Clinical trial NCT02805790
Conditions: Primary Mitochondrial Disease
Keywords: Primary Mitochondrial Disease Mitochondrial Myopathy Elamipretide MTP-131 Bendavia™
Sponsor: Stealth BioTherapeutics Inc.
Start date: 2016-08-22; Completion date: 2017-03-23
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This randomized, double-blind, placebo-controlled, crossover study screened 32 subjects with primary mitochondrial myopathy (PMM) to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of subcutaneous elamipretide in this patient population.

Detailed description:
This randomized, double-blind, placebo-controlled, crossover study screened 32 subjects with primary mitochondrial myopathy (PMM) who had completed participation in the SPIMM-201 study where they had received 5 days of intravenous (IV) elamipretide (0.01, 0.10, or 0.25 mg/kg/hour infused for 2 hours) or placebo (randomized 3:1). The primary objective was to evaluate the effect of single daily subcutaneous (SC) doses of elamipretide administered for 4 weeks on the 6-minute walking distance (6MWD).

Subjects were randomized (1:1) to one of two sequence groups: 4-weeks of treatment with 40 mg elamipretide administered once daily SC in Treatment Period 1 followed by 4-weeks of treatment with placebo administered once daily SC in Treatment Period 2 (separated by a 4-week washout period), or vice versa. Each sequence group went through 5 distinct periods: Screening, Treatment Period 1, Washout, Treatment Period 2, and Follow-Up. Safety, tolerability, pharmacokinetics (PK), and efficacy of subcutaneous elamipretide in this patient population were analyzed.

Arms: arm 1: Participants first received 40 mg of elamipretide once daily subcutaneously for 4 weeks. After a washout period of 4 weeks, they then received placebo administered once daily subcutaneously for 4 weeks. arm 2: Participants first received placebo once daily subcutaneously for 4 weeks. After a washout period of 4 weeks, they then received 40 mg of elamipretide once daily subcutaneously for 4 weeks.
Interventions: intervention 1: Elamipretide intervention 2: Placebo
Intervention descriptions: intervention 1: 4 weeks of treatment with 40 mg elamipretide administered once daily subcutaneously intervention 2: 4 weeks of treatment with placebo administered once daily subcutaneously

Protocol documents:
Prot_000.pdf: 
Elamipretide (MTP-131 for SC Injection)  
SPIMM-202 Version 5.0  
21 October 2016  
Stealth BioTherapeutics Inc.  
1 
 
Title: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Crossover Study to 
Evaluate the Safety, Tolerability, and Efficacy of Subcutaneous Injections of 
Elamipretide (MTP-131) in Subjects with Genetically Confirmed Mitochondrial Disease 
Previously Treated in the Stealth BioTherapeutics SPIMM-201 Study 
 
NCT02805790 
 
Document Date: 21 October 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Elamipretide (MTP-131 for SC Injection)  
SPIMM-202 Version 5.0  
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Stealth BioTherapeutics Inc.  
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CLINICAL STUDY PROTOCOL  
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Crossover Study 
to Evaluate the Safety, Tolerability, and Efficacy of Subcutaneous Injections 
of Elamipretide (MTP-131) in Subjects with Genetically Confirmed 
Mitochondrial Disease Previously Treated in the Stealth BioTherapeutics  
SPIMM-201 Study  
Study Phase:  
Phase 2  
Study Number:  
SPIMM-202  
Document Version:  
Version 5.0  
Final Approval Date:  
21 October 2016  
Sponsor:  
Stealth BioTherapeutics Inc.  
275 Grove Street, Suite 3-107  
Newton, MA 02466  
Unites States of America  
Sponsor Medical 
Monitor:  
        Doug Weaver, MD  
        Chief Medical Officer  
        275 Grove Street 3-107, Newton, MA 02466  
        Doug.Weaver@stealthbt.com      
        +1 313-806-4194  
Confidentiality Statement  
 
The information contained in this document is confidential and is the property of Stealth  
BioTherapeutics Inc.  No part of it may be transmitted, reproduced, published, or used by 
anyone without the written permission of Stealth BioTherapeutics Inc.   
 


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CONFIDENTIAL  
PROTOCOL APPROVAL  
Protocol Title:  
A Phase 2 Randomized, Double-Blind, Placebo- 
Controlled Crossover Study to Evaluate the Safety,  
Tolerability, and Efficacy of Subcutaneous Injections of  
Elamipretide (MTP-131) in Subjects with Genetically 
Confirmed Mitochondrial Disease Previously Treated in 
the Stealth BioTherapeutics SPIMM-201 Study  
Protocol Number:  
SPIMM-202  
Protocol Date:  
21 October 2016  
 
CONFIDENTIAL  
Doug Weaver, MD  
Medical Monitor, Stealth BioTherapeutics  
Date  
10/22/2016 


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INVESTIGATOR’S AGREEMENT  
I have received and read the Investigator’s Brochure for elamipretide (MTP-131).  I have read 
the SPIMM-202 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 
subInvestigator(s) and other relevant members of my staff have access to copies of this 
protocol, and the ICH GCP guidelines to enable them to work in accordance with the 
provisions of these documents.  I agree to maintain the confidentiality of all information 
received or developed in connection with this protocol.  
 
Printed Name of Investigator  
 
Signature of Investigator  
 
Date (DD/MMM/YYYY)  


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CONFIDENTIAL  
1. 
SYNOPSIS  
Name of Sponsor/Company:  Stealth BioTherapeutics Inc.  
Investigational Product:  MTP-131 (elamipretide)  
Title of Study:  A Phase 2 Randomized, Double-Blind, Placebo-Controlled Crossover Study 
to Evaluate the Safety, Tolerability, and Efficacy of Subcutaneous Injections of MTP-131  
Elamipretide (MTP-131) in Subjects with Genetically Confirmed Mitochondrial Disease  
Previously Treated in the Stealth BioTherapeutics SPIMM-201 Study  
Study Center(s): This study will be conducted in 4 centers in the United States (US)  
Objectives:  
Primary  
• 
To evaluate the effect of single daily subcutaneous (SC) doses of elamipretide 
administered for 4 weeks on 6-minute walking distance (6MWD). 
Secondary  
• 
To evaluate the safety and tolerability of single daily SC doses of elamipretide 
administered for 4 weeks 
• 
To evaluate the effects of single daily SC doses of elamipretide administered for 4 
weeks on: 
o Accelerometry 
o Triple Timed Up and Go (3TUG) Test o Patient Reported Outcomes o 
Exploratory biomarkers 
o Physician Global Assessment (PhGA) 


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Study Design:  This randomized, double-blind, placebo-controlled crossover study will 
enroll up to 36 subjects with genetically confirmed mitochondrial disease who have 
completed participation in the SPIMM-201 study.  Subjects will have previously received 5 
days of intravenous elamipretide (0.01, 0.10 or 0.25 mg/kg/hour infused for 2 hours) or 
placebo (randomized 3:1) in the SPIMM-201 study.   
Subjects will be randomized (1:1) to one of two sequence groups: 4-weeks of treatment with 
40 mg elamipretide administered once daily SC in Treatment Period 1 followed by 4-weeks 
of treatment with placebo administered once daily SC in Treatment Period 2 (separated by 
4week washout period), or vice versa (Attachment 3).   
Given the challenges of scheduling Visiting Nurses visits to subject’s homes (e.g. remote 
geographic locations, subject scheduling conflicts, extreme weather or other natural disasters 
etc.), in consultation and agreement with the Sponsor and Investigator, Visiting Nurse visits 
may be postponed, changed or cancelled.  
Screening:  Screening will begin with the signature of the informed consent form (ICF) and 
will last at least 7 days and no more than 30 days. During Screening, subjects will undergo 
screening procedures as described in the Study Schedule (Attachment 1) and will be 
instructed to wear a wrist accelerometer daily (24 hours per day), wear a hip accelerometer  
CONFIDENTIAL  


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daily during waking hours (minimum of at least 7 consecutive days immediately prior to the 
Baseline Visit), and complete daily Mitochondrial Disease (MD) Symptom Assessments in 
an electronic or paper diary to characterize their baseline disease status.  Subjects who 
complete Screening and continue to meet all study requirements, including all inclusion and 
none of the exclusion criteria, may enter Treatment Period 1.  
Treatment Period 1:  Treatment Period 1 will begin on the day of the Baseline Visit, which 
is defined as Study Day 1.  At the Baseline Visit, following completion of all Baseline 
procedures described in the Study Schedule, subjects will be administered study drug SC at 
the study center.  Subjects or caregivers will receive instructions on scheduling daily home 
(or other location) visits with the Visiting Nurse and will be assigned a Visiting Nurse who 
may administer (or observe) study drug subcutaneously on a daily basis for the first week of 
Treatment Period 1 and at least weekly thereafter. The Visiting Nurse visit on Day 2 is 
required, however, the Visiting Nurse Visits during Days 3-7 are not mandatory and the 
patient (or caregiver) and the Visiting Nurse should determine the frequency and necessity of 
these visits.  Subjects (or caregivers) will be trained on the procedure for administration of 
study drug and will administer study drug on a daily basis (except for days corresponding to 
study center visits and potentially Visiting Nurse Visits) at approximately the same time each 
day. If, for any reason, a subject (or caregiver) is unable/unwilling to administer study drug, 
a Visiting Nurse may be provided for daily administration of study drug.  The Visiting Nurse 
will also draw blood for safety labs at Week 1 and Week 2 Visits.  The Visiting Nurse will 
administer (or observe) study drug at the Week 3 Visit and remind subjects to wear the hip 
accelerometer during waking hours for at least 7 consecutive days immediately prior to the 
Week 4 Visit. Subjects will continue to follow all study requirements, including completing 
daily MD Symptom Assessments and recording the location and time of the study drug 
administration in an electronic or paper diary as well as wearing the wrist accelerometer 
daily. Treatment Period 1 will conclude with a visit to the study center at the Week 4 Visit 
and subjects will return all used and unused vials to the study center at this visit.   
Washout: Washout will begin on the day after the Week 4 Visit and will last for at least 4 
weeks.  The Visiting Nurse will visit at the Week 6 Visit to provide the subject with the 
Neuro-QoL Fatigue questionnaire to complete, and will collect the completed questionnaire. 
The Visiting Nurse will also draw blood for safety labs. The Visiting Nurse will ensure the 
subject is wearing a wrist accelerometer daily (24 hours per day), remind the subject to wear 
a hip accelerometer daily during waking hours (minimum of at least 7 consecutive days 
immediately prior to the Week 8 Visit), and complete daily MD Symptom Assessments in an 
electronic or paper diary.   
Treatment Period 2: Treatment Period 2 will begin with a visit to the study center for the 
Week 8 Visit. Subjects will be administered study drug SC at the study center following 
completion of all baseline procedures described in the Study Schedule. A Visiting Nurse will 
administer (or observe) study drug on a weekly basis at home (or other location) and will 
draw blood for safety labs on Week 9 and Week 10, as described in the Study Schedule.  
Subjects (or caregivers) will administer study drug on a daily basis at approximately the 
same time each day (except for days corresponding to study center visits and potentially 
Visiting Nurse Visits). The Visiting Nurse will administer (or observe) study drug at the 


Elamipretide (MTP-131 for SC Injection)  
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Week 11 Visit and will remind subjects to wear the hip accelerometer during waking hours 
for at least 7 consecutive days immediately prior to the Week 12 Visit.  Subjects will  


Elamipretide (MTP-131 for SC Injection)  
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continue to follow all study requirements, including completing daily MD Symptom 
Assessments and recording the location and time of the study drug administration in an 
electronic or paper diary as well as wearing the wrist accelerometer daily. Treatment Period 
2 will conclude with a visit to the study center at the Week 12 Visit and subjects will return 
all used and unused vials to the study center at this visit.  
Follow-Up: Follow-Up will begin after completion of Treatment Period 2 and will last for 2 
weeks.  During follow-up, subjects will continue to follow all study requirements, including 
completing daily MD Symptom Assessments in an electronic or paper diary as well as 
wearing the wrist accelerometer daily.  At the end of Follow-up, subjects will return to the 
study center for the End-of-Study/Early Discontinuation Visit for final safety and efficacy 
assessments and to return all remaining study equipment, as described in the Study Schedule.  
Number of Subjects (planned):  Up to 36 subjects   
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 dose of 
elamipretide will be 40 mg administered as a once daily 1 mL SC injection. Study drug will 
be administered by either the study center clinical staff, a Visiting Nurse, caregiver or the 
subject via daily SC injection, preferably in the abdomen (rotating around the four 
abdominal quadrants), at approximately the same time each day.  
Reference Product: Matching placebo will be administered subcutaneously according to the 
same schedule and conditions as elamipretide.  
Inclusion Criteria:  
A subject must meet the following criteria prior at the Baseline Visit 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. Subject completed participation in the SPIMM-201 study without a significant 
protocol deviation that would suggest the subject may not be able to complete all 
study requirements in the opinion of the Sponsor.  
3. Subject must reside in North America for the duration of the study.   
4. Subject agrees to adhere to the study requirements for the length of the trial.  
5. Subject has not received study drug in the SPIMM-201 study within 3 weeks prior to 
Screening.  


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6. 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 drug:  
a. Abstinence, when it is in line with the preferred and usual lifestyle of the 
subject.  Subject agrees to use an acceptable method of contraception should 
they become sexually active.  
b. Maintenance of a monogamous relationship with a male partner who has been 
surgically sterilized by vasectomy (the vasectomy procedure must have been 
conducted at least 60 days prior to the Screening Visit or confirmed via sperm 
analysis).  
c. Barrier method (e.g., condom or occlusive cap) with spermicidal 
foam/gel/film/cream AND either hormonal contraception (oral, implanted, or 
injectable) or an intrauterine device or system.  
Note: Non-childbearing potential is defined as surgical sterilization (e.g., bilateral 
oophorectomy, hysterectomy, or tubal ligation) or postmenopausal (defined as 
permanent cessation of menstruation for at least 12 consecutive months prior to the 
Screening Visit).  
7. Subject has been on stable medications (including over-the-counter treatments, 
vitamins, or supplements), or medications that will not impact the safety or efficacy 
endpoints of the trial, in the opinion of the Investigator for at least 1 month prior to 
the Baseline Visit.  


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Exclusion Criteria:  
A subject who meets any of the following criteria at Screening will be excluded from the study: 
1. Subject has any prior or current medical condition that, in the judgment of the  
Investigator, would prevent the subject from safely participating in and/or completing 
all study requirements (i.e. unstable angina or recent myocardial infarction).  
2. Subject has received any investigational compound and/or has participated in another 
interventional clinical study within 30 days prior to the Baseline Visit or is 
concurrently enrolled in any non-interventional research of any type judged to be 
scientifically or medically incompatible with the study as deemed by the Investigator 
in consultation with the Sponsor.   
3. Subject experienced an adverse reaction to study drug in the SPIMM-201 study that 
contraindicates further treatment with elamipretide in the opinion of the Investigator 
and/or Sponsor.  
4. Female subjects who are pregnant, planning to become pregnant, or lactating.  
5. Subject has undergone an in-patient hospitalization within the 1 month prior to the 
Screening Visit or is likely to need in-patient hospitalization or a surgical procedure 
during the course of the study  
6. Subject has a creatinine clearance ≤30 mL/min as calculated by the Cockcroft Gault 
equation.  
7. Subject has QTc elongation defined as a QTc >450 msec in male subjects and >480  
msec in female subjects.  
Note: At the initial electrocardiogram (ECG), if QTc exceeds these parameters, the 
ECG may be repeated 2 more times, and the average of the 3 QTc values used to 
determine the subject’s eligibility.  
8. Subject has uncontrolled hypertension in the judgment of the Investigator (e.g.  
elevated above >160 mmHg systolic or >100 mmHg diastolic despite appropriate 
treatment on two consecutive readings).  
9. Subject has a history of clinically significant hypersensitivity or allergy to any of the 
excipients contained in the study drug.  
10. Subject has a history of active alcoholism or drug addiction during the year before the 
Screening Visit.  
11. Subject is an Investigator/study center personnel or immediate family* of 
Investigator/study center personnel.  
12. Subject is a Sponsor employee (permanent, temporary contract worker, or designee 
responsible for the conduct of the study) or immediate family* of a Sponsor 
employee.    
* Immediate family is defined as a spouse, parent, child, or sibling, whether 
biological or legally adopted  


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Planned Study Duration:   
Screening: 7-30 days  
Treatment Period 1: 4 weeks  
Washout: 4 weeks  
Treatment Period 2: 4 weeks  
Follow-up: 2 weeks  
Criteria for Evaluation:  
Primary Endpoint  
• Distance walked (meters) on the 6-minute walk test (6MWT) Secondary Endpoints  
• Adverse Events (AEs)   
• Vital Signs  
• ECGs  
• Clinical laboratory evaluations  
• Accelerometer counts  
• Patient reported outcomes (Neuro-QoL Fatigue questionnaire, Mitochondrial Disease 
[MD] Symptom Assessment, and Patient Global Assessment [PGA])  3TUG Test score  
• Exploratory biomarkers   
• Physician Global Assessment (PhGA)  
Statistical Methods:    
After all subjects complete the first treatment period, at the discretion of the Sponsor, the 
data from the first treatment period may be unblinded and an interim analysis may be  


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conducted.  
Analysis Populations   
All subjects who receive at least one dose of study drug will be included in both the Safety 
Population and in the Intention-to-Treat (ITT) Population.   
Safety Analyses   
Safety analyses will include incidence of AEs and SAEs, deaths, premature discontinuation 
from the study due to an AE (regardless of relationship to study drug), and change in ECG, 
clinical laboratory data, and vital signs.  
Efficacy Analyses   
Efficacy analyses will be conducted on the ITT population. In general, categorical variables 
will be summarized by the count (N) and percentage of subjects (%). Continuous variables 
will be summarized by the number of non-missing observations (N), mean, standard 
deviation, median, minimum, and maximum values.  All study data are to be displayed in the 
data listings.  
Additional details regarding analyses will be included in separate statistical analysis plan.  
Subject disposition summaries will include the number of subjects enrolled and the 
numbers included in the ITT populations. The number and percentage of subjects who 
complete or discontinue from the study will be summarized by reason for discontinuation. 
Subject’s age, sex, weight, height, body mass index (BMI), and other demographic 
characteristics will be recorded and summarized.  Medical history will be listed.  
  
Sample Size:  
Subject numbers (up to 36 subjects) are limited to those residing in North America having 
previously completed participation in the SPIMM-201 study and who meet all eligibility 
criteria.  
  
2. 
TABLE OF CONTENTS  
PROTOCOL APPROVAL ........................................................................................................................................ 3 
INVESTIGATOR’S AGREEMENT ............................................................................................................................ 4 
1.  SYNOPSIS ....................................................................................................................................................... 5 
2.  TABLE OF CONTENTS ................................................................................................................................... 14 
3.  ABBREVIATIONS AND DEFINITIONS ............................................................................................................. 17 
4.  INTRODUCTION ........................................................................................................................................... 19 
4.1.  MITOCHONDRIAL MYOPATHY ............................................................................................................................. 19 
4.2.  ELAMIPRETIDE RISK/BENEFIT ASSESSMENT ........................................................................................................... 19 
4.2.1.  Potential Benefits ................................................................................................................................. 19 
4.2.2.  Potential Risks ...................................................................................................................................... 21 
4.2.2.1.  Safety findings – Nonclinical studies ...............................................................................................................21 
4.2.2.2.  Human safety ..................................................................................................................................................22 
4.2.3.  Conclusions .......................................................................................................................................... 22 


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5.  OBJECTIVES .................................................................................................................................................. 23 
5.1.  PRIMARY OBJECTIVE ......................................................................................................................................... 23 
5.2.  SECONDARY OBJECTIVES ................................................................................................................................... 23 
6.  INVESTIGATIONAL PLAN .............................................................................................................................. 24 
6.1.  STUDY DESIGN ................................................................................................................................................ 24 
6.2.  DISCUSSION OF DESIGN AND CONTROL ................................................................................................................ 25 
6.3.  STUDY SCHEDULE ............................................................................................................................................. 26 
6.3.1.  Screening: At least 7 days and no longer than 30 days ....................................................................... 26 
6.3.2. Treatment Period 1 ............................................................................................................................... 28 
6.3.2.1. Baseline Visit (Day 1) ........................................................................................................................................28 
6.3.2.2.  Visiting Nurse Visits: Days 2 – 7.......................................................................................................................29 
6.3.2.3.  Visiting Nurse Visits: Week 1 (Day 8 ± 1), Week 2 (Day 15 ± 2), and Week 3 (Day 22 ± 2) ..............................29 
6.3.2.4.  Week 4 (Day 29 + 6 days) ................................................................................................................................30 
6.3.3.  Washout ............................................................................................................................................... 31 
6.3.4.  Treatment Period 2 .............................................................................................................................. 31 
6.3.4.1.  Week 8 (Day 57 + 5) ........................................................................................................................................31 
6.3.4.2.  Visiting Nurse Visits: Week 9 (Day 64 ± 2), Week 10 (Day 71 ± 2), Week 11 (Day 78 ± 2) ...............................32 
6.3.4.3.  Week 12 (Day 85 + 6) ......................................................................................................................................32 
6.3.5.  Follow-up Period .................................................................................................................................. 33 
6.3.5.1.  End-of-Study/Early Discontinuation Visit (Day 99 + 7 days /Early Discontinuation) .......................................34 
6.4.  STUDY ASSESSMENTS ........................................................................................................................................ 35 
6.4.1. Medical History and Physical Examination ........................................................................................... 35 
6.4.2. Columbia Suicide Severity Rating Scale (C-SSRS) .................................................................................. 35 
6.4.3.  Vital signs ............................................................................................................................................. 36 
6.4.4.  Electrocardiograms (ECGs) ................................................................................................................... 36 
6.4.5.  Clinical Laboratory Testing ................................................................................................................... 36 
6.4.5.1.  Blood chemistries ............................................................................................................................................36 
6.4.5.2.  Hematology .....................................................................................................................................................36 
6.4.5.3.  Urinalysis .........................................................................................................................................................37 
6.4.5.4.  Pregnancy tests ...............................................................................................................................................37 
6.4.6.  6-Minute Walk Test (6MWT) ............................................................................................................... 37 
6.4.7.  Triple Timed Up and Go (3TUG) Test.................................................................................................... 37 
6.4.8.  The Neuro-QoL Fatigue Questionnaire ................................................................................................ 37 
6.4.9.  Mitochondrial Disease (MD) Symptom Assessment ............................................................................ 37 
6.4.10.  Accelerometry .................................................................................................................................... 37 
6.4.11.  Exploratory biomarkers ...................................................................................................................... 38 
6.4.12.  Physician Global Assessment (PhGA) ................................................................................................. 38 
6.4.13.  Patient Global Assessment (PGA) ...................................................................................................... 38 
7.  STUDY POPULATION .................................................................................................................................... 39 
7.1. INCLUSION CRITERIA .......................................................................................................................................... 39 
7.2. EXCLUSION CRITERIA ......................................................................................................................................... 41 
7.3.  PROHIBITED MEDICATIONS ................................................................................................................................ 42 
7.4.  DISCONTINUATIONS ......................................................................................................................................... 43 


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7.4.1.  Discontinuation of Subjects .................................................................................................................. 43 
7.4.2.  Discontinuation of Study Center .......................................................................................................... 43 
7.4.3.  Discontinuation of the Study ................................................................................................................ 44 
8.  TREATMENT ................................................................................................................................................. 44 
8.1.  TREATMENTS ADMINISTERED ............................................................................................................................. 44 
8.2.  MATERIALS AND SUPPLIES ................................................................................................................................. 45 
8.2.1.  Elamipretide ......................................................................................................................................... 45 
8.2.2.  Placebo ................................................................................................................................................. 45 
8.3.  TREATMENT LOGISTICS AND ACCOUNTABILITY ....................................................................................................... 46 
8.4.  METHOD OF ASSIGNMENT TO TREATMENT AND RANDOMIZATION ............................................................................. 46 
8.5.  RATIONALE FOR SELECTION OF DOSES IN THE STUDY ............................................................................................... 46 
8.5.1.  Comparison of the PK and Metabolism of IV and SC Administration ................................................... 47 
8.6.  CONTINUED ACCESS TO INVESTIGATIONAL MEDICINAL PRODUCT .............................................................................. 48 
8.7.  BLINDING AND UNBLINDING PROCEDURES ............................................................................................................ 49 
8.8.  TREATMENT COMPLIANCE ................................................................................................................................. 49 
9.  EFFICACY AND SAFETY EVALUATIONS AND APPROPRIATENESS OF MEASUREMENTS .................................. 50 
9.1.  EFFICACY MEASURES ........................................................................................................................................ 50 
9.1.1.  Primary efficacy measure ..................................................................................................................... 50 
9.1.2.  Secondary efficacy measure ................................................................................................................. 50 
9.1.3.  Safety measures ................................................................................................................................... 50 
9.1.4.  Adverse Events ..................................................................................................................................... 51 
9.2.  PRE-TREATMENT EVENTS .................................................................................................................................. 51 
9.3.  BASELINE MEDICAL CONDITIONS......................................................................................................................... 51 
9.4.  ABNORMAL LABORATORY AND OTHER ABNORMAL INVESTIGATIONAL FINDINGS ........................................................... 52 
9.5.  SERIOUS ADVERSE EVENTS ................................................................................................................................. 52 
9.5.1.  Events that Do Not Meet the Definition of a Serious Adverse Event.................................................... 53 
9.6.  RECORDING OF ADVERSE EVENTS ........................................................................................................................ 53 
9.6.1.  Investigator Assessments ..................................................................................................................... 54 
9.6.1.1.  Severity/Intensity ............................................................................................................................................54 
9.6.1.2.  Relationship to the Investigational Medicinal Product (IMP) ..........................................................................54 
9.6.2.  Adverse Event Reporting Period ........................................................................................................... 54 
9.7.  SERIOUS ADVERSE EVENT EXPEDITED REPORTING................................................................................................... 55 
9.7.1.  Pregnancy and Contraception .............................................................................................................. 56 
9.7.2.  Responsibilities to Regulatory Authorities, Investigators and Ethics Committees ............................... 57 
9.8.  APPROPRIATENESS OF MEASUREMENTS ............................................................................................................... 57 
10.  DATA QUALITY ASSURANCE ....................................................................................................................... 58 
10.1.  DATA CAPTURE SYSTEM .................................................................................................................................. 58 
11.  SAMPLE SIZE AND STATISTICAL METHODS ................................................................................................. 59 
11.1. DETERMINATION OF SAMPLE SIZE ...................................................................................................................... 59 
11.2. STATISTICAL AND ANALYTICAL PLANS .................................................................................................................. 59 
11.2.1.  General Considerations ...................................................................................................................... 59 


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11.2.2.  Subject Disposition ............................................................................................................................. 59 
11.2.3.  Subject Characteristics ....................................................................................................................... 59 
11.2.4.  Endpoints and Methodology .............................................................................................................. 59 
11.2.4.1.  General Considerations .................................................................................................................................59 
11.2.4.2.  Analysis Populations .....................................................................................................................................59 
11.2.5.  Efficacy Analyses ................................................................................................................................ 60 
11.2.6.  Interim Analysis .................................................................................................................................. 60 
11.2.7.  Safety Analyses .................................................................................................................................. 60 
11.2.7.1.  Adverse Events ..............................................................................................................................................60 
11.2.7.2.  Deaths and Other Serious Adverse Events ....................................................................................................61 
11.2.7.3.  Clinical Laboratory Evaluations .....................................................................................................................61 
11.2.7.4.  Vital Signs ......................................................................................................................................................61 
11.2.7.5.  Electrocardiogram .........................................................................................................................................61 
11.2.7.6.  Other Safety Parameters ...............................................................................................................................62 
12.  INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY CONSIDERATIONS ........................................ 62 
12.1.  INFORMED CONSENT ...................................................................................................................................... 62 
12.2.  ETHICAL REVIEW ............................................................................................................................................ 62 
12.3.  REGULATORY CONSIDERATIONS ........................................................................................................................ 62 
12.3.1. Protocol Approval ............................................................................................................................... 63 
12.3.2. Final Report Approval ......................................................................................................................... 63 
12.3.3. Study Monitoring ................................................................................................................................ 63 
12.3.4.  Retention of Records .......................................................................................................................... 63 
12.3.5.  Disclosure of Information ................................................................................................................... 63 
13.  REFERENCES............................................................................................................................................... 65 
14.  ATTACHMENTS .......................................................................................................................................... 65 
 
  
3. 
ABBREVIATIONS AND DEFINITIONS  
Term  
Definition  
 
3TUG  
Triple Timed Up and Go Test  
6MWD  
Six-minute walk distance  
6MWT  
Six-minute walk test  
AE  
Adverse event  
ALT  
Alanine aminotransferase  
AST  
Aspartate aminotransferase  
ATP  
Adenosine triphosphate  
AUC  
Area under the plasma concentration versus time curve  


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AUC0-τ  
Area under the plasma concentration vs time curve from time 0 to end of the dosing 
interval   
AUC0-inf  
Area under the plasma concentration curve from baseline to infinity  
AUC0-24  
Area under the plasma concentration curve from baseline to 24 hours postdose  
BMI  
Body mass index  
CIOMS  
Council for International Organizations of Medical Sciences  
Cmax  
Maximum plasma concentration  
C-SSRS  
Columbia-Suicide Severity Rating Scale  
EC  
Ethics Committee  
ECG  
Electrocardiogram  
eCRF  
electronic Case Report Form  
EDC  
Electronic data capture  
GCP  
Good Clinical Practice  
IB  
Investigator’s Brochure  
ICF  
informed consent form  
ICH  
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use  
IMP  
investigational medicinal product  
IV  
intravenous  
ITT  
intention-to-treat  
MedDRA  
Medical Dictionary for Regulatory Activities  
MM  
Mitochondrial myopathy  
mL  
milliliter  
MTP-131  
SS-31, elamipretide, or Bendavia™  
Term  
Definition  
 
mtDNA  
mitochondrial DNA  
nDNA  
nuclear DNA  
PK  
pharmacokinetic(s)  
PGA  
Patient Global Assessment   
PhGA  
Physician Global Assessment  
PMD  
Primary mitochondrial disease  
PT  
preferred term  
SAE  
serious adverse event  
SAP  
Statistical Analysis Plan  


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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 drug 
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. 
Mitochondrial Myopathy  
Mitochondrial Myopathy (MM) is a condition resulting from respiratory chain dysfunction in 
the mitochondria that, when involving of skeletal muscle, leads to muscle weakness and 
atrophy, and limited exercise capacity and tolerance. MM is a functional consequence of 
Primary Mitochondrial Disease (PMD) of either mitochondrial DNA (mtDNA) or nuclear 
DNA (nDNA) origin. Normally, in response to exercise and physical activity, ventilation and 
cardiac output are increased resulting in the delivery of more oxygen to the muscle via the 
bloodstream. In MM, there is an exaggerated response to physical exercise because the 
increased oxygen available in the arterial bloodstream cannot be effectively utilized by the 
skeletal muscle. This results in limited exercise capacity and easy fatigability. The severity of 
MM is variable and frequently involves progressive reduction in exercise capacity that impacts 
the patient’s ability to live a normal life. It is a rare condition for which there are no 
FDAapproved treatments (DiMauro et al. 2003, DiMauro & Schon 2003; Pfeffer and Chinnery 
2013; Tarnopolsky 2004; Elson et al. 2013).  
4.2. 
Elamipretide Risk/Benefit Assessment  
4.2.1. 
Potential Benefits  
MTP-131 has not been studied in any preclinical models specific to MM.  However, MTP-131 
has been shown to be effective in preclinical models in numerous disease states, including 
skeletal and cardiac muscle dysfunction, which are of relevance to MM. For example, MTP131 
restored adenosine triphosphate (ATP) production in the skeletal muscle of aged mice. (Siegel 
et al. 2013)  In this study, skeletal muscle energetics were measured in vivo one hour after 
injection of either MTP-131 or saline using a combination of optical and 31P magnetic 


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resonance spectroscopy in old and young mice (27 months and 5 months, respectively [n=5-7 
per group]). ATP production in old (27 months) mice was found to be comparable to that in 
young (5 months) mice one hour after a single treatment with MTP-131 (Figure 1).  These 
results demonstrated a rapid reversal of age-related declines in resting and maximal 
mitochondrial ATP production, without any observable effect on young muscle. Consistent 
results were observed after 8 days of dosing with MTP-131, with a favorable difference in the 
exercise tolerance of old mice (n=7-8), and no significant effect in young mice (n=5) (Figure  
2).   
Figure 1  
ATP Production (Mean ±SEM) in Young and Aged Mice Following a Single 
Treatment with MTP-131  
  
Figure 2  
Exercise Tolerance in Young and Old Mice Following One Week of 
Treatment with MTP-131  


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Also, in a rat model of muscle wasting, MTP-131 reduced functional loss of the diaphragm 
muscles after animals were placed on a ventilator for 12 hours. (Powers et al. 2011) Similarly, 
MTP-131 prevented casting-induced skeletal muscle atrophy via protecting mitochondrial 
function. (Talbert et al. 2013)  
In a study using a mouse model of immobilization induced skeletal muscle atrophy, it was 
shown that MTP-131 rescues skeletal muscle from disuse-induced atrophy via prevention of 
mitochondrial ROS production and is, therefore, suggestive of therapeutic potential in this 
clinical situation (Min et al. 2011).  
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 nonclinical safety studies 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 
MTP-131. MTP-131 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 MTP-131 plasma concentration (Cmax) and were rapidly reversible as plasma 
concentrations of MTP-131 and histamine decreased. Dose administration was not associated 
with any adverse effects on cardiovascular, respiratory or central nervous system function; 
offtarget non-adverse effects were limited to transient decrease of blood pressure and heart 


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rate, which is thought to be consistent with histaminergic-like reactions. In all studies, the 
severity of the effects was proportional to Cmax for MTP-131; thus, the safety margin is 
estimated based on Cmax, and not area under the plasma concentration-time curve (AUC). The 
plasma MTP-131 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 this trial.  
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 MM 
patients.  Though the trial is ongoing (and blinded), elamipretide doses up to 0.2 mg/kg 
administered IV over 2 hours were safe and well-tolerated in 24 patients with mitochondrial 
myopathy in the SPIMM-201 study.  No SAEs or deaths have been recorded.    
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 of elamipretide doses 
of up to 80 mg/day, 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 injection site 
erythema with intercurrent mild pruritus and/or pain reported with similar frequency after 
single and multiple doses; injection site reactions generally resolved within 4 hours and were 
not associated with long-term effects in any subject.    
4.2.3. 
Conclusions  
In summary, based on the clinical and nonclinical study data, acceptable safety risks are 
expected for the proposed current study.  
  
  
 


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5. 
OBJECTIVES  
5.1. 
Primary Objective  
To evaluate the effect of single daily subcutaneous (SC) doses of elamipretide administered for 
4 weeks on 6-minute walking distance (6MWD).  
5.2. 
Secondary Objectives  
• 
To evaluate the safety and tolerability of single daily SC doses of elamipretide 
administered for 4 weeks  
• 
To evaluate the effects of single daily SC doses of elamipretide administered for 4 
weeks on:  
o Accelerometry o Triple Timed Up and Go (3TUG) Test o 
Patient Reported Outcomes o Exploratory biomarkers   
o Physician Global Assessment (PhGA)   
  
  


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6. 
INVESTIGATIONAL PLAN  
6.1. 
Study Design  
This randomized, double-blind, placebo-controlled crossover study will enroll up to 36 subjects 
with genetically confirmed mitochondrial disease who have completed participation in the  
SPIMM-201 study. Subjects will have previously received 5 days of intravenous elamipretide 
(0.01, 0.10 or 0.25 mg/kg/hour infused for 2 hours) or placebo (randomized 3:1) in the 
SPIMM-201 study.  
Subjects will be randomized (1:1) to one of two sequence groups: 4-weeks of treatment with 40 
mg elamipretide administered once daily SC in Treatment Period 1 followed by 4-weeks of 
treatment with placebo administered once daily SC in Treatment Period 2 (separated by 4-week 
washout period), or vice versa (Attachment 3).   
Given the challenges of scheduling Visiting Nurses visits to subject’s homes (e.g. remote 
geographic locations, subject scheduling conflicts, extreme weather or other natural disasters 
etc.), in consultation and agreement with the Sponsor and Investigator, Visiting Nurse visits 
may be postponed, changed or cancelled.  
Screening:  Screening will begin with the signature of the informed consent form (ICF) and 
will last at least 7 days and no more than 30 days. During Screening, subjects will undergo 
screening procedures as described in the Study Schedule (Attachment 1) and will be instructed 
to wear a wrist accelerometer daily (24 hours per day), wear a hip accelerometer daily during 
waking hours (minimum of at least 7 consecutive days immediately prior to the Baseline Visit), 
and complete daily Mitochondrial Disease (MD) Symptom Assessments in an electronic or 
paper diary to characterize their baseline disease status.  Subjects who complete Screening and 
continue to meet all study requirements, including all inclusion and none of the exclusion 
criteria, may enter Treatment Period 1.  
Treatment Period 1:  Treatment Period 1 will begin on the day of the Baseline Visit, which is 
defined as Study Day 1.  At the Baseline Visit, following completion of all Baseline procedures 
described in the Study Schedule, subjects will be administered study drug SC at the study 
center.  Subjects or caregivers will receive instructions on scheduling daily home (or other 
location) visits with the Visiting Nurse and will be assigned a Visiting Nurse who may 
administer (or observe) study drug subcutaneously on a daily basis for the first week of 
Treatment Period 1 and at least weekly thereafter. The Visiting Nurse visit on Day 2 is 
required, however, the Visiting Nurse Visits during Days 3-7 are not mandatory and the patient 
(or caregiver) and the Visiting Nurse should determine the frequency and necessity of these 
visits. Subjects (or caregivers) will be trained on the procedure for administration of study drug 
and will administer study drug on a daily basis (except for days corresponding to study center 
visits and potentially Visiting Nurse Visits) at approximately the same time each day. If, for 
any reason, a subject (or caregiver) is unable/unwilling to administer study drug, a Visiting 
Nurse may be provided for daily administration of study drug.  The Visiting Nurse will also 
draw blood for safety labs at Week 1 and Week 2 Visits.  The Visiting Nurse will administer 
(or observe) study drug at the Week 3 Visit and remind subjects to wear the hip accelerometer 
during waking hours for at least 7 consecutive days immediately prior to the Week 4 Visit. 
Subjects will continue to follow all study requirements, including completing daily MD  


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Symptom Assessments and recording the location and time of the study drug administration in 
an electronic or paper diary as well as wearing the wrist accelerometer daily. Treatment Period 
1 will conclude with a visit to the study center at the Week 4 Visit and subjects will return all 
used and unused vials to the study center at this visit.   
Washout: Washout will begin on the day after the Week 4 Visit and will last for at least 4 
weeks.  The Visiting Nurse will visit at the Week 6 Visit to provide the subject with the Neuro-
QoL Fatigue questionnaire to complete, and will collect the completed questionnaire. The 
Visiting Nurse will also draw blood for safety labs. The Visiting Nurse will ensure the subject 
is wearing a wrist accelerometer daily (24 hours per day), remind the subject to wear a hip 
accelerometer daily during waking hours (minimum of at least 7 consecutive days immediately 
prior to the Week 8 Visit), and complete daily MD Symptom Assessments in an electronic or 
paper diary.   
Treatment Period 2: Treatment Period 2 will begin with a visit to the study center for the 
Week 8 Visit. Subjects will be administered study drug SC at the study center following 
completion of all baseline procedures described in the Study Schedule. A Visiting Nurse will 
administer (or observe) study drug on a weekly basis at home (or other location) and will draw 
blood for safety labs on Week 9 and Week 10, as described in the Study Schedule.  Subjects 
(or caregivers) will administer study drug on a daily basis at approximately the same time each 
day (except for days corresponding to study center visits and potentially Visiting Nurse Visits). 
The Visiting Nurse will administer (or observe) study drug at the Week 11 Visit and will 
remind subjects to wear the hip accelerometer during waking hours for at least 7 consecutive 
days immediately prior to the Week 12 Visit.  Subjects will continue to follow all study 
requirements, including completing daily MD Symptom Assessments and recording the 
location and time of the study drug administration in an electronic or paper diary as well as 
wearing the wrist accelerometer daily. Treatment Period 2 will conclude with a visit to the 
study center at the Week 12 Visit and subjects will return all used and unused vials to the study 
center at this visit.  
Follow-Up: Follow-Up will begin after completion of Treatment Period 2 and will last for 2 
weeks.  During follow-up, subjects will continue to follow all study requirements, including 
completing daily MD Symptom Assessments in an electronic or paper diary as well as wearing 
the wrist accelerometer daily.  At the end of Follow-up, subjects will return to the study center 
for the End-of-Study/Early Discontinuation Visit for final safety and efficacy assessments and 
to return all remaining study equipment, as described in the Study Schedule.    
6.2. 
Discussion of Design and Control  
This is a randomized, double-blind, placebo-controlled, multi-center two-period crossover 
study in subjects with genetically confirmed mitochondrial disease who completed 
participation in the SPIMM-201 study.  
Up to thirty-six subjects will be randomized (1:1) to one of two sequence groups: 4-weeks of 
treatment with 40 mg elamipretide administered once daily SC in Treatment Period 1 followed 
by 4-weeks of treatment with placebo administered once daily subcutaneously in Treatment 


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Period 2 (separated by 4-week washout period), or vice versa.  A four week washout was 
selected to considerably reduce the likelihood of a carryover effect based on the known  
Stealth BioTherapeutics Inc.   
  
pharmacokinetics of elamipretide and anticipated turnover of mitochondria.  The crossover 
design was selected because of the additional anticipated power due to subjects serving as their 
own control.  
Blinded treatment will be used to reduce potential bias during data collection and evaluation of 
endpoints.  
6.3. 
Study Schedule  
Study procedures and their timing are summarized in the Schedule of Clinical Assessments 
(Attachment 1), Schedule of Visiting Nurse Assessments (Attachment 2), and Study Schematic 
(Attachment 3). A list of all clinical laboratory tests to be performed is found in Attachment 4.  
6.3.1. 
Screening: At least 7 days and no longer than 30 days   
NOTE: When possible, all study procedures should be completed in the order described below:  
• 
Review and sign the Informed Consent Form (ICF) 
• 
Record demographics (age, gender, ethnicity, race) 
• 
Update relevant medical history since participation in the SPIMM-201 study 
• 
Document concomitant medication (including supplements and vitamins) 
• 
Collect Vital signs (as described in Section 6.4.3) 
• 
Complete 12-lead resting ECG (as described in Section 6.4.4) 
• 
Draw blood for clinical laboratory testing as outlined in Attachment 4 
• 
Collect urine for clinical urinalysis as outlined in Attachment 4 
• 
Complete a serum pregnancy for women of child-bearing potential 
• 
Review all inclusion and exclusion criteria 
• 
Complete the Columbia Suicide Severity Rating Scale (C-SSRS) “Lifetime” (as 
described in Section 6.4.2 and outlined in Attachment 11) 
• 
Complete a physical examination (as described in Section 6.4.1) 
• 
Complete the Neuro-QoL Fatigue questionnaire (as described in Section 6.4.8 and as 
outlined in Attachment 6) 
• 
Complete the Mitochondrial Disease (MD) Symptom Assessment (as described in 
Section 6.4.9 and as outlined in Attachment 7) and collect results in an electronic or 
paper diary. The MD Symptom Assessment should be completed daily during the study 


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(Baseline Visit to End-of-Study/Early Discontinuation Visit) in an electronic or paper 
diary. 
• 
Train the subject on wrist and hip accelerometer; wrist and hip accelerometer are to be 
worn daily during Screening (hip accelerometer is to be worn at minimum during the 7 
consecutive days immediately prior to the Baseline Visit). All efforts should be made to 
wear the wrist accelerometer on the same wrist throughout the entirety of the study. 


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Conduct the 6MWT (as described in Section 6.4.6 and as outlined in Attachment 5)  
Complete the 3TUG Test. The 3TUG Test should be started after completion of 6MWT 
and after at least 15 minutes rest (as described in Section 6.4.7 and as outlined in 
Attachment 8) 
6.3.2. 
Treatment Period 1  
6.3.2.1. 
Baseline Visit (Day 1)  
NOTE:  Subjects who have been deemed eligible during Screening Period will return for 
randomization and the following procedures will be performed. All study procedures must be 
completed prior to administering study drug. When possible, all study procedures should be 
completed in the order described below:  
• 
Collect of medical history since the Screening Visit 
• 
Document concomitant medication (including supplements and vitamins)  Document 
AEs related to a study procedure and/or meet seriousness criteria that occurred since the 
signing of the informed consent form as Section 9.6.2. 
• 
Collect Vital signs (as described in Section 6.4.3) 
• 
Complete 12-lead resting ECG (as described in Section 6.4.4) 
• 
Draw blood for clinical laboratory testing as outlined in Attachment 4 
• 
Draw blood for exploratory biomarkers (as described in Section 6.4.11) 
• 
Collect urine for clinical urinalysis as outlined in Attachment 4 
• 
Complete a urine pregnancy for women of child-bearing potential 
• 
Review all inclusion and exclusion criteria 
• 
Complete a physical examination (as described in Section 6.4.1) 
• 
Complete the C-SSRS “Since Last Visit” (as described in Section 6.4.2 and outlined in 
Attachment 12) 
• 
Complete the Neuro-QoL Fatigue questionnaire (as described in Section 6.4.8 and as 
outlined in Attachment 6) 
• 
Complete the Mitochondrial Disease (MD) Symptom Assessment (as described in 
Section 6.4.9 and as outlined in Attachment 7) and collect results in an electronic or 
paper diary. The MD Symptom Assessment should be completed daily during the study 
(Baseline Visit to End-of-Study/Early Discontinuation Visit) in an electronic or paper 
diary. 


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• 
Complete the Physician’s Global Assessment (PhGA) (as described in Section 6.4.12 
and as outlined in Attachment 9) 
• 
Complete the Patient’s Global Assessment (PGA) (as described in Section 6.4.13 and 
as outlined in Attachment 10) 
• 
Conduct the 6MWT (as described in Section 6.4.6 and as outlined in Attachment 5)  
Complete the 3TUG Test. The 3TUG Test should be started after completion of 6MWT 
and after at least 15 minutes rest (as described in Section 6.4.7 and as outlined in 
Attachment 8) 
• 
Sync wrist and hip accelerometers and confirm subject is wearing wrist accelerometer 
 Inject study drug record the location and time of the study drug administration in an 
electronic or paper diary 
• 
Schedule and discuss home (or other location) visit schedule by the Visiting Nurse 
6.3.2.2. 
Visiting Nurse Visits: Days 2 – 7  
A Visiting Nurse may administer (or observe) study drug at approximately the same time each 
day on Days 2 through Day 7 and will train subjects and/or caregivers on the storage and 
procedures for administration of study drug.  The Visiting Nurse visit on Day 2 is required, 
however, the Visiting Nurse Visits during Days 3-7 are not mandatory and the patient (or 
caregiver) and the Visiting Nurse should determine the frequency and necessity of these visits. 
The Visiting Nurse will also confirm the subject is wearing his/her wrist accelerometer and 
ensure the accelerometer is charged.  The Visiting Nurse should confirm the subject is also 
completing the MD Symptom Assessment and recording the study drug injection location and 
time in an electronic or paper diary. Refer to the Schedule of Visiting Nurse Assessments in 
Attachment 2.  
6.3.2.3. 
Visiting Nurse Visits: Week 1 (Day 8 ± 1), Week 2 (Day 15 ± 2), and Week 3 
(Day 22 ± 2)  
A Visiting Nurse will administer (or observe) study drug and confirm both accelerometers are 
charged and ensure the subject is wearing wrist accelerometer. The Visiting Nurse will also 
ensure appropriate storage and use of the study drug at each Visit.  At the Week 1 and Week 2  
Visits, blood for clinical chemistry and clinical hematology will be collected.  The Visiting 
Nurse should confirm the subject is also completing the MD Symptom Assessment and 
recording the study drug injection location and time in an electronic or paper diary. At the 
Week 3 Visit, the Visiting Nurse will instruct the subject to wear hip accelerometer for 7 
consecutive days immediately prior to Week 4 Visit.  Refer to the Schedule of Visiting Nurse 
Assessments in Attachment 2.  


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6.3.2.4. 
Week 4 (Day 29 + 6 days)  
NOTE: Subjects will be instructed to wear the hip accelerometer for the 7 consecutive days 
immediately prior to the Week 4 Visit.  Study drug administration should occur before all 
study procedures. When possible, all study procedures should be completed in the order 
described below:   
The following evaluations will be performed:  
• 
Inject study drug record the location and time of the study drug administration in an 
electronic or paper diary 
Document concomitant medication (including supplements and vitamins) 
• 
Document AEs 
• 
Complete a physical examination (as described in Section 6.4.1) 
• 
Complete the C-SSRS “Since Last Visit” (as described in Section 6.4.2 and outlined in 
Attachment 12) 
• 
Collect Vital signs (as described in Section 6.4.3) 
• 
Complete 12-lead resting ECG (as described in Section 6.4.4) 
• 
Draw blood for clinical laboratory testing as outlined in Attachment 4 
• 
Draw blood for exploratory biomarkers (as described in Section 6.4.11) 
• 
Collect urine for clinical urinalysis as outlined in Attachment 4 
• 
Complete the Neuro-QoL Fatigue questionnaire (as described in Section 6.4.8 and as 
outlined in Attachment 6) 
• 
Complete the Mitochondrial Disease (MD) Symptom Assessment (as described in 
Section 6.4.9 and as outlined in Attachment 7) and collect results in an electronic or 
paper diary. The MD Symptom Assessment should be completed daily during the study 
(Baseline Visit to End-of-Study/Early Discontinuation Visit) in an electronic or paper 
diary. 
• 
Complete the Physician’s Global Assessment (PhGA) (as described in Section 6.4.12 
and as outlined in Attachment 9) 
• 
Complete the Patient’s Global Assessment (PGA) (as described in Section 6.4.13 and 
as outlined in Attachment 10) 
• 
Conduct the 6MWT (as described in Section 6.4.6 and as outlined in Attachment 5)  
Complete the 3TUG Test. The 3TUG Test should be started after completion of 6MWT 
and after at least 15 minutes rest (as described in Section 6.4.7 and as outlined in 
Attachment 8) 


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• 
Sync wrist and hip accelerometers and confirm subject is wearing wrist accelerometer 
• 
Collect all used and unused study drug vials from the subject 
6.3.3. 
Washout  
Washout will be at least 4 weeks in duration. If all used and unused study drug vials were not 
returned at the Week 4 Visit, the unscheduled Visiting Nurse Visit will be scheduled to collect 
all remaining vials (or other arrangements will be made to ship the remaining vials back to the 
site). The subject will be instructed to continue to wear an accelerometer on his/her wrist and 
will continue to complete the MD Symptom Assessment (as described in Section 6.4.9 and as 
outlined in Attachment 7) collect the results in an electronic or paper diary. The MD Symptom 
Assessment should be completed daily during Washout Period. The Visiting Nurse will visit at 
the Week 6 Visit to provide the subject with the Neuro-QoL Fatigue questionnaire to complete, 
and will collect the completed questionnaire. The Visiting Nurse will also draw blood for 
safety labs. The Visiting Nurse will ensure the subject is wearing a wrist accelerometer daily  
(24 hours per day), remind the subject to wear a hip accelerometer daily during waking hours 
(minimum of at least 7 consecutive days immediately prior to the Week 8 Visit).   
6.3.4. 
Treatment Period 2  
6.3.4.1. 
Week 8 (Day 57 + 5)  
NOTE:  All study procedures must be completed prior to administering study drug. When 
possible, all study procedures should be completed in the order described below:  
• 
Document concomitant medication (including supplements and vitamins) 
• 
Document AEs 
• 
Complete a physical examination (as described in Section 6.4.1) 
• 
Complete the C-SSRS “Since Last Visit” (as described in Section 6.4.2 and outlined in 
Attachment 12) 
• 
Collect Vital signs (as described in Section 6.4.3) 
• 
Complete 12-lead resting ECG (as described in Section 6.4.4) 
• 
Draw blood for clinical laboratory testing as outlined in Attachment 4 
• 
Draw blood for exploratory biomarkers (as described in Section 6.4.11) 
• 
Collect urine for clinical urinalysis as outlined in Attachment 4 
• 
Complete the Neuro-QoL Fatigue questionnaire (as described in Section 6.4.8 and as 
outlined in Attachment 6) 


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• 
Complete the Mitochondrial Disease (MD) Symptom Assessment (as described in 
Section 6.4.9 and as outlined in Attachment 7) and collect results in an electronic or 
paper diary. The MD Symptom Assessment should be completed daily during the study 
(Baseline Visit to End-of-Study/Early Discontinuation Visit) in an electronic or paper 
diary. 
• 
Complete the Physician’s Global Assessment (PhGA) (as described in Section 6.4.12 
and as outlined in Attachment 9) 
• 
Complete the Patient’s Global Assessment (PGA) (as described in Section 6.4.13 and 
as outlined in Attachment 10) 
• 
Conduct the 6MWT (as described in Section 6.4.6 and as outlined in Attachment 5) 
• 
Complete the 3TUG Test. The 3TUG Test should be started after completion of 6MWT 
and after at least 15 minutes rest (as described in Section 6.4.7 and as outlined in 
Attachment 8) 
• 
Sync wrist and hip accelerometers and confirm subject is wearing wrist accelerometer 
Inject study drug record the location and time of the study drug administration in an 
electronic or paper diary 
6.3.4.2. 
Visiting Nurse Visits: Week 9 (Day 64 ± 2), Week 10 (Day 71 ± 2), Week 11 
(Day 78 ± 2)  
A Visiting Nurse will administer (or observe) study drug and confirm both accelerometers are 
charged and ensure the subject is wearing wrist accelerometer.  The Visiting Nurse will also 
ensure appropriate storage and use of the study drug at each Visit.  At the Week 9 and Week 10  
Visits, blood for clinical chemistry and clinical hematology will be collected.  The Visiting 
Nurse should confirm the subject is also completing the MD Symptom Assessment and 
recording the study drug injection location and time in an electronic or paper diary. At the 
Week 11 Visit, the Visiting Nurse will instruct the subject to wear hip accelerometer for 7 
consecutive days immediately prior to Week 12 Visit.  Refer to the Schedule of Visiting Nurse 
Assessments in Attachment 2.  
6.3.4.3. 
Week 12 (Day 85 + 6)  
NOTE: Subjects will be instructed to wear the hip accelerometer for the 7 consecutive days 
immediately prior to the Week 12 Visit. Study drug administration should occur before all 
study procedures. When possible, all study procedures should be completed in the order 
described below:   
• 
Inject study drug record the location and time of the study drug administration in an 
electronic or paper diary 
• 
Document concomitant medication (including supplements and vitamins) 


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• 
Document AEs 
• 
Complete a physical examination (as described in Section 6.4.1) 
• 
Complete the C-SSRS “Since Last Visit” (as described in Section 6.4.2 and outlined in 
Attachment 12) 
• 
Collect Vital signs (as described in Section 6.4.3) 
• 
Complete 12-lead resting ECG (as described in Section 6.4.4) 
• 
Draw blood for clinical laboratory testing as outlined in Attachment 4 
• 
Draw blood for exploratory biomarkers (as described in Section 6.4.11) 
• 
Collect urine for clinical urinalysis as outlined in Attachment 4 
• 
Complete the Neuro-QoL Fatigue questionnaire (as described in Section 6.4.8 and as 
outlined in Attachment 6) 
• 
Complete the Mitochondrial Disease (MD) Symptom Assessment (as described in 
Section 6.4.9 and as outlined in Attachment 7) and collect results in an electronic or 
paper diary. The MD Symptom Assessment should be completed daily during the study 
(Baseline Visit to End-of-Study/Early Discontinuation Visit) in an electronic or paper 
diary.   
• 
Complete the Physician’s Global Assessment (PhGA) (as described in Section 6.4.12 
and as outlined in Attachment 9) 
• 
Complete the Patient’s Global Assessment (PGA) (as described in Section 6.4.13 and 
as outlined in Attachment 10) 
• 
Conduct the 6MWT (as described in Section 6.4.6 and as outlined in Attachment 5) 
• 
Complete the 3TUG Test. The 3TUG Test should be started after completion of 6MWT 
and after at least 15 minutes rest (as described in Section 6.4.7 and as outlined in 
Attachment 8) 
• 
Sync wrist and hip accelerometers and confirm subject is wearing wrist accelerometer 
• 
Collect all used and unused study drug vials from the subject 
6.3.5. 
Follow-up Period  
Follow-Up will be approximately 2 weeks in duration. If all used and unused study drug vials 
were not returned at the Week 4 Visit, the unscheduled Visiting Nurse Visit will be scheduled 
to collect all remaining vials (or other arrangements will be made to ship the remaining vials 
back to the site). The subject will be instructed to continue to wear an accelerometer on his/her 


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wrist and will continue to complete the MD Symptom Assessment (as described in Section 
6.4.9 and as outlined in Attachment 7) collect the results in an electronic or paper diary during 
the Follow-Up Period.   
6.3.5.1. 
End-of-Study/Early Discontinuation Visit (Day 99 + 7 days /Early 
Discontinuation)  
NOTE: When possible, all study procedures should be completed in the order described below:  
• 
Document concomitant medication (including supplements and vitamins) 
• 
Document AEs 
• 
Complete a physical examination (as described in Section 6.4.1) 
• 
Complete the C-SSRS “Since Last Visit” (as described in Section 6.4.2 and outlined in 
Attachment 12) 
• 
Collect Vital signs (as described in Section 6.4.3) 
• 
Complete 12-lead resting ECG (as described in Section 6.4.4) 
• 
Draw blood for clinical laboratory testing as outlined in Attachment 4 
• 
Draw blood for exploratory biomarkers (as described in Section 6.4.11) 
• 
Collect urine for clinical urinalysis as outlined in Attachment 4 
• 
Complete a urine pregnancy for women of child-bearing potential 
Complete the Neuro-QoL Fatigue questionnaire (as described in Section 6.4.8 and as 
outlined in Attachment 6) 
• 
Complete the Mitochondrial Disease (MD) Symptom Assessment (as described in 
Section 6.4.9 and as outlined in Attachment 7) and collect results in an electronic or 
paper diary. The MD Symptom Assessment should be completed daily during the study 
(Baseline Visit to End-of-Study/Early Discontinuation Visit) in an electronic or paper 
diary. 
• 
Complete the Physician’s Global Assessment (PhGA) (as described in Section 6.4.12 
and as outlined in Attachment 9) 
• 
Complete the Patient’s Global Assessment (PGA) (as described in Section 6.4.13 and 
as outlined in Attachment 10) 
• 
Conduct the 6MWT (as described in Section 6.4.6 and as outlined in Attachment 5) 
• 
Complete the 3TUG Test. The 3TUG Test should be started after completion of 6MWT 
and after at least 15 minutes rest (as described in Section 6.4.7 and as outlined in 
Attachment 8) 


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• 
Collect and sync the wrist and hip accelerometers. 
6.4. 
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 4.  
6.4.1. 
Medical History and Physical Examination  
At the Screening Visit, a medical history (since participation in the SPIMM-201 study) will be 
taken, including measurement of height.   
At the Baseline Visit, a review of the medical history (including concomitant medication and 
procedures) since the Screening visit will be taken.    
At the Screening, Baseline, Week 4, Week 8, Week 12, and End-of-Study/Early  
Discontinuation Visits, a complete physical examination will be performed. This will include a 
full review of the following systems: general appearance, skin, head, eyes (only if ptosis is 
present [i.e. an upper marginal reflex distance below 2 mm or an asymmetry of more than 2 
mm between the eyes] the marginal reflex distance should be measured and recorded for both 
eyes as shown below in Figure 3), ears, nose, throat, neck (including thyroid), lymph nodes, 
chest, heart, abdomen, extremities, and nervous system. The Scale for the Assessment and 
Rating of Ataxia (SARA) (provided in Attachment 13) will be completed during every physical 
examination for all subjects. Height will only be measured at the Screening Visit. Weight 
should be taken during each physical examination.   
Figure 3  
Marginal Reflex Distance  
 
6.4.2. 
Columbia Suicide Severity Rating Scale (C-SSRS)  
At the Screening Visit, the C-SSRS “Lifetime Recent” will be recorded.  The C-SSRS  
“Lifetime Recent” is included in Attachment 11.  At all subsequent clinical visits, the C-SSRS 
“Since Last Visit” will be recorded.  The C-SSRS “Since Last Visit” is included in Attachment  
12.  


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6.4.3. 
Vital signs  
During all study center visits, the vital signs measurements will include temperature, heart rate, 
respiration rate and blood pressure, recorded in the sitting position after at least 5 minutes rest. 
At the Baseline Visit these vital signs measurements will be performed as part of the study 
eligibility confirmation.    
6.4.4. 
Electrocardiograms (ECGs)  
A 12-lead ECG will be obtained after the subjects has rested quietly for 10 minutes in the 
supine position at all study center 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. The QTc 
correction factor used to calculate the QTc value will be collected from each site.   
6.4.5. 
Clinical Laboratory Testing  
Sample collection, processing and handling details are provided in the Laboratory Manual.  
6.4.5.1. 
Blood chemistries  
Blood will be collected at all study center visits as well as Visiting Nurse visits on Week 1, 
Week 2, Week 6, Week 9, and Week 10. Analysis will include testing for parameters included 
in Attachment 4.  
6.4.5.2. 
Hematology  
Blood will be collected at all study center visits as well as Visiting Nurse visits on Week 1, 
Week 2, Week 6, Week 9, and Week 10. Analysis will include testing for parameters included 
in Attachment 4.  


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6.4.5.3. 
Urinalysis  
Urine will be collected at all study center visits and will include testing for parameters included 
in Attachment 4.  
6.4.5.4. 
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 at the Baseline Visit 
and the results of the Baseline Visit pre-dose pregnancy test must be evaluated before 
randomization to ensure eligibility.  A urine pregnancy test will also be performed for women 
of childbearing potential at the End-of-Study/Early Discontinuation Visit.  
6.4.6. 
6-Minute Walk Test (6MWT)  
At all study center visits, the distance walked (in meters) during the 6MWT will be recorded.  
The 6MWT instructions are provided in Attachment 5.  Study centers will be provided with a 6 
Minute Walk Test Kit (if needed), as well as standardized training.    
6.4.7. 
Triple Timed Up and Go (3TUG) Test  
At all study center visits, the time (in seconds) to complete the 3TUG Test will be recorded.  
The 3TUG Test instructions are provided in Attachment 8.  The 3TUG Test should be 
performed after completion of the 6MWT and at least 15 minutes rest.   
6.4.8. 
The Neuro-QoL Fatigue Questionnaire  
At all study center visits, subjects will be instructed to complete the Neuro-QoL Fatigue 
questionnaire. The Neuro-QoL questionnaire should be completed prior to administration of 
study drug during Treatment Period 1 and Treatment Period 2. The Visiting Nurse will visit at 
the Week 6 Visit to provide the subject with the Neuro-QoL Fatigue questionnaire to complete, 
and will collect the completed questionnaire. The Neuro-QoL Fatigue questionnaire is in 
Attachment 6.  
6.4.9. 
Mitochondrial Disease (MD) Symptom Assessment  
Starting at the Screening Visit, subjects will be instructed to complete the Mitochondrial  
Disease (MD) Symptom Assessment daily for the duration of the study (Screening through 
End-of-Study/Early Discontinuation Visit).  The MD Symptom Assessment will be completed 
and recorded in an electronic or paper diary. The MD Symptom Assessment is in Attachment  
7.   
6.4.10. 
Accelerometry  
Starting at the Screening Visit, subjects will be provided with a wrist and hip accelerometer 
and instructions for use.  Subjects will be instructed to wear the wrist accelerometer from the 
Screening Visit through the End-of-Study/Early Discontinuation Visit 24 hours per day.   
Subjects will be encouraged to wear the hip accelerometer during waking hours from the 
Screening Visit through the End-of-Study/Early Discontinuation Visit. All efforts should be 
made to wear the wrist accelerometer on the same wrist throughout the entirety of the study.   


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Subjects will be specifically instructed to wear the hip accelerometer during waking hours for a 
minimum of 7 consecutive days immediately prior to the Baseline, Week 4, Week 8, and Week 
12 Visits.  Subjects will return both the wrist and hip accelerometers by the completion of 
his/her participation in the study.  
6.4.11. 
Exploratory biomarkers  
Blood will be collected at the Baseline, Week 4, Week 8, Week 12, and End-of-Study/Early 
Discontinuation Visits for analysis of exploratory biomarkers as outlined in Attachment 4.  
Blood samples for analysis of exploratory biomarkers will be collected prior to study drug 
administration on the Baseline and Week 8 Visits. Additional blood samples at the Baseline of 
Treatment Period 1 and End-of-Study/Early Discontinuation Visits will be collected and stored 
for assessing the immunogenicity potential of the study drug.  
6.4.12. 
Physician Global Assessment (PhGA)  
The Investigator or designee will provide an overall assessment of the subject’s mitochondrial 
disease symptoms at the Baseline, Week 4, Week 8, Week 12, and End-of-Study/Early 
Discontinuation Visits. The PhGA is provided in Attachment 9. The same Investigator or 
designee should administer the PhGA at each visit for a particular subject.  
6.4.13. 
Patient Global Assessment (PGA)  
The Investigator or designee should ask the subjects for their overall assessment of their 
mitochondrial disease symptoms at the Baseline, Week 4, Week 8, Week 12, and Endof-
Study/Early Discontinuation Visits. The PGA is provided in Attachment 10.    


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CONFIDENTIAL  
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 the following criteria prior at the Baseline Visit 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. Subject completed participation in the SPIMM-201 study without a significant protocol 
deviation that would suggest the subject may not be able to complete all study 
requirements in the opinion of the Sponsor. 
3. Subject must reside in North America for the duration of the study. 
4. Subject agrees to adhere to the study requirements for the length of the trial. 
5. Subject has not received study drug in the SPIMM-201 study within 3 weeks prior to 
Screening. 


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6. 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 
drug:  
a. Abstinence, when it is in line with the preferred and usual lifestyle of the 
subject.  Subject agrees to use an acceptable method of contraception should 
they become sexually active.  
b. Maintenance of a monogamous relationship with a male partner who has been 
surgically sterilized by vasectomy (the vasectomy procedure must have been 
conducted at least 60 days prior to the Screening Visit or confirmed via sperm 
analysis).  
c. Barrier method (e.g., condom or occlusive cap) with spermicidal 
foam/gel/film/cream AND either hormonal contraception (oral, implanted, or 
injectable) or an intrauterine device or system.  
Note: Non-childbearing potential is defined as surgical sterilization (e.g., bilateral 
oophorectomy, hysterectomy, or tubal ligation) or postmenopausal (defined as 
permanent cessation of menstruation for at least 12 consecutive months prior to the 
Screening Visit).  
7. Subject has been on stable medications (including over-the-counter treatments, 
vitamins, or supplements), or medications that will not impact the safety or efficacy 
endpoints of the trial, in the opinion of the Investigator for at least 1 month prior to the 
Baseline Visit.  
  
  
7.2. 
Exclusion Criteria  
A subject who meets any of the following criteria at Screening will be excluded from the study:  
1. Subject has any prior or current medical condition that, in the judgment of the 
Investigator, would prevent the subject from safely participating in and/or 
completing all study requirements (i.e. unstable angina or recent myocardial 
infarction). 
2. Subject has received any investigational compound and/or has participated in 
another interventional clinical study within 30 days prior to the Baseline Visit or is 
concurrently enrolled in any non-interventional research of any type judged to be 
scientifically or medically incompatible with the study as deemed by the 
Investigator in consultation with the Sponsor. 
3. Subject experienced an adverse reaction to study drug in the SPIMM-201 study that 
contraindicates further treatment with elamipretide in the opinion of the Investigator 
and/or Sponsor. 
4. Female subjects who are pregnant, planning to become pregnant, or lactating. 
5. Subject has undergone an in-patient hospitalization within the 1 month prior to the 
Screening Visit or is likely to need in-patient hospitalization or a surgical procedure 
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6. Subject has a creatinine clearance ≤30 mL/min as calculated by the Cockcroft Gault 
equation. 
7. Subject has QTc elongation defined as a QTc >450 msec in male subjects and >480 
msec in female subjects. 
Note: At the initial ECG, if QTc exceeds these parameters, the ECG may be 
repeated 2 more times, and the average of the 3 QTc values used to determine the 
subject’s eligibility. 
8. Subject has uncontrolled hypertension in the judgment of the Investigator (e.g. 
elevated above >160 mmHg systolic or >100 mmHg diastolic despite appropriate 
treatment on two consecutive readings); 
9. Subject has a history of clinically significant hypersensitivity or allergy to any of 
the excipients contained in the study drug. 
10. Subject has a history of active alcoholism or drug addiction during the year 
beforethe Screening Visit. 
11. Subject is an Investigator/study center personnel or immediate family* 
ofInvestigator/study center personnel. 
12. Subject is a Sponsor employee (permanent, temporary contract worker, or 
designeeresponsible for the conduct of the study) or immediate family* of a 
Sponsor employee. 
* Immediate family is defined as a spouse, parent, child, or sibling, whether 
biological or legally adopted  
CONFIDENTIAL  
  
7.3. 
Prohibited Medications  
The use of any other investigational drug except elamipretide is prohibited during the conduct 
of the current trial.   
All medications, including over-the-counter treatments, vitamins, or supplements, must have 
been stable, or medications that will not impact the safety or efficacy endpoints of the trial, in 
the opinion of the Investigator for at least 1 month prior to the Baseline Visit.  All concomitant 
medications will be recorded in the source data and the Electronic Case Report Form (eCRF). 
Changes in dosages of current medications (including over-the-counter vitamins or 
supplements) during the conduct of the study will be discouraged, unless required to treat an 
Adverse Event.  
Subjects will be instructed to maintain their normal diet, daily caffeine and fiber intake 
throughout the study period.    


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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 study center should document and sign the reason for 
the subject’s failure to withdraw consent in writing.   
o The subject is lost to follow-up after a reasonable number of attempts to contact 
the subject (including documented phone calls and/or emails, and a certified 
letter) have been completed.  
• 
Sponsor Decision o The Sponsor or its designee stops the study or stops the subject’s 
participation in the study for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP guidelines.  
• 
Adverse Event 
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 Center  
Study center (research center) participation may be discontinued if the Sponsor or its designee, 
the Investigator, or the Ethics Committee (EC) of the study center judges it necessary for 
medical, safety, regulatory, or other reasons consistent with applicable laws, regulations, and 
GCP guidelines.  


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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.  
CONFIDENTIAL  
8. 
TREATMENT  
8.1. 
Treatments Administered  
Up to 36 subjects will receive study drug administered as a single daily subcutaneous (SC) 
injection containing either 40 mg elamipretide or placebo for at least 28 consecutive days in 
Treatment Period 1 and at least 28 consecutive days in Treatment Period 2.  Study drug will be 
administered daily to the subject, preferably in the abdomen (rotating around the four 
abdominal quadrants), by either the study center clinical staff, a Visiting Nurse, a caregiver, or 
the subject.  Administration of study drug will occur at approximately the same time every day 
during each Treatment Period.    
At the Baseline Visit, study drug will occur after completion of all baseline procedures (see 
Section 6.3.2.1).  Study drug injection will occur at the study center at the Baseline Visit.  


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Subjects or caregivers will receive instruction on scheduling daily home (or other location) 
visits with the Visiting Nurse and will be assigned a Visiting Nurse who may administer (or 
observe) study drug subcutaneously on a daily basis for the first week of Treatment Period 1 
and at least weekly thereafter. The Visiting Nurse visit on Day 2 is required, however, the  
Visiting Nurse Visits during Days 3-7 are not mandatory and the patient (or caregiver) and the 
Visiting Nurse should determine the frequency and necessity of these visits. Subjects (or 
caregivers) will be trained on the procedure for administration of study drug and will 
administer study drug on a daily basis (except for days corresponding to study center visits and 
potentially Visiting Nurse Visits) at approximately the same time each day.   
Study drug injection will occur at the study center on Week 8 and subjects will be instructed to 
schedule weekly Visiting Nurse visits for the duration of Treatment Period 2.    
If, for any reason, a subject (or caregiver) is unable/unwilling to administer study drug, a 
Visiting Nurse may be provided for daily administration of study drug.  
8.2. 
Materials and Supplies  
Study drug (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 contains sufficient volume to extract one milliliter of 
drug product containing 40 mg elamipretide, 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.    


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8.3. 
Treatment Logistics and Accountability  
All drug accountability records must be kept current, and the Investigator must be able to 
account for all used and unused vials of study drug.  These records should contain the dates, 
quantity, and study drug:  
• 
Received at study center  
• 
Administered to each subject,  
• 
Dispensed to each subject,  
• 
Returned from each subject, and  
• 
Disposed of at the study center or returned to the Sponsor or designee  
The clinical monitor responsible for the study center will provide written approval for the 
destruction or return of unused study drug vials following reconciliation of all clinical supplies.  
8.4. 
Method of Assignment to Treatment and Randomization  
At the Baseline Visit, 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 2 treatment sequences in a 1:1 fashion to 
receive either elamipretide 40 mg followed by placebo (after 4 week washout) or placebo 
followed by elamipretide 40 mg (after 4 week washout).  
8.5. 
Rationale for Selection of Doses in the Study  
The dose and route of administration (i.e., 40 mg in 1 mL via SC injection) for the current 
study has previously been tested in a clinical trial involving healthy subjects (SPISC-101).  
Five consecutive daily IV doses ranging from 0.02 mg/kg to 0.5 mg/kg administered over 2 
hours have been tested in subjects with genetically confirmed mitochondrial disease 
(SPIMM201).  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, pain, or swelling, which resolved spontaneously, generally within 4 
hours post-dose, without sequelae.    


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Elamipretide demonstrated an acceptable safety and tolerability profile with multiple IV 
infusions of up to 0.5 mg/kg administered over 2 hours in subjects with genetically confirmed 
mitochondrial disease in an ongoing Phase 1/2 trial (SPIMM-201).    
8.5.1. 
Comparison of the PK and Metabolism of IV and SC Administration  
MTP-131 given by SC injection demonstrates rapid absorption, with parent Tmax occurring 
approximately 0.6 hours following administration. When administered by IV infusion, parent 
Tmax is controlled by the duration of infusion, and occurs at the end of drug delivery (either 2 
hours or 4 hours in studies completed to date) and a similar pattern is noted for the metabolites. 
As expected, from the point of Tmax, MTP-131, M1 and M2 demonstrate similar elimination 
profiles following IV and SC administration, with t½ for parent generally occurring between 2 
and 3 hours post-dose completion.  A strong correlation between Cmax and AUC0-24 following 
repeat administration of MTP-131 at 20 mg by a 1 hour IV infusion and Cmax and AUC0-24 
following administration of MTP-131 at 20 mg by SC injection is evident (Table 1).  
Table 1:  
Comparative Pharmacokinetics of MTP-131, M1 and M2 in Clinical 
Studies Following a 7-day Repeat Administration of MTP-131 at Approximately 20 
mg/day by IV or SC Administration   
  
Analyte  
Route  
Day of 
Dosing  
Mean* Pharmacokinetic Parameters   
Tmax  
(hr)  
Cmax 
(ng/mL)  
AUC0-2412 or  
AUC0- τ 2  
(ng.hr/mL)  
Accumulation  
Ratio3  
MTP-131  
SC  
1  
0.64  
715  
1990  
  
7  
0.63  
663  
1890  
1.01  
IV  
1  
1  
921  
2409  
  
7  
1  
938  
2355  
0.98  
M1  
SC  
1  
2.25  
197  
1330  
  
7**  
2.00  
215  
1420  
1.13  
IV  
1**  
2  
201  
1662  
  
7  
2  
201  
1637  
0.98  
 
1  AUC0-24 calculated for Day 1 values  
2  AUC0- τ calculated for Day 7 values where τ =48hrs  
3  Accumulation ratio calculated as AUC0- τ (Day 7)/AUC0-24(Day 1)  


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M2  
SC  
1  
4.88  
24.5  
350  
  
7  
4.84  
34.9  
580  
1.72  
IV  
1  
6  
22.2  
393  
  
7  
6  
35.1  
635  
1.62  
^SC dose = 20 mg (as 0.5 mL x 40 mg/mL); IV dose ~ 20 mg (as 0.25 mg/kg/hr X 1 h; assuming 80 kg body 
weight)  
*SC Administration (Ref. SPISC-101) - mean values calculated from n=8, except as noted; IV administration 
(Ref. SPICP-101) – mean values calculated from n=6  
** Mean values calculated from n=6  
Table 2 describes the pharmacokinetic parameters generated following daily administration of 
elamipretide by subcutaneous injection at 40 mg/day.  
  
  
Table 2:  
Pharmacokinetic Parameters on Days 1 and 7 Following Once Daily 
Administration of MTP-131 as a Subcutaneous Injection of 40 mg/day (as a 1 mL 
injection of 40 mg/mL)  
Analyte  
Day of Dosing  
Mean* Pharmacokinetic Parameters (CV %)  
Tmax  
(hr)  
Cmax 
(ng/mL)  
AUC0-241 or  
AUC0- τ 2  
(ng.hr/mL)  
t½ (hr)  
MTP- 
131  
1  
0.77  (22.0)  
1210  (20.3)  
3750  (11.8)  
2.97  (11.4)  
7  
0.66  (19.7)  
1320  (21.0)  
3810  (13.4)  
3.36  (16.2)  
M1  
1  
2.50  (21.4)  
439  (23.1)  
3160  (17.2)  
3.20  (12.1)  
7  
2.63  (34.9)  
436  (15.3)  
3200  (13.5)  
3.97  (12.8)  
M2  
1  
6.25  (32.8)  
51.1  (16.2)  
773  (17.5)  
11.2  (13.4)  
7  
5.00  (32.1)  
88.8  (14.4)  
1410  (16.5)  
20.9  (20.5)  
*Mean values calculated from n=8  
1 AUC0-24 calculated for Day 1 values  
2 AUC0- τ calculated for Day 7 values where τ =48hrs  
  
8.6. 
Continued Access to Investigational Medicinal Product  
Study subjects will not have access to clinical trial medication following the conclusion of the 
study.  


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8.7. 
Blinding and Unblinding Procedures  
The 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 sequence 
unless in the instance of a medical emergency.  
In case of an immediate medical emergency or if directed by the Sponsor, and only if the 
information is required by the Investigator to manage a subject’s AE, is a subject’s treatment 
assignment to be unblinded prematurely. In cases of medical emergency, the Investigator may 
unblind a subject’s treatment assignment using the computerized system according to the 
instructions received. The Sponsor must be notified as soon as possible regarding the reason 
for unblinding.  
Whenever the treatment assignment of an individual subject is unblinded, the individual who 
performed the unblinding, the date, time and reason for the unblinding must be logged in the 
computerized unblinding system (IWRS) and also included in source documentation. The 
name of the individual who broke the blind must be included in the study center’s source 
documentation.   
The Sponsor designated CRO will control and document, according to the appropriate Standard 
Operating Procedures, the disclosure of treatment assignments, and treatment identity. These 
procedures ensure that no blinded staff (CRO, study center, Sponsor) will have premature 
access to the subjects’ treatment assignments.   
At completion of Treatment Period 1 and at the discretion of the Sponsor, the data may be 
unblinded to inform Phase 3 planning.  Designated Sponsor and CRO personnel will be 
documented and will not be involved in the conduct of the remainder of the study.   
8.8. 
Treatment Compliance  
During the treatment period, study drug will be administered by study center clinical staff, 
Visiting Nurse, caregiver, or subject.  Injection times and locations will be recorded.  


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9. 
EFFICACY AND SAFETY EVALUATIONS AND 
APPROPRIATENESS OF MEASUREMENTS  
Study procedures and their timing are summarized in Attachment 1, Attachment 2 and in 
Attachment 3.  
9.1. 
Efficacy Measures   
9.1.1. 
Primary efficacy measure  
Distance walked (meters) during 6MWT.  
9.1.2. 
Secondary efficacy measure  
• 
Accelerometer counts  
• 
Patient reported outcomes (Neuro-QoL Fatigue questionnaire, Mitochondrial Disease  
[MD] Symptom Assessment and Patient Global Assessment [PGA])  
• 
3TUG Test score  
• 
Exploratory biomarkers   
• 
Physician Global Assessment (PhGA)   
9.1.3. 
Safety measures  
The safety and tolerability end-points will be assessed by:  
• 
AEs   
• 
Vital signs  
• 
ECGs  
• 
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 


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informed consent.  Study center personnel will report any AE, whether observed by the 
Investigator or reported by the subject.  The reporting period for AEs is described in Section 
9.6.2.  
9.1.4. 
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 drug.  
• 
Other medical experiences, regardless of their relationship with the study drug, 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 drug 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.   
9.2. 
Pre-Treatment Events  
Untoward events and/or incidental diagnoses that occur prior to study drug administration are 
by definition, unrelated to the study drug. Pre-treatment events or incidental diagnoses will be 
recorded on the past medical history electronic case report form (eCRF).  However, if a 
pretreatment 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.  
9.3. 
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 drug, 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.  


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9.4. 
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” rather than “decreased red blood cell count” or “hemoglobin = 10.5 g/dL”.  
9.5. 
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 9.7.  


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9.5.1. 
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.  
9.6. 
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 drug, 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.  


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9.6.1. 
Investigator Assessments  
9.6.1.1. 
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.  
9.6.1.2. 
Relationship to the Investigational Medicinal Product (IMP)  
Investigators must systematically assess the causal relationship of AEs to the study drug using 
the following definitions (the decisive factor being the temporal relationship between the AE 
and administration of the study drug):   
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 drug, 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 drug.  
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.  
9.6.2. 
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 drug.    
Note that AEs that occur between the time subject signs the ICF and the time the subject is 
dosed with study drug will be summarized in the medical history eCRF and not as an AE 
unless the event meets the definition of an SAE or is related to a study procedure.  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.    


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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.  
9.7. 
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, study center number, subject number)  
• 
Study drug 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 drug (e.g., 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 drug and study drug dosing information) will automatically be sent via the EDC 
system when the SAE form is submitted.  
The names, addresses, telephone and fax numbers for SAE back-up reporting (paper), are 
included in the Safety Reporting Plan.    


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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.  
9.7.1. 
Pregnancy and Contraception  
Any pregnancies must be reported to the Investigator in the two months after the last dose of 
study drug.  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 drug:  
a) Abstinence, when it is in line with the preferred and usual lifestyle of the 
subject.  Subject agrees to use an acceptable method of contraception should 
they become sexually active.  
b) Maintenance of a monogamous relationship with a male partner who has been 
surgically sterilized by vasectomy (the vasectomy procedure must have been 
conducted at least 60 days prior to the Screening Visit or confirmed via sperm 
analysis).  
c) Barrier method (e.g., condom or occlusive cap) with spermicidal 
foam/gel/film/cream AND either hormonal contraception (oral, implanted, or 
injectable) or an intrauterine device or system.  
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 
last dose of study drug. Highly effective methods of contraception is defined as the usage by 
the female partner of any form of hormonal contraception or intra-uterine device (which should 
be established prior to the start of the study) plus usage by one of the partners of an additional 
spermicide-containing barrier method of contraception. Male subjects with pregnant partners 
must use a condom with spermicide from the start of treatment until at least 2 months after the 
last dose of study drug. Sperm or egg donation by subjects is not permitted from the start of 
treatment until 2 months after the study drug was administered.  
Only pregnancies considered by the Investigator as related to study treatment (e.g., resulting 
from an interaction between study drug and a contraceptive drug) are considered AEs unto 
themselves.  However, all pregnancies with an estimated conception date that occurred during 
the AE reporting period, as defined in Section 9.6.2, 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  


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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 9.7, 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.  
9.7.2. 
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.  
9.8. 
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.  
  
  


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


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11. 
SAMPLE SIZE AND STATISTICAL METHODS  
11.1. 
Determination of Sample Size  
Subject numbers (up to 36 subjects) are limited to those having previously participated in the 
SPIMM-201 study, who meet all eligibility criteria.   
11.2. 
Statistical and Analytical Plans  
11.2.1. 
General Considerations  
All study data are to be displayed in the data listings.  
Statistical analysis of this study will be the responsibility of the Sponsor or its designee.    
Additional details regarding analyses will be included in separate statistical analysis plan 
(SAP).  
11.2.2. 
Subject Disposition  
All subjects who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported.  If known, a reason for their discontinuation will be 
given.  
11.2.3. 
Subject Characteristics  
Subject’s age, sex, weight, height, body mass index (BMI), and other demographic 
characteristics will be recorded and summarized.  
Medical history will be listed.   
11.2.4. 
Endpoints and Methodology  
11.2.4.1. General Considerations  
Data will be summarized using descriptive statistics (number of subjects, mean, median, 
standard deviation, minima, and maxima) for continuous variables and using frequencies and 
percentages for discrete variables. Data will be presented by treatment group as appropriate, 
where treatment is defined fore subjects within a specific period.  Formal statistical tests 
(where performed) will be 2-sided and teste active vs. placebo at the alpha=0.05 level of 
significance.  
11.2.4.2. Analysis Populations  
Up to thirty-six subjects will be randomized and will receive either elamipretide or placebo (in 
the first treatment period, followed by the alternative treatment in the second treatment period) 
according to the randomly assigned treatment sequence.   
Statistical analysis will be performed in the following populations:  


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Intention-to-Treat (ITT) Population – Includes all study subjects who receive at least 1 dose of 
study drug, according to the assigned treatment in a given period.  
Safety Population – Includes all study subjects who receive at least 1 dose of study drug 
according to treatment received within a period.  
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 ITT population. All test of treatment effects will be 
conducted at a 2-sided alpha level of 0.05.  
Analyses will be conducted utilizing a mixed model repeated measures (MMRM) approach.  
No adjustments to alpha-levels will be made for secondary endpoints.  Details of the model 
will be specified in the Statistical Analysis Plan.  
11.2.6. 
Interim Analysis  
When all subjects have had opportunity to complete the first treatment period, an interim 
analysis may be conducted at the discretion of the sponsor.  The purpose of the interim analysis 
will be for the planning of future studies.  The study will not be stopped at the interim to claim 
benefit.      
11.2.7. 
Safety Analyses  
Safety data analysis will be conducted on all subjects in the Safety Population with treatment 
group determined by treatment received in a particular period (i.e., subjects dosing in both 
periods will be counted in both treatment groups).  
11.2.7.1. Adverse Events  
The number and percentage of subjects experiencing 1 or more AEs will be summarized by 
treatment group, relationship to study drug, and severity. AEs will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) terminology.  AEs will be summarized by 
system organ class (SOC), preferred term (PT), and treatment group.  
All reported AEs will be listed, but only treatment-emergent adverse events (TEAEs) will be 
summarized.  
The incidence of all TEAEs, drug relationship with TEAEs, and severity of TEAE will be 
summarized. In the summary tables, subjects may be counted under multiple SOCs and PTs, 
but for each SOC and PT, subjects are only counted once (within a treatment group). If a 
subject has the same AE on multiple occasions (with a treatment period), the highest severity 


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(severe > moderate > mild) or drug relationship (probable > possibly related > unlikely related 
> unrelated) recorded for the event will be presented. If severity is missing, subjects will be 
included as missing (for severity). If drug relationship is missing, subjects will be included in 
related tables (e.g., considered related).  
11.2.7.2. Deaths and Other Serious Adverse Events  
Listings will be provided for the following:  
• 
Deaths  
• 
SAEs  
• 
AEs leading to discontinuation of study drug  
11.2.7.3. Clinical Laboratory Evaluations  
Summary tables for laboratory parameters (including hematology, chemistry, and urinalysis) 
will include descriptive statistics of change relative to baseline where appropriate, and data 
listings of clinically significant abnormalities.  
Subjects with laboratory data outside the normal range will be listed with abnormal values 
flagged.  
Shift tables (e.g., tables that show the number of subjects who are low, normal, or high at 
baseline versus each post-baseline scheduled assessment) will be produced.  
The number and percentage of subjects with urinalysis results outside the normal range will be 
presented by endpoint and visit for each treatment group. Shift tables for urinalysis will show 
the number of subjects who are normal/abnormal at baseline and normal/abnormal at the end of 
study.  
11.2.7.4. Vital Signs  
Vital signs data will be summarized by changes from baseline values at each treatment group 
using descriptive statistics.  
Shift tables for heart rate and blood pressure (e.g., tables that show the number of subjects who 
are low, normal, or high at baseline versus each post-baseline scheduled assessment) will be 
produced.  
11.2.7.5. Electrocardiogram  
ECG data will be summarized by changes from baseline values at each treatment group using 
descriptive statistics.  
Electrocardiogram results (normal versus abnormal) and an assessment of the clinical 
significance of any abnormalities (in the opinion of the Investigator) will be listed for 
individual subjects.  Intervals of PR, QRS, QT, and QTc will also be listed.  


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11.2.7.6. 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 
study center.  All ICFs must be compliant with the ICH guideline on GCP.  
Documentation of EC approval of the protocol and the ICF must be provided to the Sponsor 
before the study may begin at the investigative study center.  The EC will review the protocol 
as required.  
The study center’s EC should be provided with the following:  
• 
The current IB and updates during the course of the study  
• 
ICF  
• 
Relevant curricula vitae  
12.3. 
Regulatory Considerations  
This study will be conducted in accordance with:  
1) Consensus ethics principles derived from international ethics guidelines, including the 
CIOMS International Ethical Guidelines  
2) The ICH GCP Guideline [E6]  


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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 100% against the source documentation.  
Deviations from the protocol with regard to subject enrollment or study conduct will also be 
noted in the source documentation, in the eCRF and a complementary database.  A Sponsor 
representative will visit the study center to initiate the study, prior to the first treatment of the 
first subject, and at agreed times throughout the study, including at the end of the study.  Drug 
dispensing and clinical drug supply records will be 100% verified at the study center by the 
study monitor.  It is understood that all subject specific information is confidential and no 
documentation that can link study information to the specific subject will be collected or 
retained by the Sponsor.  
12.3.4. 
Retention of Records  
All study related material including source documents, eCRFs, Central Authority, and EC 
correspondence and analyses and any other documentation required by applicable laws and 
regulations will be maintained for 15 years after completion of the study or notification from 
the Sponsor that the data can be destroyed, whichever comes first.  
12.3.5. 
Disclosure of Information  
Information concerning the investigational medication and patent application processes, 
scientific data or other pertinent information is confidential and remains the property of Stealth 
BioTherapeutics Inc.  The Investigator may use this information for the purposes of the study 
only.  It is understood by the Investigator that Stealth BioTherapeutics Inc., will use 
information developed in this clinical study in connection with the development of the 
investigational medication and therefore may disclose it as required to other clinical 


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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.  
  
  
 


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13. 
REFERENCES  
DiMauro S, Bonilla E, Mancuso M, Filosto M, Sacconi S, Salviati L, Hirano M.  Mitochondrial 
Myopathies. Basic Appl Myol. 13(3):145-155, 2003.   
DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med. 2003 Jun 
26;348(26):2656-68.  
Elson JL, Cadogan M, Apabhai S, Whittaker RG, Phillips A, Trennell MI, Horvath R, Taylor 
RW, McFarland R, McColl E, Turnbull DM, Gorman GS. Initial development and validation 
of a mitochondrial disease quality of life scale. Neuromuscul Disord. 2013 Apr;23(4):324-9.  
Min K, Smuder AJ, Kwon OS, Kavazis AN, Szeto HH, Powers SK. Mitochondrial-targeted 
antioxidants protect skeletal muscle against immobilization-induced muscle atrophy. J Appl 
Physiol (1985). 2011 Nov;111(5):1459-66.  
Pfeffer G, Chinnery PF. Diagnosis and treatment of mitochondrial myopathies. Ann Med. 2013 
Feb;45(1):4-16.   
Powers SK, Hudson MB, Nelson WB, Talbert EE, Min K, Szeto HH, Kavazis AN, Smuder AJ. 
Mitochondria-targeted antioxidants protect against mechanical ventilation-induced diaphragm 
weakness. Crit Care Med. 2011 Jul;39(7):1749-59.  
Siegel MP, Kruse SE, Percival JM, Goh J, White CC, Hopkins HC, Kavanagh TJ, Szeto HH, 
Rabinovitch PS, Marcinek DJ. Mitochondrial targeted peptide rapidly improves mitochondrial 
energetics and skeletal muscle performance in aged mice. Aging Cell. 2013 Oct;12(5):763-771.  
Talbert E, Smuder A, Min K, Kwon OS, Szeto HH, Powers SK.  Immobilization-induced 
activation key proteolytic systems in skeletal muscles is prevented by a mitochondria-targeted 
antioxidant.  J Appl Physiol. 115:529-538, 2013.  
Tarnopolsky M. Exercise testing as a diagnostic entity in mitochondrial myopathies. 
Mitochondrion. 2004 Sep;4(5-6):529-42. Epub 2004 Sep 30.   
  
  
  
  
14. 
ATTACHMENTS 


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Attachment 1   
Schedule of Assessments (Study Center Visits)  
Parameter  
Screening   
Treatment Period 1  
Washout  
Treatment Period 2  
Follow-Up/Early 
Discontinuation  
Visit 1  
(Screening  
Visit)  
Visit 2 
(Baseline)  
Visit 3  
(Week 4)  
  
Visit 4  
(Week 8)  
Visit 5  
(Week 12)  
Visit 6  
(End-of-Study/Early  
Discontinuation Visit)  
< -30 Day ≥ -7   
Day 1  
Day 29 (+6)    
Day 57 (+5)  
Day 85 (+6)  
Day 99 (+7)  
Informed Consenta  
X  
  
  
  
  
  
  
Demographics  
X  
  
  
  
  
  
  
Review of Inclusion/Exclusion Criteria  
X  
X  
  
  
  
  
  
Medical and Surgical History  
X  
X (update)  
  
  
  
  
  
Concomitant Medication Review  
X  
X  
X  
  
X  
X  
X  
Review AEs  
  
X  
X  
  
X  
X  
X  
Physical Examinationb   
X  
X  
X  
  
X  
X  
X  
C-SSRS “Lifetime Recent”  
X  
  
  
  
  
  
  
C-SSRS “Since Last Visit”  
  
X  
X  
  
X  
X  
X  
Vital Signsc  
X  
X  
X  
  
X  
X  
X  
12-Lead ECGd  
X  
X  
X  
  
X  
X  
X  
Clinical Chemistry & Hematologye  
X  
X  
X  
  
X  
X  
X  
Clinical Urinalysis  
X  
X  
X  
  
X  
X  
X  
Exploratory Biomarkersf  
  
X  
X  
  
X  
X  
X  
Pregnancy Testg  
X  
X  
  
  
  
  
X  
Hip & Wrist Accelerometer Sync  
  
X  
X  
  
X  
X  
X  
Hip Activity Monitoringh  
Days -7 to -1  
  
Days 22-28  
Days 51-57  
  
Days 79-86  
  
Wrist Activity Monitoringh  
X------------------------------------------------------Daily-----------------------------------------------------X  


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Neuro-QoL Fatigue Questionnaire  
X  
X  
X  
  
X  
X  
X  
MD Symptom Assessmenti   
X------------------------------------------------------Daily-----------------------------------------------------X  
Parameter  
Screening   
Treatment Period 1  
Washout  
Treatment Period 2  
Follow-Up/Early 
Discontinuation  
Visit 1  
(Screening  
Visit)  
Visit 2 
(Baseline)  
Visit 3  
(Week 4)  
  
Visit 4  
(Week 8)  
Visit 5  
(Week 12)  
Visit 6  
(End-of-Study/Early  
Discontinuation Visit)  
< -30 Day ≥ -7   
Day 1  
Day 29 (+6)    
Day 57 (+5)  
Day 85 (+6)  
Day 99 (+7)  
PhGA  
  
X  
X  
  
X  
X  
X  
PGA  
  
X  
X  
  
X  
X  
X  
Six Minute Walk Testj  
X  
X  
X  
  
X  
X  
X  
3TUG Testj,k  
X  
X  
X  
  
X  
X  
X  
Study Drug Administrationl  
  
X-----Daily------ X  
  
X-----Daily-----X  
  
a. 
The ICF must be signed prior to any study related procedures are performed.  Subjects, who are <18 years of age, may be required by the study center to have a minor 
assent in addition to the ICF of the parent/guardian.   
b. Height will only be measured at the Screening Visit, and used in the study to calculate BMI.  Physical examination will include: general appearance, skin, head, eyes, ears, 
nose, throat, neck (including thyroid), lymph nodes, chest, heart, abdomen, extremities, and nervous system. Weight should be taken during each physical examination. c. 
 
Vital signs will include HR, RR, and BP after sitting for 5 min, and temperature.    
d. All scheduled ECGs must be performed after the subject has rested quietly for at least 10 min in the supine position.  
e. 
See Attachment 4 for clinical laboratory tests.  The Visiting Nurse will collect blood for clinical chemistry and clinical hematology during his/her Week 1, Week 2, Week 6, 
Week 9, and Week 10 Visits.  
f. 
Blood will be collected for the analysis of biomarkers as specified in the lab manual.  Blood samples will be collected prior to study drug administration on the Baseline and 
Week 8 Visits. Additional blood samples at the Baseline of Treatment Period 1 and End-of-Study/ Early Discontinuation Visits will be collected and stored for assessing the 
immunogenicity potential of the study drug.  
g. Serum pregnancy test will be done for women of childbearing potential at screening. Results of the Baseline Visit pre-dose urine pregnancy test must be evaluated before 
randomization to ensure eligibility. Urine Pregnancy test will also be performed for women of childbearing potential at the End-of-Study/Early Discontinuation Visit.  
h. Subjects will wear an activity monitor on their wrist daily (from the Screening Visit to the End-of-Study/Early Discontinuation Visit). All efforts should be made to wear the 
wrist accelerometer on the same wrist throughout the entirety of the study.  In addition, subjects will wear an activity monitor on their belt for a minimum of 7 consecutive 
days immediately prior to the Baseline, Week 4, Week 8, and Week 12 Visits.    
i. 
On a daily basis during the study (from the Screening Visit to the End-of-Study/Early Discontinuation Visit), subjects will use an electronic or paper diary to complete the MD 
Symptom Assessment questionnaire (Attachment 7).  
j. 
The 6MWT (Attachment 5) and 3TUG Test (Attachment 8) should be performed after all other study procedures (except for study drug administration at the Baseline and 
Week 8 Visits).   


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k. The 3TUG Test (Attachment 8) should be performed after the 6MWT and after at least 15 minutes rest.   
l. 
On days of study visits, study drug will be administered by study center clinical staff.  At Baseline and Week 8 Visit, study drug administration will occur after the completion 
of all Visit procedures.  At the Week 4 and Week 12 Visits, study drug administration should occur prior to all other study procedures. During the first week of Treatment 
Period 1, study drug may be administered (or observed) by a Visiting Nurse and subsequently the Visiting Nurse will administer (or observe) study drug on a weekly basis, 
while subjects (or caregivers) will self-administer on all other days of Treatment Period 1. During Treatment Period 2, a Visiting Nurse will administer (or observe) study drug 
on a weekly basis, while subjects (or caregivers) will self-administer on all other days of Treatment Period 2. The location (preferably in the abdomen [rotating around the 
four abdominal quadrants]) and time of the study drug administration (at approximately the same time each day) will be recorded in an electronic or paper diary.   
Attachment 2   
Schedule of Visiting Nurse Assessments  
Parameter  
Treatment Period 1  
 
Washout   
Treatment Period 2  
  
Week 1  
Week 2  
Week 3  
Week 6  
Week 9  
Week 10  
Week 11  
Days 2-7a   
Day 8 ± 1  
Day 15 ± 2  
Day 22 ± 2  
Day 43 ± 2  
Day 64 ± 2  
Day 71 ± 2  
Day 78 ± 2  
Confirm Study Drug Storage Conditions  
  
  
  
  
  
  
  
  
Study Drug Administrationb  
X  
X  
X  
X  
  
X  
X  
X  
Clinical Chemistry & Hematologyc  
  
X  
X  
  
X  
X  
X  
  
Review wrist activity monitoringd  
X  
X  
X  
X  
X  
X  
X  
X  
Remind hip activity monitoringe  
  
  
  
X  
X  
  
  
X  
Review Study drug compliancef  
  
X  
X  
X  
  
X  
X  
X  
Review completion of daily MD Symptom  
Assessment  
X  
X  
X  
X  
X  
X  
X  
X  
Neuro-QoL questionnaire  
  
  
  
  
X  
  
  
  
a. 
The Visiting Nurse visit on Day 2 is required, however, the Visiting Nurse Visits during Days 3-7 are not mandatory and the patient (or caregiver) and the Visiting Nurse 
should determine the frequency and necessity of these visits.  
b. During the first week of Treatment Period 1, study drug may be administered by a Visiting Nurse and subsequently the Visiting Nurse will administer (or observe) study drug 
on a weekly basis, while subjects (or caregivers) will administer on all other days of Treatment Period 1. During Treatment Period 2, a Visiting Nurse will administer (or 
observe) study drug on a weekly basis, while subjects (or caregivers) will self-administer on all other days of Treatment Period 2. If, for any reason, a subject (or caregiver) is 
unable/unwilling to administer study drug, a Visiting Nurse may be provided for daily administration of study drug. c.  See Attachment 4 for clinical laboratory tests.    
d. Subjects will be asked to wear an activity monitor on their wrist daily (from the Screening Visit to the End-of-Study/Early Discontinuation Visit) 24 hours per day. All efforts 
should be made to wear the wrist accelerometer on the same wrist throughout the entirety of the study. The Visiting Nurse will remind the subject to wear the wrist activity 
monitor 24 hours per day and will remind the subject to charge the monitor.  


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e. 
Subjects will be encouraged to wear an activity monitor on their belt daily during waking hours and at minimum, must wear the hip activity monitor for 7 consecutive days 
immediately prior to the Baseline, Week 4, Week 8, and Week 12 Visits.  The Visiting Nurse will ensure the hip accelerometers are changed and remind subjects at the Week 
3, Week 6, and Week 11 Visits to wear the hip accelerometer for the a minimum of 7 consecutive days immediately prior to the Week 4, Week 8, and Week 12 Visits, 
respectively.  
f. 
The Visiting Nurse will assess compliance with study drug administration and may re-train the subject or caregiver on proper administration technique, as appropriate.  
g. On a daily basis during the study (from the Screening Visit to the End-of-Study/Early Discontinuation Visit), subjects will use an electronic or paper diary to complete the MD  
 
Symptom Assessment (Attachment 7).   
  
Attachment 3   
Study Schematic   
Screening  
  
Treatment Period 1  
Washout  
Treatment Period 2  
Follow-up  
  
  
 
  
  
            Visiting Nurse (Home)                Visiting Nurse (Home)                             Visiting Nurse (Home)             
   Visiting Nurse (Home)        
  
                    Days 2-7                                Weeks 1, 2, 3          
  
            Weeks 6          
          
       Weeks 9, 10, 11        
  
  
  
  
                
  
  
  
  
  
  
 
 
  
  
  
  
  
  
Screening   Baseline (Day 1)       Week 4                      Week 8     Week 12                End-of-Study/Early  (Clinic)      (Clinic)                      (Clinic)                          (Clinic)     
(Clinic)                      Discontinuation   
(Clinic)  
 
 
 
 
  
Randomization  
Elamipretide 40 mg SC QD  
Elamipretide 40 mg SC QD  
Placebo SC QD  
Placebo SC QD  


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71 
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 Attachment 4  
Clinical Laboratory Tests  
  
Clinical Hematology:  
Clinical Chemistry:  
Hemoglobin  
Sodium  
Hematocrit  
Potassium  
Erythrocyte count (RBC)  
Total bilirubin  
Leukocytes (WBC)  
Direct bilirubin  
Neutrophils, segmented  
Alkaline phosphatase (ALK-P)  
Lymphocytes  
Alanine aminotransferase (ALT)  
Monocytes  
Aspartate aminotransferase (AST)  
Eosinophils  
Blood urea nitrogen (BUN)  
Basophils  
gamma-glutamyl transpeptidase (GGTP)  
Platelets  
Creatine kinase (CK)  
  
Creatinine  
Urinalysis:  
Calcium  
Specific gravity  
Glucose (non-fasting)  
pH  
Albumin  
Protein  
Chloride  
Glucose  
Triglycerides  
Ketones  
LDL  
Blood  
HDL  
Leukocyte esterase  
  
  
Exploratory Biomarkers  
  
  
GDF-15 
  
FGF-21  
  
Glutathione 
  
  


 
  
  
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Attachment 5   
Six Minute Walk Test  
  
  


 
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CONFIDENTIAL   
Six-Minute Walk Test  
  
PURPOSE AND SCOPE  
  
This document serves as a guideline for the 6-minute walk test (6 MWT) for the study. It 
outlines the set-up, patient preparation, step-by step procedures, and safety measures.  
REQUIRED EQUIPMENT  
  
1. Countdown timer (or stopwatch)   
2. Mechanical lap counter   
3. Two small cones to mark the turnaround points   
4. A chair that can be easily moved along the walking course   
5. Worksheets on a clipboard   
6. A source of oxygen   
7. Sphygmomanometer   
8. Telephone   
9. Automated electronic defibrillator  
10. Bean bag  
  
SET-UP   
  
• 
The 6MWT should be performed indoors, along a long, flat, straight, enclosed corridor 
with a hard surface that is seldom traveled. The walking course must be 30 m in length. 
A 100-ft hallway which is equivalent to 30 meters is, desirable. The length of the 
corridor should be marked every 3 m. The turnaround points should be marked with a 
cone (such as an orange traffic cone). A starting line, which marks the beginning and 
end of each 60-m lap, should be marked on the floor using brightly colored tape.  
  
  
  
• 
The patient should sit at rest in a chair, located near the starting position, for at least 
10 minutes before the test starts.  During this time, check for contraindications, 
measure pulse and blood pressure, and make sure that clothing and shoes are 
appropriate.   
  
• 
A “warm-up” period before the test should not be performed.   
  
  
  
  
  
  
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74 
SAFETY ISSUES  
  
1. 
Testing should be performed in a location where rapid appropriate response to an 
emergency is possible.  
  
2. 
Available supplies must include oxygen, sub lingual nitroglycerine, aspirin, albuterol 
MDI. A telephone and other means should be in place to enable a call for help.  
  
3. 
The technician should be certified in cardiopulmonary resuscitation with a minimum 
of basic life support by an AHA approved CPR course or local country equivalent. 
ACLS certification is desirable.  
  
4. 
Physicians are not required to be present during all tests, and may be present 
depending on physician’s judgment.  
  
5. 
If a patient is on chronic oxygen therapy, oxygen should be given at their standard 
rate or as directed by a physician or protocol.  
  
PATIENT PREPARATION  
  
1. 
Comfortable clothing should be worn.   
2. 
Patients should not have nail polish.  
3. 
Appropriate shoes for walking should be worn.   
4. 
Patients should use their usual walking aids during the test (cane, walker, etc.).   
5. 
Patients usual medical regimen should be continued.   
6. 
A light meal is acceptable before early morning or early afternoon tests.   
7. 
Patients should not have exercised vigorously within 2 hours of beginning the test.  
  
  


  
  
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75 
2 
SUPPLEMENTAL OXGEN  
  
1. 
If oxygen supplemental is needed during the walks and serial tests are planned (after 
an intervention other than oxygen therapy), then during all walks by that patient 
oxygen should be delivered in the same way with the same flow.  
  
2. 
If the flow must be increased during subsequent visits due to worsening gas 
exchange, this should be noted on the worksheet and considered during 
interpretation of the change noted in documentation.  
  
3. 
The type of oxygen delivery device should also be noted on the report. For instance, 
the patient carried liquid oxygen or received oxygen via an oxygen tank.  It is not 
recommended that the patient pushes or pulls the oxygen tank themselves, nor 
should the technician walk close to the patient to pull or push the oxygen tank, as 
that may result in them “pacing” the patient and influencing the distance walked.  If 
technician is walking with the oxygen tank, an extension tubing of at least 10 feet 
should be used (document that the oxygen delivery is stable) so that the technician 
is not close to the patient. Pulsed oxygen delivery is not recommended for this study; 
all oxygen delivery should be continuous.   
  
4. 
Measurements of the pulse and SpO2 should be made after waiting at 10 minutes 
after any change in oxygen delivery.  
  
RECOMMENDATIONS  
• 
All testing should be performed about the same time of day to minimize intraday 
variability.  
  
• 
It is preferred that the same technician perform the test for each patient.  
  
PRE-TEST  
  
1. Record start time.  Provide a paper copy of the Borg scale to the patient.  Have the 
patient stand and rate their baseline dyspnea and over fatigue by circling the most 
appropriate number on the Borg scale.  
  
2. Measure baseline blood pressure, respiratory rate and oxygen saturation (SpO2).  
Check pulse rate from the oximeter.  Complete the first portion of the 6MWT 
worksheet.  
  


  
  
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76 
3. Set the lap counter to zero and the timer to 6 minutes. Assemble all necessary 
equipment (lap counter, timer, clip- board, Borg Scale, worksheet) and move to the 
starting point.  
  
4. Instruct the patient as follows using the exact script provided:  
3 
  
• The object of this test is to walk as far as possible for 6 minutes. You will walk back and 
forth in this hallway.  Six minutes is a long time to walk, so you will be exerting yourself. 
You will probably get out of breath or become exhausted.  You are permitted to slow 
down, to stop, and to rest as necessary.  You may lean against the wall while resting, but 
resume walking as soon as you are able.  
  
• You will be walking back and forth around the cones.  You should pivot briskly around the 
cones and continue back the other way without hesitation.  Now I’m going to show you.   
Please watch the way I turn without hesitation.”  
  
• Demonstrate by walking one lap yourself.  Walk and pivot around a cone briskly.  
  
• “Are you ready to do that?  I am going to use this counter to keep track of the number of 
laps you complete.  I will click it each time you turn around at this starting line.  
Remember that the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don’t run 
or jog.  
  
• Start now or whenever you are ready.”  
  
5. Position the patient at the starting line. You should also stand near the starting line 
during the test. Do not walk with the patient. As soon as the patient starts to walk, 
start  
the timer.  
  
7. Do not talk to anyone other than the patient during the walk. Use an even tone of voice 
when using the standard phrases of encouragement. Watch the patient. Do not get 
distracted and lose count of the laps. Each time the patient returns to the starting line, 
click the lap counter once (or mark the lap on the worksheet). Let the patient see you 
do it. Exaggerate the click using body language, like using a stop-watch at a race.  
  
• After the first minute, tell the patient the following (in even tones): “You are doing well. 
You have 5 minutes to go.”  
  
• When the timer shows 4 minutes remaining, tell the patient the following: “Keep up the 
good work. You have 4 minutes to go.”  
  


  
  
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77 
• When the timer shows 3 minutes remaining, tell the patient the following: “You are doing 
well. You are halfway done.”  
  
• When the timer shows 2 minutes remaining, tell the patient the following: “Keep up the 
good work. You have only 2 minutes left.”  
  
• When the timer shows only 1 minute remaining, tell the patients: “You are doing well. 
You have only 1 minute to go.”  
  
• Do not use other words of encouragement (or body language to speed up).  
  
• If the patient stops walking during the test and needs a rest, say this: “You can lean 
against the wall if you would like; then continue walking whenever you feel able.” Do not 
stop the timer. If the patient stops before the 6 minutes are up and refuses to continue (or 
you decide  
4 
that they should not continue), wheel the chair over for the patient to sit on, discontinue the 
walk, and note on the worksheet the distance, the time stopped, and the reason for stopping 
prematurely.   
 
• When the timer is 15 seconds from completion, say this: “In a moment I’m going to tell 
you to stop. When I do, just stop right where you are and I will come to you.”  
  
• When the timer rings (or buzzes), say this: “Stop!” Walk over to the patient. Consider 
taking the chair if they look exhausted. Mark the spot where they stopped by placing a 
bean bag or a piece of tape on the floor.  
  
8. Note the distance walked.   
  
9. Reasons for stopping the 6MWT immediately:  
  
• 
Chest Pain  
• 
Intolerable dyspnea  
• 
Leg cramps, staggering  
• 
Diaphoresis, pale or ashen appearance  
• 
There are no specific limits of oxygen saturation or heart rate that automatically 
mandate cessation of the test; the Tester is to observe the patient throughout the 
walk for clinical signs of severe desaturation or tachycardia.  
• 
Tester’s judgment that it is unsafe to continue, if there is doubt whether a test 
should be stopped early because of patient symptoms, it is better to err on the side 
of safety and stop the test early.  
  


  
  
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78 
o Have a chair available near the course for the patient to sit in and recover. o 
If a severe prolonged desaturation occurs, consult with the supervising 
physician as needed and treat the patient as needed, e.g., provide 
supplemental oxygen.  
  
  
Post-Test:  
  
1. Record stop time.  Immediately upon stopping, provide a paper copy of the 
Borg scale for patient to complete.  Have the patient circle the most 
appropriate number on the scale for the post walk Borg dyspnea and fatigue 
levels and ask this: “How did you feel during the test?  What if anything kept 
you from walking further?  
2. Measure blood pressure and respiratory rate.  Complete the second portion 
of the  
6MWT worksheet.  
  
3. Measure SpO2 and check for at least 20 seconds. Record and check pulse 
rate from the oximeter.  Oxygen should be administered as appropriate.   
  
4. It is not necessary to report all the reasons for stopping the 6MWT as 
adverse events, medical judgment should be employed for making this 
determination.  
  
5 
5. Record the number of laps from the counter (or tick marks on the 
worksheet).  
  
6. Record the additional distance covered (the number of meters in the final partial lap) 
using the markers on the wall as distance guides. Calculate the total distance walked, 
rounding to the nearest meter, and record it on the worksheet.  
  
7. Congratulate the patient on good effort and offer a drink of water.  
  
  
  
  
  
  
  
  
  


  
  
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79 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
6 
THE BORG SCALE  
  
0 
Nothing at all  
0.5   Very, very slight (just noticeable)  
1 
Very slight  
2 
Slight (light)  
3 
Moderate  
4 
Somewhat severe  
5 
Severe (heavy)  
6  


  
  
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80 
7      Very severe  
8  
9  
10     Very, very severe (maximal)  
  
At the beginning of the 6-Minute exercise, the patient will be given a paper copy of the 
Borg scale with the following instructions given in the writing at the time the scale is 
administered.  “Please grade your level of shortness of breath using this scale.”  
Then ask this:  “Please grade your level of fatigue using this scale.”  
After the post-test recovery period, remind the patient of the breathing number that they 
chose before the exercise and ask the patient to grade their breathing level again.  Then 
ask the patient to grade their level of fatigue, after reminding them their grade before the 
exercise.  
  
    
7 


 
 
Six-Minute Walk Test Worksheet  
  
  
Patient ID#: ______________________   
  
Visit Name: _______________________  
  
Date:  ______________________  
  
  
  
  
□Not Done  
If 6 MWT not done, mark applicable box:  Specify: ________________________________________________  
  
  
  
  
  
  
  
  
  
Supplemental oxygen during the test:   
□ Yes    □ No  
 
If yes, specify O2 flow:  ______ L/min  
  
Type: ____________________  
 
Pre-walk   
 
  
  
Post-walk  
Time     
  
  
 
___:___   
 
  
  
___:___  
Blood Pressure   
  
 
_______  
 
  
  
_______  
Heart Rate  
  
  
 
_______   
 
  
  
_______  
Respiratory Rate   
  
 
_______  
 
  
  
_______  
SpO2  
  
  
  
 
_______ %   
 
  
  
_______%  
Dyspnea (Borg Scale)  
  
 
_______  
 
  
  
_______  
Fatigue (Borg Scale)   
  
 
 
_______  
 
  
  
_______  
Stopped during the test?     
□ Yes    □ No    
If yes, mark applicable box:  
 □ Diaphoresis   
□ Angina   
 
□ Light headedness 
□ Leg cramps   
□ Intolerable dyspnea    
□ Mental confusion/headache  
  
□ Other (specify): ______________________________    
  


 
 
  
Number of laps: ______ (x 60 meters) + final partial lap: _______ meters =  Total distance walked in 6 minutes: _________ meters  
  
Tech Comments:  
  
Name and signature of technician: ___________________________________________________  
  
Date: _______________________________________ 
 
  
  
  
Page 8 of 8  
  
73 


 
83 
Elamipretide (MTP-131 for SC Injection)  
 
SPIMM-202 Version 5.0  
21 October 2016  
 
  
 
Attachment 6   
Neuro-QoL Item Bank v1.0 - Fatigue  
  
  
  


 
84 
Stealth BioTherapeutics Inc.   
  
CONFIDENTIAL  Neuro-QOL Item Bank v1.0 –Fatigue  
  
  
        Fatigue  
  
  
Please respond to each question or statement by marking one box per row.  
  
  
  
 
In the past 7 days…  
Never  
Rarely  
Sometimes  
Often  
Always  
NQFTG13  I felt exhausted…………………………...   
  
1  
  
2  
  
3  
  
4  
  
5  
  
 
 
 
 
 
 
NQFTG11    
I felt that I had no energy………………...  
   
1  
   
2  
   
3  
   
4  
   
5  
  
 
 
 
 
 
 
NQFTG15   I felt 
fatigued……………………………..  
   
1  
   
2  
   
3  
   
4  
   
5  
  
 
 
 
 
 
 
NQFTG06    
I was too tired to do my household chores.  
   
1  
   
2  
   
3  
   
4  
   
5  
  
 
 
 
 
 
 
NQFTG07    
I was too tired to leave the house………...   
   
1  
   
2  
   
3  
   
4  
   
5  
  
 
 
 
 
 
 
NQFTG10  
  
I was frustrated by being too tired to do  
the things I wanted to do…………………   
   
1  
   
2  
   
3  
   
4  
   
5  
  
 
 
 
 
 
 
NQFTG14    
I felt tired…………………………………   
   
1  
   
2  
   
3  
   
4  
   
5  
  
 
 
 
 
 
 
NQFTG02  
  
I had to limit my social activity because I  
was tired………………………………….  
   
1  
   
2  
   
3  
   
4  
   
5  
  
 
 
 
 
 
 
NQFTG01  
  
I needed help doing my usual activities  
because of my fatigue…………………….  
  
  
1  
  
  
2  
  
  
3  
  
  
4  
  
  
5  
  
 
 
 
 
 
 


 
85 
NQFTG03    
I needed to sleep during the day………….  
   
1  
   
2  
   
3  
   
4  
   
5  
  
 
 
 
 
 
 
NQFTG04  
  
I had trouble starting things because I was  
too tired…………………………………..   
   
1  
   
2  
   
3  
   
4  
   
5  
  
 
 
 
 
 
 
NQFTG05  
  
I had trouble finishing things because I  
was too tired……………………………...   
   
1  
   
2  
   
3  
   
4  
   
5  
  
 
 
 
 
 
 
NQFTG08    
I was too tired to take a short walk……….  
   
1  
   
2  
   
3  
   
4  
   
5  
  
 
 
 
 
 
 
NQFTG09    
I was too tired to eat………………….......  
   
1  
   
2  
   
3  
   
4  
   
5  
  
 
 
 
 
 
 
NQFTG12  
  
I was so tired that I needed to rest during  
the day……………………………………  
  
  
1  
  
  
2  
  
  
3  
  
  
4  
  
  
5  
  
 
 
 
 
 
 
NQFTG16    
I felt weak all over………………………..  
   
1  
   
2  
   
3  
   
4  
   
5  
  
  
©2008-2013 David Cella and the PROMIS Health Organization on behalf of the National Institute for Neurological  
Disorders and Stroke (NINDS). Used with permission.  
 
 
English  
  
November 4, 2014  
Page 1 of 2 
  
Neuro-QOL Item Bank v1.0 –Fatigue  
   
    
   
   
   
   
   
  
 
In the past 7 days…  
Never  
Rarely  
Sometimes  
Often  
Always  
NQFTG17  I needed help doing my usual activities 
because of weakness……………………...  
  
1  
  
2  
  
3  
  
4  
  
5  
  
 
 
 
 
 
 
NQFTG18  
  
I had to limit my social activity because I  
was physically weak……………………...  
   
1  
   
2  
   
3  
   
4  
   
5  
  
 
 
 
 
 
 


 
86 
NQFTG20  
  
I had to force myself to get up and do 
things because I was physically too weak..   
   
1  
   
2  
   
3  
   
4  
   
5  
  
©2008-2013 David Cella and the PROMIS Health Organization on behalf of the National Institute for Neurological  
Disorders and Stroke (NINDS). Used with permission.  
 
 
English  
  
November 4, 2014  
Page 2 of 2 
  


Elamipretide (MTP-131 for SC Injection)  
SPIMM-202 Version 5.0  
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Stealth BioTherapeutics Inc.   
  
CONFIDENTIAL   
87 
Attachment 7   
Mitochondrial Disease (MD) Symptom Assessment  
  
  
Not at all  
Mild  
Moderate   
Severe  
1. During the past 24 hours, how severe 
was your worst feeling of tiredness 
at rest?   
□  
□  
□  
□  
2. During the past 24 hours, how severe 
was your worst feeling of tiredness 
during activities?  
□  
□  
□  
□  
3. During the past 24 hours, how severe 
was your worst feeling of muscle 
weakness at rest?  
□  
□  
□  
□  
4. During the past 24 hours, how 
severe was your worst feeling of 
muscle weakness during 
activities?  
□  
□  
□  
□  
5. During the past 24 hours, how severe 
were your worst balance problems?  
□  
□  
□  
□  
6. During the past 24 hours, how severe 
were your worst vision problems?   
□  
□  
□  
□  
7. During the past 24 hours, how severe 
was your worst abdominal 
discomfort (feeling nauseous, 
bloated, or in pain)?  
□  
□  
□  
□  
8. During the past 24 hours, how 
severe was your worst muscle 
pain?  
□  
□  
□  
□  
9. During the past 24 hours, how 
severe was your worst 
numbness?  
□  
□  
□  
□  
10. During the past 24 hours, how 
severe was your worst headache?  
□  
□  
□  
□  
  
  
     
  


Elamipretide (MTP-131 for SC Injection)  
SPIMM-202 Version 5.0  
21 October 2016  
  
Stealth BioTherapeutics Inc.   
  
CONFIDENTIAL   
88 
At Screening Visit Only:   
Of the symptoms included in the list below, which do you consider to be your most 
bothersome symptom?  Please select only one response from the options listed below.  
• 
Tiredness at rest  
• 
Tiredness during activities  
• 
Muscle weakness at rest  
• 
Muscle weakness during activities  
• 
Balance problems  
• 
Vision problems  
• 
Abdominal discomfort (feeling nauseous, bloated, or in pain)  
• 
Muscle pain  
• 
Numbness  
• 
Headache  
  
  
  
 


Elamipretide (MTP-131 for SC Injection)  
SPIMM-202 Version 5.0  
21 October 2016  
  
Stealth BioTherapeutics Inc.   
  
CONFIDENTIAL   
89 
Attachment 8   
Triple Timed Up and Go (3TUG) Test  
  
The 3TUG Test is a modification of the Timed Up and Go Test. The 3TUG Test is the Timed 
Up and Go Test repeated 3 times without pause.    
  
Equipment:  A stopwatch  
  
Directions:  Patients wear their regular footwear and can use a walking aid if needed. Begin by 
having the patient sit back in a standard arm chair and identify a line 3 meters or 10 feet away 
on the floor.  
  
Instructions to the patient:  
When I say “Go,” I want you to:  
1. Stand up from the chair  
2. Walk to the line on the floor at your normal pace  
3. Turn  
4. Walk back to the chair at your normal pace  
5. Sit down again  
6. Repeat this for a total of 3 times without pause  
  
On the word “Go” begin timing.  
  
Record the time it takes the subject to complete the 3TUG Test (Steps 1-6 above), without 
stopping the timer until the 3TUG Test is complete.   
  
Record time:    
  
_____________ seconds  
  
  
  
  
Attachment 9   
Physician Global Assessment (PhGA)  
Make an estimate of the overall health status of the examinee based on your findings from the 
physician’s examination, regardless of the completeness of the examination.  
1. Excellent  
2. Very Good  
3. Good  
4. Fair  


Elamipretide (MTP-131 for SC Injection)  
SPIMM-202 Version 5.0  
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Stealth BioTherapeutics Inc.   
  
CONFIDENTIAL   
90 
5. Poor  
  
  
  
 


Elamipretide (MTP-131 for SC Injection)  
SPIMM-202 Version 5.0  
21 October 2016  
  
Stealth BioTherapeutics Inc.   
  
CONFIDENTIAL   
91 
Attachment 10  
  
Patient Global Assessment  
The patient global assessment should be completed by the Investigator asking the patient:  
In general, would you say your health is…  
1. Excellent  
2. Very Good  
3. Good  
4. Fair  
5. Poor  
  
  
 


Elamipretide (MTP-131 for SC Injection)  
SPIMM-202 Version 5.0  
21 October 2016  
  
Stealth BioTherapeutics Inc.   
  
CONFIDENTIAL   
92 
Attachment 11  
Columbia-Suicide Severity Rating Scale (C-SSRS) “Lifetime 
Recent”  
  
  


 
93 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE (C-SSRS) 
Lifetime Recent - Clinical  
Version 1/14/09  
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.   
Disclaimer:  
This scale is intended to be used by individuals who have received training in its administration. The questions contained in 
the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of suicidal 
ideation or behavior depends on the judgment of the individual administering the scale.  
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History Form, 
developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders  
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A.,  
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.)  
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, 
New York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu © 2008 The 
Research Foundation for Mental Hygiene, Inc. 
SUICIDAL IDEATION  
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to 
question 2 is “yes”, ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete 
“Intensity of Ideation” section below.  
Lifetime: Time  
He/She Felt  
Most Suicidal  
Past 1 
month  
1. Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?   
If yes, describe:  
Yes    No □ 
□  
Yes     No 
□   □  


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


 
 
© 2008 Research Foundation for Mental Hygiene, Inc.  
  C-SSRS—Lifetime Recent - Clinical (Version 1/14/09)   
  Page 1 of 2  
SUICIDAL BEHAVIOR  
(Check all that apply, so long as these are separate events; must ask about all types)  
Lifetime  
Past 3 
months  
Actual Attempt:   
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill 
oneself. Intent does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide 
attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in 
mouth but gun is broken so no injury results, this is considered an attempt.    
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a 
highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a 
high floor/story). Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.   
Have you made a suicide attempt?  
Have you done anything to harm yourself?  
Have you done anything dangerous where you could have died?  
What did you do?  
Did you______ as a way to end your life?   
Did you want to die (even a little) when you_____?   
Were you trying to end your life when you _____?  
Or Did you think it was possible you could have died from_____?  
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel 
better, get sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) If yes, describe:  
Has subject engaged in Non-Suicidal Self-Injurious Behavior?  
Yes     No □ 
□  
Total # of 
Attempts  
______  
Yes     No  
□   □  
Yes     No □ 
□  
Total # of 
Attempts  
______  
Yes     No  
□   □  
Interrupted Attempt:    
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would 
have occurred).  
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted 
attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once 
they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge.  
Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so.  
Has there been a time when you started to do something to end your life but someone or something stopped you before 
you actually did anything?  
If yes, describe:  
Yes  No □ 
□  
Total # of 
interrupted  
______  
Yes   No □ 
□  
Total # of 
interrupted  
______  
Aborted or Self-Interrupted Attempt:    
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any selfdestructive 
behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else.  
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything?  
If yes, describe:  
Yes   No □ 
□  
Total # of 
aborted or 
self- 
interrupted  
______ 
Yes   No □ 
□  
Total # of 
aborted or 
self- 
interrupted  
______ 
Preparatory Acts or Behavior:  
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as 
assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a 
suicide note).   
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, 
getting a gun, giving valuables away or writing a suicide note)?  
If yes, describe:  
Yes   No □ 
□  
Total # of 
preparatory 
acts  
______  
Yes   No □ 
□  
Total # of 
preparatory 
acts  
______  
 
Most Recent 
Attempt 
Date:  
Most Lethal  
 
 
Attempt 
Date:  
Initial/First  
Attempt 
Date:  


 
 
Actual Lethality/Medical Damage:   
0. No physical damage or very minor physical damage (e.g., surface scratches). 
1. Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2. Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel).  
3. Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with 
reflexesintact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures).  
4. Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree 
burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 5. Death 
Enter Code  
______  
Enter Code  
______  
Enter Code  
______  
Potential Lethality: Only Answer if Actual Lethality=0  
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had 
potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying 
on train tracks with oncoming train but pulled away before run over).  
0 = Behavior not likely to result in injury  
1 = Behavior likely to result in injury but not likely to cause death  
2 = Behavior likely to result in death despite available medical care  
Enter Code  
______  
Enter Code  
______  
Enter Code  
______  
© 2008 Research Foundation for Mental Hygiene, Inc.   
  C-SSRS—Lifetime Recent - Clinical (Version 1/14/09)   
  Page 2 of 2  
Elamipretide (MTP-131 for SC Injection)  
 
SPIMM-202 Version 5.0  
21 October 2016  
 
Attachment 12  
Columbia-Suicide Severity Rating Scale (C-SSRS) “Since Last Visit”  


 
 
 
Stealth BioTherapeutics Inc.  
CONFIDENTIAL   
86 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE (C-SSRS)  
Since Last Visit - Clinical  
Version 1/14/09  
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.   
Disclaimer:  
This scale is intended to be used by individuals who have received training in its administration. The questions contained 
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale.  
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History  
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A.,  
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.)  
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu © 2008 The 
Research Foundation for Mental Hygiene, Inc. 
87 
SUICIDAL IDEATION  


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


 
 
Reasons for Ideation What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to 
end the pain or stop the way you were feeling (in other words you couldn’t go on living with this pain or how you were 
feeling) or was it to get attention, revenge or a reaction from others? Or both?  
 
(1) Completely to get attention, revenge or a reaction from others    (4) Mostly to end or stop the pain (you couldn’t go on  
(2) Mostly to get attention, revenge or a reaction from others      
     living with the pain or how you were feeling)  
(3) Equally to get attention, revenge or a reaction from others       
and to end/stop the pain  
 (5) Completely to end or stop the pain (you couldn’t go 
on  living with the pain or  how you were feeling)  (0)  
Does not apply  
____  
© 2008 Research Foundation for Mental Hygiene, Inc.  
  C-SSRS—Since Last Visit - Clinical (Version 1/14/09)   
  Page 1 of 2  
SUICIDAL BEHAVIOR  
(Check all that apply, so long as these are separate events; must ask about all types)  
Since Last 
Visit 
Actual Attempt:   
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury 
results, this is considered an attempt.    
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly 
lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story).  
Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.   
Have you made a suicide attempt?  
Have you done anything to harm yourself?  
Have you done anything dangerous where you could have died?  
What did you do?  
Did you______ as a way to end your life?   
Did you want to die (even a little) when you_____?   
Were you trying to end your life when you _____?  
Or did you think it was possible you could have died from_____?  
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, 
get sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) If yes, describe:  
Has subject engaged in Non-Suicidal Self-Injurious Behavior?  
Yes   No □ 
□  
Total # of 
Attempts  
______  
Yes     No  
□   □  
Interrupted Attempt:    
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have occurred).  
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around 
neck but has not yet started to hang - is stopped from doing so.  
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything?  
If yes, describe:  
Yes   No □ 
□  
Total # of 
interrupted  
______  
Aborted or Self-Interrupted Attempt:    
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior.  
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else.  
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything?  
If yes, describe:  
Yes   No □ 
□  
Total # of 
aborted or 
self- 
interrupted  
______  
Preparatory Acts or Behavior:  
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a 
specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a suicide note).   
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a 
gun, giving valuables away or writing a suicide note)?  
If yes, describe:  
Yes   No □ 
□  
Total # of 
preparatory 
acts  
______  


 
 
Suicide:  
Death by suicide occurred since last assessment.  
   Yes    No □ 
□  
 
Most Lethal 
Attempt 
Date:  
Actual Lethality/Medical Damage:  
0. No physical damage or very minor physical damage (e.g., surface scratches). 
1. Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2. Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree burns; bleeding of major vessel). 
3. Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes intact; third-degree burnsless 
than 20% of body; extensive blood loss but can recover; major fractures).  
4. Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree burns over 20% of 
body;extensive blood loss with unstable vital signs; major damage to a vital area). 5. Death  
Enter Code  
______  
Potential Lethality: Only Answer if Actual Lethality=0  
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for very serious 
lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away 
before run over).  
0 = Behavior not likely to result in injury  
1 = Behavior likely to result in injury but not likely to cause death  
2 = Behavior likely to result in death despite available medical care  
Enter Code  
______  
 © 2008 Research Foundation for Mental Hygiene, Inc.  
  C-SSRS—Since Last Visit - Clinical (Version 1/14/09)   
  Page 2 of 2  


 
101 
Elamipretide (MTP-131 for SC Injection)  
SPIMM-202 Version 5.0  
21 October 2016  
 
Attachment 13  
Scale for the Assessment and Rating of Ataxia  


 
102 
Stealth BioTherapeutics Inc.  
CONFIDENTIAL   
Rater: ____________________________date: ______________patient:_______________________  
Scale for the assessment and rating of ataxia (SARA)  
  
1) Gait  
Proband is asked (1) to walk at a safe distance parallel 
to a wall including a half-turn (turn around to face the 
opposite direction of gait) and (2) to walk in tandem 
(heels to toes) without support.   
 
 
 
0  
Normal, no difficulties in walking, turning 
and         walking tandem (up to one misstep 
allowed)    1     Slight difficulties, only visible when 
walking 10            consecutive steps in tandem  
2 
Clearly abnormal, tandem walking >10 steps not  
possible  
3 
Considerable staggering, difficulties in half-turn, 
but           without support  
4 
Marked staggering, intermittent support of the 
wall            required  
5 
Severe staggering, permanent support of one 
stick or           light support by one arm required  
6 
Walking > 10 m only with strong support (two       
special sticks or stroller or accompanying person)  7 
Walking < 10 m only with strong support (two       
special sticks or stroller or accompanying person)   
  8     Unable to walk, even supported  
2) Stance  
Proband is asked to stand (1) in natural position, (2) with 
feet together in parallel (big toes touching each other) 
and (3) in tandem (both feet on one line, no space 
between heel and toe). Proband does not wear shoes, 
eyes are open. For each condition, three trials are 
allowed. Best trial is rated.  
 
0 
Normal, able to stand in tandem for > 10 s  
1 
Able to stand with feet together without sway, but  
not in tandem for > 10s  
2 
Able to stand with feet together for > 10 s, but 
only           with sway  
3 
Able to stand for > 10 s without support in natural 
position, but not with feet together  
4 
Able to stand for >10 s in natural position only 
with            intermittent support  
5 
Able to stand >10 s in natural position only with     
constant support of one arm   
6 
Unable to stand for >10 s even with constant 
support            of one arm  
  
  Score  
  
  Score  
  


 
103 
3) Sitting  
Proband is asked to sit on an examination bed without 
support of feet, eyes open and arms outstretched to the 
front.  
 
0 
Normal, no difficulties sitting >10 sec  
1 
Slight difficulties, intermittent sway  
2 
Constant sway, but able to sit > 10 s without support  
3 
Able to sit for > 10 s only with intermittent support  
4 
Unable to sit for >10 s without continuous support  
 
4) Speech disturbance  
Speech is assessed during normal conversation.  
 
 
 
0 
Normal  
1 
Suggestion of speech disturbance  
2 
Impaired speech, but easy to understand  
3 
Occasional words difficult to understand  
4 
Many words difficult to understand  
5 
Only single words understandable  
6 
Speech unintelligible / anarthria  
  Score   
  
  Score  
  
 
  
1  
Rater: ____________________________date: ______________patient:_______________________  
5) Finger chase   
Rated separately for each side  
Proband sits comfortably. If necessary, support of feet 
and trunk is allowed. Examiner sits in front of proband 
and performs 5 consecutive sudden and fast pointing 
movements in unpredictable directions in a frontal 
plane, at about 50 % of proband´s reach. Movements 
have an amplitude of 30 cm and a frequency of 1 
movement every 2 s. Proband is asked to follow the 
movements with his index finger, as fast and precisely 
as possible. Average performance of last 3 movements 
is rated.   
 
0 
No dysmetria   
1 
Dysmetria, under/ overshooting target <5 cm  
2 
Dysmetria, under/ overshooting target < 15 cm   
3 
Dysmetria, under/ overshooting target > 15 cm  
4 
Unable to perform 5 pointing movements  
  
6) Nose-finger test   
Rated separately for each side  
Proband sits comfortably. If necessary, support of feet 
and trunk is allowed. Proband is asked to point 
repeatedly with his index finger from his nose to 
examiner’s finger which is in front of the proband at 
about 90 % of proband’s reach. Movements are 
performed at moderate speed. Average performance of 
movements is rated according to the amplitude of the 
kinetic tremor.   
 
 
 
0 
No tremor   
1 
Tremor with an amplitude < 2 cm  
2 
Tremor with an amplitude < 5 cm     3     Tremor 
with an amplitude > 5 cm   
  4     Unable to perform 5 pointing movements   
Score  
 Right  
Left  
Score  
 Right  
Left  
mean of both sides (R+L)/2  
  
mean of both sides (R+L)/2  
  


 
104 
7) Fast alternating hand movements   
Rated separately for each side   
Proband sits comfortably. If necessary, support of feet 
and trunk is allowed. Proband is asked to perform 10 
cycles of repetitive alternation of pro- and supinations 
of the hand on his/her thigh as fast and as precise as 
possible. Movement is demonstrated by examiner at a 
speed of approx. 10 cycles within 7 s. Exact times for 
movement execution have to be taken.  
 
0 
Normal, no irregularities (performs <10s)  
1 
Slightly irregular (performs <10s)  
2 
Clearly irregular, single movements difficult          
to distinguish or relevant interruptions, but             
performs <10s  
3 
Very irregular, single movements difficult            
to distinguish or relevant interruptions,            performs 
>10s  
4 
Unable to complete 10 cycles  
  
8) Heel-shin slide   
Rated separately for each side  
Proband lies on examination bed, without sight of his 
legs. Proband is asked to lift one leg, point with the heel 
to the opposite knee, slide down along the shin to the 
ankle, and lay the leg back on the examination bed. The 
task is performed 3 times. Slide-down movements should 
be performed within 1 s. If proband slides down without 
contact to shin in all three trials, rate 4.   
 
0 
Normal  
1 
Slightly abnormal, contact to shin maintained  2 
 
Clearly abnormal, goes off shin up to 3 times          
during 3 cycles  
3 
Severely abnormal, goes off shin 4 or more times    
during 3 cycles  
4 
Unable to perform the task  
  
  Score  
Right  
Left  
  Score  
Right  
Left  
  mean of both sides (R+L)/2  
  
  mean of both sides (R+L) / 2  
  
  
 
  
2  


 
 
BU53Y3I9LLW98R8SYICFA8 
Doug Weaver 
Party ID: 7BTBATIBX4T6EYYIAV7FB7 
IP Address: 38.100.136.100 
VERIFIED EMAIL: doug.weaver@stealthbt.com 
Multi-Factor 
Digital Fingerprint Chec ksum 
5 fb9f67e5a4793f62006d1bbb13b56197e3fbfc 4 
Timestamp 
Audit 
2016-10-22 11:45:46 -0700 
All parties have signed document. Signed copies sent to: Doug Weaver and 
Anthony Aiudi. 
2016-10-22 11:45:46 -0700 
Document signed by Doug Weaver (doug.weaver@stealthbt.com) with drawn 
signat ure. - 38.100.136.100 
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SAP_001.pdf: 
 
 
 
 
Title: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Crossover Study to Evaluate 
the Safety, Tolerability, and Efficacy of Subcutaneous Injections of Elamipretide (MTP-131) 
in Subjects with Genetically Confirmed Mitochondrial Disease Previously Treated in the 
Stealth BioTherapeutics SPIMM-201 Study 
 
 
NCT02805790 
 
April 21, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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       CONFIDENTIAL  
Statistical Analysis Plan   
Protocol No. SPIMM-202  
Last Revision Date: 21APR2017   
STATISTICAL ANALYSIS PLAN  
 
Trial Sponsor:  
Protocol Number:  
Stealth BioTherapeutics Inc.  
SPIMM-202  
IND Number:  
123,553  
Investigational Drug: 
Indication:  
Elamipretide (MTP-131) 
Mitochondrial Disease  
Dosage Form/Strength:  
Elamipretide (MTP-131) administered as  
40 mg/mL of sterile solution for 
subcutaneous injection once daily for four 
weeks  
Protocol Title:  A Phase 2 Randomized, Double-Blind, Placebo-Controlled Crossover Study 
to Evaluate the Safety, Tolerability, and Efficacy of Subcutaneous Injections of Elamipretide 
(MTP-131) in Subjects with Genetically Confirmed Mitochondrial Disease Previously Treated 
in the Stealth BioTherapeutics SPIMM-201 Study  
 
Last Revision Date:  
21 APR 2017  
Final Sign-off Date:  
___________________________________________________________________________________  
The information in this document is confidential and is proprietary to Stealth BioTherapeutics. It is understood 
that information in this document shall not be disclosed to any third party, in any form, without prior written 
consent of an authorized officer of Stealth BioTherapeutics.  
Version 1.0  
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       CONFIDENTIAL  
CHANGE LOG FOR CHANGES MADE AFTER THE INITIAL APPROVAL  
Revision 
Date*  
Section(s) 
Modified  
Brief Description of Revision(s) or 
Reason(s) for Revision  
Modifications Reviewed and 
Approved by**  
Statistical Analysis Plan   
Protocol No. SPIMM-202  
Last Revision Date: 21APR2017   


 
 
Sponsor, Everest  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* 
Update the Last Revision Dates on the cover page and the document header. 
** Provide person’s initial and last name.  
.  


 
 


  
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Statistical Analysis Plan   
Protocol No. SPIMM-202  
Last Revision Date: 21APR2017   
TABLE OF CONTENTS  
  
1.  INTRODUCTION ................................................................................................................................................... 8 
2. STUDY OBJECTIVES ............................................................................................................................................ 8 
2.1 PRIMARY OBJECTIVES ...................................................................................................................................... 8 
2.2  SECONDARY OBJECTIVES ................................................................................................................................ 8 
3. STUDY DESIGN ...................................................................................................................................................... 9 
3.1 STUDY DESIGN ................................................................................................................................................. 9 
3.2  RANDOMIZATION ............................................................................................................................................ 9 
3.3  HYPOTHESIS TESTING ..................................................................................................................................... 9 
3.4  INTERIM ANALYSIS ....................................................................................................................................... 10 
3.5  SAMPLE SIZE ................................................................................................................................................. 10 
3.6  STUDY PROCEDURES AND SCHEDULE OF ASSESSMENTS ............................................................................... 10 
4.  DATA AND ANALYTICAL QUALITY ASSURANCE ................................................................................... 15 
5. ANALYSIS POPULATIONS ................................................................................................................................ 15 
5.1 SAFETY POPULATION ..................................................................................................................................... 15 
5.2  INTENTION-TO-TREAT (ITT) POPULATION .................................................................................................... 15 
5.3  PER-PROTOCOL (PP) POPULATION ................................................................................................................ 15 
6.  SPECIFICATION OF ENDPOINTS AND VARIABLES ................................................................................. 15 
6.1  DEMOGRAPHIC AND BASELINE CHARACTERISTICS ....................................................................................... 15 
6.2  EFFICACY ...................................................................................................................................................... 16 
6.2.1  Study Day and Visit Window Definitions ...................................................................................... 16 
6.2.2  Primary Efficacy Variables ............................................................................................................. 17 
6.2.3  Secondary Efficacy Variables ......................................................................................................... 18 
6.3  SAFETY ......................................................................................................................................................... 21 
6.3.1  Study Day and Visit Window Definitions ...................................................................................... 21 
6.3.2  Extent of Exposure to Study Medication ........................................................................................ 21 
6.3.3  Adverse Events ............................................................................................................................... 22 
6.3.4  Vital Signs ...................................................................................................................................... 23 
6.3.5  Electrocardiogram (ECG) ............................................................................................................... 24 
6.3.6  Laboratory Data .............................................................................................................................. 24 
6.3.7 Columbia-Suicide Severity Rating Scale (C-SSRS) ........................................................................ 25 
6.3.8 Physical Examination ...................................................................................................................... 25 
6.3.9  Pregnancy Test ............................................................................................................................... 26 
6.3.10  Concomitant Medications/Treatments .......................................................................................... 26 
7.  STATISTICAL ANALYSIS ................................................................................................................................. 27 
7.1  GENERAL DATA HANDLING RULES AND DEFINITIONS .................................................................................. 27 
7.2  PATIENT DISPOSITION ................................................................................................................................... 27 
7.3  DEMOGRAPHIC AND BASELINE CHARACTERISTICS ....................................................................................... 27 
7.4  EFFICACY ANALYSES .................................................................................................................................... 27 
7.4.1  Primary Efficacy ............................................................................................................................. 27 
7.4.2  Secondary Efficacy ......................................................................................................................... 28 
7.5  SAFETY ANALYSES ....................................................................................................................................... 29 
7.5.1 Extent of Exposure to Study Medication ......................................................................................... 29 
7.5.2 Adverse Events ................................................................................................................................ 29 
7.5.3 Deaths .............................................................................................................................................. 30 


  
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7.5.4  Laboratory Data .............................................................................................................................. 30 
7.5.5  Vital Signs ...................................................................................................................................... 30 
7.5.6  Electrocardiogram (ECG) ............................................................................................................... 30 
7.5.7  Columbia-Suicide Severity Rating Scale (C-SSRS) ....................................................................... 31 
7.5.8  Physical Examination ..................................................................................................................... 31 
7.5.9  Scale for Assessment and Rating of Ataxia (SARA) ...................................................................... 31 
7.5.10  Pregnancy Test ............................................................................................................................. 31 
7.5.11  Concomitant Medications/Treatments .......................................................................................... 31 
8.  ANALYSES PERFORMED BEFORE DATABASE CLOSURE ..................................................................... 31 
9.  CHANGES FROM METHODS PLANNED IN THE PROTOCOL ................................................................ 31 
10.  STATISTICAL SOFTWARE ............................................................................................................................ 32 
11.  REFERENCES .................................................................................................................................................... 32 
12.  APPENDIX 1  DATA HANDLING RULES ..................................................................................................... 33 
13.  APPENDIX 2  ANALYSIS DATASET SPECIFICATIONS ........................................................................... 33 
14.  APPENDIX 3  SAS CODE FOR STATISTICAL ANALYSES ...................................................................... 33 
15.  APPENDIX 4  MOCKUP TABLES, LISTINGS, AND GRAPHS (TLGS) ................................................... 34 
 
 
 


  
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GLOSSARY OF ABBREVIATIONS  
  
Abbreviation  
Term  
3TUG   
Triple Timed Up and Go Test  
6MWD   
Six-minute walk distance  
6MWT   
Six-minute walk test  
AE   
Adverse event  
BMI   
Body mass index  
CSR  
clinical study report  
C-SSRS   
Columbia-Suicide Severity Rating Scale  
ECG   
Electrocardiogram  
eCRF   
electronic Case Report Form  
IMP   
investigational medicinal product  
IV   
intravenous  
ITT   
intention-to-treat  
IWRS  
Interactive Web-Response System  
MedDRA   
Medical Dictionary for Regulatory Activities  
MTP-131   
SS-31, elamipretide, or Bendavia™  
PGA   
Patient Global Assessment  
PhGA   
Physician Global Assessment  
PP  
Per-Protocol  
PT   
preferred term  
QTcB  
QT corrected for HR using Bazett's method  
SAE   
serious adverse event  
SAP   
Statistical Analysis Plan  
SARA  
Scale for the Assessment and Rating of Ataxia  
SC   
subcutaneous  
SOC  
system organ class  
TEAE   
treatment-emergent adverse event  
  


  
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Statistical Analysis Plan   
Protocol No. SPIMM-202  
Last Revision Date: 21APR2017   
1. INTRODUCTION  
This Statistical Analysis Plan (SAP) outlines the statistical methods for the display, summary and analysis 
of data collected within the scope of Stealth BioTherapeutics Inc. protocol SPIMM-202 version 5.0, dated 
21 October 2016. The analysis of the data should allow changes in the plan to the extent that deviations 
from the original plan would provide a more reliable and valid analysis of the data. As such, deviations 
from this SAP must be substantiated by a sound statistical rationale and described in the clinical study 
report (CSR).  
This SAP should be read in conjunction with the study protocol and the electronic Case Report Forms 
(eCRFs). This version of the SAP has been developed using the final version of the protocol mentioned 
above and the final version of the annotated eCRFs dated 21 July 2016.   
This SAP details the analysis of the data collected in the study and the presentation of the results of the 
analyses. The table, listing, and figure (TLF) shells are displayed in a companion document which 
provides information on the layout of the data displays. Analysis dataset specifications will be developed 
to detail the programming specifications and mapping rules needed to create the analysis datasets and the 
TLFs.   
All statistical analyses will be performed using SAS® version 9.4. Adverse events will be coded using the 
latest version of the Medical Dictionary for Regulatory Activities (MedDRA version 20.0 or newer).  
This randomized, double-blind, placebo-controlled crossover study will enroll up to 36 subjects with 
genetically confirmed mitochondrial disease who have completed participation in the SPIMM-201 study. 
Subjects will have previously received 5 days of intravenous elamipretide (0.01, 0.10 or 0.25 mg/kg/hour 
infused for 2 hours) or placebo (randomized 3:1 within each of the dose escalation cohorts) in the 
SPIMM201 study. (See SPIMM-202 Protocol Section 6.1 for details).  
2. STUDY OBJECTIVES  
2.1  Primary Objectives  
•  To evaluate the effect of single daily subcutaneous (SC) doses of elamipretide administered for 4 
weeks on 6-minute walking distance (6MWD).   
2.2 Secondary Objectives  
• 
To evaluate the safety and tolerability of single daily SC doses of elamipretide administered for 4 
weeks.  
• 
To evaluate the effects of single daily SC doses of elamipretide administered for 4 weeks on:  
o Accelerometry  
o Triple Timed Up and Go (3TUG) Test o Patient Reported Outcomes o Exploratory 
biomarkers  
o Physician Global Assessment (PhGA)  
  


  
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3. STUDY DESIGN  
3.1 Study Design  
This randomized, double-blind, placebo-controlled crossover study will enroll up to 36 subjects with 
genetically confirmed mitochondrial disease who have completed participation in the SPIMM-201 study. 
Subjects will have previously received 5 days of intravenous elamipretide (0.01, 0.10 or 0.25 mg/kg/hour 
infused for 2 hours) or placebo (randomized 3:1 within each of the dose escalation cohorts) in the 
SPIMM201 study.  
Subjects will be randomized (1:1) to one of two sequence groups: 4-weeks of treatment with 40 mg 
elamipretide administered once daily SC in Treatment Period 1 followed by 4-weeks of treatment with 
placebo administered once daily SC in Treatment Period 2 (separated by 4-week washout period), or vice 
versa. See table below.  
  
The following treatment sequences are defined for this study:  
Sequence  
Period 1 (Visit 2)  
Period 2 (Visit 4)  
A  
Elamipretide 40 mg  
Placebo  
B  
Placebo  
Elamipretide 40 mg  
3.2 Randomization  
Randomization will be used in this study to avoid bias in the assignment of subjects to study treatment 
sequences, to increase the likelihood that known and unknown subject attributes (e.g., demographics and 
baseline characteristics) are balanced across treatment sequences, and to enhance the possible validity of 
statistical comparisons. Blinded treatment will be used to reduce potential bias during data collection and 
evaluation of endpoints.  
At the Baseline Visit, after eligibility criteria have been confirmed, treatment kit numbers will be assigned 
to each subject on the basis of a centralized computer-generated randomization schedule.   
3.3 Hypothesis Testing  
For the analysis of primary efficacy endpoints, the following two-sided hypotheses will be carried out to 
evaluate the treatment effect of elamipretide group against placebo group in the 6-minute walk test 
(6MWT) endpoints:  
  
𝐻𝐻0: 𝜇𝜇6𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 = 𝜇𝜇6𝑀𝑀𝑃𝑃𝑃𝑃𝑀𝑀𝑀𝑀𝑀𝑀 𝑣𝑣𝑣𝑣. 𝐻𝐻𝑎𝑎: 𝜇𝜇6𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 
≠𝜇𝜇6𝑀𝑀𝑃𝑃𝑃𝑃𝑀𝑀𝑀𝑀𝑀𝑀  
  where 𝜇𝜇6PLBMWT is the mean 6MWT at the end of the treatment period for the placebo treatment 
group, and µMTP6MWT, is the mean in 6MWT at the end of the treatment period for the elamipretide 
treatment group.  
Similarly, the two-sided hypotheses will be performed to evaluate the treatment effect of elamipretide 
versus placebo on the secondary efficacy endpoints: accelerometer counts, patient reported outcomes 
(Neuro-QoL Fatigue-Short Form, Mitochondrial Disease [MD] Symptom Assessment and Patient Global 
Assessment [PGA]), 3TUG Test score, exploratory biomarkers, and Physician Global Assessment 
(PhGA).  
No hypothesis testing will be performed for safety analyses in the study.   


  
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The above hypothesis will be tested for the 6MWT treatment comparison at α=0.05 level of significance 
and additional statistical tests (where performed) will be 2-sided.  
Conditional upon significance for the primary endpoint, for the secondary efficacy measures, Type I error 
control will be achieved by testing sequentially using a two-sided alpha level of 0.05 for the following 
measures below.   
The hierarchy of comparison is as follows:  
• 
Mitochondrial Disease Symptom Assessment – 4 questions [Total fatigue score (sum of scores 
from Q1, Q2, Q3, and Q4)]  
• 
Mitochondrial Disease Symptom Assessment – 2 questions [Total fatigue during activities score 
(sum of scores from Q2 and Q4)]  
• 
3TUG  
• 
Neuro-QoL Fatigue-Short Form  
If the comparison of first secondary endpoint, Mitochondrial Disease Symptom Assessment [Total fatigue 
score (sum of scores from Q1, Q2, Q3, and Q4)], at end of treatment evaluations is statistically significant 
(two-sided, alpha=0.05), the second secondary endpoint on Mitochondrial Disease Symptom Assessment 
[Total fatigue during activities score (sum of scores from Q2 and Q4)] will be compared. If the second 
secondary endpoint comparison is statistically significant (two-sided, alpha=0.05), the third secondary 
endpoint, 3TUG, will be compared. If the third secondary endpoint comparison is statistically significant 
(two-sided, alpha=0.05), the fourth secondary endpoint, Neuro-QoL Fatigue-Short Form, will be 
compared.  Irrespective, nominal p-values will be provided.  
3.4 Interim Analysis  
Interim analysis was not conducted in this study. See Section 9 for details.  
3.5 Sample Size  
Subject numbers (up to 36 subjects) are limited to those residing in North America having previously 
completed participation in the SPIMM-201 study and who meet all eligibility criteria.  
3.6 Study Procedures and Schedule of Assessments  
Study procedures and their timing are summarized in the Schedule of Assessments (Study Center Visits) 
(Table 1), Schedule of Visiting Nurse Assessments (Table 2), and Study Schematic (Table 3).   


  
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Table 1: Schedule of Assessments (Study Center Visits)  
  
  


  
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Table 2: Schedule of Visiting Nurse Assessments  


  
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Table 3: Study Schematic  
  
  
  
  
  
  


  
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4. DATA AND ANALYTICAL QUALITY ASSURANCE  
The overall quality assurance procedures for the study data, statistical programming and analyses are 
described in Everest’s Standard Operating Procedures. Detailed data management procedures are 
documented in the Data Management Plan, Data Validation Check Specifications, and Data Review Plan. 
Detailed statistical and programming quality control (QC) and quality assurance (QA) procedures are 
documented in the Statistical Analysis and Programming QC/QA Plan.   
The study endpoints and analytic approaches are both prospectively defined and documented in the 
protocol and in this SAP.  
5. ANALYSIS POPULATIONS  
Three subject populations will be evaluated during this study and are defined as follows:  
5.1 Safety Population  
The Safety Population includes all study subjects who receive at least 1 dose of study drug and analyzed 
according to treatment received within a period. Safety data analysis will be conducted on all subjects in 
the Safety Population with treatment group determined by treatment received in a particular period (i.e., 
subjects dosed in both periods will be counted in both treatment groups).  
5.2 Intention-to-Treat (ITT) Population  
The Intention-to-Treat Population includes all study subjects who receive at least 1 dose of study drug, 
and analyzed according to the treatment randomized in a given period. Efficacy analyses will be 
conducted on the ITT population.  
5.3 Per-Protocol (PP) Population  
The Per-Protocol Population (PP) will consist of all ITT subjects without major protocol violations/ 
deviations. The list of major protocol violations/deviations will be identified by the Sponsor prior to final 
database lock for the study that would lead to exclusion for the PP analysis. Efficacy analyses will also be 
conducted on the PP Population according to the treatment group to which the subjects were randomized 
in a given period.  
No analysis will be performed on the PP population if there are no exclusions from the ITT Population 
for the PP analysis.  
6. SPECIFICATION OF ENDPOINTS AND VARIABLES  
6.1 Demographic and Baseline Characteristics  
Demographic variables consist of the following:  
• 
Age in years (continuous) derived as the integer value of   
(Informed consent date – date of birth + 1) / 365.25  
• 
Gender  
• 
Race  
• 
Ethnicity  


  
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Baseline characteristics consist of the following:  
• 
Weight (kg)   
• 
Height (cm)   
• 
BMI (kg/m²) derived as weight in kg divided by (height in m)²  
• 
Vital signs (heart rate, respiratory rate, systolic blood pressure, diastolic blood pressure, and 
temperature)  
• 
Medical and surgical history coded using the latest version of MedDRA (version 20.0 or newer)  
• 
Prior medications coded using the latest version of the World Health Organization Drug 
Dictionary (WHO-DD, 3Q2016 or newer)  
• 
ECG (electrocardiogram)  
• 
Physical examination, Ptosis assessment, and SARA  
6.2 Efficacy  
6.2.1 Study Day and Visit Window Definitions  
Data obtained during unscheduled visits will be allocated to the scheduled visit corresponding to the visit 
window they fall in as specified in Tables 4.1 and 4.2. Safety data obtained during unscheduled time 
point will be allocated to the scheduled time point corresponding to the time window they fall. Data will 
be analyzed based on the nominal visits and nominal time points. If the data from the nominal visit or 
time point is missing, data from unscheduled visits for the same nominal visit or time point will be used. 
If multiple unscheduled assessments fall in the same visit window or time point, the non-missing 
assessment closest to target time point will be selected for analysis. If multiple values are the same 
number of days away from the target study day, then the latter value will be used.  
First date on which subject received the study drug during Treatment Period 1 will be used as the Study 
Day 1. Study days for other visits will be calculated as follows:  
 
Before Study Day 1 visit:   
Study Day = date of assessment – date of Study Day 1.  
On or after Study Day 1 visit:  Study Day = date of assessment – date of Study Day 1 + 1.  
  
Last study date is the last visit date of any scheduled, unscheduled or early discontinuation visits. Last 
Study Day is calculated as:  
Last Study Day = last study date – date of Study Day 1 + 1.  
The target study days of Study Center Visits are summarized in Table 4.1 below.   
Table 4.1  Time Windows for Efficacy Assessments  
 
 
Scheduled Visit Number  Visit (label)  
Time Interval (day)  
Target Time Point 
(day)  
1  
Screening  
-30 to -1  
-30 to -1  
2  
Visit 2 (Predose for Period 1)  
1  
1  
3  
Visit 3 (Week 4)  
2 to (Actual Visit 4 day 
minus 1 day)  
29  


  
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4  
Visit 4 (Week 8)  
(Predose for Period 2)  
Actual Visit 4 day to  
(Actual Visit 5 day 
minus 1)   
57  
5  
Visit 5 (Week 12)  
Actual Visit 5 day to  
(Actual Visit 6 day 
minus 1)  
85  
6  
Visit 6 (End-of-Study)  
 
  day +  
99  
  
For laboratory assessments, there are visiting nurse assessments of hematology and chemistry at Weeks 1 
and 2 in Treatment Period 1, Week 6 in washout period, and Weeks 9 and 10 in Treatment Period 2. The 
visit windows are defined as follows:  
Table 4.2  Time Windows for Laboratory Assessments  
 
Scheduled Visit Number  Visit (label)  
Time Interval (day)  
Target Time Point 
(day)  
1  
Screening  
-30 to -1  
-30 to -1  
2  
Visit 2 (Baseline)  
1  
1  
3  
Week 1  
2 to 11  
8  
4  
Week 2  
12 to 18  
15  
5  
Visit 3 (Week 4)  
19 to (Actual Visit 4 day 
minus 1 day)  
29  
  
Wash-out (Week 6)  
use nominal  visit  
  
6  
Visit 4 (Week 8)  
Actual Visit 4 day to 60   
57  
7  
Week 9  
61 to 67  
64  
8  
Week 10  
68 to 74  
71  
9  
Visit 5 (Week 12)  
75 to (Actual Visit 6 day 
minus 1)  
85  
10  
Visit 6 (End-of-Study)  
 ≥ (Actual Visit 5 day + 
29 days)  
99  
  
6.2.2 Primary Efficacy Variables  
The primary efficacy variable represents skeletal muscle function and will be evaluated by the 6MWT:  
6MWT:  
•  Distance walked (meters) on the 6-minute walk test as evaluated at the end of treatment period 
assessments.  


  
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6.2.3 Secondary Efficacy Variables  
The secondary efficacy variables will be evaluated by the wrist and hip Accelerometer counts, patient 
reported outcomes (Neuro-QoL Fatigue-Short Form, Mitochondrial Disease [MD] Symptom Assessment 
and Patient Global Assessment [PGA]), 3TUG Test score, exploratory biomarkers, and Physician Global 
Assessment (PhGA). All secondary variables will be evaluated at the end of treatment period 
assessments.  
Accelerometer Counts  
• 
Average accelerometer counts per day. Subjects should be ensured to wear wrist accelerometer 
daily (24 hours per day), but wear hip accelerometer daily during waking hours (minimum of at 
least 7 consecutive days) immediately prior to Predose, Week 4, Week 8 and Week 12 visits.   
• 
For both wrist and hip monitors, ActiGraph will be transforming the data from 30hz data into 1 
minute epoch data; this 1 minute epoch data will be used for the analysis of both mean vertical 
axis (Y) counts for the hip monitor, as well as the vector magnitude of the wrist data.  
• 
Wrist data:  
o Wrist data (per minute) that are provided by ActiGraph include 3 axes (i.e. X axis counts, 
Y axis counts, and Z axis counts). o Vector magnitude of acceleration (vm) for each 
minute epoch = √((X 2 + (Z axis counts)2)  
axis counts)2 + (Y axis counts) 
o For each day, compute the average of all the calculated vector magnitude of accelerations 
over the timeframe on the day to obtain the mean vector magnitude per day.   
o Mean vector magnitude per day will be presented by treatment group.  
o It is confirmed that the WEAR variable is not reliable to check whether subjects wear the 
wrist accelerometer for at least 10 hours. In other words, there is no need to check 
whether the subject has worn the wrist accelerometer for at least 10 hours in the day for 
validity.   
o Time window: recording starts 7 days prior to the visit. Eliminate the day of the visit 
since it is a partial day.  
o If data is right skewed, data used in model will be log transformed. That is, transform 
counts per day (not by minute since too many 0’s).  
o A Mixed model repeated measures (MMRM) analysis on the last 7 days prior to the end 
of the treatment period visit will be performed. Response variable is the daily assessment 
(only for the last 7 days prior to the visit).  
o Plots of mean vector magnitude per day and week by treatment group will be presented. 
For plot of mean vector magnitude per week, the mean vector magnitude per week will 
be calculated as follows:  
▪ 
Compute the average of all the calculated vector magnitude of accelerations over 
the timeframe over a week to obtain the mean vector magnitude per week.   


  
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▪ 
Use the last 7 days prior to the visit for the analysis (and not include data from 
date of visit).   
▪ 
For descriptive purposes, the end of treatment visit will be calculated based on 
the average of the counts over the last 7 days.  
• 
Hip data:   
o Hip data are available as ‘counts per minute’ (Y axis counts) in the raw dataset.  
o As the ‘Wear’ variable (indicating whether the patient is wearing the device) can be 
reported inaccurately as ‘False’ for a subject who is sedentary, the calculation should 
take into account the average of counts per minute across the entire time period of 8am- 
8pm. In other words, use all data available on each subject’s 8am-8pm time window  
(local time zone), regardless of wearing the hip accelerometer or not (i.e. WEAR = 
TRUE or FALSE will be counted). It is confirmed that the device is calibrated to record 
time in the subject’s local time zone.  
o For each subject, compute the average of ‘counts per minute’ over the entire 12 hour 
period of 8am-8pm time window to get the average counts per day.  
o Average count per day will be presented by treatment group.  
o Time window: recording starts 7 days prior to the visit. Eliminate the day of the visit 
since it is a partial day.  
o If data is right skewed, data used in model will be log transformed. That is, transform 
counts per day (not by minute since too many 0’s).  
o A Mixed model repeated measures (MMRM) analysis on the last 7 days prior to the end 
of the treatment period visit will be performed. Response variable is the daily assessment 
(only for the last 7 days prior to the visit).  
o Plots of average counts per day and week by treatment group will be presented. For plot 
of average counts per week, the average counts per week will be calculated as follows:  
▪ 
Compute the average of all the calculated vector magnitude of accelerations over 
the timeframe over a week to obtain the average counts per week.   
▪ 
Use the last 7 days prior to the visit for the analysis (and not include data from 
date of visit).   
▪ 
For descriptive purposes, the end of treatment visit will be calculated based on 
the average of the counts over the last 7 days.  
  
Neuro-QoL Fatigue-Short Form  
• 
Total Neuro-QoL Fatigue scores. Each question in Neuro-QoL Fatigue question has a possible 
score from 1 to 5, where 1=Never, 2=Rarely, 3=Sometimes, 4=Often, and 5=Always.   
• 
The primary analysis of the Neuro-QOL Fatigue Item Bank is the Neuro-QoL Fatigue-Short 
Form (the first 8 questions). The first 8 questions include: I felt exhausted, I felt that I had no 


  
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energy, I felt fatigued, I was too tired to do my household chores, I was too tired to leave the 
house, I was frustrated by being too tired to do the things I wanted to do, I felt tired, and I has to 
limit my social activity because I was tired. For an 8-item form that includes items with 5 
response options ranging from 1 to 5, the lowest possible raw score is 8 (8 x 1); the highest 
possible raw score is 40 (8 x 5).  
• 
At least 50% of the items are answered in order to calculate the summed score. Otherwise, the 
summed score is set to missing.  
• 
8-item short form T-scores will be calculated from the short form scoring table provided by the 
instrument authors (Neuro-QoL User Manual, 2015). This table converts simple summed scores 
to an Item Response Theory metric. This version of the Neuro-QOL Fatigue score will be 
reported in the T-score metric. Refer to Fatigue scoring table below to convert summed scores to 
T-scores.  
• 
Mean T-scores will be presented by treatment group.  
• 
Raw score of each individual item (Q1-Q19) will also be summarized by treatment group.  
  
Mitochondrial Disease [MD] Symptom Assessment  
• 
Each question in Mitochondrial Disease Symptom Assessment has four answers: 1=Not at all, 
2=Mild, 3=Moderate, and 4=Severe.   
• 
Total fatigue score (sum of Q1, Q2, Q3, and Q4) as primary analysis from this assessment. If less 
than 3 out of 4 questions are answered, the total fatigue score will be set to missing.   
• 
Total fatigue during activities score (sum of Q2 and Q4). If one of the 2 questions is not 
answered, the total fatigue during activities score will be set to missing.  


  
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• 
Individual score for all questions (Q1-Q10) will also be summarized by treatment group. Weekly 
score will be calculated as the average of the daily scores over a week. If 4 or more daily scores 
are missing, the weekly score will be set to missing.  
Most bothersome assessment symptom (as identified prior to the start of treatment) will be analyzed in a 
similar fashion to the individual question scores.  
Patient Global Assessment [PGA]  
• 
Patient-reported current disease status: 1=Excellent, 2=Very good, 3=Good, 4=Fair, and 5=Poor.  
3TUG Test  
•  The total time (in seconds) of completing the three tests. The 3TUG Test is the Timed Up and Go 
Test repeated 3 times without pause.  
Exploratory biomarkers  
• 
GDF-15  
• 
FGF-21  
• 
Glutathione  
Physician Global Assessment (PhGA)  
•  Physician-reported overall health status: 1=Excellent, 2=Very good, 3=Good, 4=Fair, and 
5=Poor.  
6.3 Safety  
Safety variables include the following:  
1. Adverse events   
2. Vital signs  
3. ECGs  
4. Clinical laboratory measurements  
5. C-SSRS scores  
6. Physical examination  
7. Pregnancy test  
8. Concomitant medications/treatments  
6.3.1 Study Day and Visit Window Definitions  
Study day and visit window for the safety parameters are defined in the same way as those for the 
efficacy parameters. Please refer to Section 6.2.1 for details.  
6.3.2 Extent of Exposure to Study Medication  
Subjects will receive either 40 mg elamipretide administered once daily for 4-weeks SC in Treatment  
Period 1 followed by 4-weeks of treatment with placebo administered once daily SC in Treatment Period  
2 (separated by 4-week washout period), or receive placebo administered once daily for 4-weeks SC in 
Treatment Period 1 followed by 4-weeks of treatment with 40 mg elamipretide administered once daily 


  
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SC in Treatment Period 2 (separated by 4-week washout period). The study medication exposure 
variables include:  
  
• 
Treatment duration (days) defined as the sum of treatment duration in each period:  
(Last dose date in Period i +1) – (First dose date in Period i), where i=1, 2.  
• 
Cumulative dose defined as the sum of cumulative dose in two Periods  
6.3.3 Adverse Events  
The AE reporting period begins when the subject signs the informed consent and continues through the 
clinical study’s post-treatment follow-up period, defined as 14 days after last administration of study 
drug. Within a study, all subjects who receive at least 1 dose of elamipretide, whether they complete the 
treatment period or not, should enter the 14-day period as defined above.   
Adverse events will be collected and coded using latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA 20.0 or newer).   
6.3.3.1 Treatment-Emergent AE (TEAE)  
An AE is considered treatment-emergent if the date of onset is on or after the date of first dose of study 
drug, or worsening after date of first dose of study drug (intensity/severity changed to worsen grades) and 
will be associated with the treatment most recently received by the subject at the time of onset or 
worsening. Any AE with an onset during the washout period will be attributed to treatment in 
Treatment Period 1.  
6.3.3.2 Serious Adverse Events (SAE)  
Adverse events will be categorized as serious or non-serious using the definition specified in Section 9.5 
of the study protocol.   
6.3.3.3 Adverse Events Counting Rules  
1. A subject with more than one different adverse event in a particular system organ class (SOC) 
will be counted only once in the total of subjects experiencing adverse events in that particular 
SOC within a given treatment group.   
2. A subject having experienced the same event (AE preferred term) more than once associated with 
a given treatment period will be counted only once in the number of subjects with that event, 
within a treatment group.   
3. A subject having experienced the same event (AE preferred term) more than once associated with 
a given treatment period with a different severity or seriousness, it will be counted only once 
within a treatment group with the worst grade and seriousness respectively.   
4. A subject having experienced the same event (AE preferred term) more than once associated with 
a given treatment period with a different causal relationship to the study drug, it will be counted 
only once within a treatment group by considering the most-related documented degree of 
relationship associated with the particular treatment.  


  
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6.3.3.4 AE Severity  
The severity of AEs will evaluated as “Mild”, “Moderate”, and “Severe” using the criteria specified in 
Section 9.6.1.1 of study protocol.  
6.3.3.5 Relationship to the Investigational Medicinal Product  
AEs will be qualified as either related (probable, possible, or unlikely related) or unrelated to study drug 
using the criteria specified in Section 9.6.1.2 of study protocol.  
6.3.3.6 AE with Irregular Start/End Dates  
Partial dates may be imputed when appropriate. Imputed dates will be used to determine Study Day. If 
a partial date is reported for the start of an adverse event, a complete date will be imputed by the 
following algorithm:  
1. Only the year is reported: If the subject started receiving study drug in the previous year 
associated with a given treatment period, then January 1 will be used as the starting date of the 
event. If the subject started receiving study drug in the year reported within the same treatment 
period, then the date of the first dose of study drug within the same treatment period will be 
used as the start of the event.   
2. The month and year is reported: If the subject started receiving study drug prior to the month 
and year reported associated with a given treatment period, then the first day of the month will 
be used as the starting date of the event. If the subject started receiving study drug during the 
month and year reported within the same treatment period, then the date of the first dose of 
study drug within the same treatment period will be used as the start of the event.  
If a partial date is reported for the end of an adverse event and the adverse event is not continuing, a 
complete date will be imputed by the following algorithm:   
1. Only the year is reported: If the subject started receiving study drug in the previous year associated 
with a given treatment period, then the date of final study contact with the subject will be used as 
the end of the adverse event. If the subject started receiving study drug in the year reported within 
the same treatment period, then the earlier of December 31 or the date of final study contact with 
the subject within the same treatment period will be used as the end of the adverse event.   
2. The month and year reported: The earlier of the last date of the month or the date of final contact 
with the subject within the same treatment period will be used as the end of the adverse event.  The 
above rules are subject to logical sense, for example, imputed start date should be on or prior to 
imputed end date.  
6.3.4 Vital Signs  
During all study center visits, the vital signs measurements will include temperature (oC), heart rate 
(beats/min), respiration rate (breaths/min) and blood pressure (mmHg), recorded in the sitting position 
after at least 5 minutes rest. At the Baseline Visit these vital signs measurements will be performed as 
part of the study eligibility confirmation.  
Baseline values for vital sign parameters are those measured at last evaluation prior to the first dose of 
study drug in Treatment Period 1. Change from baseline to a time point t, denoted by Changet, will be 
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Changet = Valuet – ValueBaseline.  
6.3.5 Electrocardiogram (ECG)  
ECG parameters, including PR interval, QRS interval, QT interval, and QTcB (msec), will be collected 
according to the study assessment schedule as specified in Table 1. Baseline ECGs will be defined as the 
last evaluation performed prior to the first dose of study drug in Treatment Period 1. The results of ECG 
with any clinical significant abnormalities (Yes/No) will be reported on the eCRF.  
6.3.6 Laboratory Data   
Table 5 below summarizes the clinical laboratory tests that will be performed in this study. Changes from 
baseline at each visit will be performed.  
  
Conversion to the International System of Units  
All laboratory data will be stored in the database with the units in which they are originally reported.  
Laboratory data in summary tables and subject data listings will be presented in the International System 
of Units (SI units; Système International d’Unités).  Laboratory data not reported in SI units will be 
converted to SI units before further processing or data analysis.  
  
Abnormal Values  
Based upon laboratory normal ranges, laboratory test results will be categorized according to the normal 
range as low, normal, and high. Subjects with laboratory data outside the normal range will be listed with 
abnormal values flagged.  
 


  
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Table 5. Clinical Laboratory Tests  
  
6.3.7 Columbia-Suicide Severity Rating Scale (C-SSRS)  
The Columbia–Suicide Severity Rating Scale (C-SSRS) (see protocol Attachment 11 and 12) is an 
assessment tool that evaluates suicidal ideation and behavior. C-SSRS will be assessed for each subject at 
each schedule Study Center Visits to evaluate the suicidal risk of the subjects.  
6.3.8 Physical Examination  
Physical examination, including a full review of general appearance, skin, head, eyes (if ptosis is present 
[i.e. an upper marginal reflex distance below 2 mm or an asymmetry of more than 2 mm between the 
eyes] the marginal reflex distance should be measured and recorded for both eyes), ears, nose, throat, 
neck (including thyroid), lymph nodes, chest, heart, abdomen, extremities, and nervous system, as well as 
weight and height measurements will be collected according to the study assessment schedule as 
specified in Table 1. The results of physical examination with any clinical significant abnormalities 
(Yes/No) will be reported on the eCRF.  
Baseline values for physical examination parameters are those measured at last evaluation prior to the 
first dose of study drug in Treatment Period 1.  
The Scale for the Assessment and Rating of Ataxia (SARA) will be completed during every physical 
examination. Ataxia will be assessed using SARA using the 8 items related to gait, stances, sitting, 
speech disturbance, finger chase, nose-finger test, fast alternating hand movements, and heel-shin slide. 
The total SARA score ranges from 0 (no ataxia) to 40 (severe ataxia). The individual item scores are as 
follows: gait (0 to 8), stance (0 to 6), sitting (0 to 4), speech disturbance (0 to 6), finger chase (0 to 4), 
nose-finger test (0 to 4), fast alternating hand movements (0 to 4), and heel-shin slide (0 to 4).  


  
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6.3.9 Pregnancy Test  
Women of child-bearing potential will have a serum pregnancy test performed at the Screening Visit. 
Women of child-bearing potential will have a urine pregnancy test at the Baseline Visit and the results of 
the Baseline Visit pre-dose pregnancy test must be evaluated before randomization to ensure eligibility. A 
urine pregnancy test will also be performed for women of childbearing potential at the End-of-Study 
/Early Discontinuation Visit.  
  
Only pregnancies considered by the Investigator as related to study treatment (e.g., resulting from an 
interaction between study drug and a contraceptive drug) are considered AEs unto themselves. However, 
all pregnancies with an estimated conception date that occurred during the AE reporting period, as 
defined in Protocol Section 9.6.2, 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.  
6.3.10  Concomitant Medications/Treatments  
Prior and concomitant medications will be recorded at Screening and during the study. Prior medication 
is defined as any medication taken before the first dose of the IMP. Concomitant medication is defined as 
any medication taken during the study between the date of the first dose of IMP and the last study date of 
the subject. Any medications started after the last study date of the subject will not be considered 
concomitant medications.  
All relevant information, including reason for use, dose, frequency and route, will be recorded for any 
medication administered or received prior and during the study.  
Summaries of all concomitant medications taken during the course of the study will be presented in 
tabular form using Anatomical Therapeutic Chemical 4 classification codes and preferred drug name via 
the World Health Organization Drug Dictionary (WHO-DD) with latest version to be specified in the 
Clinical Study Report. For the summary tables, if a subject has taken a concomitant medication more than 
once, the subject will be counted only once for the medication.  
For medications with incomplete dates, imputation will be used to convert to a complete date. Imputed 
dates will be used to determine Study Day.  
Partial medication start dates will be imputed as follows:   
1. Only the year is reported: If the subject started receiving study drug in the year reported, then the 
date of the first dose of study drug will be used as the starting date of the medication. Otherwise, 
January 1 will be used as the start of the medication.  
2. The month and year is reported: If the subject started receiving study drug during the month and 
year reported, then the date of first dose of study drug will be used as the starting date of the 
medication. Otherwise, the first day of the month will be used as the start of the medication. Partial 
medication end dates will be imputed for non-ongoing medications as follows:   
1. Only the year is reported: If the subject stopped receiving study drug in the year reported, then the 
date of the last dose of study drug will be used as the end date of the medication. Otherwise, 
December 31 will be used as the end of the medication.   
2. The month and year is reported: If the subject stopped receiving study drug during the month and 
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medication. Otherwise, the last day of the month will be used as the end of the medication. The 
above rules are subject to logical sense, for example, imputed start date should be on or prior to 
imputed end date.  
  
7. STATISTICAL ANALYSIS  
7.1 General Data Handling Rules and Definitions  
All data collected on case report forms will be provided in listings, except data collected only for 
confirmation of study entry criteria and for study administrative purposes. If any randomized subject is 
found not to have valid documented informed consent, that subject’s data will be excluded from the 
report, except as necessary to document the error.   
Except where specified all continuous variables will be summarized with descriptive statistics (the 
number of non-missing values, mean, standard deviation, median, minimum and maximum) and all 
categorical variables will be summarized with frequency counts and percentages, by treatment group. 
Unless otherwise specified, the mean and median will be displayed to 1 more decimal place than the 
original data, and standard deviation and standard error of the mean (if presented) should also be 
displayed to 2 more decimal place than the original data. All percentages for frequencies will be rounded 
to 1 decimal place.  
Missing data will be maintained as missing unless specified otherwise. For variables where missing data 
is imputed, the analysis dataset will contain 1 variable with the imputed value and the original variable 
with missing maintained as missing.   
Treatment sequence and study periods will be included in the subject data listings.  
7.2 Patient Disposition  
A disposition table for all subjects will be provided. This tabulation will include the number of subjects 
who receive the study treatment, and discontinue prematurely or complete the study. The number and 
percentage of randomized subjects who are included in the ITT and Safety Populations will also be 
tabulated.  
Reasons for early discontinuation will be summarized for all subjects randomized. The number and 
percentage of subjects in the Safety and ITT Populations withdrawn for each reason of withdrawal will be 
tabulated by treatment group. Corresponding listings will also be provided.  
7.3 Demographic and Baseline Characteristics  
Demographic and baseline characteristics which are listed in Section 6.1 will be summarized by treatment 
sequence. Medical and surgical history, as well as prior and concomitant medications will be listed.  
7.4 Efficacy Analyses  
7.4.1 Primary Efficacy  
Efficacy analyses will include comparisons between two treatment groups for the 6MWT distance walked 
(meters) considering the assessments at the end of each treatment period in the ITT population.  


  
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A mixed effect model will be used to explore the treatment effect on primary 6MWT distance measured 
at the end of each treatment period. For the mixed effect model, the actual 6MWT values are considered 
as dependent variables. The analysis model will include terms for treatment (two levels), period (two 
levels), and sequence (two levels) as fixed effects and subjects nested within sequence as a random effect. 
The model may use the unstructured or Toeplitz (whichever has a better fit by AICC value) withinsubject 
variance-covariance matrix. The estimated least square (LS) means and their standard errors as well as 
the estimated treatment effect (differences between treatments) will be summarized by treatment at the 
end of each treatment period. Refer to SAS code in Appendix 3.  
The carryover effect will be tested from the treatment-by-period interaction using alpha=0.1. If the 
treatment-by-period interaction is significant, data only in Treatment Period 1 may also be analyzed, 
using an analysis of covariance (ANCOVA) model with baseline as a covariate.  
The reasons for 6MWT terminated prior to 6 minutes will be listed.   
Pre- and post-vitals such as systolic/diastolic blood pressure, heart rate, respiratory rate, SpO2 (%), 
dyspnea (Borg), fatigue (Borg) will also be presented.  
Sensitivity Analysis  
Sensitivity analysis will be performed on 6MWT distance will be performed at the end of treatment 
period assessments by removing any subjects with clinically significant abnormality reported during the 
6MWT.   
A subgroup analysis of 6WMT distance will also be performed at the end of treatment period assessments 
by baseline distance (≥450 m vs. < 450 m).  
7.4.2 Secondary Efficacy  
Secondary efficacy analyses will be performed as follows:   
• 
Accelerometer counts: average counts per day for hip and mean vector magnitude per day for 
wrist will be summarized over the last seven days prior to the end of treatment period visit.  The 
model will not include a day by treatment interaction, thereby estimating an effect “averaged” (in 
some sense) across the 7 days. Average counts per week for hip and mean vector magnitude per 
week for wrist may also be presented descriptively, if missing data is not a concern.  
• 
Patient reported outcomes  o Neuro-QoL Fatigue-Short Form: Neuro-QOL Fatigue T-scores on 
the sum of 8 questions and individual raw score or each question will be summarized by visits.  
o Mitochondrial Disease [MD] Symptom Assessment: Total fatigue score, total fatigue 
during activities score, and individual score (Q1-Q10) will be summarized by visits 
(including the 7 days prior to the date of visit). Most bothersome symptoms will also be 
summarized.  
o Patient Global Assessment [PGA]: current disease status (continuous and categorical) 
will be summarized by visits.  
• 
3TUG Test score: total time (in seconds) of completing the 3TUG will be summarized by visits.  
• 
Exploratory biomarkers: biomarker values will be summarized by visits   
• 
Physician Global Assessment (PhGA): current disease status will be summarized by visits.  


  
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A mixed effect model (when there’s only one measured value for the response variable at the end of each 
treatment period), if appropriate, will be performed on the secondary efficacy variables (i.e. Neuro-QoL 
Fatigue, PGA, PhGA, 3TUG, and exploratory biomarkers).  
For Mitochondrial Disease [MD] Symptom Assessment, a similar mixed effect model will be performed 
on each defined timepoint (i.e. week).  
For hip and wrist accelerometer counts, mixed model repeated measures (MMRM) analyses on the last 7 
days prior to the end of the treatment period visit will be performed. The response (dependent) variable is 
the daily assessment (only for the last 7 days prior to the visit). The analysis model will include terms for 
treatment (two levels), period (two levels), sequence (two levels), and weekend (as an indicator, Y/N) as 
fixed effects and subjects nested within sequence as a random effect. The model may use the unstructured 
or Toeplitz (whichever has a better fit by AICC value) within-subject variance-covariance matrix. The 
estimated least square (LS) means and their standard errors as well as the estimated treatment effect 
(differences between treatments) will be summarized by treatment at the end of each treatment period. 
Refer to SAS code in Appendix 3.  
Plots of hip accelerometer average counts per day and week by treatment group will be presented. 
Similarly, plots of wrist accelerometer counts (mean vector magnitude of accelerations) per day and week 
by treatment group will also be presented.  
7.5 Safety Analyses  
Safety analyses will be performed using the Safety Population. Safety measurements will include AEs, 
clinical laboratory tests (i.e. serum chemistry, hematology and urinalysis), ECGs, physical exams and 
vital signs. All safety data will be summarized by treatment group. Baseline values for clinical laboratory 
tests, vital signs and ECGs will be defined as the last evaluation performed prior to administration of 
study drug given in the first period.  
7.5.1 Extent of Exposure to Study Medication  
The study drug exposure variables as listed in Section 6.3.2 will be summarized by treatment groups. 
Study drug dosing information will be listed by subject.  
7.5.2 Adverse Events  
All AEs will be coded to system organ class (SOC) and preferred term (PT) using the latest Medical 
Dictionary for Regulatory Activities coding dictionary, version 20.0. 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 by 
treatment group. In the summary tables, subjects may be counted under multiple SOCs and PTs, but for 
each SOC and PT, subjects are only counted once for each treatment group. If a subject has the same AE 
on multiple occasions, the highest severity (severe > moderate > mild) or drug relationship (probable > 
possibly related > unlikely related > unrelated) recorded for the event associated with a given treatment 
period will be presented as defined in Section 6.3.3.1. If severity is missing, subjects will be included as 
missing (for severity). If drug relationship is missing, subjects will be included in related tables (i.e., 
considered related). Summary tables will be organized by SOC, then PT.  
The following summaries will be presented for TEAE by treatment groups:   
• 
Overall Summary of Treatment-Emergent Adverse Events  


  
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• 
Incidence of Treatment-Emergent Adverse Events by System Organ Class and Preferred Term  
• 
Incidence of Treatment-Emergent Serious Adverse Events by System Organ Class and Preferred 
Term   
• 
Incidence of Treatment-Emergent Adverse Events by System Organ Class, Preferred Term and 
Severity  
• 
Incidence of Treatment-Emergent Adverse Events by System Organ Class, Preferred Term and 
Relationship to Study Drug   
• 
Incidence of Study Drug Related Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term and Severity  
• 
Incidence of Treatment-Emergent Adverse Events Leading to Discontinuation of Study Drug by 
System Organ Class and Preferred Term  
7.5.3 Deaths  
Deaths will be provided as a listing, displaying treatment group, date of death and reason for death, 
whether autopsy performed, and date of first and last study drug.  
7.5.4 Laboratory Data   
Summary tables for laboratory parameters (including hematology, chemistry, and urinalysis) will include 
descriptive statistics of change relative to baseline where appropriate.  
Subjects with laboratory data outside the normal range will be listed with abnormal values flagged.  
Shift tables (e.g., tables that show the number of subjects who are low, normal, or high at baseline versus 
each post-baseline scheduled assessment) will be produced.  
The number and percentage of subjects with urinalysis results outside the normal range will be presented 
by endpoint and visit for each treatment group. Shift tables for urinalysis will show the number of 
subjects who are normal/abnormal at baseline and normal/abnormal at the end of each treatment period.  
7.5.5 Vital Signs  
Vital signs data will be summarized by changes from baseline values at each visit, for each treatment 
group using descriptive statistics.   
Listing of vital signs data will be provided for all subjects in the safety population.  
7.5.6 Electrocardiogram (ECG)  
ECG data (PR interval, QRS interval, QT interval, and QTcB) will be summarized by changes from 
baseline values by treatment group and visit using descriptive statistics.  
ECG data will be summarized by changes from baseline values at each visit, for 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 QTcB will also be listed.  


  
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7.5.7 Columbia-Suicide Severity Rating Scale (C-SSRS)  
Summary of the suicidal ideation, suicidal behavior, and self-injurious behavior without suicidal intent 
for screening/baseline and post-screening will be presented in frequency table by treatment group.   
7.5.8 Physical Examination  
Physical examinations results will be presented in individual subject data listings. The number and 
percentage of subjects experiencing clinically significant abnormalities (Yes/No) in physical examination 
will be tabulated by treatment group.   
7.5.9 Scale for Assessment and Rating of Ataxia (SARA)   
The total SARA scores will be presented by treatment group. Listing of individual item scores will also 
be provided for all subjects.  
7.5.10  Pregnancy Test  
Pregnancy test results after start of study treatment will be listed.  
7.5.11  Concomitant Medications/Treatments  
The number and percentage of subjects have reported concomitant therapies during the course of the 
study will be tabulated by using Anatomical Therapeutic Chemical 4 classification codes and preferred 
drug name via the World Health Organization Drug Dictionary (WHO-DD) in latest version (3Q2016), 
with version to be specified in the Clinical Study Report. All medications will be summarized by 
treatment group and sorted alphabetically by ATC class and preferred drug name. For the summary 
tables, if a subject has taken a concomitant medication more than once, the subject will be counted only 
once for the medication, within a treatment group.  
All prior and concomitant medication data will be presented in individual subject data listings.  
8. ANALYSES PERFORMED BEFORE DATABASE CLOSURE  
No analysis is planned before database closure. See Section 9 for details.  
9. POST-HOC ANALYSES   
Post-hoc analyses are planned to investigate the 6MWT distance by investigator submitted mitochondrial 
disease diagnosis collected in the prior study for these subjects (Study SPIMM-201).   
10. CHANGES FROM METHODS PLANNED IN THE PROTOCOL   
•  Interim analysis – it was confirmed by the sponsor that this interim analysis as stated in Protocol 
section 11.2.6 was no longer to be required.  
  
Section 11.2.6: When all subjects have had opportunity to complete the first treatment period, an 
interim analysis may be conducted at the discretion of the sponsor. The purpose of the interim 
analysis will be for the planning of future studies. The study will not be stopped at the interim to 


  
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claim benefit and definitive conclusions regarding efficacy (for the purpose of the trial) will be 
made based on the final results once both treatment periods have completed.  
  
Any other changes to methods planned in this statistical analysis plan will be documented in a revision to 
this statistical plan prior to database lock, or identified in the clinical study report.  
11. STATISTICAL SOFTWARE  
The statistical software to be used for generation of the tables, listings, and figures is SAS® version 9.4.  
12. REFERENCES  
1. Nilsson, et al. Columbia-Suicide Severity Rating Scale – Scoring and Data Analysis Guide.   
2. NINDS User Manual. Quality of Life in Neurological Disorders (Neuro-QoL) Measures. Version 2.0, 
March 2015.  
  
 


  
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13. APPENDIX 1  DATA HANDLING RULES  
Category  
Description  
Data Handling Rules  
Demographics  
Age at informed consent  
Age = integer ((date of informed consent signed – date of birth+1) /  
365.25)  
For date of birth, if only day is missing, it is imputed by 15th of the 
month of birth. If both day and month are missing, it is imputed by 
July 1st of the year of birth.   
Baseline  
Baseline assessment for 
efficacy data  
Baseline assessment for Period 1 is defined as last assessment prior to 
the first dose of study drug in Period 1.   
Similarly, baseline assessment for Period 2 is defined as last 
assessment prior to the first dose of study drug in Period 2.  
Timing  
Study Day 1  
First day subject is administrated the study drug during Period 1  
Timing  
Study Day   
Study day = date of assessment – date of Study Day 1 + 1  
Timing  
Time from administrated 
study drug   
Time from dosing start = time of assessment – time of administration 
of study drug  
Vital Signs/Lab  
Change from baseline  
Changet = Value t – ValueBaseline..   
Baseline value is defined as the last evaluation performed prior to 
administration of study drug given in the first period.  
Drug  
Administration  
Treatment duration 
(days)  
Sum of treatment duration in each periods:   
(Last dose date in Period i +1) – (First dose date in Period i), where 
i=1, 2.  
  
14. APPENDIX 2  ANALYSIS DATASET SPECIFICATIONS   
Analysis datasets (ADaM) will be built to gain efficiency and ensure consistency in data analyses and 
presentation for this trial. The specifications for the analysis data sets will be prepared in a separate 
document.  
  
15. APPENDIX 3  SAS CODE FOR STATISTICAL ANALYSES  
The following table presents the SAS codes for the analyses.  
  
Statistical Inference  
Table/Figure  
SAS Code  
Mixed effect model (when 
only one measured value 
for the response variable at 
the end of each treatment 
period)  
Endpoints with one 
measured value for the 
response variable at the 
end of each treatment 
period  
PROC MIXED METHOD=xx;  
CLASS SUBJECT SEQUENCE PERIOD TRT;  
MODEL Y = SEQUENCE PERIOD TRT;  
REPEATED / TYPE = UN SUB=SUBJECT  
(SEQUENCE); ** unstructured or Toeplitz  
LSMEANS TRT/ PDIFF CL;  
  


  
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Mixed model repeated 
measures (MMRM)  
Accelerometry  
PROC MIXED METHOD=xx;  
CLASS SUBJECT SEQUENCE PERIOD TRT 
WEEKEND;  
MODEL Y = SEQUENCE PERIOD TRT 
WEEKEND;  
REPEATED / TYPE = UN SUB=SUBJECT  
(SEQUENCE); ** unstructured or Toeplitz  
LSMEANS TRT/ PDIFF CL SLICE=AVISITNL  
  
  
16. APPENDIX 4  MOCKUP TABLES, LISTINGS, AND GRAPHS (TLGs)  
Mockup tables, listings, and graphs are presented in a separate document.