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
Phase: PHASE2
Conditions: Heart Failure
Sponsor: Stealth BioTherapeutics Inc.

 
 
 
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