing 2.2]   
[Remove footnote for indexing to BSA]  
  
Table 3.26  
Summary of Change From Baseline in Left Ventricular Global Longitudinal Strain, Assessed by Echocardiography  
Per-Protocol Population  
  


Stealth BioTherapeutics,Inc.  
  
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[Change 2nd column header to:  LV GLS, Change Timepoints to Weeks 4 and 6, Change footnote to Listing 2.2]  
[Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations,  
according to the treatment group to which the subjects were randomized.]  
[Remove footnote for indexing to BSA]    
 


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Table 3.27  
Summary of Change From Baseline in Left Ventricular End Diastolic Volume (LV EDV), Assessed by Echocardiography ITT 
Population  
  
LV EDV Elamipretide Elamipretide  
(mL) 4 mg 40 mg Placebo Time Point [a] (N=xx) 
(N=xx) (N=xx)  


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Baseline  
 
 
 
 
 
Week 4  
 
 
 
 
Change 
from 
Baseline 
to Week 4  
[a]   
 
 
 
 
 
Week 6  
 
 
 
 
Change 
from 
Baseline 
to Week 6  
[a]   
n Mean 
SD  
Median 
Min,  
Max  
n 
Mean 
SD  
Median 
Min,  
Max   
n Mean 
SD  
Median 
Min,  
Max   
n 
Mean 
SD  
Median 
Min,  
Max   
n Mean 
SD  
Median  
xx xx.x  
xx.xx 
xx.x 
xx, xx  
xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx   
xx xx.x  
xx.xx 
xx.x 
xx, xx  
  
xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx   
xx xx.x  
xx.xx 
xx.x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
xx 
xx.x  
xx.xx 
xx.x 
xx, xx 
xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx   
xx 
xx.x  
xx.xx 
xx.x 
xx, xx 
  
xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx   
xx 
xx.x  
xx.xx 
xx.x  


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ITT Population = all subjects who were randomized and receive at least 1 dose of IMP, according to the treatment group to which the 
subjects were randomized.  
Baseline value is the last available measure prior to treatment.  
[Source: Listings 2.2a] Change from Baseline at time point t: Change  
t = Value t – ValueBaseline.  
  
Table 3.28  
Summary of Change From Baseline in Left Ventricular End Diastolic Volume (LV EDV), Assessed by Echocardiography  
Per-Protocol Population  
  
 [Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations, 
according to the treatment group to which the subjects were randomized.]  
  
Table 3.29  
Summary of Change From Baseline in Left Ventricular End Systolic Volume (LV ESV), Assessed by Echocardiography  
ITT Population  
  
Table 3.30  
Summary of Change From Baseline in Left Ventricular End Systolic Volume (LV ESV), Assessed by Echocardiography  
Per-Protocol Population  
  
 [Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations, 
according to the treatment group to which the subjects were randomized.]  
  
Table 3.31  
Summary of Change From Baseline in Biplane Ejection Fraction (EF), Assessed by Echocardiography  
ITT Population  
Time Point   
LV EDV  
( mL)  
] 
[ a   
E lamipretide  
4  mg  
( N=xx )   
E lamipretide  
 mg  
40 
) 
N=xx 
( 
  
Placebo  
N=xx ) 
( 
  
  
Min,  
Max   
xx, xx   
  
xx, xx   
  
  
  
  
  


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 Table 3.32  
Summary of Change From Baseline in Biplane Ejection Fraction (EF), Assessed by Echocardiography  
Per-Protocol Population  
  
 [Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations, 
according to the treatment group to which the subjects were randomized.]  
  
Table 3.33  
Summary of Change From Baseline in Left Ventricular Mass, Assessed by Echocardiography  
ITT Population  
  
Table 3.34  
Summary of Change From Baseline in Left Ventricular Mass, Assessed by Echocardiography  
Per-Protocol Population  
  
 [Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations, 
according to the treatment group to which the subjects were randomized.]  
  
Table 3.35  
Summary of Change From Baseline in Mitral Regurgitation Severity, Assessed by Echocardiography  
ITT Population  
  
 Table 3.36  
Summary of Change From Baseline in Mitral Regurgitation Severity, Assessed by Echocardiography  
Per-Protocol Population  
  
 [Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations, 
according to the treatment group to which the subjects were randomized.]   
  
Table 3.37  


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Summary of Change From Baseline in Tricuspid Regurgitation Severity, Assessed by Echocardiography  
ITT Population  
   
Table 3.38  
Summary of Change From Baseline in Tricuspid Regurgitation Severity, Assessed by Echocardiography  
Per-Protocol Population  
  
  [Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations, 
according to the treatment group to which the subjects were randomized.]  
  
Table 3.39  
Summary of Change From Baseline in Right Ventricular Fractional Area Change, Assessed by Echocardiography  
ITT Population  
  
  
Table 3.40  
Summary of Change From Baseline in Right Ventricular Fractional Area Change, Assessed by Echocardiography  
Per-Protocol Population  
  
  [Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations, 
according to the treatment group to which the subjects were randomized.]  
  
Table 3.41  
Summary of Change From Baseline in Right Ventricular Systolic Pressure (RVSP), Assessed by Echocardiography  
ITT Population  
  
  
Table 3.42  
Summary of Change From Baseline in Right Ventricular Systolic Pressure (RVSP), Assessed by Echocardiography  
Per-Protocol Population  
  


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[Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations, 
according to the treatment group to which the subjects were randomized.]  
  
  
Table 3.43  
Summary of Change From Baseline in Distance Walked (meters) During 6-minute Walking Test (6MWT)  
ITT Population  
  
[From Table 3.1 mock, Change 2nd column header to:  6MWT, Change Timepoints to Week 4, Change footnote to Listing 2.3]  [Remove 
footnote for indexing to BSA]  
[Change footnote [b] to:  
[b] 95% confidence interval is based on the t-distribution and Lsmean of between treatment group difference from an ANCOVA model for the change from baseline which includes 
treatment group, ischemic/non-ischemic, and treatment-by-ischemic/non-ischemic interaction as factors and the baseline value as a continuous covariate.  P-value corresponds to 
a 2-sided significance level of the between treatment group difference from the ANCOVA model.]  
  
Table 3.44  
Summary of Change From Baseline in Distance Walked (meters) During 6-minute Walking Test (6MWT)  
Per-Protocol Population  
  
[From Table 3.1 mock, Change 2nd column header to:  6MWT, Change Timepoints to Week 4, Change footnote to Listing 2.3]  
[Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations,  
according to the treatment group to which the subjects were randomized.]  [Remove 
footnote for indexing to BSA]  
[Change footnote [b] to:  
[b] 95% confidence interval is based on the t-distribution and Lsmean of between treatment group difference from an ANCOVA model for the change from baseline which includes 
treatment group, ischemic/non-ischemic, and treatment-by-ischemic/non-ischemic interaction as factors and the baseline value as a continuous covariate.  P-value corresponds to 
a 2-sided significance level of the between treatment group difference from the ANCOVA model.]  
  
Table 3.45  
Summary of Change From Baseline in Levels of NT-pro-BNP  
ITT Population  
  


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[From Table 3.1 mock, Change 2nd column header to:  NT-pro-BNP, Change Timepoints to Weeks 1, 2, 4, and 6, Change footnote to Listing 2.3]  [Remove 
footnote for indexing to BSA]  
[Change footnote [b] to:  
[a] Difference between treatments and inferential statistics based on log10 (NT-pro-BNP). 95% confidence interval is based on the t-distribution and Lsmean of between treatment 
group difference from a mixed model repeated measures for the change from baseline which includes treatment group, treatment-by-visit interaction, ischemic/non-ischemic as 
factors and the baseline value and baseline value-by-visit interaction as continuous covariates. P-value corresponds to a 2-sided significance level of the between treatment 
group difference from the mixed model repeated measures.]  
[Change footnote [c] to:  
[b] Linear trend test of log10 (NT-pro-BNP).]  
Table 3.46  
Summary of Change From Baseline in Levels of NT-pro-BNP  
Per-Protocol Population  
  
[From Table 3.1 mock, Change 2nd column header to:  NT-pro-BNP, Change Timepoints to Weeks 1, 2, 4, and 6, Change footnote to Listing 2.3]  [Remove 
footnote for indexing to BSA]  
[Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations,  
according to the treatment group to which the subjects were randomized.]  
[Change footnote [b] to:  
[a] Difference between treatments and inferential statistics based on log10 (NT-pro-BNP). 95% confidence interval is based on the t-distribution and Lsmean of between 
treatment group difference from a mixed model repeated measures for the change from baseline which includes treatment group, treatment-by-visit interaction, ischemic/non-
ischemic as  
factors and the baseline value and baseline value-by-visit interaction as continuous covariates. P-value corresponds to a 2-sided significance level of the between treatment group  
difference from the mixed model repeated measures.]  
[Change footnote [c] to:  
[b] Linear trend test of log10 (NT-pro-BNP).]  
  
Table 3.47  
Summary of Change From Baseline in Levels of hsTroponin  
ITT Population  
  
[From Table 3.1 mock, Change 2nd column header to:  hsTroponin, Change Timepoints to Weeks 1, 2, 4, and 6, Change footnote to Listing 6.4]   
[Remove footnote for indexing to BSA]  


Stealth BioTherapeutics,Inc.  
  
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Table 3.48  
Summary of Change From Baseline in Levels of hsTroponin  
Per-Protocol Population  
  
[From Table 3.1 mock, Change 2nd column header to:  hsTroponin, Change Timepoints to Weeks 1, 2, 4, and 6, Change footnote to Listing 6.4]  [Remove 
footnote for indexing to BSA]  
[Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations, 
according to the treatment group to which the subjects were randomized.]  
  
  
Table 3.49  
Summary of Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score  
ITT Population  
  
[From Table 3.1 mock, Change 2nd column header to:  KCCQ, Change Timepoints to Week 4, Change footnote to Listing 2.3]  [Remove 
footnote for indexing to BSA]  
[Change footnote [b] to:  
[b] 95% confidence interval is based on the t-distribution and Lsmean of between treatment group difference from an ANCOVA model for the change from baseline which includes 
treatment group, ischemic/non-ischemic, and treatment-by-ischemic/non-ischemic interaction as factors and the baseline value as a continuous covariate.  P-value corresponds to 
a 2-sided significance level of the between treatment group difference from the ANCOVA model.]  
  
Table 3.50  
Summary of Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score  
Per-Protocol Population  
  
[From Table 3.1 mock, Change 2nd column header to:  KCCQ, Change Timepoints to Week 4, Change footnote to Listing 2.3]  [Remove 
footnote for indexing to BSA]  
[Change first footnote to:  Per-Protocol Population = all subjects who were randomized and receive at least 1 dose of IMP, without major protocol violations/deviations,  
according to the treatment group to which the subjects were randomized.]  


Stealth BioTherapeutics,Inc.  
  
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[Change footnote [b] to:  
[b] 95% confidence interval is based on the t-distribution and Lsmean of between treatment group difference from an ANCOVA model for the change from baseline which includes 
treatment group, ischemic/non-ischemic, and treatment-by-ischemic/non-ischemic interaction as factors and the baseline value as a continuous covariate.  P-value corresponds to 
a 2-sided significance level of the between treatment group difference from the ANCOVA model.]  
  
  
  
4. PLASMA CONCENTRATION ANALYSIS  
Table 4.1  
Summary of Plasma Concentrations of Elamipretide and Metabolites (M1, M2)  by Time Point 
Safety Population  
  
  
Day 1  
  
  
  
Pre-dose  
  
  
  
  n  
xx   
xx  
xx   
  Mean (CV%)  
xx.x (xx.xx)  
xx.x (xx.x)  
xx.x (xx.xx)  
  SD  
xx.xx  
xx.x  
xx.xx  
  Median  
xx.x  
xx  
xx.x  
  Min, Max  
xx, xx  
xx, xx  
xx, xx  
  Geometric Mean (CV%)   
xx.x (xx.xx)  
xx.x (xx.x)  
xx.x (xx.xx)  
  
  
  
 Post-dose  
  
  
  
  N  
xx   
xx  
xx   
  Mean (CV%)  
xx.x (xx.xx)  
xx.x (xx.x)  
xx.x (xx.xx)  
  SD  
xx.xx  
xx.x  
xx.xx  
  Median  
xx.x  
Xx  
xx.x  
  Min, Max  
xx, xx  
xx, xx  
xx, xx  
  Geometric Mean (CV%)   
xx.x (xx.xx)  
xx.x (xx.x)  
xx.x (xx.xx)  
  
  
  
 Week 1  
  
  
 Pre-dose  
  
  
  
  n  
xx   
xx  
xx   
  Mean (CV%)  
xx.x (xx.xx)  
xx.x (xx.x)  
xx.x (xx.xx)  
  SD  
xx.xx  
xx.x  
xx.xx  
  Median  
xx.x  
xx  
xx.x  
  Min, Max  
xx, xx  
xx, xx  
xx, xx  
  Geometric Mean (CV%)   
xx.x (xx.xx)  
xx.x (xx.x)  
xx.x (xx.xx)  
  
  
  
 Post-dose  
  
  
  
  N  
xx   
xx  
xx   
  Mean (CV%)  
xx.x (xx.xx)  
xx.x (xx.x)  
xx.x (xx.xx)  
  SD  
xx.xx  
xx.x  
xx.xx  
Elamipretide   
M1   
M2   
Concentration (unit)   
) 
( N=xx   
( N=xx )   
( N=xx )   


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  Median 
 
xx.x 
 
Xx 
 
xx.x  
  Min, Max 
 
xx, xx 
 
xx, xx 
 
xx, xx  
  
Geometric 
Mean (CV%)  
 
xx.x 
(xx.xx) 
 
xx.x 
(xx.x) 
 
xx.x 
(xx.xx)  
  
  
  
 Week 2  
  
  
 Pre-dose  
  
  
  
  n  
xx   
xx  
xx   
  Mean (CV%)  
xx.x (xx.xx)  
xx.x (xx.x)  
xx.x (xx.xx)  
  SD xx.xx xx.x xx.xx   Median xx.x xx xx.x  
  
N = number of subjects treated with Elamipretide. n 
= number of subjects with data.  
SD = standard deviation.  
CV = coefficient of variation.  
Values below Lower Limit of Quantification (LLQ) are set to LLQ/2.  
Source: Listing 4.1  
  
  
  
5. EXTENT OF EXPOSURE TO STUDY MEDICATION  
Table 5.1  
Extent of Exposure to Study Medication by Treatment Group 
Safety Population  
  
  
Elamipretide 4 mg 
(N=xx)  
Elamipretide 40 mg 
(N=xx)  
Placebo (N=xx)  
All Subjects 
(N=xx)  
 Min, Max  
 Geometric Mean (CV%)   
 
Post-dose   
N  
 Mean (CV%)  
 SD  
 Median  
 Min, Max  
 Geometric Mean (CV%)   
Week 
4   n  
 Mean (CV%)  
 SD  
 Median  
 Min, Max  
 Geometric Mean (CV%)   
Week 
6   n  
 Mean (CV%)  
 SD  
 Median  
 Min, Max  
 Geometric Mean (CV%)   
xx, xx xx.x 
(xx.xx)  
 xx  xx.x 
(xx.xx) 
xx.xx xx.x 
xx, xx xx.x 
(xx.xx)  
 xx  xx.x 
(xx.xx) 
xx.xx xx.x 
xx, xx xx.x 
(xx.xx)  
 xx  xx.x 
(xx.xx) 
xx.xx xx.x 
xx, xx xx.x 
(xx.xx)  
xx, xx xx.x 
(xx.x)  
 xx xx.x 
(xx.x) 
xx.x Xx 
xx, xx 
xx.x 
(xx.x)  
 xx xx.x 
(xx.x) 
xx.x xx 
xx, xx 
xx.x 
(xx.x)  
 xx xx.x 
(xx.x) 
xx.x xx 
xx, xx 
xx.x 
(xx.x)  
xx, xx xx.x 
(xx.xx)  
 xx  xx.x 
(xx.xx) 
xx.xx xx.x 
xx, xx xx.x 
(xx.xx)  
 xx  xx.x 
(xx.xx) 
xx.xx xx.x 
xx, xx xx.x 
(xx.xx)  
 xx  xx.x 
(xx.xx) 
xx.xx xx.x 
xx, xx xx.x 
(xx.xx)  


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Study Treatment Exposure (days) [a]  
 N  
 Mean   SD  
 Median  
 Min, Max  
xx 
xxx.x  
xxx.xx 
xxx.x 
xxx, 
xxx  
xx 
xxx.x  
xxx.xx 
xxx.x 
xxx, xxx  
xx 
xxx.x  
xxx.xx 
xxx.x 
xxx, xxx  
xx 
xxx.x  
xxx.xx 
xxx.x 
xxx, 
xxx  
  
Study Treatment Compliance (%)  
n  Mean   SD  
 Median  
 Min, Max  
 xx 
xxx.x  
xxx.xx 
xxx.x 
xxx, 
xxx  
 xx 
xxx.x  
xxx.xx 
xxx.x 
xxx, xxx  
 xx 
xxx.x  
xxx.xx 
xxx.x 
xxx, xxx  
 xx 
xxx.x  
xxx.xx 
xxx.x 
xxx, 
xxx  
SD = Standard deviation.  
n represents the number of subjects contributing to summary statistics. Percentages are based on n for each characteristic.  
Percentages are based on n.  
[a] Study treatment exposure (days) = Treatment end date - treatment start date – number of days of missed doses + 1. Source: 
Listing 3.1  
  
  
  
  
6. ADVERSE EVENTS  
Table 6.1  
Overall Summary of Treatment-Emergent Adverse Events by Treatment Group 
Safety Population  
  
 
 
Elamipretide 4 mg 
(N=xx)  
Elamipretide 40 mg 
(N=xx)  
Placebo 
(N=xx)  
All Subjects 
(N=xx)  
# of  
Subjects n 
(%)  
  
  
E  
# of  
Subjects n 
(%)  
  
  
E  
# of  
Subjects n 
(%)  
  
  
E  
# of  
Subjects n 
(%)  
  
  
E  
Subjects with at least one TEAE  
xx (xx.x%)  
xx  
xx (xx.x%)  
xx  
xx (xx.x%)  
xx  
xx (xx.x%)  
xx  
Subjects with TEAEs Related to Study 
Treatment [a]  
xx (xx.x%)  
xx  
xx (xx.x%)  
xx  
xx (xx.x%)  
xx  
xx (xx.x%)  
xx  
Subjects with Serious TEAEs  
xx (xx.x%)  
xx  
xx (xx.x%)  
xx  
xx (xx.x%)  
xx  
xx (xx.x%)  
xx  


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Subjects with Serious TEAEs 
Related to Study Treatment [a]  
xx (xx.x%)  
xx  
xx (xx.x%)  
xx  
xx (xx.x%)  
xx  
xx (xx.x%)  
xx  
Subjects with TEAEs Leading to 
Discontinuation of Study Drug  
xx (xx.x%)  
xx  
xx (xx.x%)  
xx  
xx (xx.x%)  
xx  
xx (xx.x%)  
xx  
Deaths – All 
Causes   
xx (xx.x%)   
xx   
xx (xx.x%)   
xx   
xx (xx.x%)   
xx   
xx (xx.x%)   
xx   
Percentages are based on N.  
TEAE = Treatment-Emergent Adverse Event. An adverse event is considered treatment-emergent if the date of onset is on or after the date 
of first dose of study medication, or worsening during the treatment period + 30 days.   
E = number of events  
[a] Related = unlikely related, probably related or possibly related to study drug.  
  
Source: Listing 5.1  
Program:  /data/dev/client29/SPIHF201/programs/statout/xxxxxxx.sas   DDMMMYYYY:HH:MM      (Page x of y)  
  
  
Table 6.2  
Incidence of Treatment-Emergent Adverse Events by System Organ Class and Preferred Term  
Safety Population  
  
  
System Organ Class    
Preferred Term  
Elamipretide 4 mg  
(N=xx) 
n (%)  
Elamipretide 40 mg  
(N=xx) 
n (%)  
Placebo  
(N=xx) 
n (%)  
All Subjects  
(N=xx) n 
(%)  
  
  
At Least One TEAE  
  
  
xx (xx.x%)  
  
  
xx (xx.x%)  
  
  
xx (xx.x%)  
  
xx (xx.x%)   
MedDRA SOC1  
  Preferred Term 1  
  Preferred Term 2   
…  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%)   
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%)   
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%)   
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%)   
  
MedDRA SOC2  
  Preferred Term 1  
  Preferred Term 2  
  …  
   
 Etc.    
  
  
  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%)  
  
  
  
  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%)  
  
  
  
  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%)  
  
  
  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  


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Percentages are based on N.  
TEAE = Treatment Emergent Adverse Event. An adverse event is considered treatment-emergent if the date of onset is on or after the date 
of first dose of study medication, or worsening during the treatment period + 30 days.  
If more than one adverse event is coded to the same preferred term for a subject, the subject will be counted only once for that 
preferred term. If more than one preferred term is coded to the same System Organ Class for a subject, the subject will be counted 
only once for that System Organ Class. Adverse events coded using MedDRA version 20.0.  
Source: Listing 5.1  
  
Note to Programmer: SOCs sorted alphabetically. PTs sorted within SOCs in decreasing order of frequency in the all subject group.   
Subjects having several AEs with the same SOC will be counted only once for that particular SOC.  
Subjects having several AEs with the same PT will be counted only once for that particular PT.  
Table 6.3  
Incidence of Treatment-Emergent Serious Adverse Events by System Organ Class and Preferred Term 
Safety Population  
  
  
System Organ Class    
Preferred Term  
Elamipretide 4 mg  
(N=xx) 
n (%)  
Elamipretide 40 mg  
(N=xx) 
n (%)  
Placebo  
(N=xx) 
n (%)  
All Subjects  
(N=xx) n 
(%)  
  
  
At Least One TESAE  
  
  
xx (xx.x%)  
  
  
xx (xx.x%)  
  
  
xx (xx.x%)  
  
xx (xx.x%)   
MedDRA SOC1  
  Preferred Term 1  
  Preferred Term 2   
…  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%)   
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%)   
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%)   
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%)   


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MedDRA SOC2  
  Preferred Term 1  
  Preferred Term 2  
  …  
   
 Etc.    
  
  
  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%)  
  
  
  
  
  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%)  
  
  
  
  
  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%)  
  
  
  
  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
TESAE (Treatment Emergent Serious Adverse Event) = serious adverse events occurring on or after the date of first dose of study 
medication, or worsening during the treatment period + 30 days. The definition of serious adverse event is in Protocol Section 9.6. If 
more than one serious adverse event is coded to the same preferred term for a subject, the subject will be counted only once for that 
preferred term. If more than one preferred term is coded to the same System Organ Class for a subject, the subject will be counted 
only once for that System Organ Class.  
Percentages are based on N.  
Adverse events coded using MedDRA version 20.0.  
Source: Listings 5.2  
  
Note to Programmer: SOCs sorted alphabetically. PTs sorted within SOCs in decreasing order of frequency in the all subject group.   
Subjects having several SAEs with the same SOC will be counted only once for that particular SOC. Subjects 
having several SAEs with the same PT will be counted only once for that particular PT.  
  
Table 6.4  
Incidence of Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and Intensity  
Safety Population  
System Organ  
Elamipretide 4 mg  
  
Elamipretide 40 mg  
Placebo  
All Subjects  
Class  
(N=xx)  
(N=xx)  
  
(N=xx)  
  
(N=xx)  
Moderate  Severe  
     Preferred Mild Moderate  Severe  Mild Moderate  Severe  
Mild Moderate  Severe  
Mild  
Term  
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  n (%)  
n (%)  
n (%)  n (%)  
n (%)  
n (%)  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 At Least One  xx 
 xx  
xx  
  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
TEAE  
(xx.x%) (xx.x%) (xx.x%)  
(xx.x%) (xx.x%) (xx.x%)  (xx.x%) (xx.x%) (xx.x%)  (xx.x%) (xx.x%) (xx.x%)  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
MedDRA SOC1  
xx  
xx  
xx  
  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
 
(xx.x%) (xx.x%) (xx.x%)  
(xx.x%) (xx.x%) (xx.x%)  (xx.x%) (xx.x%) (xx.x%)  (xx.x%) (xx.x%) (xx.x%)  


Stealth BioTherapeutics,Inc.  
  
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  Preferred  
xx  
xx  
xx  
  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
Term 1  
(xx.x%) (xx.x%) (xx.x%)  
(xx.x%) (xx.x%) (xx.x%)  (xx.x%) (xx.x%) (xx.x%)  (xx.x%) (xx.x%) (xx.x%)  
  Preferred  
xx  
xx  
xx  
  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
Term 2  
(xx.x%) (xx.x%) (xx.x%)  
(xx.x%) (xx.x%) (xx.x%)  (xx.x%) (xx.x%) (xx.x%)  (xx.x%) (xx.x%) (xx.x%)  
  …  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
   
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
MedDRA SOC2  
xx  
xx  
xx  
  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
 
(xx.x%) (xx.x%) (xx.x%)  
(xx.x%) (xx.x%) (xx.x%)  (xx.x%) (xx.x%) (xx.x%)  (xx.x%) (xx.x%) (xx.x%)  
  Preferred  
xx  
xx  
xx  
  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
Term 1  
(xx.x%) (xx.x%) (xx.x%)  
(xx.x%) (xx.x%) (xx.x%)  (xx.x%) (xx.x%) (xx.x%)  (xx.x%) (xx.x%) (xx.x%)  
  Preferred  
xx  
xx  
xx  
  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
Term 2  
(xx.x%) (xx.x%) (xx.x%)  
(xx.x%) (xx.x%) (xx.x%)  (xx.x%) (xx.x%) (xx.x%)  (xx.x%) (xx.x%) (xx.x%)  
  …  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 Etc.    
 
 
  
  
  
  
  
  
  
  
  
  
  
  
   
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
Percentages are based on N.  
TEAE = Treatment Emergent Adverse Event. An adverse event is considered treatment-emergent if the date of onset is on or after the 
date of first dose of study medication, or worsening during the treatment period + 30 days. Only the worst grade of intensity is 
counted for multiple occurrences of the same adverse event for a given subject. Adverse events coded using MedDRA version 20.0.  
Source: Listing 5.1  
  
Note to Programmer: SOCs and PTs sorted alphabetically.   
  
  
Table 6.5  
Incidence of Study Treatment Related Adverse Events by System Organ Class, Preferred Term, and Intensity Safety 
Population  
System  
Elamipretide 4 mg  
  
Elamipretide 40 mg  
Placebo  
All Subjects  
Organ Class  
(N=xx)  
(N=xx)  
  
(N=xx)  
  
(N=xx)  
      
Preferred  
Term  
  
At Least  
One Study  
Treatment  
Related AE  
Mild  
n (%)   
xx  
(xx.x%)  
  
Moderate  
n (%)   
xx  
(xx.x%)  
  
  
Severe n 
(%)  
  
  
 xx  
(xx.x%)  
Mild  
n (%)   
xx  
(xx.x%)  
  
Moderate  
n (%)   
xx  
(xx.x%)  
  
Severe  
n (%)   
  
  
xx  
(xx.x%)   
  
  
Mild  
n (%)   
xx  
(xx.x%)  
  
Moderate  
n (%)   
xx  
(xx.x%)  
  
Severe  
n (%)   
Mild  
n (%)  
Moderate   
n (%)  
Severe  
n (%)  
  
  
xx  
(xx.x%)   
  
xx  
(xx.x%)  
  
xx  
(xx.x%)  
  
xx  
(xx.x%)  


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MedDRA SOC1  
  Preferred  
Term 1  
  Preferred  
Term 2  
  …   
xx  
(xx.x%) 
xx  
(xx.x%) 
xx  
(xx.x%)  
  
  
xx  
(xx.x%) 
xx  
(xx.x%) 
xx  
(xx.x%)  
  
  
xx   
(xx.x%)  
xx   
(xx.x%)  
xx   
(xx.x%)  
  
  
  
  
xx  
(xx.x%) 
xx  
(xx.x%) 
xx  
(xx.x%)  
  
  
xx  
(xx.x%) 
xx  
(xx.x%) 
xx  
(xx.x%)  
  
  
xx  
(xx.x%)  xx  
(xx.x%)  xx  
(xx.x%)   
  
  
  
  
xx  
(xx.x%) 
xx  
(xx.x%) 
xx  
(xx.x%)  
  
  
xx  
(xx.x%) 
xx  
(xx.x%) 
xx  
(xx.x%)  
  
  
xx  
(xx.x%)  xx 
(xx.x%)  xx 
(xx.x%)   
  
  
  
  
xx  
(xx.x%) 
xx  
(xx.x%) 
xx  
(xx.x%)  
  
  
xx  
(xx.x%) 
xx  
(xx.x%) 
xx  
(xx.x%)  
  
  
xx  
(xx.x%) 
xx  
(xx.x%) 
xx  
(xx.x%)  
  
  
MedDRA SOC2  
  Preferred  
Term 1  
  Preferred  
Term 2  
  …  
Etc.  
xx  
(xx.x%) 
xx  
(xx.x%) 
xx  
(xx.x%)  
  
  
xx  
(xx.x%) 
xx  
(xx.x%) 
xx  
(xx.x%)  
  
  
xx   
(xx.x%)  
xx   
(xx.x%)  
xx   
(xx.x%)  
  
  
  
  
xx  
(xx.x%) 
xx  
(xx.x%) 
xx  
(xx.x%)  
  
  
xx  
(xx.x%) 
xx  
(xx.x%) 
xx  
(xx.x%)  
  
  
xx  
(xx.x%)  xx  
(xx.x%)  xx  
(xx.x%)   
  
  
  
  
xx  
(xx.x%) 
xx  
(xx.x%) 
xx  
(xx.x%)  
  
  
xx  
(xx.x%) 
xx  
(xx.x%) 
xx  
(xx.x%)  
  
  
xx  
(xx.x%)  xx 
(xx.x%)  xx 
(xx.x%)   
  
  
  
  
xx  
(xx.x%) 
xx  
(xx.x%) 
xx  
(xx.x%)  
  
  
xx  
(xx.x%) 
xx  
(xx.x%) 
xx  
(xx.x%)  
  
  
xx  
(xx.x%) 
xx  
(xx.x%) 
xx  
(xx.x%)  
  
  
Percentages are based on N.  
Study Treatment Related AE is a treatment-emergent adverse event classified by investigators as unlikely related,probably related or 
possibly related to study drug.   
Only the worst grade of intensity is counted for multiple occurrences of the same adverse event for a given subject. Adverse 
events coded using MedDRA version 20.0.  
Source: Listing 5.1  
  
Note to Programmer: SOCs and PTs sorted alphabetically.   
  
  
Table 6.6  
Incidence of Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and Relationship to Study Drug  
Safety Population  
Elamipretide 4 mg 
(N=xx)  
Elamipretide 40 mg 
(N=xx)  
Placebo  (N=xx)  
All Subjects  
(N=xx)  


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System Organ Class      
Preferred Term  
Not Related  
Related n 
(%)  n (%)  
Not Related  
Related n 
(%)  n (%)  
Not Related  
Related n 
(%)  n (%)  
Not Related  
Related n 
(%)  n (%)  
  
At Least One TEAE  
  
  
xx (xx.x%)  
  
  
xx (xx.x%)  
  
  
xx (xx.x%)  
  
  
xx (xx.x%)  
  
  
xx (xx.x%)  
  
  
xx (xx.x%)  
  
  
xx (xx.x%)  
  
  
xx (xx.x%)  
  
MedDRA SOC1  
  Preferred Term 1  
  Preferred Term 2  
  …  
  
MedDRA SOC2  
  Preferred Term 1  
  Preferred Term 2  
  …   
Etc.  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
  
  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
  
  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
  
  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
  
  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
  
  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
  
  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
  
  
  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%)  
  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%)  
  
  
  
  
Percentages are based on N.  
TEAE = treatment Emergent Adverse Event. An adverse event is considered treatment-emergent if the date of onset is on or after the 
date of first dose of study medication, or worsening during the treatment period + 30 days.  
Not Related = unrelated to study drug; Related = unlikely related, probably related or possibly related to study drug. If 
a subject had more than one occurrence in the same event category, only the most related occurrence was counted. Adverse 
events coded using MedDRA version 20.0.  
Source: Listing 5.1  
  
Note to Programmer: SOCs sorted alphabetically. PTs sorted within SOCs in decreasing order of frequency in the related-all subject column.   
  
Table 6.7  
Incidence of Treatment-Emergent Adverse Events Leading to Discontinuation of Study Drug by System Organ Class and Preferred Term 
Safety Population  
  
System Organ Class  
Preferred Term  
Elamipretide 4 mg 
(N=xx)  
Elamipretide 40 mg (N=xx) Placebo  
(N=xx)  
All Subjects  
(N=xx)  
n (%)  
n (%)  
n (%)  
n (%)  


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Any Adverse Event Leading to 
Discontinuation of  
Study Drug  
  
 
  
Any  
 
  
  
    xx (xx.x%)  
     
  
  
xx (xx.x%)  
      
  
  
xx (xx.x%)  
    
  
 xx (xx.x%)  
MedDRA SOC1  
  
  
  
MedDRA SOC2  
  
  
Etc.  
  
  
Any  
PT1  
PT2  
…  
 
Any  
PT1  
PT2   
 
 
    xx (xx.x%)  
   
xx (xx.x%)  
          
xx (xx.x%)  
      
  
    xx (xx.x%)  
   
xx (xx.x%)  
          
xx (xx.x%)  
      
  
  
  
xx (xx.x%)  
     
xx (xx.x%)  
     
xx (xx.x%)  
      
  
xx (xx.x%)  
     
xx (xx.x%)  
     
xx (xx.x%)  
      
  
  
  
xx (xx.x%)  
   
xx (xx.x%)  
   
xx (xx.x%)  
    
  
xx (xx.x%)  
   
xx (xx.x%)  
   
xx (xx.x%)  
    
  
  
  
 xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)  
 xx (xx.x%)   
xx (xx.x%)   
xx (xx.x%)  
  
  
  
Percentages are based on N.  
  
Adverse events coded using MedDRA version 20.0. Source: 
Listing 5.3  
  
Note to Programmer: SOCs sorted alphabetically. PTs sorted within SOCs in decreasing order of frequency in the all subject group.   
  
  
  
Table 6.8  
Deaths  
Safety Population  
  
Subject ID   Study Treatment  
 
Age/Sex [a]  
  
Date of Death  
Study Day of Death [b]  
Was Autopsy   
Performed? (Yes/No)  
xxxx  
Elamipretide 4 mg  73/F  
  
yyyy-mmm-dd  
xx  
Xxx  


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xxxx  
Placebo   
75/M  
  
yyyy-mmm-dd  
xx   
Xx   
[a] Age is age at informed consent in years. F = Female, M = Male.  
[Source: b]Study Day = date of death – date of first dose + 1. Listing 5.2  
  
  
  
 


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7. CLINICAL LABORATORY EVALUATIONS  
Table 7.1a  
Change From Baseline in Hematology Parameters by Visit Safety 
Population  
  
 
Time Point  
  
Value  
Baseline  
Value  
Baseline  
Value  
Baseline  
Value  
Baseline  
  
  
Parameter 
(unit)  
Elamipretide 4 mg 
(N=xx)  
Elamipretide 40 mg 
(N=xx)  
Placebo  (N=xx)  
All Subjects (N 
= xxx)  
Actual  
Change From  
Actual  
Change From  
Actual  
Change From  
Actual  
Change From  


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Baseline[a]  
  
  
  
  
  
Week 1   
  
  
  
  
Week 2   
  
  
  
  
Week 4  
  
  
  
  
  
Week 6  
  
  
  
 
n  Mean   
SD  
Median  
Min,  
Max  
 
n  Mean  
SD  
Median  
Min,  
Max  
 
n  Mean  
SD  
Median  
Min,  
Max  
 
n  Mean  
SD  
Median  
Min,  
Max  
 
n  Mean  
SD  
Median  
Min,  
  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x,  
  
  
  
  
  
  
 xx xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
 xx xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
 xx xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
 xx xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x,  
  
  
  
  
  
  
 xx xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
 xx xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
 xx xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
 xx xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x,  
  
  
  
  
  
  
 xx xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
 xx xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
 xx xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
 xx xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x,  
  
 
 
 
 
 
xx xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  


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<Parameter 1>     
  
  
  
  
  
  
  
 (unit) 
 
  


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Parameter  
(unit)  
Time Point  
 
 
Elamipretide 4 mg 
(N=xx)  
Elamipretide 40 mg 
(N=xx)  
Placebo  (N=xx)  
All Subjects (N 
= xxx)  
Actual Change From Value 
Baseline  
Actual Change From Value 
Baseline  
Actual 
Value  
Change From 
Baseline  
Actual Change From Value 
Baseline  
Max  
xx.x  
xx.x  
xx.x  
xx.x  
SD = Standard deviation.  
n represents the number of subjects contributing to summary statistics.  
[Source: Listinga] Baseline assessment is defined as last assessment prior to the first dose of study medication.  6.1   
  
 


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Parameter  
(unit)  
Treatment 
Group  
<Parameter  
1> (unit)  
 
Elamipretid 
e 4 mg  
 
 
 
 
Elamipretid 
e 40 mg  
 
 
 
 
Placebo  
 
 
 
Baselin 
e   
 
N  
Low  
Normal  
High  
 
N  
Low  
Normal  
High  
 
N  
Low  
Normal  
High  
 
 
Low  
n (%)  
  
  
xx xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)   
xx xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
  
xx xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
  
  
Week 1 
Normal n 
(%)  
  
  
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
  
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)   
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
High  
n (%)  
  
  
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
  
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)   
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Low  
n (%)  
  
  
xx xx 
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)   
xx xx 
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
  
xx xx 
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)   
  
Week 2 
Normal n 
(%)  
  
  
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
  
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)   
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)   
High  
n (%)  
  
  
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
  
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)   
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)   
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Low  
n (%)  
  
  
xx xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)   
xx xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
  
xx xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
  
  
Week 4  
Normal  High n 
(%) n (%)  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Low  
n (%)  
  
  
xx xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)   
xx xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
  
xx xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
  
  
Week 6  
Normal  High n 
(%) n (%)  
  
  
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
  
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)   
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
  
  
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
  
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)   
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
  
  
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
  
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)   
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
  
  
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
  
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)   
  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  
xx  
(xx.x% 
)  


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Table 7.1b  
Shift Table of Hematology Parameters From Baseline to Post Baseline 
Visits  
 
 
<Parameter  
2> (unit)  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


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Safety Population  
 


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Parameter  
  
Week 1  
  
Week 2  
  
Week 4  
  
Week 6  
(Treatment unit)  
  
Low  
Normal High  
Low  
Normal  High  
Low  
Normal  High  
 
Baselin 
Low  
Normal High  
Group  
e  
n (%) n (%) n (%)  
n (%) n (%) n (%)  n (%) n (%) n (%)  n (%) n (%) n (%)  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Percentages are based on N, number of subjects with assessment value at both the post-baseline visit and baseline. Source: 
Listing 6.1  
  
Table 7.2a  
Change From Baseline in Blood Chemistry Parameters by Visit 
Safety Population  
  
Note to Programmer: Same layout as Table 7.1a.   
Source: Listing 6.2  
Table 7.2b  
Shift Table of Blood Chemistry Parameters From Baseline to Post Baseline Visits 
Safety Population  
  
Note to Programmer: Same layout as Table 7.1b.   
Source: Listing 6.2   
Table 7.3a  
Change From Baseline in Urinalysis Parameters by Visit 
Safety Population  
  
Note to Programmer: Table layout is similar to Table 7.1a. The time points are baseline and Week 4. Only the parameters with continuous values will be presented.  
Source: Listing 6.3  
Table 7.3b  
Shift Table of Urinalysis Parameters From Baseline to Post Baseline Visits Safety 
Population  
  


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Note to Programmer: Table layout is similar Table 7.1b. Low, Normal, High replaced with Normal and Abnormal.  Time points are baseline and Week 4. All the 
parameters in urinalysis will be presented. Source: Listing 6.3  
Table 7. 4a  
Change From Baseline in Levels of hsTroponin by Visit 
Safety Population  
  
Note to Programmer: Same layout as Table 7.1a.  Include parameters: hsTroponin, Log hsTroponin.  For Log hsTroponin, use Log Ratio for Change from 
Baseline.    
  
Source: Listing 6.4  
  
  
  
 


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8. ELECTROCARDIOGRAM EVALUATIONS  
Table 8.1  
Change From Baseline in Electrocardiogram (ECG) Parameters by Visit Safety 
Population  
  
 
Time Point  
  
Value  
Baseline  
Value  
Baseline  
Value  
Baseline  
Value  
Baseline  
<Parameter 1>  
  
  
  
  
  
  
  
  
  
  
  
Parameter 
(unit)  
Elamipretide 4 mg 
(N=xx)  
Elamipretide 40 mg 
(N=xx)  
Placebo  (N=xx)  
All Subjects (N 
= xxx)  
Actual  
Change From  
Actual  
Change From  
Actual  
Change From  
Actual  
Change From  


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(unit)  
 
 
Baseline[a]  
  
  
  
  
  
Week 1   
  
  
  
  
Week 2   
  
  
  
  
Week 4  
  
  
  
  
  
Week 6  
  
 
n  
Mean   
SD  
Median  
Min,  
Max  
 
n  
Mean  
SD  
Median  
Min,  
Max  
 
n  
Mean  
SD  
Median  
Min,  
Max  
 
n  
Mean  
SD  
Median  
Min,  
Max  
 
n  
Mean  
  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx   
  
  
  
  
  
  
 xx xx.xx  
xx.xxx 
xx.xx 
xx.x, xx.x  
 xx xx.xx  
xx.xxx 
xx.xx 
xx.x, xx.x  
 xx xx.xx  
xx.xxx 
xx.xx 
xx.x, xx.x  
 xx 
xx.xx   
  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx   
  
  
  
  
  
  
 xx xx.xx  
xx.xxx 
xx.xx 
xx.x, xx.x  
 xx xx.xx  
xx.xxx 
xx.xx 
xx.x, xx.x  
 xx xx.xx  
xx.xxx 
xx.xx 
xx.x, xx.x  
 xx 
xx.xx   
  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx   
  
  
  
  
  
  
 xx xx.xx  
xx.xxx 
xx.xx 
xx.x, xx.x  
 xx xx.xx  
xx.xxx 
xx.xx 
xx.x, xx.x  
 xx xx.xx  
xx.xxx 
xx.xx 
xx.x, xx.x  
 xx 
xx.xx   
  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx 
xx.xx   
  
 
 
 
 
 
xx xx.xx  
xx.xxx 
xx.xx 
xx.x, xx.x  
xx xx.xx  
xx.xxx 
xx.xx 
xx.x, xx.x  
xx xx.xx  
xx.xxx 
xx.xx 
xx.x, xx.x  
xx 
xx.xx   


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Parameter  
(unit)  
Time Point  
 
 
Elamipretide 4 mg (N=xx)  Elamipretide 40 mg 
(N=xx)  
Placebo  (N=xx)  
All Subjects (N 
= xxx)  
Actual 
Value  
Change From 
Baseline  
Actual 
Value  
Change From 
Baseline  
Actual 
Value  
Change From 
Baseline  
Actual 
Value  
Change From 
Baseline  
  
  
  
SD  
Median  
Min, Max  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx.xxx 
xx.xx xx.x, 
xx.x  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx.xxx 
xx.xx xx.x, 
xx.x  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx.xxx 
xx.xx xx.x, 
xx.x  
xx.xxx 
xx.xx 
xx.x, 
xx.x  
xx.xxx 
xx.xx xx.x, 
xx.x  
SD = Standard deviation. n represents the number of subjects 
contributing to summary statistics.  
[Source: Listinga] Baseline assessment is defined as last assessment prior to the first dose of study medication.  7.2   
  
  
  
 


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9. VITAL SIGNS  
Table 9.1  
Change From Baseline in Vital Signs Safety 
Population  
  
  
Parameter  
  
(unit)  
Time  
Point  
Heart Rate  
  
(bpm)  
  
 Baseline   
  
  
  
  
  
  
  
  n Mean 
SD  
Median  
Min, Max  
Elamipretide 4 mg (N=xx)  Elamipretide 40 mg (N=xx)  
Placebo  (N=xx)  
All Subjects (N=xx) 
Actual  
Value  
  
  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
Change From  
Baseline  
  
  
 
  
 
  
 
  
 
  
 
  
Actual  
Value  
  
  
n Mean 
SD  
Median  
Min, Max  
Change From  
Baseline  
  
  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
Actual  
Value  
  
  
 
 
 
 
 
Change From  
Baseline  
  
  
 
 
 
 
 
Actual 
Value  
Change From 
Baseline  
  
  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
  
  
 
 
 
 
 
   Week 1   
  
  
  
  
  
  
  
  
n Mean 
SD  
Median  
Min, Max  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
 
 xx  
 
xx.x    xx.xx   
xx.x  
 xx.x, 
xx.x   
n Mean 
SD  
Median  
Min, Max  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
   Week 2   
  
  
  
  
  
   
  
  
n Mean 
SD  
Median  
Min, Max  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
 
 xx  
 
xx.x    xx.xx   
xx.x  
 xx.x, 
xx.x   
n Mean 
SD  
Median  
Min, Max  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
Week 4  
  
  
  
  
  
  
   
  
  
n Mean 
SD  
Median  
Min, Max  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
 
xx  
 xx.x    
xx.xx   xx.x   
xx.x, xx.x   
  
n Mean 
SD  
Median  
Min, Max  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  


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   Week 6   
  
  
  
  
  
   
  
  
n Mean 
SD  
Median  
Min, Max  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
 
 xx  
 
xx.x    xx.xx   
xx.x  
 xx.x, 
xx.x   
n Mean 
SD  
Median  
Min, Max  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
xx xx.x  
xx.xx xx.x 
xx.x, xx.x  
 
  
Elamipretide 4 mg  
Elamipretide 40 mg  
Placebo   
All Subjects  
  
(N=xx)  
(N=xx)  
(N=xx)  
(N=xx)  
Parameter  
  
(unit)  
 
Time  
Actual  
Change From  
Actual  
Change From  
Actual  
Change From  
Actual  
Change From  
Point  
Value  
Baseline  
Value  
Baseline  
Value  
Baseline  
Value  
Baseline  
SD = Standard deviation, BP = Blood pressure.  
n represents the number of subjects contributing to summary statistics. Source: Listing 7.1  
  
Note to Programmer: Repeat for Respiration Rate (breaths/min), Systolic BP (mmHg), Diastolic BP (mmHg), and Temperatures(oC)  


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10. PHYSICAL EXAMINATION  
Table 10.1  
Cardiovascular Physical Examination Results by Visit 
Safety Population  
  
  
Elamipretide 4 mg  
Elamipretide 40 mg  
Placebo  
All Subjects  
 
(N=xx)  
(N=xx)  
(N=xx)  
(N=xx)  
  
n (%)  
n (%)  
n (%)  
n (%)  
Screening  
Clinical Significant Abnormality Noted  
Yes  
No   
Not Done   
  
 
xx 
xx 
xx   
 
 
( xx.x%)  
( xx.x%)  
( xx.x%)  
 
  
 
xx 
xx 
xx   
  
  
( xx.x%)  
( xx.x%)  
( xx.x%)  
 
  
 
xx 
xx 
xx   
  
  
( xx.x%)  
( xx.x%)  
( xx.x%)  
  
  
 
xx 
xx 
xx   
 
 
 ( 
xx.x%)  
( xx.x%)  
( xx.x%)  
 
Baseline  
Clinical Significant Abnormality Noted  
Yes  
No   
Not Done   
  
 
xx 
xx 
xx   
 
 
( xx.x%)  
( xx.x%)  
( xx.x%)  
 
  
 
xx 
xx 
xx   
 
 
( xx.x%)  
( xx.x%)  
( xx.x%)  
 
  
 
xx 
xx 
xx   
  
  
( xx.x%)  
( xx.x%)  
( xx.x%)  
  
  
 
xx 
xx 
xx   
 
 
 ( 
xx.x%)  
( xx.x%)  
( xx.x%)  
 
Week 1  
Clinical Significant Abnormality Noted  
Yes  
No   
Not Done   
  
 
xx 
xx 
xx   
 
 
( xx.x%)  
( xx.x%)  
( xx.x%)  
 
  
 
xx 
xx 
xx   
 
 
( xx.x%)  
( xx.x%)  
( xx.x%)  
 
  
 
xx 
xx 
xx   
  
  
( xx.x%)  
( xx.x%)  
( xx.x%)  
  
  
 
xx 
xx 
xx   
 
 
 ( 
xx.x%)  
( xx.x%)  
( xx.x%)  
 
Week 2  
Clinical Significant Abnormality Noted  
Yes  
No   
Not Done  
  
 
xx 
xx 
xx  
 
 
( xx.x%)  
( xx.x%)  
( xx.x%)  
  
 
xx 
xx 
xx  
 
 
( xx.x%)  
( xx.x%)  
( xx.x%)  
  
 
xx 
xx 
xx  
  
  
( xx.x%)  
( xx.x%)  
( xx.x%)  
  
 
xx 
xx 
xx  
 
 
 ( 
xx.x%)  
( xx.x%)  
( xx.x%)  
  
Week 4  
Clinical Significant Abnormality Noted  
Yes  
No   
  
  
 
xx 
 
 
 
( xx.x%)  
  
  
 
xx 
 
 
 
( xx.x%)  
  
  
 
xx 
  
  
  
( xx.x%)  
  
  
 
xx 
 
 
 
 ( 
xx.x%)  


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Not Done  
xx 
xx  
( xx.x%)  
( xx.x%)  
xx 
xx  
( xx.x%)  
( xx.x%)  
xx 
xx  
( xx.x%)  
( xx.x%)  
xx 
xx  
( xx.x%)  
( xx.x%)  
  
Week 6  
Clinical Significant Abnormality Noted  
Yes  
No   
Not Done  
  
  
 
xx 
xx 
xx  
 
 
 
( xx.x%)  
( xx.x%)  
( xx.x%)  
  
  
 
xx 
xx 
xx  
  
  
  
( xx.x%)  
( xx.x%)  
( xx.x%)  
  
  
 
xx 
xx 
xx  
  
  
  
( xx.x%)  
( xx.x%)  
( xx.x%)  
  
  
 
xx 
xx 
xx  
 
 
 
 ( 
xx.x%)  
( xx.x%)  
( xx.x%)  
% = 100*n/N, where n = number of subjects in the specific row category and N = number of subjects in the column category. Source: 
Listing 7.3  
Table 10.2  
Physical Measurement Results by Visit Safety 
Population  
  


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Median  
xx.x  
xx.x  
xx.x  
xx.x  
  
Screening  
Clinical Significant Abnormality 
Noted n  Yes  
No   
Not Done  
Elamipretide 4 mg 
(N=xx)  
Elamipretide 40 mg 
(N=xx)  
Placebo (N=xx)  
All Subjects 
(N=xx)  
 xx xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
 
  
xx xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
 
  
xx xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
 xx xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
Weight (kg)  
 
n  
 
Mean   
 
SD  
 
Median  
 
Min, Max  
  
 xx 
xx.x  
xx.xx 
xx.x 
xx, xx   
 xx 
xx.x  
xx.xx 
xx.x 
xx, xx   
 xx 
xx.x  
xx.xx 
xx.x 
xx, xx   
 xx 
xx.x  
xx.xx 
xx.x 
xx, xx   
Height (cm)  
 
n  
 
Mean   
 
SD  
 
Median  
 
Min, Max  
xx 
xx.x  
xx.xx 
xx.x 
xx, xx  
xx 
xx.x  
xx.xx 
xx.x 
xx, xx  
xx 
xx.x  
xx.xx 
xx.x 
xx, xx  
xx 
xx.x  
xx.xx 
xx.x 
xx, xx  
  
Body Mass Index (kg/m2)  
 
n  
 
Mean   
 
SD  
 
Median  
 
Min, Max  
 xx 
xx.x  
xx.xx 
xx.x 
xx, xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, xx  
 xx 
xx.x  
xx.xx 
xx.x 
xx, xx  
  
Baseline  
Clinical Significant Abnormality 
Noted n  Yes  
No   
Not Done   
 
 xx xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%)   
 
 xx xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%)   
 
 xx xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%)   
 
 xx xx 
(xx.x%) xx 
(xx.x%) xx 
(xx.x%)   
Weight (kg)  
 
n  
 
Mean   
 
SD  
xx 
xx.x  
xx.xx  
xx 
xx.x  
xx.xx  
xx 
xx.x  
xx.xx  
xx 
xx.x  
xx.xx  


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Min, Max  
xx, xx  
 
 Week 1  
  
Clinical Significant Abnormality Noted   
n   
xx  
Yes  
xx (xx.x%)  
No   
xx (xx.x%)  
Not Done  
xx (xx.x%)  
  
 Weight (kg)    
 n  
xx  Mean   
xx.x 
 
 
SD 
 xx.xx  
 Median  
xx.x  
 Min, Max  
xx, xx  
 
 Week 2  
  
Clinical Significant Abnormality Noted   
n   
xx  
Yes  
xx (xx.x%)  
No   
xx (xx.x%)  
Not Done  
xx (xx.x%)  
  
 Weight (kg)    
 n  
xx  Mean   
xx.x 
 
 
SD 
 xx.xx  
 Median  
xx.x  
 Min, Max  
xx, xx  
 
 Week 4  
  
Clinical Significant Abnormality Noted   
n   
xx  
Yes  
xx (xx.x%)  
No   
xx (xx.x%)  
Not Done  
xx (xx.x%)  
  
 Weight (kg)    
 n  
xx  Mean   
xx.x 
 
 
SD 
 xx.xx  
 Median  
xx.x  
 Min, Max  
xx, xx  
 
 Week 6  
  
Clinical Significant Abnormality Noted   
n   
xx  
Yes  
xx (xx.x%)  
No   
xx (xx.x%)  
xx, xx  
 
 xx xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%)  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 
 xx xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%)  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 
 xx xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%)  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 
 xx xx 
(xx.x%) 
xx, xx  
 
 xx xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%)  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 
 xx xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%)  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 
 xx xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%)  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 
 xx xx 
(xx.x%) 
xx, xx  
 
 xx xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%)  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 
 xx xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%)  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 
 xx xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%)  
 xx 
xx.x  
xx.xx 
xx.x 
xx, 
xx  
 
 xx xx 
(xx.x%) 


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xx 
(xx.x%)  
xx 
(xx.x%)  
xx 
(xx.x%)  


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Not Done  
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%)  
  
  
  
  
 Weight (kg)    
  
  
  n  
xx  
xx  
xx  
xx  Mean  
 
xx.x   xx.x   xx.x   xx.x   SD  
xx.xx  xx.xx  xx.xx  xx.xx  Median  xx.x  
xx.x  
xx.x  
xx.x  
 
 Min, Max  
xx, xx  
xx, xx  
xx, xx  
xx, xx  
  
  
  
  
  
% = 100*n/N, where n = number of subjects in the specific row category and N = number of subjects in the column category. Source: 
Listing 7.3  
  
  
 


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11. CONCOMITANT MEDICATIONS/TREATMENTS  
Table 11.1  
Concomitant Medications by ATC and Preferred Drug Name Safety 
Population  
  
ATC Class      Preferred Drug Name  
Elamipretide 4 mg 
(N=xx)  
Elamipretide 40 mg 
(N=xx)  
Placebo  (N=xx)  
All Subjects  
(N=xx)  
n (%)  
n (%)  
n (%)  
n (%)  
Taking at Least One Concomitant Medication  
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%)  
xx (xx.x%)  
  
ATC Highest Level Class 1  
   Medication 1[a]  
   Medication 2  
…  
ATC Highest Level Class 2   
   Medication 1  
   Medication 2   
Etc.  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
xx (xx.x%) xx 
(xx.x%) xx 
(xx.x%)  
  
  
ATC = Anatomic-Therapeutic-Chemical 3 Classification code.  
[a] Preferred drug name via the World Health Organization Drug Dictionary (WHO-DD).  
Percentages are based on N.  
Included any medications taken during the study (from the date of first dose of investigational product to the date of last visit).   
Source: Listing 3.2  
  
Note to Programmer: ATCs sorted alphabetically. All medications will be sorted alphabetically by medication class and medication subclass.  
  
  
LISTINGS  
  
LISTINGS – SUBJECT DISPOSITION, DEMOGRAPHICS, AND BASELINE CHARACTERISTICS   
  


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Listing 1.1  
Study Completion or Early Discontinuation Status 
All Randomized Subjects  
  
  
Subject  
ID  
Age/Sex[a]  
Date of  
Randomization/  
Treatment 
Assigned  
Study Drug  
Administered  
Treatment  
Start/End  
Date   
Study Completion  
Status/  
Last Study Date [b]   
(Study Day) [c]  
Reason for Early 
Discontinuation  
Included in  
Safety/ITT/Per- 
Protocol  
Population?   
xxx-xxx 
xxx-xxx 
xxx-xxx 
xxx-xxx 
xxx-xxx  
73/F  
66/M 69/F 
xx/X xx/X  
yyyy-mmm-dd 
Elamipretide 4 mg  
yyyy-mmm-dd 
Elamipretide 40 
mg  
yyyy-mmm-dd 
Elamipretide 4 mg  
yyyy-mmm-dd 
Placebo yyyy-mmm-
dd  
Placebo  
Elamipretide 4 mg  
Elamipretide 40 
mg  
Elamipretide 40 
mg  Placebo  
Placebo  
 
yyyy-mmm-dd/ 
yyyy-mmm-dd  
yyyy-mmm-dd/ 
yyyy-mmm-dd  
yyyy-mmm-dd/ 
yyyy-mmm-dd  
 
yyyy-mmm-dd / 
yyyy-mmmdd  
Completed yyyy-mmm-dd 
(xxx) Discontinued 
yyyy-mmm-dd (xxx) 
Discontinued yyyy-
mmm-dd (xxx) 
Discontinued yyyy-
mmm-dd (xxx) 
Discontinued yyyy-
mmm-dd (xxx)  
 
Adverse event  
Sponsor decision, 
specific reason 
Withdrawal of 
consent 
Investigator 
reason, specific 
reason  
 
Yes/Yes/Yes  
Yes/Yes/No  
No/No/No  
No/No/No  
Yes/Yes/No  
 
[a] Age is age at informed consent. Sex: M = Male, F = Female.  
[b] Last Study Date = date of last visit.  
[c] Study Day = study date – date of randomization + 1.  
  
Note to Programmer: Listing is sorted by Treatment Group and Subject ID.  
  
  
  
Listing 1.2  
Violations of Inclusion/Exclusion Criteria  
All Subjects  
 
Informed Consent  
Date Informed  
Satisfied All Inclusion/  
Subject ID Form Signed  
Consent Signed  
Exclusion Criteria  
Inclusion/Exclusion Criteria Failed  


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xxx-xxx  
Yes  
yyyy-mmm-dd  
No  
INCL. # 3, EXCL # 6, Other: xxxxxxxx 
xxx-xxx  
 
 
 
Yes  
 
 
 
yyyy-mmm-dd  
 
 
 
Yes  
 
 
 
 
 
 
 
 
 
 
 
 
  
Note to Programmer: Listing is sorted by Randomized Treatment Group and Subject ID.  
  
  
  
 


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CONFIDENTIAL  
  
  
Listing 1.3  
Randomization Status  
All Subjects  
Subject ID 
xxx-xxx  
Randomized? 
Yes  
Randomized Treatment Assignment 
Elamipretide 4 mg  
Randomization Number 
xxxxx  
Randomization Date  
Reason not Randomized  
yyyy-mmm-dd  
 
xxx-xxx  
No  
  
  
  
xxxxxxxxxxxxxxxxxxxxxx  
  
  
  
  
  
  
  
  
  
Note to Programmer: Listing is sorted by Subject ID.  
  
  
 


Stealth BioTherapeutics,Inc.  
  
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CONFIDENTIAL  
  
  
Listing 1.4  
Demographic Information  
All Randomized Subjects  
 
 
Randomized   
Baseline  
[a] Age is age at informed consent. Sex: M = Male, F = Female.  
  
  
  
  
Note to Programmer: Listing is sorted by Randomized Treatment Group and Subject ID.  
  
  
  
 
Subject 
ID  
Treatment   
Assignment  
Age/Sex [a]  
Race  
  
Ethnicity   
Height 
(cm)  
Weight 
(kg)  
BMI  
(kg/m2)  
xxx-xxx  
Elamipretide  
4 mg  
73/F  
White  
  
Hispanic or Latino  
xxx.x  
xxx.x  
xx.x  
xxx-xxx  
Placebo  
66/M  
Black  
  
Not Hispanic or Latino  
xxx.x  
xxx.x  
xx.x  


Stealth BioTherapeutics,Inc.  
  
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CONFIDENTIAL  
  
  
Listing 1.5  
Medical and Surgical History  
All Randomized Subjects  
Subject 
ID  
Randomized  
Treatment 
Age/Sex 
Assignment [a]  
Any  
Medical/  
Surgical 
History  
Category  
Diagnosis or 
Surgery  
Start Date  
Is Condition Still  
Present at 
Screening?  
End Date  
xxx-xxx  
Elamipretide 73/F 4 
mg  
Yes  
Drug Allergy  xxxxxxxxx  
yyyy-mmm-dd  
No  
yyyy-mmm-dd  
  
  
 
  
 
  
 
 
Hepatic   
xxxxxxxxx   
yyyy-mmm-dd   
Yes   
 
 
xxx-xxx  
  
Elamipretide 66/M  
40 mg  
 
  
Yes  
 
Psychiatric  
 
xxxxxxxxxx  
 
yyyy-mmm-dd  
 
No  
 
yyyy-mmm-dd  
 
xxx-xxx Placebo  
78/F  
No  
  
  
  
  
  
  
  
  
  
  
  
  
  
   
  
  
  
  
[a] Age is age at informed consent. Sex: M = Male, F = Female.  
  
Note to Programmer: Listing is sorted by Randomized Treatment Group and Subject ID.  
  
  
  
LISTINGS – EFFICACY   
  
Listing 2.1  
Cardiac MRI Assessments – Actual and Change from Baseline Values  
ITT Population  
  


Stealth BioTherapeutics,Inc.  
  
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4 mg  
73/F  
(LV ESV)  
 
Subject 
ID  
Treatment 
Age/Sex 
Assignment [a]  
Visit  
Visit date  
Parameter   
Value  
Change from 
Screening 
(Baseline 
value)  
xxx-xxx  Elamipretide  
Screening  
yyyy-mmm-dd  
Left Ventricular End Systolic Volume  
xxx.xx  
 
 
  
  
  
 
  
  
  
 
  
  
  
 
  
  
  
 
  
  
  
 
  
  
  
 
  
  
  
 
  
  
  
 
  
  
  
 
  
  
  
 
  
  
  
 
  
  
  
 
  
  
  
 
  
  
  
 
  
  
  
 
  
  
  
 
  
  
  
 
  
  
Week 1  
 
  
  
  
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Left Ventricular End Systolic Volume (LV 
ESV), Indexed by BSA  
Left Ventricular Ejection Fraction  
(LVEF)  
Left Ventricular End Diastolic Volume  
(LV EDV)  
Left Ventricular End Diastolic Volume 
(LV EDV), Indexed by BSA  
Left Ventricular Myocardial Mass (LV  
Mass)  
Left Ventricular Myocardial Mass (LV  
Mass), Indexed by BSA  
Left Ventricular Stroke Volume (LVSV)  
Left Ventricular Cardiac Output (LVCO)  
Right Ventricular End Systolic Volume  
(RV ESV)  
Right Ventricular End Systolic Volume 
(RV ESV), Indexed by BSA  
Right Ventricular End Diastolic Volume  
(RV EDV)  
Right Ventricular End Diastolic Volume 
(RV EDV), Indexed by BSA  
Right Ventricular Myocardial Mass (RV  
Mass)  
Right Ventricular Myocardial Mass (RV 
Mass), Indexed by BSA  
Right Ventricular Ejection Fraction  
(RVEF)  
Ischemic/Non-ischemic Status  
  
LV ESV  
LV ESV, Indexed by BSA  
LVEF  
xxx.xx xxx.xx 
xxx.xx xxx.xx 
xxx.xx xxx.xx 
xxx.xx xxx.xx 
xxx.xx xxx.xx 
xxx.xx xxx.xx 
xxx.xx xxx.xx 
xxx.xx  
Xxxxxxx  
xxx.xx 
xxx.xx 
xxx.xx  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxx.xx 
xxx.xx 
xxx.xx  
 
yyyy-mmm-dd  
 
 


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Week 4  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
yyyy-mmm-dd  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LV EDV  
LV EDV, Indexed by BSA  
LV Mass  
LV Mass, Indexed by BSA  
LVSV  
LVCO  
RV ESV  
RV ESV, Indexed by BSA  
RV EDV  
RV EDV, Indexed by BSA  
RV Mass  
RV Mass, Indexed by BSA  
RVEF   
LV ESV  
LV ESV, Indexed by BSA  
LVEF  
LV EDV  
LV EDV, Indexed by BSA  
LV Mass  
LV Mass, Indexed by BSA  
LVSV  
LVCO  
RV ESV  
RV ESV, Indexed by BSA  
RV EDV  
RV EDV, Indexed by BSA  
RV Mass  
RV Mass, Indexed by BSA  
RVEF  
 
 
 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx  
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx  
 
 
 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx  
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
 
 
 


Stealth BioTherapeutics,Inc.  
  
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 xxx-
xxx  
 
 
 
 
 
 
  
Elamipretide  
40 mg  
65/M  
 
Screening  
 
  
  
  
  
[a] Age is age at informed consent. Sex: M = Male, F = Female.  
  
Note to Programmer: Listing is sorted by Randomized Treatment Group, Subject ID, and Visit Date.  Ischemic/Non-ischemic status only needs to 
be reported at Screening.    
  
  
Listing 2.2  


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Echocardiography Assessments– Actual and Change from Baseline Values 
ITT Population  
  
Subject Treatment  
Age/Sex  
Change from  
xxx-xxx  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Elamipretide 73/F 4 
mg  
Screening  
yyyy-mmm-dd  
E/A (Ratio Between Early And Late Mitral 
Inflow Velocity)  
E/e' (Ratio Between Early Mitral  
Inflow Velocity and Mitral Annular Early 
Diastolic Velocity)  
Left Ventricular End Systolic Volume  
(LV ESV)  
Left Ventricular End Systolic Volume  
(LV ESV), Indexed by BSA  
Biplane Ejection Fraction (EF)  
Left Ventricular End Diastolic Volume  
(LV EDV)  
Left Ventricular End Diastolic Volume 
(LV EDV), Indexed by BSA  
Left Ventricular Global Longitudinal  
Strain (LV GLS)  
Left Atrial Volume (LAV)  
Left Atrial Volume (LAV), Indexed by  
BSA  
Left Ventricular Mass (LVM)  
Left Ventricular Mass (LVM), Indexed by 
BSA  
Mitral Regurgitation Severity (MRS)  
Tricuspid Regurgitation Severity (TRS)  
Right Ventricular Fractional Area  
Change (RV FAC)  
Right Ventricular Systolic Pressure  
(RVSP)   
E/A  
E/e'  
LV ESV  
LV ESV, Indexed by BSA  
EF  
xxx.xx   xxx.xx 
 xxx.xx 
 xxx.xx 
  
xxx.xx   xxx.xx 
 xxx.xx 
 xxx.xx 
  
xxx.xx   xxx.xx 
  
xxx.xx   xxx.xx 
  
xxx.xx   xxx.xx 
 xxx.xx 
 xxx.xx 
  
 
 xxx.xx 
 xxx.xx 
 xxx.xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Stealth BioTherapeutics,Inc.  
  
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CONFIDENTIAL  
  
  
ID 
 
Assignment  
[a]  
Visit  
Visit date  
Parameter   
Value  
Baseline  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline  
 
 
 
 
 
 
 
 
 
 
 
 
 
yyyy-mmm-dd  
 
 
 
 
 
 
 
 
 
 
 
 
LV EDV  
LV EDV, Indexed by BSA  
LV GLS  
LAV  
LAV, Indexed by BSA  
LVM  
LVM, Indexed by BSA  
MRS  
 xxx.xx 
 xxx.xx 
 xxx.xx 
 xxx.xx 
 xxx.xx 
 xxx.xx 
 xxx.xx 
 xxx.xx 
 xxx.xx 
 xxx.xx 
  


Stealth BioTherapeutics,Inc.  
  
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CONFIDENTIAL  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 4  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 6  
 
 
 
 
 
 
 
 
 
 
  
yyyy-mmm-dd  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
yyyy-mmm-dd  
 
 
 
 
 
 
 
 
 
 
TRS  
RV FAC  
RVSP   
E/A  
E/e'  
LV ESV  
LV ESV, Indexed by BSA  
EF  
LV EDV  
LV EDV, Indexed by BSA  
LV GLS  
LAV  
LAV, Indexed by BSA  
LVM  
LVM, Indexed by BSA  
MRS  
TRS  
RV FAC  
RVSP   
E/A  
E/e'  
LV ESV  
LV ESV, Indexed by BSA  
EF  
LV EDV  
LV EDV, Indexed by BSA  
LV GLS  
LAV  
LAV, Indexed by BSA  
LVM  
LVM, Indexed by BSA  
MRS  
TRS  
RV FAC  
RVSP  
 
 
 
 
xxx.xx 
xxx.xx 
xxx.xx  
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx  
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx  
 
 
 
 
 
 
 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx  
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
 
 
 
 


Stealth BioTherapeutics,Inc.  
  
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CONFIDENTIAL  
  
  
 
 
 
 
 
 
 
 xxx-
xxx  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Elamipretide 65/M  
40 mg  
 
  
 
Screening  
 
 
  
  
  
  
[a] Age is age at informed consent. Sex: M = Male, F = Female.  


Stealth BioTherapeutics,Inc.  
  
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CONFIDENTIAL  
  
  
  
Note to Programmer: Listing is sorted by Randomized Treatment Group, Subject ID, and Visit Date.  
  
  
Listing 2.3  
Exploratory Assessments – Actual and Change from Baseline Values  
ITT Population  
  
Was a 6MWT  
Subject Treatment  
Age/Sex  
Change from  
performed?  
ID  
Assignment  
[a]  
Visit  
Visit date Parameter   
Value  
Baseline [b] [c]  


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[a] Age is age at informed consent. Sex: M = Male, F = Female.  
  
[b] Log ratio for log-transformed parameters.  
[c] Assessed only at Baseline and Week 4.  
  
Note to Programmer: Listing is sorted by Randomized Treatment Group, Subject ID, and Visit Date.  
Listing 2.4.1  
Six-Minute Walk Test – Part I  
ITT Population  
  
Subje ct 
ID  
Treatment 
Assignmen 
t  
Age/S 
ex 
[a]  
Visit 
Baseli 
ne  
 
Vis 
it 
dat 
e 
yyy 
ymmm 
-dd   
Was a 
6MWT 
perform 
ed? Yes  
If No, 
Reason  
 
Supplemen 
tal 
oxygen 
used 
If  
Yes 
, 
O2 
Flo 
w, 
Tim 
e 
Pre  
Vita 
ls 
Time  
HH:M 
M  
Blood 
Pressu 
re 
(mmHg) 
Heart 
Rate 
(beat 
s/ 
Respirat 
ory Rate 
(breaths 
/ min)  
Sp 
O2 
(% 
)  
Dyspn 
ea 
(Borg 
)  
Fatig 
ue 
(Borg 
)  
xxx-xxx  
  
  
  
Elamipretide  
4 mg  
73/F  
 
  
 
  
 
  
Baseline  
 
 
 
yyyy-mmmdd  
 
 
 
Distance Walked (meters) During 6-
minute Walking Test (6MWT)  
Levels of NT-pro-BNP (Log value)  
Kansas City Cardiomyopathy 
Questionnaire (KCCQ) Score   
xxx.xx  
xxx.xx 
(xx.xx) 
xxx.xx   
 
 
 
 
Yes  
 
 
 
  
 
  
Week 1  
yyyy-mmmdd  
NT-pro-BNP (Log value)  
xxx.xx (xx.xx)  xxx.xx (xx.xx)   
  
  
  
 
  
 
  
 
  
 
Week 2  
 
yyyy-
mmmdd   
 
NT-pro-BNP (Log value)  
 
xxx.xx 
(xx.xx)  
 
xxx.xx 
(xx.xx)  
 
 
 
 
  
  
  
  
 
  
 
  
 
  
 
  
Week 4  
 
 
 
yyyy-mmmdd  
 
 
 
6MWT  
NT-pro-BNP (Log value)  
KCCQ  
 
xxx.xx  
xxx.xx 
(xx.xx) 
xxx.xx   
xxx.xx  
xxx.xx 
(xx.xx) 
xxx.xx   
No  
 
 
 
  
 
  
Week 6  
yyyy-mmmdd  
NT-pro-BNP (Log value)  
xxx.xx (xx.xx)  xxx.xx (xx.xx)   
 xxx-xxx  
  
 
  
Elamipretide  
40 mg  
65/M  
 
  
 
Baseline  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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xxxxxx  
  
  
Elamipret 
ide 4 mg  
 
 
73/F  
 
 
 
 
 
 
 
 
during 
test? Yes  
 
 
Typ 
e 
xx. 
x, 
xxx 
xx   
 
 
 
 
 
xxx/xx 
x  
 
 
min) 
xxx  
 
 
xx  
 
 
xx 
x  
 
 
xx.x  
 
 
xx.x  
 
 
  
  
  
 
 
 
 
 
 
 
Week 4  
 
yyy 
ymmm 
-dd  
 
 
No  
 
New 
unstab 
le 
angina 
or MI   
 
No  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx   Elamipret 
ide 40 mg  
 
65/M  
 
Baseli 
ne   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[a] Age is age at informed consent. Sex: M = Male, F = Female.  
  
  
Note to Programmer: Listing is sorted by Randomized Treatment Group, Subject ID, and Visit Date.  
  
  
Listing 2.4.2  
Six-Minute Walk Test – Part II  
ITT Population  
  
Subje 
ct  
 
Sit  
If  
 
Subject  
at  
Yes,  
Any  
Any  
 
Experience  
If  
any  
Time  
Interruptio Clinically  
Vis Sta Sto Total any If Other Point Subje n Require Significan Treatment Age/S it rt p Distan 
Interrupti Yes, , Durin ct Discontinua t Subje Assignmen ex dat Tim Tim Tim ce ons During Reas Speci g First tion of Abnormalit ct ID t 
[a] Visit e e e e Walked 6MWT? on fy Test? Sat 6MWT? ies Noted?  
xxx- 
Elamipret 
Baseli yyy 
Pre HH: 
HH: 
xxx  
Yes  
Leg   
Yes  
HH:MM Yes  
  
xxx  
ide 4 mg  ne  
y- 
MM  
MM  
Cram mmm
 ps  


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73/F  
-dd  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Week 4 yyy 
Pos HH: 
HH: 
xxx  
No  
  
  
  
  
  
  
 
y- 
t  
MM  
MM  
mmm -
dd  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 xxx-
 Elamipret 
Baseli    
  
  
  
  
  
  
  
  
  
 xxx  
ide 40 mg 65/M ne  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
[a] Age is age at informed consent. Sex: M = Male, F = Female.  
  
  
Note to Programmer: Listing is sorted by Randomized Treatment Group, Subject ID, and Visit Date.  
  
  


Stealth BioTherapeutics,Inc.  
  
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CONFIDENTIAL  
  
  
Listing 2.5.1  
Kansas City Cardiomyopathy Questionnaire – Page 1  
ITT Population  
  
Doing  
Yardwork, Climbing a 
Walking 1 Housework, Flight of  
 
Block on  
or  
Stairs  
Subject Treatment  
Age/Sex  
Visit Dressing  
Showering Level  
Carrying  
Without ID 
 Assignment  
[a]  
Visit  date Yourself  / Bathing Ground  
Groceries Stopping  
xxx-xxx Elamipretide  
4 mg  
73/F  
 
  
  
 
  
  
 
  
  
 
  
  
 
  
  
xxx-xxx Elamipretide  
40 mg  
65/M  
 
  
  
Baseline yyyy- 
mmmdd  
 
  
 
  
 
  
Week 4  
yyyy- 
mmmdd  
 
  
Baseline   
 
  
Extremely  
Limited  
 
 
 
 
 
 
 
  
  
  
  
  
  
  
 Moderately   
Limited  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Not at All 
Limited  
 
 
 
  
  
  
  
  
  
  
[a] Age is age at informed consent. Sex: M = Male, F = Female.  
  
Note to Programmer: Listing is sorted by Randomized Treatment Group, Subject ID, and Visit Date.  
  
  
Compared 
Hurrying  
with 2 
or Jogging Weeks Ago, 
(as if to Have  
Catch a Symptoms Bus) 
Changed?  
  
Much Worse  
  
  
  
  
  
  
 Much  
Better  
  
  
  
  
  
  
  
   
Listing 2.5.2  
Kansas City Cardiomyopathy Questionnaire – Page 2  
ITT Population  
  
Activity   


  
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Page 101 of 112  
CONFIDENTIAL  
Subject Treatment  
Age/Sex  
ID  
Assignment  
[a]  
Visit  
How Many Times Visit 
Did you Have date Swelling? 
How Much Has  
Swelling  
Bothered You?  
How Many Times 
Has Fatigue 
Limited Your  
Ability?  
How Much Has  
Fatigue  
Bothered You?  
How Many Times 
Has Shortness 
of Breath 
Limited Your  
Ability?  
xxx-xxx Elamipretide  
Baseline 
4 mg  
73/F  
  
  
  
  
  
  
  
  
yyyymmmdd   
 
Every morning  
 
 
Quite a bit 
bothersome  
 
 
All of the time  
 
 
Quite a bit 
bothersome  
 
 
All of the time 
 
 
  
  
  
  
 
  
  
Week 4  
  
  
  
  
xxx-xxx Elamipretide Baseline 40 mg 65/M  
  
  
  
  
yyyymmmdd   
 
 
 
1-2 times a 
week  
 
 
 
 
Slightly 
bothersome  
 
 
 
 
Less than once 
a week  
 
 
 
 
Slightly 
bothersome  
 
 
 
 
Less than once 
a week  
 
 
 
[a] Age is age at informed consent. Sex: M = Male, F = Female.  
  
  
Note to Programmer: Listing is sorted by Randomized Treatment Group, Subject ID, and Visit Date.  
  
  
Listing 2.5.3  
Kansas City Cardiomyopathy Questionnaire – Page 3  
ITT Population  
  


  
ElamipretideTM (MTP-131 for SC Injection)  
  
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Page 102 of 112  
CONFIDENTIAL  
[a] Age is age at informed consent. Sex: M = Male, F = Female.  
  
  
Note to Programmer: Listing is sorted by Randomized Treatment Group, Subject ID, and Visit Date.  
  
  
Listing 2.5.4  
Kansas City Cardiomyopathy Questionnaire – Page 4  
ITT Population  
  
Treatment  
Age/Sex  
Assignment  
[a]  
Visit  
How Often Have  
Activity  
Subject Treatment  
Age/Sex  
ID  
Assignment  
[a]  
Visit  
How Much Has  
Shortness of  
Breath 
Visit 
Bothered 
date You?  
How Many 
Times Forced 
to Sleep 
Sitting Up  
Because of 
Shortness of  
Breath?  
How Sure Are  
You That You  
Know What to  
Do if Heart 
Failure Gets  
Worse?  
Understand  
What Things 
You are Able 
to Do to Keep 
Heart Failure 
Symptoms from 
Getting  
Worse?  
Heart  
Failure  
Limited 
Enjoyment of  
Life?  
If You Had to 
Spend the 
Rest of Your  
Life with 
Heart  
Failure, How 
Would You  
Feel?  
xxx-xxx Elamipretide  
Baseline 
4 mg  
73/F  
  
  
  
  
  
  
  
  
yyyymmmdd  
 
 
Quite a bit 
bothersome  
 
 
Every night  
 
 
Not very 
sure  
 
 
Somewhat 
understand  
 
 
It has 
limited my 
enjoyment 
of life 
quite a bit   
 
Mostly 
dissatisfied  
 
 
  
  
  
  
 
  
  
Week 4  
  
  
  
  
xxx-xxx Elamipretide Baseline 40 mg 65/M  
  
  
  
  
yyyymmmdd  
 
 
 
 
Slightly 
bothersome  
 
 
 
 
1-2 times a 
week  
 
 
 
 
Mostly sure  
 
 
 
Mostly 
understand  
 
 
 
It has 
slightly 
limited my 
enjoyment 
of life  
 
 
 
Mostly 
satisfied  
 
 
 


  
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CONFIDENTIAL  
Subject 
ID xxx-
xxx  
  
  
Elamipretide  
Baseline 
4 mg  
73/F  
 
  
  
 
  
  
Visit 
date 
yyyymmmdd   
 
You Felt 
Discouraged?  
 
 
 
Hobbies,  
Recreational  
Activities  
Severely  
Limited  
 
 
Working or  
Visiting Family Intimate  
Doing Household or Friends Out Relationships  
Chores  of Your Home  with Loved Ones   
 
  
 
  
  
 
  
  
  
  
  
 
  
  
 
  
Week 4  
 
  
  
yyyymmmdd   
 
 
 
 
 
 
 
  
 Moderately  
  
  
Limited  
 
  
  
xxx-xxx  
  
Elamipretide  
Baseline 
40 mg  
65/M  
 
  
  
 
 
 
 
 
 
 
  
Did not limit  
at all  
 
  
  
  
[a] Age is age at informed consent. Sex: M = Male, F = Female.   
  
Note to Programmer: Listing is sorted by Randomized Treatment Group, Subject ID, and Visit Date.  
  
  


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Listing 2.5.5  
Kansas City Cardiomyopathy Questionnaire – Summary Scores  
ITT Population  
  
 
Sympt 
Overal Clinic 
 
Symptom Symptom om  
Total Self- 
Quali 
l  
al  
 
Age/S 
Visi Physical Stabili Frequen Burde 
Sympt 
Effica 
ty of Social  
Summar Summar 
Subje 
Treatment ex  
t  
Limitati ty  
cy  
n  
om  
cy  
Life  
Limitati y  
y  
ct ID Assignment [a]  
Visit  
date on Score Score  
Score  
Score Score Score  
Score on Score Score Score  
xxx- Elamipreti Baseli yyyy          xxx de 4 mg ne - 
mmm- 
 
73/F  
dd  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Week 4 yyyy  
  
  
  
  
  
  
  
  
  
mmmdd  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 xxx- 
Elamipreti
 Baseli   
  
  
  
  
  
  
  
  
  
 xxx  
de 40 mg  
65/M  
ne  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
[a] Age is age at informed consent. Sex: M = Male, F = Female.  
  
  
Note to Programmer: Listing is sorted by Randomized Treatment Group, Subject ID, and Visit Date.  


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LISTINGS – STUDY DRUG AND PRIOR/CONCOMITANT MEDICATIONS  
  
Listing 3.1  
Study Drug Injection Records Safety 
Population  
  
If Incomplete Injection,  
Total Volume  
 
Study  
Vial  
Any  
Injected (mL, Reason(s) for  
Entire  
Subject Study Drug Dose Number(s) Date of Time of Incomplete % of Incomplete Dose ID Treatment  Injected (mg) Used Injection Injection 
Injections? Expected) Injection Injected xxx-xxx Elamipretide Yes xxx.xx xxxx- yyyy-mmm- hh:mm Yes 0.5 mL, 50% xxxxxxxxxxxxxxx Yes  
 
4 mg  
xxxx,  
dd  
xxxx-xxxx  
  
  
  
  
  
  
  
  
  
  
 xxx-xxx Placebo  
No,  
  
  
  
 
  
  
  
  
Reason:  
xxxxxx  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


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Listing 3.2  
Prior and Concomitant Medications by Subject 
Safety Population  
  
Subject 
ID  
Study  
Treatment  
Age/Sex 
[a]  
Medication  
Class/Preferred 
Term  
(Investigator  
Text)  
Reason  
Dose  
Unit  
Route  Frequency  
Prior/ 
Concomita 
nt[b]  
Start Date  
End Date / 
Ongoing  
Date of 
First dose 
of Study 
Treatment  
xxx-xxx  
  
Elamipret 
ide 4 mg  
 
73/F  
 
XXXXXXXXXXXX  
 
XXXXXXXX  
(XXXXXXXXXX)  
XXXXXXXXXXXX  
 
XXXXXXXX  
(XXXXXXXXXX)  
xxxxxxx 
xxxx  
xxxxxxx 
xxxx  
xxxxx  
xxxxx  
xxxxx  
xxxxx  
xxxxx  
xxxxx  
xxx  
xxx  
Y/N  
N/Y  
yyyy-mmm-dd 
Ongoing  
yyyy-mmm-dd 
yyyy-mmm-dd  
yyyy-mmm-dd  
yyyy-mmm-dd  
  
xxx-xxx   
 
Placebo   
 
65/M  
 
 
XXXXXXXXXXXX  
 
XXXXXXXX  
(XXXXXXXXXX)  
 
 
xxxxxxx 
xxxx   
 
xxxxx   
 
xxxxx   
 
xxxxx   
 
xxx   
 
Y/Y   
 
yyyy-mmm-dd 
yyyy-mmm-dd   
 
yyyy-mmm-dd   
[a] Age is age at informed consent. Sex: M = Male, F = Female.  
[b] Prior = any medications taken prior to the date of first dose of investigational product.  
Concomitant = any medications taken during the study (from the date of first dose of investigational product to the date of last 
visit).  
  
Note to Programmer: Listing is sorted by Study Treatment, Subject ID  
  
  
LISTINGS – PLASMA CONCENTRATION  
  
Listing 4.1  
Plasma Concentrations of Elamipretide and Metabolites (M1, M2) 
Safety Population  
  


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Plasma Concentration (unit)  
Subject ID  
Treatment Assignment  
Age/Sex [a]  
Date  
Time label  
Elamipretide M1  
M2  
xxx-xxx  
Elamipretide 4 mg  
73/F  
yyyy-mmm-dd  
Day 1 Pre-dose  
xxx.xx  
xxx.xx  
xxx.xx  
  
 
 
 
Day 1 Post-dose  
xxx.xx  
xxx.xx  
xxx.xx  
  
 
 
 
Week 1 Pre-dose  
xxx.xx  
xxx.xx  
xxx.xx  
  
 
 
 
Week 1 Post-dose  
xxx.xx  
xxx.xx  
xxx.xx  
  
 
 
 
Week 2 Pre-dose  
xxx.xx  
xxx.xx  
xxx.xx  
  
 
 
 
Week 2 Post-dose  
xxx.xx  
xxx.xx  
xxx.xx  
  
 
 
 
Week 4  
xxx.xx  
xxx.xx  
xxx.xx  
  
 
 
 
Week 6  
xxx.xx  
xxx.xx  
xxx.xx  
 xxx-xxx  
  
 
Elamipretide 40 mg  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[a] Age is age at informed consent. Sex: M = Male, F = Female.  
  
Note to Programmer: Listing is sorted by Subject ID, Visit Date, and Time.  
  
  
LISTINGS – ADVERSE EVENTS  
  
Listing 5.1  
Adverse Events  
Safety Population  
  
Subject Study  
ID  
Treatment  
Age/ 
Sex 
[a]  
System Organ  
Class/Preferred 
Term  
(Investigator  
Term)  
Onset Date  
(Study day)/  
Resolution 
Date(Study Day)/ 
ongoing [b]  
Intensity/ 
Relationship 
to Study Drug  Outcome  
Treatment for 
AE?  
Medication  Action  
or  
Taken with  
Procedure Study Drug  
Serious  
AE [c]  


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xxx-xxx  
  
  
Elamipretide  
4 mg  
 
 
73/F  
 
 
XXXXXXXXXXXX  
XXXXXXXXX    
(XXXXXXXXXX) 
XXXXXXXXXXXX  
XXXXXXXXX    
(XXXXXXXXXX)  
 
yyyy-mmm-dd 
(xxx) yyyy-
mmm-dd (xxx) 
yyyy-mmm-dd 
(xxx) ongoing  
 
Severe 
Probably 
related  
Severe 
Unlikely 
related  
 
Recovered/Resolved  
Not recovered/not 
resolved  
 
Yes  
Interrupted 
Medication  
Yes  
None Procedure  
 
  
Yes  
No  
 
xxx-xxx  
  
  
  
  
Placebo  
 
  
 
  
65/M  
 
  
 
  
XXXXXXXXXXXX  
XXXXXXXXX    
(XXXXXXXXXX) 
XXXXXXXXXXXX  
XXXXXXXXX    
(XXXXXXXXXX)  
 
 
  
yyyy-mmm-dd (xxx) 
yyyy-mmm-dd (xxx) 
yyyy-mmm-dd (xxx) 
yyyy-mmm-dd  
(xxx)  
 
 
xxxxx 
xxxxxxxxxxxx  
xxxxx/ 
xxxxxxxxxxxx  
 
 
xxxx/xxxx xxxxxxxxx  
 
 
xxx   
xxxxxxxxx  
xxxx 
 
xxxxxxxx  
 
  
  
   
xxx xxx  
 
 
 
AE = adverse event.   
[a] Age is age at informed consent in years. F = Female, M = Male.  
[b] Study Day = Onset/Resolution date – date of first dose of study drug + 1. [c] Serious AE criteria are 
defined in protocol Section 9.6.   
Note to Programmer: Listing is sorted by Subject ID, AE Onset Date.  
  
  
Listing 5.2  
Serious Adverse Events Safety 
Population  
  
Subject 
ID  
Study  
Treatment  
Age/ 
Sex [a] 
System Organ  
Class/Preferred 
Term  
(Investigator  
Term)  
Onset Date (Study 
day)/Resolution 
Date(Study Day)/ 
ongoing [b]  
Intensity/ 
Relationship to 
Study Drug/Date 
of last study 
treatment  
prior to the  
event  
Outcome  
Treatment for 
AE?  
Medication  Action Taken  
or  
with Study  
Procedure Drug  
Seriousness 
criteria  
[c]  


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xxx-xxx  
   
Elamipret 
ide 4 mg  
  
73/F  
  
XXXXXXXXXXXX  
XXXXXXXXX    
(XXXXXXXXXX)  
  
yyyy-mmm-dd (xxx) 
yyyy-mmm-dd (xxx)  
  
Severe Recovered Probably 
/Resolved  
related yyyy-mmm-dd  
Additional case details  
Relevant diagnostic tests  
Yes  
Medication  
Interrupted  
Stopped:  
yyyy-mmm-dd 
hh:mm   
AE abated  
Restarted: 
yyyy-mmm-dd 
hh:mm AE 
reoccurred  
Hospitaliza 
tion/prolon 
gation.  
Admission on 
yyyymmm-dd  
Discharged 
on yyyy- 
mmm-dd 
 xxx-xxx  
  
  
  
 
Placebo  
 
 
 
 
65/M  
 
 
 
 
XXXXXXXXXXXX  
XXXXXXXXX    
(XXXXXXXXXX)  
 
 
 
 
yyyy-mmm-dd 
(xxx) ongoing  
 
 
 
 
  
Severe  
Not  
Unlikely 
recovered 
related  /not resolved 
yyyy-mmm-dd 
Additional case details  
Relevant diagnostic tests  
 
  
 
Yes  
Procedure  
 
 
None  
 
 
Death on 
yyyy-mmm-dd  
Autopsy  
performed 
 
xxx-xxx  
  
  
Placebo  
 
  
65/M  
 
  
XXXXXXXXXXXX  
XXXXXXXXX    
(XXXXXXXXXX)  
 
  
yyyy-mmm-dd 
(xxx) ongoing  
 
Severe  
Not  
Unlikely 
recovered 
related  /not resolved 
yyyy-mmm-dd 
 
  
Yes  
Procedure  
 
Permanently 
discontinued 
Last dose  
date  
  
yyyy-mmm-dd 
  
xxxxxxx  
  
[a] Age is age at informed consent in years. F = Female, M = Male.  
[b] Study Day = Onset/Resolution date – date of first dose of study drug + 1. [c] Serious AE criteria 
are defined in protocol Section 9.6.   
Note to Programmer: Listing is sorted by Study Treatment, and Subject ID.  
Listing 5.3  
Adverse Events Leading to Discontinuation of Study Drug 
Safety Population  
  


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System Organ  
Class/Preferred Term 
(Investigator Term)  
Subject 
ID  
Study  
Treatment  
Age/ 
Sex 
[a]  
Onset Date (Study 
day)/Resolution 
Date(Study Day)/ 
ongoing [b]  
Intensity/ 
Relationship 
to Study Drug  
Outcome  
Treatment for 
AE? 
Medication   
or  
Serious   
Procedure AE [c]  
XXXXXXXXXXXX  
 XXXXXXXXX   
  (XXXXXXXXXX)  
  
  
xxx-xxx 
xxx-xxx  
 
Elamipretide 
4 mg  
Elamipretide  
40 mg  
 
73/F  
78/M  
 
yyyy-mmm-dd d  
(xxx)  
yyyy-mmm-dd (xxx) 
yyyy-mmm-dd (xxx) 
ongoing   
Severe 
Probably 
related 
Severe 
Possibly 
related   
Recovered/Resolved  
Not recovered/not 
resolved   
Yes  
Yes  
Medication  
Yes  
No  
Procedure  
 
  
XXXXXXXXXXXX  
 XXXXXXXXX   
  (XXXXXXXXXX)  
  
  
xxx-xxx 
xxx-xxx   
Placebo  
Elamipretide  
4 mg   
65/M  
68/F  
  
yyyy-mmm-dd (xxx) 
yyyy-mmm-dd (xxx)  
yyyy-mmm-dd (xxx) 
yyyy-mmm-dd (xxx)   
xxxxx 
xxxxxxxxxxxx  
xxxxx/ 
xxxxxxxxxxxx   
xxxx/xxxx 
xxxxxxxxx   
xxx   
xxx  
xxxx 
 
xxx  
 
  
AE = adverse event.   
[a] Age is age at informed consent in years. F = Female, M = Male.  
[b] Study Day = Onset/Resolution date – date of first dose of study drug + 1. [c] Serious AE criteria are 
defined in protocol Section 9.6.  
  
Note to Programmer: Include all AEs with Action taken with study drug = permanently discontinued. Sorted by PT in decreasing order of total 
frequency, Study Treatment, and Subject ID.  
  
  
LISTINGS – LABORATORY DATA  
  
Listing 6.1  
Hematology Results by Subject and Visit Safety 
Population  
Subject Study Age/Sex Parameter ID Treatment 
[a] (Unit)   
Timepoint  
Screening  
Sample Date yyyy-
mmm-dd yyyy-mmm-dd 
Sample 
Time 
Value 
xxx.xx 
Markedly Abnormal Criteria  
Result  
(N/H/L)  


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Elamipretide  
xxx-xxx 4 mg  
73/F  
XXXXXX   
(xxx)  
 
 
 
 
XXXXXX   
(xxx)  
 
 
 
 
 
XXXXXX   
(xxx)  
 
 
 
 
 
Baseline  
Week 1  
Week 2  
Week 4  
Week 6  
Screening  
Baseline  
Week 1  
Week 2  
Week 4  
Week 6  
 
Screening  
Baseline  
Week 1  
Week 2  
Week 4  
Week 6  
 
yyyy-mmm-dd yyyy-
mmm-dd yyyy-mmm-dd 
yyyy-mmm-dd yyyy-
mmm-dd yyyy-mmm-dd 
yyyy-mmm-dd yyyy-
mmm-dd yyyy-mmm-dd 
yyyy-mmm-dd  
 yyyy-mmm-dd 
yyyy-mmm-dd 
yyyy-mmm-dd 
yyyy-mmm-dd 
yyyy-mmm-dd 
yyyy-mmm-dd  
  
hh:mm 
hh:mm 
hh:mm 
hh:mm 
hh:mm 
hh:mm 
hh:mm 
hh:mm 
hh:mm 
hh:mm 
hh:mm 
hh:mm  
hh:mm 
hh:mm 
hh:mm 
hh:mm 
hh:mm 
hh:mm  
 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx  
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx  
 
Reference Range  
Low  - high 
xxxx 
- 
xxxx 
xxxx 
- 
xxxx 
xxxx 
- 
xxxx 
xxxx 
- 
xxxx 
xxxx 
- 
xxxx 
xxxx 
- 
xxxx 
xxxx 
- 
xxxx 
xxxx 
- 
xxxx 
xxxx 
- 
xxxx 
xxxx 
- 
xxxx 
xxxx 
- 
xxxx 
xxxx - xxxx  
xxxx - 
xxxx xxxx 
- xxxx 
xxxx - 
xxxx xxxx 
- xxxx 
xxxx - 
xxxx xxxx 
- xxxx  
 
N N  
L  
N  
N  
N  
N  
N  
H  
N  
N  
N  
 
N  
N  
N  
N  
N  
N  
 
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
xxx-xxx Placebo  
 
  
 
  
 
  
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
65/M  
 
 
 
 
 
 
N = Normal, H=High, L=Low are based on comparison to the reference 
ranges.  [a] Age is age at informed consent. Sex: M = Male, F = Female.   


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Note to Programmer: Listing is sorted by Study Treatment, Subject ID, Parameter, and Timepoint.  
  
Listing 6.2  
Blood Chemistry Results by Subject and Visit 
Safety Population  
  
Note to Programmer: Same layout as Listing 6.1.  
  
Listing 6.3  
Urinalysis Results by Subject and Visit    
  
Safety Population  
Note to Programmer: Layout similar to Listing 6.1.  The time points are Screening, Baseline, and Week 4.  
  
Listing 6.4  
Levels of hsTroponin by Subject and Visit Safety 
Population  
  
Note to Programmer: Layout similar to Listing 6.1.  The time points are Baseline, Week 1, Week 2, Week 4, and Week 6. Change “Value” column 
to “Value (Log Value)”.  
  
  
LISTINGS – OTHER SAFETY DATA  
  
Listing 7.1  
Vital Signs by Subject and Visit Safety 
Population  
  


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Subject Study   
Age/  
Sex  
ID  
Treatment  
[a]  
 
Timepoint  
 
Date  
 
Time  
Temperature  
(oC)  
Systolic Diastolic Heart Rate  
(mmHg)  
(mmHg)  
(BPM)  
Respiration 
Rate  
(breaths/min) 
Elamipretide  
xxx-xxx 4 mg  
73/F  
Screening  
yyyy-mmm-dd  
hh:mm  
xx.x  
xxx  
xxx  
xxx  
xxx 
 
  
  
Baseline  
yyyy-mmm-dd  
hh:mm  
xx.x  
xxx  
xxx  
xxx  
xxx 
 
  
  
Week 1  
yyyy-mmm-dd  
hh:mm  
xx.x  
xxx  
xxx  
xxx  
xxx 
 
  
  
Week 2  
yyyy-mmm-dd  
hh:mm   
xx.x  
xxx  
xxx  
xxx  
xxx 
 
  
  
Week 4  
yyyy-mmm-dd  
hh:mm  
xx.x  
xxx  
xxx  
xxx  
xxx 
 
  
  
Week 6  
yyyy-mmm-dd  
hh:mm  
xx.x  
xxx  
xxx  
xxx  
xxx 
 
  
  
 
 
 
 
 
  
 
 
xxx-xxx Placebo  
65/M  
Screening  
yyyy-mmm-dd  
hh:mm  
xx.x  
xxx  
xxx  
xxx  
xxx 
 
  
  
Baseline  
yyyy-mmm-dd  
hh:mm  
xx.x  
xxx  
xxx  
xxx  
xxx 
 
  
  
Week 1  
yyyy-mmm-dd  
hh:mm  
xx.x  
xxx  
xxx  
xxx  
xxx 
  
  
  
Week 2  
yyyy-mmm-dd  
hh:mm   
xx.x  
xxx  
xxx  
xxx  
xxx 
 
  
  
Week 4  
yyyy-mmm-dd  
hh:mm  
xx.x  
xxx  
xxx  
xxx  
xxx 
 
  
  
Week 6   
yyyy-mmm-dd   
hh:mm   
xx.x   
xxx   
xxx   
xxx   
xxx  
 
  
  
  
  
  
  
Blood  Pressure   
  
  


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BPM = Beats per minute.  
  
[a] Age is age at informed consent. Sex: M = Male, F = Female.  
  
Note to Programmer: Listing is sorted by Study Treatment, Subject ID, and Timepoint.  
  
  
Listing 7.2a  
Electrocardiogram (ECG) by Subject and Visit Safety 
Population  
  
Subject ID 
xxx-xxx  
Study Treatment 
Elamipretide 4 mg  
Age/Sex [a] 
73/F  
Timepoint  
Screening  
Date yyyy-
mmm-dd  
Time 
Heart 
Rate 
hh:mm xxx  
PR (msec) QRS(msec)  
xxx  
xxx  
QT (msec) 
xxx  
QTcF(msec) 
xxx  
 
 
 
Baseline  
yyyy-mmm-dd  hh:mm xxx  
xxx  
xxx  
xxx  
xxx  
 
 
 
Week 1  
yyyy-mmm-dd  hh:mm xxx  
xxx  
xxx  
xxx  
xxx  
 
 
 
Week 2  
yyyy-mmm-dd  hh:mm xxx  
xxx  
xxx  
xxx  
xxx  
 
 
 
Week 4  
yyyy-mmm-dd  hh:mm xxx  
xxx  
xxx  
xxx  
xxx  
 
 
 
Week 6  
yyyy-mmm-dd  hh:mm xxx  
xxx  
xxx  
xxx  
xxx  
 
 
 
 
 
 
  
 
 
 
 
xxx-xxx  
Placebo  
65/M  
Screening  yyyy-mmm-dd  hh:mm xxx  
xxx  
xxx  
xxx  
xxx  
 
 
 
Baseline  
yyyy-mmm-dd  hh:mm xxx  
xxx  
xxx  
xxx  
xxx  
 
 
 
Week 1  
yyyy-mmm-dd  hh:mm xxx  
xxx  
xxx  
xxx  
xxx  
  
  
 
Week 2  
yyyy-mmm-dd  hh:mm xxx  
xxx  
xxx  
xxx  
xxx  
  
  
 
Week 4  
yyyy-mmm-dd  hh:mm xxx  
xxx  
xxx  
xxx  
xxx  
  
  
 
Week 6  
yyyy-mmm-dd  hh:mm xxx  
 
  
xxx   
xxx   
xxx   
xxx   
 
  
  
  
  
[a] Age is age at informed consent. Sex: M = Male, F = Female.   QTcF 
= Fridericia corrected QT interval.  
  
Note to Programmer: Listing is sorted by Study Treatment, Subject ID and Timepoint.  
Listing 7.2b  
Electrocardiogram (ECG) by Subject and Visit with QRS Duration of <= 110 msec Safety 
Population  


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Listing 7.2c  
Electrocardiogram (ECG) by Subject and Visit with QRS Duration of >110 msec Safety 
Population  
  
  
  
Listing 7.3  
Electrocardiogram (ECG) by Subject and Visit  
Subjects with Either an Increase of >60 msec Between Baseline and End of Treatment in Their QT or QTcF or an Absolute QT or QTcF value >500 msec at Any Point in Time 
During the Study  
Safety Population  
 
 
  
Subject ID Study Treatment 
xxx-xxx  
Elamipretide 4 
mg  
Age/Sex [a] 
73/F  
Timepoint Date  
Screening yyyy-mmm-dd  
Time Heart Rate PR (msec) QRS(msec) QT (msec) QTcF(msec)  
hh:mm xxx  
xxx  
xxx  
xxx  
xxx  
 
  
  
Baseline yyyy-mmm-dd  
hh:mm xxx  
xxx  
xxx  
xxx  
xxx  
 
  
  
Week 1  
yyyy-mmm-dd  hh:mm xxx  
xxx  
xxx  
xxx  
xxx  
 
  
  
Week 2  
yyyy-mmm-dd  hh:mm xxx  
xxx  
xxx  
xxx  
xxx  
 
  
  
Week 4  
yyyy-mmm-dd  hh:mm xxx  
xxx  
xxx  
xxx  
xxx  
 
  
  
Week 6  
yyyy-mmm-dd  hh:mm xxx  
xxx  
xxx  
xxx  
xxx  
 
  
  
 
  
 
  
 
 
  
  
xxx-xxx  
Placebo  
65/M  
Screening yyyy-mmm-dd  
hh:mm xxx  
xxx  
xxx  
xxx  
xxx  
 
  
  
Baseline yyyy-mmm-dd  
hh:mm xxx  
xxx  
xxx  
xxx  
xxx  
 
  
  
Week 1  
yyyy-mmm-dd  hh:mm xxx  
xxx  
xxx  
xxx  
xxx  
  
  
  
Week 2  
yyyy-mmm-dd  hh:mm xxx  
xxx  
xxx  
xxx  
xxx  
  
  
  
Week 4  
yyyy-mmm-dd  hh:mm xxx  
xxx  
xxx  
xxx  
xxx  
  
  
  
Week 6  
yyyy-mmm-dd  hh:mm xxx  
 
  
xxx   
xxx   
xxx   
xxx   
 
  
  
  
  
[a] Age is age at informed consent. Sex: M = Male, F = Female.  QTcF 
= Fridericia corrected QT interval.  
  


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Note to Programmer: Listing is sorted by Study Treatment, Subject ID and Timepoint.  
  
  
Listing 7.4  
Cardiovascular Physical Examination and Physical Measurements by Subject and Visit Safety 
Population  
Subject Study  Age/Sex ID 
 Treatment  
[a]  
Visit  
Elamipretide  
xxx-xxx 4 mg  
73/F  
Screening 
 
  
  
Baseline  
 
  
  
Week 1  
 
  
  
Week 2  
 
  
  
Week 4  
 
  
  
Week 6  
 
  
  
 
 
Clinical  
Clinical  
 
Significant  
Physical  
Significant  
Date Examination performed? abnormalities noted? Measurements Performed? abnormalities 
noted? Weight (kg) Height (cm) BMI (kg/m2) yyyy- 
mmm-dd Yes No Yes No xxx.x xxx.x xxx.x yyyy- 
mmm-dd Yes No Yes No xxx.x xxx.x xxx.x yyyy- 
mmm-dd Yes No Yes No xxx.x xxx.x xxx.x yyyy- 
mmm-dd Yes No Yes No xxx.x xxx.x xxx.x yyyy- 
mmm-dd No  
No  
No  
No  
  
  
 yyyy- 
mmm-dd Yes  
No  
Yes  
No  
xxx.x xxx.x xxx.x  
  
  
  
  
  
  
  
  
xxx-xxx Placebo  
65/M  
Screening 
Cardiovascular Physical  
Examination   
Physical Meas urements   


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yyyy- 
mmm-dd Yes No Yes No xxx.x xxx.x xxx.x yyyy- 
mmm-dd Yes No Yes No xxx.x xxx.x xxx.x yyyy- 
mmm-dd Yes No Yes No xxx.x xxx.x xxx.x yyyy- 
mmm-dd No  
No  
No  
No  
 
   
 yyyy- 
mmm-dd Yes Yes Yes Yes xxx.x xxx.x xxx.x yyyy- 
mmm-dd Yes 
 
No 
 
Yes 
 
No  
xxx.x xxx.x xxx.x  
  
  
  
  
  
  
  
  
[a] Age is age at informed consent. Sex: M = Male, F = Female.  
  
Note to Programmer: Listing is sorted by Study Treatment, Subject ID, and Timepoint.  
  
  
Listing 7.5  
Injection Site Reaction (Nurse/Investigator Assessment)  
Safety Population  
Subject 
ID  
Study  Age/Sex 
Treatment  
[a]  
Date  
Assessment Not 
Completed   
Injection 
Site  
Other, Specify  Parameter  
Grade  
xxx-xxx  
  
  
Elamipretide  
4 mg  
 
 
73/F  
 
 
yyyy-mmm-dd yyyy-
mmm-dd yyyy-mmm-dd  
 
 
 
Upper Right 
Upper Left  
Lower Right  
 
 
 
Pain or  
Tenderness  
Erythema or 
Redness  
Induration or  
Swelling  
1  
2  
3  
  
 
 
yyyy-mmm-dd  
 
Lower Left  
 
Pruritus  
4  
   
  
  
yyyy-mmm-dd yyyy-
mmm-dd  
  
 
Other  
 
Xxxxxx  
  
  
 xxx-xxx   
Placebo  
 
65/M  
 
yyyy-mmm-dd  
 
 
 
Upper Right  
 
 
 
 
 
 
  
 
 
yyyy-mmm-dd  
 
Upper Left  
 
 
 
  
  
 
yyyy-mmm-dd  
 
Lower Right  
 
 
 
 
  
 
Baseline  
  
  
 
Week 1  
  
  
 
Week 2  
  
  
 
Week 4  
 
  
 
Week 6  
 
  
  
  


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yyyy-mmm-dd  
 
Lower Left  
 
 
 
  
  
  
 
 
 
yyyy-mmm-dd yyyy-
mmm-dd  
 
 
 
Other  
 
Xxxxxx  
 
 
 
 
[a] Age is age at informed consent. Sex: M = Male, F = Female.  
  
Note to Programmer: Listing is sorted by Study Treatment, Subject ID, and Timepoint.  
  
  
  
  
  
  
  
Listing 7.6  
Injection Site Reaction Self-Assessment Questionnaire  
Safety Population  
Subject Study  
Age/Sex  
ID  
Treatment  
[a]  
Date  
Day   
Was the ISR 
Self- 
Assessment 
Questionnaire 
completed by 
the subject?  
Pain?  
Burning 
Sensati 
on?  
Cold 
Sensati 
on?  
Itching 
?  
Redness 
?  
Swellin 
g?  
Bruisin 
g?  
xxx-xxx  
  
  
Elamipretide  
4 mg  
 
 
73/F  
 
 
yyyy-mmm-dd 
yyyy-mmm-dd 
yyyy-mmm-dd  
1  
2  
3  
Yes  
Yes  
Yes  
Not at 
all   
 
A 
little   
 
Moderat 
ely  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
yyyy-mmm-dd 
yyyy-mmm-dd  
4  
5  
Yes  
No  
 
 
 
 
 
 
Very  
 
Extreme 
ly  
 
 
 
 
  
 
 
yyyy-mmm-dd  
6  
Yes  
 
 
 
 
 
 
 


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 xxx-xxx   
Placebo  
 
65/M  
 
yyyy-mmm-dd  
 
1  
 
Yes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
yyyy-mmm-dd  
2  
Yes  
 
 
 
 
 
 
 
  
  
 
yyyy-mmm-dd  
3  
No  
 
 
 
 
 
 
 
  
  
 
yyyy-mmm-dd  
4  
Yes  
 
 
 
 
 
 
 
  
  
 
yyyy-mmm-dd  
5  
Yes  
 
 
 
 
 
 
 
  
 
 
yyyy-mmm-dd  
6  
Yes  
 
 
 
 
 
 
 
[a] Age is age at informed consent. Sex: M = Male, F = Female.  
  
Note to Programmer: Listing is sorted by Study Treatment, Subject ID, and Timepoint.  
  
  
  
  
  
  
  
Listing 7.7  
Comments  
All Subjects  
Subject ID  
Study Treatment  
Age/Sex [a]  
Visit   
Comments Applies To  
Comments  
xxx-xxx  
  
  
Elamipretide 4 mg  
 
 
73/F  
 
 
xxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxx  
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx  
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx  
 xxx-xxx  
  
  
 
Placebo  
 
 
 
65/M  
 
 
 
xxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxx  
 
 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx  
 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx  
 
[a] Age is age at informed consent. Sex: M = Male, F = Female.  


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Note to Programmer: Listing is sorted by Study Treatment, Subject ID, Visit and CRF page.  
  
  
 


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FIGURES  
  
Figure 1a  
Change From Baseline in Left Ventricular End Systolic Volume (LV ESV), Assessed by MRI, for Elamipretide 4 mg Group (By Subject) ITT 
Population  
  
Note: x-axis: Change time points to Screening, Week 1, and Week 4  
  


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Figure 1b  
Change From Baseline in Left Ventricular End Systolic Volume (LV ESV), Assessed by MRI, for Elamipretide 4 mg Group (By Subject) 
Per-Protocol Population  
  
Figure 1c  
Change From Baseline in Left Ventricular End Systolic Volume (LV ESV), Assessed by MRI, for Elamipretide 40 mg Group (By Subject)  
ITT Population  
  
Figure 1a   
Change From Baseline in Left Ventricular End Systolic Volume (LV ESV), Assessed by MRI, for Elamipretide 4 mg  
Group (By Subject)  
ITT   Population   
Change From Baseline in Left Ventricular End Systolic Volume (LV ESV) 
  


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Figure 1d  
Change From Baseline in Left Ventricular End Systolic Volume (LV ESV), Assessed by MRI, for Elamipretide 40 mg Group (By Subject) 
Per-Protocol Population  
  
  
Figure 1e  
Change From Baseline in Left Ventricular End Systolic Volume (LV ESV), Assessed by MRI, for Placebo Group (By Subject)  
ITT Population  
  
  
Figure 1f  
Change From Baseline in Left Ventricular End Systolic Volume (LV ESV), Assessed by MRI, for Placebo Group (By Subject)  
Per-Protocol Population  
  
  
Figure 1g  
LS Mean Change From Baseline in Left Ventricular End Systolic Volume (LV ESV), Assessed by MRI, (By Treatment Group) 
ITT Population  
  
Figure 1h  
LS Mean Change From Baseline in Left Ventricular End Systolic Volume (LV ESV), Assessed by MRI, (By Treatment Group) Per-
Protocol Population  
  
Note: For Figures 1g and 1h, only 3 lines, one for Elamipretide 4mg, one for Elamipretide 40 mg, and one for Placebo group. Add SE bar to the plot. Change Subject Number 
legend to Treatment Group legend.  
  
  
  
  
Figure 2a to Figure 2h (LVEF assessed by MRI)  


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Figure 3a to Figure 2h (LV EDV assessed by MRI)  
  
Figure 4a to Figure 4h (LVSV assessed by MRI)  
  
Figure 5a to Figure 5h (LVCO assessed by MRI)  
  
Figure 6a to Figure 6h (LV Myocardial Mass assessed by MRI)  
  
Figure 7a to Figure 7h (RV ESV assessed by MRI)  
  
Figure 8a to Figure 8h (RV EDV assessed by MRI)  
  
Figure 9a to Figure 9h (RVEF assessed by MRI)  
  
Figure 10a to Figure 10h (E/A assessed by Echocardiography)  
  
Figure 11a to Figure 11h (E/e’ assessed by Echocardiography)  
  
Figure 12a to Figure 12h (LA Volume assessed by Echocardiography)  
  
Figure 13a to Figure 13h (LV GLS assessed by Echocardiography)  
  
Figure 14a to Figure 14f (LV EDV assessed by Echocardiography)  
  
Figure 15a to Figure 15f (LV ESV assessed by Echocardiography)  
  
Figure 16a to Figure 16f (LVEF Biplane assessed by Echocardiography)  
  
Figure 17a to Figure 17f (LV Mass assessed by Echocardiography)  
  
Figure 18a to Figure 18f (Mitral Regurgitation Severity assessed by Echocardiography)  
  


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Figure 19a to Figure 19f (Tricuspid Regurgitation Severity assessed by Echocardiography)  
  
Figure 20a to Figure 20f (RV fractional area change assessed by Echocardiography)  
  
Figure 21a to Figure 21f (RV systolic pressure assessed by Echocardiography)  
  
Figure 22a to Figure 22h (6MWT)  
  
Figure 23a to Figure 23f (NT-pro-BNP)  
  
Figure 24a to Figure 24h (Log10 NT-pro-BNP)  
  
Figure 25a to Figure 25h (hs Troponin)  
  
Figure 26a to Figure 26h (KCCQ)  
  
  
  
  
  
  
  
 


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Figure 27a  
Mean Plasma Concentration-Time Profile of Elamipretide (Linear Scale) Safety 
Population  
  
 
  
  
Source: Table 4.1  
  
Programmer note:   
1. AXES: Display nominal time of sample on the X axis (label “Time After Dosing”). Display mean concentration value on the Y axis 
(label “Mean Plasma Concentration +/- SD <unit>”)  
2. Nominal time points marked on the x axis are Day 1 Pre-Dose, Day 1 45 min Post-Dose, Week 1 Pre-Dose, Week 1 45 min Post-Dose, 
Week 2 Pre-Dose, Week 2 45 min Post-Dose, Week 4, and Week 6  
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
0 
2 
4 
6 
8 
10 
12 
  
Mean Plasma Concentration +/ 
-   
SD (unit) 
  
Time after dosing  


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3. PLOT TYPE: line and symbol plot with error bars (+/- SD)   
Figure 27b  
Mean Plasma Concentration-Time Profile of Elamipretide Metabolite M1 (Linear Scale) Safety 
Population  
  
Figure 27c  
Mean Plasma Concentration-Time Profile of Elamipretide Metabolite M2 (Linear Scale) Safety 
Population  
  
  
  
 


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Figure 27d  
Log Mean Plasma Concentration-Time Profile of Elamipretide (Semi-logarithmic Scale) 
Safety Population  
  
 
  
Source: Table 4.1 and Listing 4.1  
Programmer note:   
1. AXES: Display nominal time of sample on the X axis (label “Time After Dosing”). Display mean of log concentration value on the 
Y axis (label “Log Mean Plasma Concentration <unit>”)  
2. Nominal time points marked on the x axis are Day 1 Pre-Dose, Day 1 45 min Post-Dose, Week 1 Pre-Dose, Week 1 45 min Post-Dose, 
Week 2 Pre-Dose, Week 2 45 min Post-Dose, Week 4, and Week 6  
3. PLOT TYPE: line and symbol plot  
  
Figure 27e  
Log Mean Plasma Concentration-Time Profile of Elamipretide Metabolite M1 (Semi-logarithmic Scale) 
Safety Population  
  
0 
2 
4 
6 
8 
10 
12 
14 
16 
0 
2 
4 
6 
8 
10 
12 
  
Log Mean Plasma Concentration (unit) 
  
Time after dosing  


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Figure 27f  
Log Mean Plasma Concentration-Time Profile of Elamipretide Metabolite M2 (Semi-logarithmic Scale)  
Safety Population  
  
Figure 27g  
Individual Plasma Concentration-Time Profile of Elamipretide (Linear Scale) 
Safety Population  
  
Similar to Figure 27a without +/- SD Source: 
Listing 4.1  
Programmer note:  
1. All individual profiles superimpose on the same graph  
2. AXES: Display actual time of sample on the X axis (label “Time After Dosing”). Display concentration value on the Y axis (label 
“Plasma Concentration, <unit>”)  
3. Nominal time points marked on the x axis are Day 1 Pre-Dose, Day 1 45 min Post-Dose, Week 1 Pre-Dose, Week 1 45 min Post-Dose, 
Week 2 Pre-Dose, Week 2 45 min Post-Dose, Week 4, and Week 6  
4. PLOT TYPE: line plot.  
  
Figure 27h  
Individual Plasma Concentration-Time Profile of Elamipretide Metabolite M1 (Linear Scale)  
Safety Population  
  
Figure 27i  
Individual Plasma Concentration-Time Profile of Elamipretide Metabolite M2 (Linear Scale) Safety 
Population  
  
Figure 27j  
Individual Plasma Concentration-Time Profile of Elamipretide (Semi-logarithmic Scale) 
Safety Population  
  
Similar to Figure 27d  
 Source: Listing 4.1  
Programmer note:  


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1. All individual profiles superimpose on the same graph   
2. AXES: Display actual time of sample on the X axis (label “Time After Dosing”). Display log concentration value on the Y axis 
(label “Log Plasma Concentration, <unit>”)  
3. Nominal time points marked on the x axis are Day 1 Pre-Dose, Day 1 45 min Post-Dose, Week 1 Pre-Dose, Week 1 45 min Post-Dose, 
Week 2 Pre-Dose, Week 2 45 min Post-Dose, Week 4, and Week 6  
4. PLOT TYPE: line plot.  
  
Figure 27k  
Individual Plasma Concentration-Time Profile of Elamipretide Metabolite M1 (Semi-logarithmic Scale)  
Safety Population  
  
Figure 27l  
Individual Plasma Concentration-Time Profile of Elamipretide Metabolite M2 (Semi-logarithmic Scale) 
Safety Population  
  
Similar to Figure 1a  
Figure 28a  
QTc for Subjects with a QTc value >500 msec at Any Point in Time During the Study (By Subject) Safety 
Population  
  
Note:  
1. 
x-axis: Change time points to Screening, Baseline, Weeks 1,2, 4, and 6  
2. 
Only generate figure if there is at least one subject who meets the criteria