Conditions: MItochondrial Myopathies
Keywords: omaveloxolone RTA 408 capsules mitochondrial myopathies
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 53
Healthy volunteers: no

Brief summary:
Mitochondrial myopathies are a multisystemic group of disorders that are characterized by a wide range of biochemical and genetic mitochondrial defects and variable modes of inheritance. Currently there are no effective treatments for this disease. Despite the heterogeneous myopathy phenotypes, a unifying feature of mitochondrial myopathies is that the pathogenic mtDNA mutations and/or nuclear mutations of the electron transport chain invariably lead to dysfunctional mitochondrial respiration. This reduction in mitochondrial respiration leads to a reduced ability to produce cellular adenosine triphosphate (ATP), often resulting in muscle weakness, exercise intolerance, and fatigue in patients with mitochondrial myopathies.

RTA 408 is a potent activator of Nrf2 and inhibitor of NF κB (nuclear factor kappa-light-chain-enhancer of activated B cells), and thus induces an antioxidant and anti-inflammatory phenotype. Several lines of evidence suggest that Nrf2 activation can increase mitochondrial respiration and biogenesis. Collectively, available data suggest that the ability of RTA 408 to activate Nrf2 and induce its target genes could potentially improve muscle function, oxidative phosphorylation, antioxidant capacity, and mitochondrial biogenesis in patients with mitochondrial myopathies.

This study will be a randomized, placebo-controlled, double-blind, dose-escalation study to evaluate the safety of omaveloxolone (RTA 408) at various doses in patients with mitochondrial myopathies.

Detailed description:

Arms:
arm 1: omaveloxolone (RTA 408) Capsules, 2.5 mg taken orally once daily for 2 weeks, then 5 mg taken orally once daily for 10 weeks arm 2: omaveloxolone (RTA 408) capsules, 10 mg taken orally once daily for 12 weeks arm 3: Placebo capsules taken orally once daily for 12 weeks arm 4: omaveloxolone (RTA 408) Capsules, 20 mg taken orally once daily for 12 weeks. arm 5: omaveloxolone (RTA 408) Capsules, 40 mg taken orally once daily for 12 weeks. arm 6: omaveloxolone (RTA 408) Capsules, 80 mg taken orally once daily for 12 weeks. arm 7: omaveloxolone (RTA 408) Capsules, 160 mg taken orally once daily for 12 weeks.

Interventions: intervention 1: Omaveloxolone capsules, 2.5 mg intervention 2: omaveloxolone capsules, 5 mg intervention 3: omaveloxolone capsules, 10 mg intervention 4: Placebo capsules intervention 5: omaveloxolone capsules, 20 mg intervention 6: omaveloxolone capsules, 40 mg intervention 7: omaveloxolone capsules, 80 mg intervention 8: omaveloxolone capsules, 160 mg
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None intervention 7: None intervention 8: None

Protocol document:
Prot_001.pdf: 
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RTA 408 
 
408-C-1403 
NCT02255422 
 
A PHASE 2 STUDY OF THE SAFETY, EFFICACY, AND 
PHARMACODYNAMICS OF RTA 408 IN THE 
TREATMENT OF MITOCHONDRIAL MYOPATHY  
  
 
VERSION 5.0 – 29 OCTOBER 2015 
 
The information contained herein is confidential and the proprietary property of 
Reata Pharmaceuticals, Inc. and any unauthorized use or disclosure of such 
information without the prior written authorization of Reata Pharmaceuticals, 
Inc. is expressly prohibited. 


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SPONSOR APPROVAL AND SIGNATURE PAGE 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
  
 
Date 
 
 
 
 
 
 
 
Date 
 
 


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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for RTA 408.  I have read the 408-C-1403 
clinical study protocol and agree to conduct the study as outlined.  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 


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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Clinical Study Manager 
 
 
 
 
 
 
 
Medical Monitor 
 
 
 
 
 
 
Serious Adverse Event 
(SAE) Reporting 
 
 
 
 
 
 
 
 
 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Reata Pharmaceuticals, Inc. 
Name of Investigational Products: 
RTA 408 Capsules 
Name of Active Ingredient: 
RTA 408 
Title of Study:  
A Phase 2 Study of the Safety, Efficacy, and Pharmacodynamics of RTA 408 in the Treatment of 
Mitochondrial Myopathy 
Study center(s): Up to 12 study centers in the United States and the European Union  
Studied period (years): Approximately 2 years 
Estimated date first patient enrolled: November 2014 
Estimated date last patient completed: December 2016 
Phase of development:  
2 
Objectives:  
In patients with mitochondrial myopathy, comparing those receiving RTA 408 versus those receiving 
the placebo, the objectives are as follows: 
Primary: 
• 
To evaluate the change in peak work during maximal exercise testing  
• 
To evaluate the safety and tolerability of RTA 408 
Secondary: 
• 
To evaluate the change in 6-minute walk test (6MWT) distance 
Exploratory: 
• 
To evaluate the change in peak oxygen utilization during maximal exercise testing  
• 
To evaluate the change in peak serum lactate and pyruvate, peak heart rate, and rating of 
perceived exertion during submaximal exercise testing  
• 
 
 
 
 
• 
 
  
• 
 
 
Methodology:  
This 2-part study will evaluate the efficacy, safety, and pharmacodynamics (PD) of RTA 408 in the 
treatment of patients with mitochondrial myopathy.   
Part 1: The first part of the study will be a randomized, placebo-controlled, double-blind, dose-ranging 
study to evaluate the safety, efficacy, and pharmacodynamic (PD) activity of RTA 408 at 2.5 mg, 5 mg, 
10 mg, 20 mg and higher dose levels (not to exceed 160 mg) in patients with mitochondrial myopathy.  
A cohort consists of the next eight eligible patients randomized 3:1 at the cohort specific dose (n=6) or 


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placebo (n=2). Approximately 8 cohorts will be enrolled in Part 1 to allow for adequate dose-ranging 
for selection of two doses of RTA 408 to be used in Part 2. 
Intra-patient dose-escalation will only be utilized in the first cohort to evaluate RTA 408 at the first two 
dose levels (2.5 mg and 5 mg).  Patients enrolling in the first cohort will be randomized to RTA 408 
2.5 mg or placebo.  After the Week 2 visit, each patient in the first cohort will dose escalate to 5 mg (or 
remain on placebo) on Day 15 unless a dose-limiting toxicity (DLT) is reported in that patient 
(Section 7.4.3).  After the last patient in the first cohort completes their Week 4 visit (i.e., 2 weeks on 
2.5 mg daily [or matching placebo] followed by 2 weeks on 5 mg daily [or matching placebo]), the data 
safety monitoring board (DSMB) and Sponsor will review all available safety information and make a 
decision regarding enrollment of the next cohort Beginning with the second 8-patient cohort, once the 
eighth patient enrolled completes their Week 2 visit the DSMB will review all available safety 
information and recommend the dose of RTA 408 for the subsequent cohort.  The DSMB dose 
recommendation for each cohort must not exceed 100% more than the highest dose of RTA 408 
evaluated in this study, and the maximum permitted dose of RTA 408 is 160 mg.  The dose-level for 
each new cohort will not exceed the DSMB recommended dose level, and it will be selected by the 
Sponsor based on review of available safety, efficacy, PK, and PD data.  Prior to opening each cohort 
in Part 1 for enrollment, the Sponsor will evaluate all available data from doses studied in Part 1 to 
determine if enough information is available to select doses for Part 2 of the study.  Once doses are 
selected for Part 2 by the Sponsor, no additional cohorts will be enrolled in Part 1 
Part 2: The second part of this study will be a randomized, placebo-controlled, double-blind, parallel 
study to evaluate the safety, efficacy, and PD of 2 dose levels of RTA 408 in patients with 
mitochondrial myopathy.  Assuming that doses tested in Part 1 have been deemed acceptable in the 
first part of the study, the first 24 eligible patients in Part 2 will be randomized 1:1:1 to receive 
RTA 408 at the selected doses or placebo (n=8 per treatment group).  The two doses to be selected are 
based on DSMB and Sponsor review of data from Part 1, including safety and available PK and PD 
data.  Patients will be stratified by peak work at baseline (>0.8 watts [W]/kg vs. ≤0.8 W/kg).  A blinded 
sample size recalculation will occur after the last patient is enrolled in Part 2 to evaluate the distribution 
of baseline peak work for all enrolled patients as described in Section 14.1.1 and assess the need for 
additional patients.  If the sample size recalculation demonstrates additional patients are needed, then 
expansion of the number of patients enrolled in Part 2 will occur and an additional 12 patients may be 
randomized, for a total of 36 patients enrolled in Part 2 (n=12 per treatment group).   
All qualified patients enrolled in the study (i.e., both Part 1 and Part 2) will follow nearly identical 
schedules of assessments (Table 3) and study drug administration.  Patients will self-administer study 
treatment once daily at the randomized dose level until they have completed 12 weeks (84 days) of 
study treatment, are discontinued from study treatment, or have withdrawn consent to participate in the 
study.  A follow-up visit for safety will occur at Week 16 (4 weeks after last dose).  The DSMB will 
perform monthly reviews of unblinded data for safety throughout the study (i.e., during both Part 1 and 
Part 2).   
Number of patients (planned):  
Approximately 100 patients will be enrolled in this study.   


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Inclusion criteria:  
Patients must: 
1. Have mitochondrial myopathy as evidenced by the following 2 criteria (must meet both): 
a. Have a history of exercise intolerance with or without weakness and/or progressive 
exercise intolerance (in which modest exercise typically provokes heaviness, 
weakness, aching of active muscles, or tachycardia) 
b. Have a known primary mitochondrial DNA mutation or a nuclear DNA defect that is 
associated with reduced activity of at least 1 mitochondrially encoded respiratory chain 
complex 
2. Be male or female and ≥18 years of age and ≤75 years of age 
3. Have no changes to their exercise regimen within 30 days prior to Study Day 1 and be willing 
to remain on the same exercise regimen during the 16-week study period 
4. Have the ability to complete maximal exercise testing 
5. Have peak work during maximal exercise testing of ≤1.5 W/kg 
6. Have adequate kidney function defined as an estimated glomerular filtration rate (eGFR) 
≥60 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) 4-variable 
formula 
7. Be able to swallow capsules 
8. Be willing and able to cooperate with all aspects of the protocol 
9. Be willing to practice the medically acceptable methods of birth control (Section 9.7.2) 
10. Provide written informed consent for study participation, approved by the appropriate 
Institutional Review Board or Ethics Committee  
Exclusion criteria: 
Patients must not: 
1. Have uncontrolled diabetes (HbA1c >11.0%) 
2. Have B-type natriuretic peptide level >200 pg/mL 
3. Have a history of clinically significant left-sided heart disease and/or clinically significant 
cardiac disease, including but not limited to any of the following: 
a. Clinically significant congenital or acquired valvular disease  
b. Pericardial constriction (based on echocardiogram performed at Screening Visit or 
within 30 days prior to Screening Visit) 
c. Restrictive or congestive cardiomyopathy (based on echocardiogram performed at 
Screening Visit or within 30 days prior to Screening Visit) 
d. Symptomatic coronary disease (prior myocardial infarction, percutaneous coronary 
intervention, coronary artery bypass graft surgery, or angina)  
e. Evidence of left ventricular diastolic dysfunction 
f. History of atrial fibrillation 
g. History of unstable arrhythmias 
h. Cardiac insufficiency, defined as New York Heart Association Class >2 
4. Have known active fungal, bacterial, and/or viral infection, including human 
immunodeficiency virus or hepatitis virus (B or C) 
5. Have known or suspected active drug or alcohol abuse, as per investigator judgment 
6. Have clinically significant abnormalities of clinical hematology or biochemistry, including but 


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not limited to elevations greater than 1.5 times the upper limit of normal of aspartate 
aminotransferase, alanine aminotransferase or creatinine.  Levels above this threshold are 
allowable if attributable to muscle injury. 
7. Have any abnormal laboratory test value or clinically significant pre-existing medical condition 
that, in the opinion of the investigator, would put the patient at risk by study enrollment 
8. Have taken any of the following drugs within 7 days prior to Study Day 1 or plan to take any 
of these drugs during the time of study participation: 
a. Sensitive substrates for cytochrome P450 2C8 or 3A4 (e.g., repaglinide, midazolam, 
sildenafil) 
b. Moderate or strong inhibitors or inducers of cytochrome P450 3A4 
(e.g., carbamazepine, phenytoin, ciprofloxacin, grapefruit juice) 
c. Substrates for p-glycoprotein transporter (e.g., ambrisentan, digoxin) 
9. Have a history of clinically significant liver disease (e.g., fibrosis, cirrhosis, hepatitis), or has, 
at screening, clinically relevant deviations in laboratory tests including any one of the 
following: 
a. alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 1.5-fold 
ULN, 
b. bilirubin > 1.2-fold ULN, 
c. alkaline phosphatase (ALP) > 2-fold ULN, 
d. kidney insufficiency as defined by creatinine level > 1.5 mg/dL, 
e. albumin < lower limit of normal (LLN) 
10. Have participated in any other interventional clinical study within 30 days prior to Study Day 1 
11. Have a cognitive impairment that may preclude ability to comply with study procedures 
12. Be unable to comply with the requirements of the study protocol or be unsuitable for the study 
for any reason, in the opinion of the investigator 
13. Have used antioxidant supplements, including but not limited to idebenone, coenzyme Q10, 
nicotinamide, and vitamin E above the recommended daily allowance, within 14 days prior to 
Study Day 1 or plan to take any of these supplements during the time of study participation 
14. Have taken chronic treatment with systemic corticosteroids within 30 days prior to 
Study Day 1 
15. Have had significant suicidal ideation within 1 month prior to Screening Visit as per 
investigator judgment or any history of suicide attempts 
16. Be pregnant or breastfeeding 
Investigational product, dosage and mode of administration:  
RTA 408 Capsules (2.5 mg, 10 mg or 50 mg) administered orally with placebos, as required per 
treatment assignment  
Duration of treatment:  
RTA 408 or placebo capsules administered orally once daily for 12 weeks 
Reference therapy, dosage, and mode of administration:  
This study does not employ a comparator drug. 


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Endpoints: 
Efficacy: Parameters collected during maximal exercise testing (including peak work and peak oxygen 
utilization) and submaximal exercise testing; 6MWT distance; Fatigue Severity Scale results; and SF-
36 test results  
Safety: Results of echocardiogram, electrocardiogram, vital sign measurements, weight, body mass 
index, physical examinations, adverse events, serious adverse events, concomitant medications, and 
laboratory test results (clinical chemistry, hematology, urinalysis, microscopy, and pregnancy tests [as 
indicated]) 
Pharmacokinetic: RTA 408 plasma concentration data 
Pharmacodynamic: Parameters assessed from serum lactate and serum pyruvate during submaximal 
exercise testing, muscle needle biopsy biomarkers. 
Statistical methods: 
Sample size: The sample size for Part 1 is based on a dose-escalation scheme to evaluate initial safety 
and PD activity of RTA 408 in this patient population.  The small number of patients at each dose in 
Part 1 is not expected to fully characterize safety, efficacy, or PD, but rather inform the DSMB and 
Sponsor of the appropriate doses to select for Part 2.   With 24 patients enrolled in Part 2 (8 patients per 
treatment cohort), this study has approximately 80% power to detect an improvement of 0.28 W/kg in 
the peak work of pooled RTA 408 (n=16) versus placebo (n=8) assuming a two-sided Type I error rate 
of 0.05, a common within-group standard deviation (SD) of 0.28 W/kg, and a drop-out rate of no more 
than 1 in the placebo group and no more than 2 in the pooled RTA 408 group.  The analysis will use 
repeated measures methodology, assuming compound symmetry for the within-subject covariance 
structure (ρ=0.20). 
Sample size recalculation: A sample size recalculation will be performed in Part 2 after all 24 patients 
have been randomized to evaluate the pooled distribution of baseline peak work.  If the SD for pooled, 
baseline peak work is greater than 0.28 W/kg or the distribution is not approximately normal, then an 
additional 12 patients will be enrolled in Part 2.  With 36 patients enrolled in Part 2 (i.e., 12 patients per 
randomized treatment cohort), the 80% power is retained to detect the same difference of 0.28 W/kg if 
the SD is up to 0.35 W/kg, under the same assumptions of a two-sided Type I error rate of 0.05, and a 
drop-out rate of no more than 1 in the placebo group and no more than 2 in the pooled RTA 408 group, 
assuming compound symmetry for the within-subject covariance structure (ρ=0.20). 
Statistical analysis: A statistical analysis plan (SAP) detailing the analyses to be performed will be 
developed prior to the database lock.  The SAP, which will describe in detail the methods used for the 
primary and secondary endpoints, will serve as the final arbiter of all statistical analyses.  Data will be 
summarized using descriptive statistics.  Continuous data will be summarized with number of patients 
(n), mean, median, minimum, maximum, SD, coefficient of variation, and geometric mean (where 
applicable).  Categorical data will be summarized using frequency counts and percentages.   
Primary efficacy analysis: Primary analysis of the efficacy data will be based on the modified intent-to-
treat population, which will include all patients enrolled in Part 2 of the study.  Peak work from Part 2 
for the pooled patients treated with RTA 408 (both dose levels will be compared with placebo after 
12 weeks of treatment by repeated measures analysis of covariance, with treatment group, time, and the 
interaction between treatment and time as fixed factors and baseline peak work as a covariate.  The 
difference between RTA 408 and placebo in change from baseline of mean peak work will be 
estimated along with the 95% confidence interval of the difference.  The SAP will describe the strategy 
used to control the Type I error rate when comparing each dose of RTA 408 with placebo.  


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3. 
TABLE OF CONTENTS AND LISTS OF TABLES AND FIGURES  
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS AND LISTS OF TABLES AND FIGURES .....................10 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................16 
5. 
INTRODUCTION ......................................................................................................19 
5.1. 
Background and Rationale for RTA 408 in Mitochondrial Myopathy .......................19 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................22 
6.1. 
Primary Objectives .....................................................................................................22 
6.2. 
Secondary Objective ...................................................................................................22 
6.3. 
Exploratory Objectives ...............................................................................................22 
7. 
INVESTIGATIONAL PLAN .....................................................................................23 
7.1. 
Overall Study Design ..................................................................................................23 
7.2. 
Number of Patients .....................................................................................................24 
7.3. 
Treatment Assignment ................................................................................................24 
7.4. 
Dose Selection and Escalation Scheme ......................................................................25 
7.4.1. 
Selection of Doses ......................................................................................................25 
7.4.2. 
Dose-Escalation Scheme ............................................................................................25 
7.4.3. 
Criteria for Determining Dose-Limiting Toxicity ......................................................26 
7.4.4. 
Intra-patient Dose Escalation ......................................................................................26 
7.5. 
Data Safety Monitoring Board ....................................................................................26 
7.6. 
Criteria for Study Termination ...................................................................................27 
7.7. 
Schedule of Assessments for Both Part 1 and Part 2 ..................................................27 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................30 
8.1. 
Patient Inclusion Criteria ............................................................................................30 
8.2. 
Patient Exclusion Criteria ...........................................................................................30 
8.3. 
Patient Rescreening ....................................................................................................32 
8.4. 
Patient Discontinuation and Termination ...................................................................33 
8.4.1. 
Patient Discontinuation Criteria .................................................................................33 
8.4.2. 
Patient Termination Criteria .......................................................................................33 
9. 
TREATMENT OF PATIENTS ..................................................................................34 


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9.1. 
Description of Study Drug ..........................................................................................34 
9.2. 
Prior and Concomitant Medications ...........................................................................34 
9.2.1. 
Excluded Medications ................................................................................................34 
9.2.2. 
Permitted Medications ................................................................................................35 
9.3. 
Compliance With Study Drug ....................................................................................35 
9.4. 
Randomization ............................................................................................................36 
9.5. 
Blinding ......................................................................................................................36 
9.5.1. 
Patient Unblinding ......................................................................................................36 
9.5.2. 
Unblinding for Regulatory Submission ......................................................................36 
9.6. 
Unscheduled Visits .....................................................................................................37 
9.7. 
Pregnancy ...................................................................................................................37 
9.7.1. 
Women of Childbearing Potential ..............................................................................37 
9.7.2. 
Methods of Birth Control............................................................................................37 
9.7.2.1. 
Methods of Birth Control for Patients Enrolled in the United States: ........................37 
9.7.2.2. 
Methods of Birth Control for Patients Enrolled in the European Union: ...................38 
9.7.3. 
Suspected Pregnancy ..................................................................................................38 
9.8. 
Treatment Interruption ................................................................................................39 
9.9. 
Study Procedures ........................................................................................................39 
9.9.1. 
Informed Consent .......................................................................................................39 
9.9.2. 
Inclusion/Exclusion Criteria .......................................................................................39 
9.9.3. 
Demographics and Baseline Disease Characteristics .................................................40 
9.9.4. 
Prior and Concomitant Medications ...........................................................................40 
9.9.5. 
Medical History ..........................................................................................................40 
9.9.6. 
Height .........................................................................................................................40 
9.9.7. 
Weight and Body Mass Index .....................................................................................40 
9.9.8. 
Echocardiogram ..........................................................................................................40 
9.9.9. 
Electrocardiogram .......................................................................................................40 
9.9.10. 
Vital Sign Measurements ............................................................................................41 
9.9.11. 
Physical Examination .................................................................................................41 
9.9.12. 
Adverse Event Collection ...........................................................................................41 
9.9.13. 
Clinical Chemistry ......................................................................................................41 
9.9.14. 
Hematology .................................................................................................................42 


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9.9.15. 
Urinalysis and Microscopy .........................................................................................43 
9.9.16. 
N-Terminal Prohormone of B-Type Natriuretic Peptide and B-Type 
Natriuretic Peptide ......................................................................................................43 
9.9.17. 
Hepatitis B and C and Human Immunodeficiency Virus ...........................................43 
9.9.18. 
Pregnancy Test ............................................................................................................44 
9.9.19. 
Study Drug Dispensation ............................................................................................44 
9.9.20. 
Study Drug Return and Pill Count ..............................................................................44 
9.9.21. 
Study Drug Administration.........................................................................................44 
9.9.22. 
Telephone Contact ......................................................................................................44 
9.9.23. 
Exercise Regimen Reporting ......................................................................................45 
9.9.24. 
Maximal Exercise Test ...............................................................................................45 
9.9.25. 
Submaximal Exercise Test .........................................................................................45 
9.9.26. 
Six-Minute Walk Test .................................................................................................45 
9.9.27. 
 
9.9.28. 
 
9.9.29. 
 
9.9.30. 
 
9.9.31. 
 
9.9.32. 
Home Health Visits .....................................................................................................47 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................48 
10.1. 
Study Drug ..................................................................................................................48 
10.2. 
Study Drug Packaging and Labeling ..........................................................................48 
10.3. 
Study Drug Storage .....................................................................................................49 
10.4. 
Study Drug Administration.........................................................................................49 
10.5. 
Study Drug Accountability .........................................................................................49 
10.6. 
Study Drug Handling and Disposal ............................................................................49 
11. 
EFFICACY ASSESSMENTS ....................................................................................50 
11.1. 
Maximal Exercise Test ...............................................................................................50 
11.2. 
Submaximal Exercise Test .........................................................................................50 
11.3. 
Six-Minute Walk Test .................................................................................................50 
11.4. 
 
11.5. 
 
12. 
SAFETY ASSESSMENTS ........................................................................................51 


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12.1. 
Safety Parameters .......................................................................................................51 
12.2. 
Adverse and Serious Adverse Events .........................................................................51 
12.2.1. 
Definition of Adverse Events .....................................................................................51 
12.2.1.1. 
Adverse Event .............................................................................................................51 
12.2.1.2. 
Serious Adverse Event ................................................................................................51 
12.3. 
Eliciting Adverse Event Information ..........................................................................52 
12.4. 
Assessment of Causality .............................................................................................52 
12.5. 
Assessment of Severity ...............................................................................................53 
12.6. 
Recording Adverse Events .........................................................................................53 
12.7. 
Reporting Serious Adverse Events .............................................................................54 
13. 
 
13.1. 
 
13.2. 
 
13.2.1. 
 
13.2.2. 
 
14. 
STATISTICS ..............................................................................................................57 
14.1. 
Sample Size ................................................................................................................57 
14.1.1. 
Sample Size Recalculation .........................................................................................57 
14.2. 
Study Variables ...........................................................................................................57 
14.2.1. 
 
14.2.2. 
 
14.2.3. 
Efficacy Variables ......................................................................................................57 
14.2.4. 
Safety Variables ..........................................................................................................58 
14.3. 
Statistical Analyses .....................................................................................................58 
14.3.1. 
Analysis Sets ...............................................................................................................58 
14.3.2. 
Primary Efficacy Analysis ..........................................................................................58 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................59 
15.1. 
Study Monitoring ........................................................................................................59 
15.2. 
Audits and Inspections ................................................................................................59 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................60 
16.1. 
Quality Assurance .......................................................................................................60 
16.2. 
Financial Disclosure ...................................................................................................60 


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16.3. 
Sponsor Obligations....................................................................................................60 
16.4. 
Investigator Documentation ........................................................................................60 
16.5. 
Clinical Study Insurance .............................................................................................61 
16.6. 
Use of Information ......................................................................................................61 
17. 
ETHICS ......................................................................................................................62 
17.1. 
Institutional Review Board Review ............................................................................62 
17.2. 
Ethical Conduct of the Study ......................................................................................62 
17.3. 
Written Informed Consent ..........................................................................................62 
17.4. 
Confidentiality ............................................................................................................63 
17.5. 
Modification of the Protocol .......................................................................................63 
17.6. 
Protocol Deviations ....................................................................................................64 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................65 
18.1. 
Retention of Records ..................................................................................................65 
18.2. 
Case Report Forms .....................................................................................................65 
19. 
PUBLICATION POLICY ..........................................................................................66 
20. 
LIST OF REFERENCES ............................................................................................67 
21. 
APPENDICES ............................................................................................................69 
APPENDIX 1. SCHEDULE OF ASSESSMENTS FOR PART 1 AND PART 2 .....................70 
APPENDIX 2. SIX-MINUTE WALK TEST INSTRUCTIONS ...............................................74 
 
 
 
 
 
 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
List of Abbreviations ..................................................................................................16 
Table 3: 
Overall Schedule of Assessments ...............................................................................28 
Table 4: 
Clinical Chemistry Assessments.................................................................................42 
Table 5: 
Hematology Assessments ...........................................................................................43 
Table 6: 
Urinalysis/Microscopy Assessments ..........................................................................43 
Table 7: 
Study Drug Information ..............................................................................................48 
Table 8: 
Serious Adverse Event Reporting Contact Information .............................................54 
Table 9: 
Schedule of Assessments for Part 1 ............................................................................70 
Table 10: Schedule of Assessments for Part 2 ............................................................................72 
 
 
LIST OF FIGURES 
Figure 1: 
Schema for Study of RTA 408 in Patients with Mitochondrial Myopathy ................24 
 
 
 








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5. 
INTRODUCTION 
5.1. 
Background and Rationale for RTA 408 in Mitochondrial Myopathy 
Mitochondrial myopathies are a multisystemic group of disorders that are characterized by a wide 
range of biochemical and genetic mitochondrial defects and variable modes of inheritance.  
Convoluted mitochondrial DNA (mtDNA) tissue heteroplasmy, the lack of a clear genotype, and 
the complex interactions between the nuclear and mitochondrial genome complicate the ability to 
predict a disease course and to classify the type of myopathy.  Indeed, the lack of a clear disease 
phenotype has frustrated treatment efforts, and currently there are no effective treatments for this 
disease (Goldstein and Wolfe, 2013).  Despite the heterogeneous myopathy phenotypes, a unifying 
feature of mitochondrial myopathies is that the pathogenic mtDNA mutations and/or nuclear 
mutations of the electron transport chain invariably lead to dysfunctional mitochondrial 
respiration.  This reduction in mitochondrial respiration leads to a reduced ability to produce 
cellular adenosine triphosphate (ATP), often resulting in muscle weakness, exercise intolerance, 
and fatigue in patients with mitochondrial myopathy.  
Although no approved treatments exist for mitochondrial myopathy, several studies have 
demonstrated that exercise training increases mitochondrial biogenesis in patients with 
mitochondrial myopathy (Taivassalo, 2001; Cejudo, 2005; Taivassalo, 2006; Adhihetty, 2007).  
Furthermore, the increases in mitochondrial biogenesis in these patients led to improvements in 
maximal workload and oxygen consumption, as well as a reduction in plasma lactate during 
exercise (Taivassalo, 2006; Adhihetty, 2007).  Previous studies have demonstrated that exercise 
stress activates nuclear factor erythroid-derived 2-related factor 2 (Nrf2) signaling and promotes 
antioxidant mechanisms (George, 2008; Irving, 2011; Muthusamy, 2012); therefore, Nrf2-
dependent mechanisms may contribute to exercise improvements in patients with mitochondrial 
myopathy.  
Several lines of evidence suggest that Nrf2 activation can increase mitochondrial respiration and 
biogenesis.  First, activation of peroxisome proliferator-activated receptor gamma coactivator 
1-alpha (PGC-1α) in a mouse model of mitochondrial myopathy showed increased mitochondrial 
mass and improved ATP production.  These results indicated that activation of PGC-1α, an Nrf2-
target gene, led to increased mitochondrial biogenesis (Wenz, 2008).  In addition, Uruno et al. 
(2013) demonstrated that genetic activation of Nrf2 signaling by Keap1 gene hypomorphic 
knockdown in mice (Keap1MuKO) markedly increased energy consumption-related genes in 
skeletal muscle.  Genetic Nrf2 activation led to increased locomotor activity, as compared to 
control (Keap1F/F) mice.  Locomotor activity was increased as determined in an open-field test 
and quantitated in terms of total distance traveled, as well as the number of zones crossed during 
the testing period (0 to 20 min).  These results suggest that activation of Nrf2 in skeletal muscle 
results in locomotor improvement due to increased efficiency of oxidative phosphorylation. 
Moreover, 2 recent studies demonstrated that genetic Nrf2 activation in Keap1-knockout mice 
increased mitochondrial respiration, oxygen consumption, and ATP production compared with 
Nrf2-deficient mice (Holmström, 2013; Ludtmann, 2014).  In essence, Nrf2 activation increased 
substrate availability for mitochondrial respiration, which led to improvements in ATP production. 


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Natural triterpenoids, such as oleanolic acid and ursolic acid that are derived from plant extracts, 
have been used extensively in Asian medicine for their antioxidant, anti-inflammatory, and anti-
cancer properties (Liu, 1995).  RTA 408 is one of a class of semi-synthetic triterpenoids 
discovered through a medicinal chemistry effort to optimize the ability of these compounds to 
inhibit the induction of nitric oxide (NO) in primary mouse macrophages treated with interferon-
gamma (IFN Honda, 1999).  Subsequent mechanistic studies have revealed that RTA 408 and the 
semi-synthetic triterpenoids are potent activators of Nrf2 and inhibitors of NF-κB (nuclear factor 
kappa-light-chain-enhancer of activated B cells), and thus induce an antioxidant and anti-
inflammatory phenotype. 
Several preclinical studies have highlighted the beneficial effects of RTA 408 analogs on muscle 
function, oxidative phosphorylation, and mitochondrial biogenesis.  Shin et al. (2009) 
demonstrated that potent Nrf2 activation with a 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid 
(CDDO)-imidazolide (CDDO-Im) triterpenoid prevented high-fat diet-induced increases in body 
weight, adipose mass, and hepatic lipid accumulation in wild-type mice.  Wild-type mice on a 
high-fat diet and treated with CDDO-Im exhibited higher oxygen consumption and energy 
expenditure than vehicle-treated mice, while food intake was lower in CDDO-Im-treated than 
vehicle-treated mice.  These results highlight the ability of potent Nrf2 activation to increase 
mitochondrial respiration.   
Saha et al. (2010) demonstrated that in high-fat diet‒fed type 2 diabetic mice, oral treatment with 
bardoxolone methyl, an RTA 408 analog (also referred to as CDDO-methyl ester [CDDO-Me]), 
for 2 weeks improved glucose uptake, fatty acid oxidation, and oxygen consumption.  Specifically, 
treatment with bardoxolone methyl led to a 48% increase in the mean glucose disposal rate, 
reflecting increased peripheral insulin responsiveness induced by bardoxolone methyl.  The 
bardoxolone methyl treatment also increased insulin-stimulated glucose transport activity in 
skeletal muscles by 71% in the soleus and by 58% in the gastrocnemius.  These results 
demonstrate that the glucose-lowering activity of bardoxolone methyl results from enhanced 
insulin action and glucose delivery to the muscles, which was associated with an increased rate of 
oxidative phosphorylation within the skeletal muscle.  
Furthermore, Neymotin et al. (2011) examined 2 additional RTA 408 analogs, CDDO ethylamide 
(CDDO-EA) and CDDO-trifluoroethylamide (CDDO-TFEA), that potently activate Nrf2 in the 
G93A superoxide dismutase 1 (SOD1) mouse model of amyotrophic lateral sclerosis (ALS).  
CDDO-EA and CDDO-TFEA significantly induced the mRNA expression of the Nrf2 target genes 
NAD(P)H dehydrogenase, quinone 1 (NQO1), glutathione S-transferase A3 (GSTA3), and heme 
oxygenase-1 (HO-1) relative to controls while suppressing pro-inflammatory NF-κB target genes.  
Moreover, genes associated with increased mitochondrial biogenesis were also induced.  
Collectively, the data suggest that the ability of RTA 408 to activate Nrf2 and induce its target 
genes could potentially improve muscle function, oxidative phosphorylation, antioxidant capacity, 
and mitochondrial biogenesis in patients with mitochondrial myopathy.  
Regarding the safety profile of RTA 408, no adverse effects were observed in the safety 
pharmacology studies.  The genotoxicity potential of RTA 408 was investigated in 2 in vitro 
genetic toxicity tests and 2 in vivo genotoxicity studies in rats.  The overall weight of evidence 
from the genotoxicity studies indicates that RTA 408 has a low genotoxicity risk to human 
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The systemic toxicity potential of RTA 408 has been evaluated in multiple nonclinical Good 
Laboratory Practice (GLP) toxicity studies in rats, minipigs, and monkeys after oral and dermal 
(which produces meaningful systemic exposure to RTA 408 in animals) administration.  The 
primary target organs for RTA 408 observed in the rat and monkey include the liver (increased 
liver weight, hepatocellular hypertrophy, bile duct hypertrophy and hyperplasia) and kidney 
(tubular degeneration/regeneration).  These effects are considered to be mostly due to the known 
pharmacologic activity of RTA 408 in animals and likely do not reflect off-target toxicity.  In rats 
(but not monkeys or minipigs), minimal to mild squamous cell hyperplasia of the forestomach 
and/or the limiting ridge of the stomach was observed and was fully reversible on treatment 
discontinuation.  The forestomach and limiting ridge of the stomach do not exist in humans, a 
monogastric species.  Therefore, this finding does not translate to humans and is not considered a 
relevant risk to humans.   
Overall, rats are more sensitive to the toxicologic effects of RTA 408 than minipigs or monkeys.  
In rats, the no-observed-adverse-effect level (NOAEL) following 28 days or 13 weeks or daily oral 
administration was 3 mg/kg/day, corresponding to an area under the plasma drug concentration-
time curve (AUC)(0-24hr) of approximately 2.0 hr*µg/mL.  Following 6 months of oral 
administration to rats, adverse effects were observed at the lowest dose tested (0.3 mg/kg), which 
was associated with an AUC(0-24hr) of approximately 0.3 hr*µg/mL.  Similar systemic exposure 
was achieved in rats at the lowest dose tested in a 13-week topical dermal toxicity study of 
RTA 408 Lotion, with similar adverse effects observed in males, but not females, in the low-dose 
group.  In monkeys, the NOAEL following 28 days or 13 weeks of daily oral administration was at 
least 100 mg/kg/day and the NOAEL following 9 months of daily oral administration was 
30 mg/kg/day, corresponding to an AUC(0-24hr) of approximately 2.0 hr*µg/mL.  In a 13-week 
minipig dermal GLP toxicity study, the NOAEL was the maximal feasible dose of 8% RTA 408 
Lotion (twice daily topical administration) with systemic exposures up to 1.7 hr*μg/mL.   
Across studies, the adverse liver findings in rats were reversible upon drug discontinuation and 
were associated with moderate to marked increases in serum gamma-glutamyl transpeptidase 
(GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin.  
With short treatment duration (i.e., 14 days), tubular degeneration/regeneration in rats was 
reversible with a 28-day treatment-free period in a non-GLP study.  Although the kidney findings 
in rats after 28 days or longer of treatment were not reversible after a 4-week or 8-week recovery 
period, they were minimal to mild, were not associated with evidence of an effect on renal function 
(i.e., no increase in blood urea nitrogen [BUN] or serum creatinine), and were not present in 
minipigs or monkeys with dosing for up to 13 weeks (minipig dermal) or 9 months (monkey oral) 
at doses that produced systemic exposures approximately 10-fold above the exposures that elicited 
adverse kidney findings in rats. 
 


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6. 
STUDY OBJECTIVES AND PURPOSE 
In patients with mitochondrial myopathy, comparing those receiving RTA 408 versus those 
receiving placebo, the objectives are as follows: 
6.1. 
Primary Objectives 
• To evaluate the change in peak work during maximal exercise testing  
• To evaluate the safety and tolerability of RTA 408  
6.2. 
Secondary Objective 
• To evaluate the change in 6-minute walk test (6MWT) distance 
6.3. 
Exploratory Objectives 
• To evaluate the change in peak oxygen utilization during maximal exercise testing  
• To evaluate the change in peak serum lactate and pyruvate, peak heart rate, and rating 
of perceived exertion during submaximal exercise testing  
• 
 
 
 
 
 
 
 
 
 
 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This 2-part study will evaluate the efficacy, safety, and PD of RTA 408 in the treatment of patients 
with mitochondrial myopathy.   
Part 1: The first part of the study will be a randomized, placebo-controlled, double-blind, dose-
ranging study to evaluate the safety, efficacy, and pharmacodynamic (PD) activity of RTA 408 at 
2.5 mg, 5 mg, 10 mg, 20 mg and  higher dose levels (not to exceed 160 mg) in patients with 
mitochondrial myopathy.  A cohort consists of the next eight eligible patients randomized 3:1 to 
RTA 408 at the cohort specific dose (n=6) or placebo (n=2).  Approximately 8 cohorts will be 
enrolled in Part 1 of the study to allow for adequate dose-ranging for selection of two doses of 
RTA 408 to be used in Part 2. 
Intra-patient dose-escalation will only be utilized in the first cohort to evaluate RTA 408 at the first 
two dose levels (2.5 mg and 5 mg).  Patients enrolling in the first cohort will be randomized to 
RTA 408 2.5 mg or placebo.  After the Week 2 visit, each patient in the first cohort will dose 
escalate to 5 mg (or remain on placebo) on Day 15 unless a dose-limiting toxicity (DLT) is reported 
in that patient (Section 7.4.3).  After the last patient in the first cohort completes their Week 4 visit 
(i.e., 2 weeks on 2.5 mg daily [or matching placebo] followed by 2 weeks on 5 mg daily [or 
matching placebo]), the data safety monitoring board (DSMB) and Sponsor will review all 
available safety information and make a decision regarding enrollment of the next cohort.  
Beginning with the second 8-patient cohort, once the eighth patient enrolled completes their Week 
2 visit, the DSMB will review all available safety information and recommend the dose of 
RTA 408 for the subsequent cohort.  The DSMB dose recommendation for each cohort must not 
exceed 100% more than the highest dose of RTA 408 evaluated in this study, and the maximum 
permitted dose of RTA 408 is 160 mg.  The dose-level for each new cohort will not exceed the 
DSMB recommended dose level, and it will be selected by the Sponsor based on review of 
available safety, efficacy, PK, and PD data.   Prior to opening each cohort in Part 1 for enrollment, 
the Sponsor will evaluate all available data from doses studied in Part 1 to determine if enough 
information is available to select doses for Part 2 of the study.  Once doses are selected for Part 2 
by the Sponsor, no additional cohorts will be enrolled in Part 1.  
Part 2: The second part of this study will be a randomized, placebo-controlled, double-blind, 
parallel study to evaluate the safety, efficacy, and PD of 2 dose levels of RTA 408 in patients with 
mitochondrial myopathy.  Assuming that the doses tested in Part 1 have been deemed acceptable in 
the first part of the study, the first 24 eligible patients in Part 2 will be randomized 1:1:1 to receive 
RTA 408 at the selected doses , or placebo (n=8 per treatment group).  The two doses to be 
selected are based on DSMB and Sponsor review of data from Part 1, including available safety 
and PK and PD data.  Patients will be stratified by peak work at baseline (>0.8 watts [W]/kg vs. 
≤0.8 W/kg).  A blinded sample size recalculation will occur after the last patient is enrolled in 
Part 2 to evaluate the distribution of baseline peak work for all enrolled patients as described in 
Section 14.1.1 and assess the need for additional patients.  If the sample size recalculation 
demonstrates additional patients are needed, then expansion of the number of patients enrolled in 
Part 2 will occur and an additional 12 patients may be randomized, for a total of 36 patients 
enrolled in Part 2 (n=12 per treatment group).   


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Figure 1: 
Schema for Study of RTA 408 in Patients with Mitochondrial Myopathy 
 
*A blinded sample size recalculation may increase the sample size to 12 patients per treatment group in Part 2.  
A schema for the protocol is shown in Figure 1 and a detailed schedule of assessments for the 
study is shown in Table 3.  All qualified patients enrolled in the study (i.e., both Part 1 and Part 2) 
will follow nearly identical schedules of assessments (Table 3) and study drug administration.  
Patients will self-administer study treatment once daily until they have completed 12 weeks 
(84 days) of study treatment, are discontinued from study treatment, or have withdrawn consent to 
participate in the study.  A follow-up visit for safety will occur at Week 16 (4 weeks after last 
dose).  The DSMB will perform monthly reviews of unblinded data for safety throughout the study 
(i.e., during both Part 1 and Part 2).  
7.2. 
Number of Patients 
Approximately 100 patients will be enrolled in this study. 
7.3. 
Treatment Assignment 
Patients enrolled in the first cohort for Part 1 will be randomized 3:1 to receive RTA 408 2.5 mg or 
placebo.  After the Week 2 visit, patients receiving RTA 408 2.5 mg will dose escalate to RTA 408 
5 mg starting on Day 15 unless a DLT is observed.  Intra-patient dose-escalation will only be 
utilized in the first cohort for Part 1. Starting with the second cohort for Part 1, patients will be 
randomized 3:1 to receive the cohort specific dose level of RTA 408 or placebo and will remain on 
the same treatment assignment throughout the study.  . Two dose levels of RTA 408 will be 
evaluated in Part 1 will be used in Part 2.  Patients enrolled in Part 2 of the study will be 
randomized 1:1:1 to RTA 408 low dose, high dose, or placebo.  All randomizations will be 


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performed using an Interactive Web Response System (IWRS). Patients enrolled in Part 2 will be 
stratified by peak work at baseline (>0.8 W/kg vs. ≤0.8 W/kg).  
7.4. 
Dose Selection and Escalation Scheme 
7.4.1. 
Selection of Doses 
This 2-part study will evaluate the safety, efficacy, and PD of RTA 408 at several dose levels 
(2.5 mg, 5 mg, 10 mg, 20 mg, and higher doses not to exceed 160 mg) in the treatment of patients 
with mitochondrial myopathy.   
 
 
 
  This observation is consistent with 
the fact that plasma RTA 408 concentrations achieved at the 2.5-mg dose level are above those 
required for in vitro activation of Nrf2.  Dose escalation by increments up to 100% increase from 
the each prior cohort, to a maximum dose of 160 mg, was selected as the highest potential dose in 
this study in an effort to adequately dose range and to provide good separation of treatment effects 
between dose groups.  Doses from Part 1 will be evaluated for safety, efficacy, and PD to select 
two doses which appear to be pharmacologically active in patients with mitochondrial myopathy to 
be used in Part 2. 
7.4.2. 
Dose-Escalation Scheme  
In Part 1 of the study, an initial cohort of 8 patients will be randomized 3:1 to RTA 408 2.5 mg 
(n=6) or placebo (n=2).  Each patient in the first cohort will be evaluated for intra-patient dose-
escalation by their investigator at the Week 2 visit.  If no DLTs are observed by Week 2 for that 
patient, the patient will dose escalate.  The patients receiving RTA 408 2.5 mg will begin receiving 
RTA 408 5 mg on Day 15 and the patients receiving placebo will remain on placebo in a blinded 
fashion.  If an investigator cannot come to a firm decision whether or not to dose escalate a patient, 
he or she should discuss the relevant safety information with the medical monitor.  Patients who 
are deemed inappropriate for dose escalation will continue on their originally randomized dose 
(i.e., 2.5 mg or placebo) throughout the remainder of the study.  After the last patient in the initial 
cohort completes their Week 4 visit, the DSMB and Sponsor will review all available safety 
information from this cohort and make a recommendation regarding opening the next cohort to be 
randomized 3:1 to the cohort specific dose level of RTA 408 or placebo.  All subsequent cohorts in 
Part 1, beginning with the second 8-patient cohort, will be evaluated for safety of the cohort 
specific dose-level by the DSMB once the eighth patient enrolled completes their Week 2 visit.  
The DSMB will recommend the dose of RTA 408 for the subsequent cohort.  The DSMB dose 
recommendation for each cohort must not exceed 100% more than the highest dose of RTA 408 
evaluated in this study, and the maximum permitted dose of RTA 408 is 160 mg.  The dose-level 
for each new cohort will not exceed the DSMB recommended dose level, and it will be selected by 
the Sponsor based on review of available safety, efficacy, PK, and PD data. 


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7.4.3. 
Criteria for Determining Dose-Limiting Toxicity  
The assessment of a DLT (i.e., a side effect serious enough to prevent an increase in dose) will be 
based on the clinical judgment of the investigator.  Suspected DLTs should be discussed with the 
medical monitor.  If an investigator cannot come to a firm decision whether or not to dose escalate 
a patient, he or she should discuss the relevant safety information with the medical monitor.   
7.4.4. 
Intra-patient Dose Escalation 
Intra-patient dose escalation will only occur for the first cohort of 8 patients randomized in Part 1 
of the study (i.e., those patients randomized to RTA 408 2.5 mg or placebo).  Investigators, and not 
the DSMB, will make intra-patient dose-escalation decisions during the first cohort of Part 1.  
Each patient will dose escalate starting on Day 15, unless a DLT is indicated by the investigator.  
Patients originally randomized to RTA 408 2.5 mg will dose escalate to RTA 408 5 mg, and those 
randomized to placebo will remain on placebo in a blinded fashion.  If the investigator cannot 
come to a firm decision whether or not to dose escalate a patient, he or she should discuss the 
relevant safety information with the medical monitor.  If the investigator determines the patient 
should not be dose escalated, that patient should continue on their originally randomized dose 
(i.e., 2.5 mg or placebo) throughout the remainder of the study visits. 
No other patients are eligible for intra-patient dose escalation.  
7.5. 
Data Safety Monitoring Board 
A DSMB will review unblinded safety data throughout the study (i.e., both Part 1 and Part 2) and 
make recommendations as appropriate.  The DSMB will begin monthly data reviews 
approximately 1 month after the first patient is enrolled in Part 1 through the last dose of the last 
patient enrolled in Part 2.   
The DSMB will consist of external clinical experts supported by an independent statistical group.  
The independent statistical group will prepare unblinded analyses for the DSMB and will not have 
a role in the statistical analysis plan (SAP) after Part 2 of the study has started enrolling patients.  
A separate, blinded statistical group will be responsible for producing and finalizing the SAP and 
executing final data analysis of the study.   
The DSMB will be governed by a charter that will describe the following: 
• 
Roles and responsibilities of the DSMB members and the independent statistical group 
• 
Meeting format and frequency 
• 
Communication channels between the DSMB, the independent statistical group, the 
Sponsor, and the blinded study statisticians 
• 
Voting process and requirements (e.g., requirement of consensus for issuance of a 
termination recommendation) 
• 
Provisions governing conflict of interest and confidentiality  
 
Briefly, the DSMB will review the progress of the study and the accumulating unblinded data 
while the study is ongoing.  The DSMB will make recommendations to Sponsor representatives 
following each meeting.  The DSMB may recommend that the study continue as is, be modified to 


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protect patient safety, or be terminated.  In addition to the monthly reviews of unblinded study 
data, the DSMB will participate with the Sponsor in the recommendation to open the 10-mg cohort 
and additional dosing cohorts for enrollment for Part 1 and opening Part 2 described in 
Section 7.4.2.  However, investigators, and not the DSMB, will make intra-patient dose-escalation 
decisions during the first cohort of Part 1. 
7.6. 
Criteria for Study Termination 
Although the Sponsor intends to complete the study, the Sponsor reserves the right to discontinue 
the study at any time for clinical or administrative reasons, or if required by regulatory agencies.  
If the Sponsor discontinues the study, all study treatment will be discontinued and the investigator 
will have the responsibility to prescribe any additional therapy to be administered. 
7.7. 
Schedule of Assessments for Both Part 1 and Part 2 
Table 3 lists the overall schedule of assessments for the study.  Schedules of assessments for Part 1 
and Part 2 are listed individually in Appendix 1. The order of assessments and duration of rest 
between assessments should be kept consistent within a patient across visits, to the extent possible.




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c All Day 1 procedures should be performed prior to administration of first dose of study drug. 
d Assessments for Visit 3 may be collected at a home health nurse visit (at appropriate locations and approved by Sponsor) or at the study center clinic.  
e Assessments for Visit 4 must be collected at the study center if patients are enrolled in Part 1 of the study.  If patients are enrolled in Part 2 of the study, Visit 4 assessments 
may be collected by a home health nurse. 
f Visit 6 should be conducted within 18 hours to 48 hours of Visit 5, and Visit 11 should be conducted within 18 hours to 48 hours of Visit 10. 
g For patients with echocardiograms and electrocardiograms collected within 30 days prior to the Screening Visit, the most recent echocardiogram and electrocardiogram can 
be used to assess cardiac function and patient eligibility. 
h At Week 2, electrocardiogram is only required for patients in Part 1 of the study. 
i A home health nurse visit may be used to collect all lab samples required at the Screening Visit. 
j Patients must be allowed to rest for a minimum period of 1 hour following maximal or submaximal exercise testing before this blood sample is collected (at the same time as 
all of the central lab blood collection).  This sample must be taken prior to the 6MWT.  This sample should be taken with the patient in the same position (e.g., sitting or semi-
recumbent) at all appropriate visits 
k Blood samples will be collected to analyze for hepatitis B and C and HIV antibodies only in patients lacking evidence of a negative titer in the past year. 
l Negative serum pregnancy test results are required at the Screening Visit before study enrollment, and negative urine pregnancy test results are required at all other times 
indicated for continued participation in the study. 
m At Week 2, study drug dispensation is only required for patients in the first cohort of Part 1 of the study. 
n A dosing diary check must be performed at study drug return and pill count. 
o At Week 2, study drug return, pill count, and diary check are only required for patients in the first cohort of Part 1 of the study. 
p Study drug should be administered in the presence of study staff in the clinic on Day 1 after all Day 1 assessments have been completed.  Study drug should also be 
administered in the clinic on Days 14, 28 (Part 2 only), 56 (Cohort 1; Part 1 only) and 84 after the blood collection for predose PK analysis.  All other doses can be administered 
at home.  RTA 408 should be administered once daily through Day 84.  
q On study days where multiple assessments are to be completed, the maximal exercise test will be the first functional assessment performed.  Blood samples will be collected 
at rest, at the completion of the test, and at 5 and 10 minutes after the test.  Maximal exercise testing should be repeated prior to randomization if the original Screening 
assessment was performed >30 days prior to Day 1. 
r As part of the submaximal exercise test, blood samples will be collected at rest and at 10-minute intervals throughout the test.   
s Muscle needle biopsy, which is optional, should be collected after all study visit assessments are performed, except on Day 1, in which muscle needle biopsy should be the 
second to last procedure performed, collected prior to study drug administration. 
t For patients enrolled in the first cohort of Part 1 of the study, blood samples for PK analysis at Visit 4 and Visit 8 should be collected prior to study drug administration as well 
as 1, 2, 4, and 8 hours after study drug administration.  A single blood sample for PK analysis at Visit 11 should be collected prior to study drug administration.  
u For patients enrolled in the second and subsequent cohorts of Part 1 of the study, blood samples for PK analysis at Visit 4 should be collected prior to study drug 
administration as well as 1, 2, 4, and 8 hours after study drug administration.  A single blood sample for PK analysis at Visit 11 should be collected prior to study drug 
administration. 
v For patients enrolled in Part 2 of the study, blood samples for PK analysis at Visit 6 and Visit 11 should be collected prior to study drug administration.   
w Blood collection for biomarkers will be optional. On Day 1, blood collection for blood biomarkers must occur prior to study drug administration.  
 
Abbreviations: 6MWT=6-minute walk test; BMI=body mass index; BNP= B-type natriuretic peptide; HIV=human immunodeficiency virus; NT-proBNP=N-terminal prohormone of 
B-type natriuretic peptide; PK=pharmacokinetic; WOCBP=women of childbearing potential


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8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
8.1. 
Patient Inclusion Criteria 
Patients must: 
1. Have mitochondrial myopathy as evidenced by the following 2 criteria (must meet both): 
a. Have a history of exercise intolerance with or without weakness and/or 
progressive exercise intolerance (in which modest exercise typically provokes 
heaviness, weakness, aching of active muscles, or tachycardia) 
b. Have a known primary mitochondrial DNA mutation or a nuclear DNA defect 
that is associated with reduced activity of at least 1 mitochondrially encoded 
respiratory chain complex 
2. Be male or female and ≥18 years of age and ≤75 years of age 
3. Have no changes to their exercise regimen within 30 days prior to Study Day 1 and be 
willing to remain on the same exercise regimen during the 16-week study period 
4. Have the ability to complete maximal exercise testing 
5. Have peak work during maximal exercise testing of ≤1.5 W/kg 
6. Have adequate kidney function defined as an estimated glomerular filtration rate (eGFR) 
≥60 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) 
4-variable formula 
7. Be able to swallow capsules 
8. Be willing and able to cooperate with all aspects of the protocol 
9. Be willing to practice the medically acceptable methods of birth control (Section 9.7.2) 
10. Provide written informed consent for study participation, approved by the appropriate 
Institutional Review Board (IRB) or Ethics Committee (EC) 
8.2. 
Patient Exclusion Criteria 
Patients must not: 
1. Have uncontrolled diabetes (HbA1c >11.0%) 
2. Have B-type natriuretic peptide (BNP) level >200 pg/mL 
3. Have a history of clinically significant left-sided heart disease and/or clinically 
significant cardiac disease, including but not limited to any of the following: 
a. Clinically significant congenital or acquired valvular disease 
b. Pericardial constriction (based on echocardiogram performed at Screening Visit 
or within 30 days prior to Screening Visit) 


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c. Restrictive or congestive cardiomyopathy (based on echocardiogram performed at 
Screening Visit or within 30 days prior to Screening Visit) 
d. Symptomatic coronary disease (prior myocardial infarction, percutaneous 
coronary intervention, coronary artery bypass graft surgery, or angina) 
e. Evidence of left ventricular diastolic dysfunction 
f. History of atrial fibrillation 
g. History of unstable arrhythmias 
h. Cardiac insufficiency, defined as New York Heart Association Class >2 
4. Have known active fungal, bacterial, and/or viral infection, including human 
immunodeficiency virus (HIV) or hepatitis virus (B or C)  
5. Have known or suspected active drug or alcohol abuse, as per investigator judgment 
6. Have clinically significant abnormalities of clinical hematology or biochemistry, 
including but not limited to elevations greater than 1.5 times the upper limit of normal of 
AST, ALT, or creatinine.  Levels above this threshold are allowable if attributable to 
muscle injury 
7. Have any abnormal laboratory test value or clinically significant pre-existing medical 
condition that, in the opinion of the investigator, would put the patient at risk by study 
enrollment 
8. Have taken any of the following drugs within 7 days prior to Study Day 1 or plan to take 
any of these drugs during the time of study participation: 
a. Sensitive substrates for cytochrome P450 2C8 or 3A4 (e.g., repaglinide, 
midazolam, sildenafil) 
b. Moderate or strong inhibitors or inducers of cytochrome P450 3A4 
(e.g., carbamazepine, phenytoin, ciprofloxacin, grapefruit juice) 
c. Substrates for p-glycoprotein transporter (e.g., ambrisentan, digoxin) 
9. Have a history of clinically significant liver disease (e.g., fibrosis, cirrhosis, hepatitis), or 
has, at screening, clinically relevant deviations in laboratory tests including any one of 
the following: 
a. alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) 
> 1.5-fold ULN, 
b. bilirubin > 1.2-fold ULN, 
c. alkaline phosphatase (ALP) > 2-fold ULN, 
d. kidney insufficiency as defined by creatinine level > 1.5 mg/dL, 
e. albumin < lower limit of normal (LLN) 
10. Have participated in any other interventional clinical study within 30 days prior to Study 
Day 1 
11. Have a cognitive impairment that may preclude ability to comply with study procedures 


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12. Be unable to comply with the requirements of the study protocol or be unsuitable for the 
study for any reason, in the opinion of the investigator 
13. Have used antioxidant supplements, including but not limited to idebenone, coenzyme 
Q10, nicotinamide, and vitamin E above the recommended daily allowance, within 
14 days prior to Study Day 1 or plan to take any of these supplements during the time of 
study participation 
14. Have taken chronic treatment with systemic corticosteroids within 30 days prior to Study 
Day 1 
15. Have had significant suicidal ideation within 1 month prior to Screening Visit as per 
investigator judgment or any history of suicide attempts 
16. Be pregnant or breastfeeding 
8.3. 
Patient Rescreening 
Patients may repeat the screening procedures once to qualify for the study if they have: 
• Taken systemic corticosteroids within 30 days prior to Study Day 1 (rescreening may be 
performed 30 days or more after discontinuation of corticosteroids) 
• Used antioxidant supplements, including but not limited to idebenone, coenzyme Q10, 
nicotinamide, and vitamin E above the recommended daily allowance, within 14 days 
prior to Study Day 1 (rescreening may be performed 14 days or more after 
discontinuation of supplement) 
• Participated in any other interventional clinical study within 30 days prior to Study Day 1 
(rescreening may be performed 30 days or more after completion of the clinical study) 
• An abnormal laboratory test value that may normalize, in the opinion of the investigator 
(rescreening may be performed once test value is within normal range)  
• Modified their exercise regimen within 30 days prior to Study Day 1 (rescreening may be 
performed 30 days or more after modification of exercise regimen) 
• Taken any of the following drugs within 7 days prior to Study Day 1 (rescreening may be 
performed 7 days or more after discontinuation of the drug): 
o Sensitive substrates for cytochrome P450 2C8 or 3A4 (e.g., repaglinide, 
midazolam, sildenafil) 
o Moderate or strong inhibitors or inducers of cytochrome P450 2C8 or 3A4 
(e.g., carbamazepine, phenytoin, ciprofloxacin, grapefruit juice) 
o Substrates for p-glycoprotein transporter (e.g., ambrisentan, digoxin) 
• Failed screening because of operational challenges (rescreening may be performed no 
fewer than 2 weeks from the date of screen failure) 


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8.4. 
Patient Discontinuation and Termination 
Patients have the right to withdraw from the study at any time for any reason, without prejudice 
to their medical care.  Furthermore, the investigator may discontinue a patient from study drug or 
terminate the patient from the study.  The reason for a patient’s withdrawal or discontinuation 
from the study will be recorded in the electronic case report form (eCRF).  
8.4.1. 
Patient Discontinuation Criteria 
Discontinuation refers to a patient stopping administration of study drug.  Reasons for study drug 
discontinuation may include the following: 
• Occurrence of an AE or change in medical status that leads the investigator to be 
concerned about the patient’s welfare 
• Protocol violations 
• Administrative reasons (e.g., inability to continue) 
• Sponsor termination of the study 
• Voluntary withdrawal 
• Pregnancy during the study 
• Investigator unblinding 
Patients who are discontinued from study drug should still complete all study visits and undergo 
all scheduled study assessments, if possible.   
8.4.2. 
Patient Termination Criteria 
Termination refers to a patient stopping study drug and all study assessments and visits.  Reasons 
for study termination include the following: 
• Administrative reasons (e.g., inability to continue, lost to follow-up) 
• Death 
• Withdrawal of consent 
Patients who terminate the study for any reason may not re-initiate study drug or study 
assessments at any time. 


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9. 
TREATMENT OF PATIENTS 
9.1. 
Description of Study Drug 
Depending on cohort dose level (or doses selected for Part 2), patients will ingest either 3 or 4 
capsules of study drug (1 from each bottle included in study treatment kit) daily throughout the 
study; study drug is described in Section 10.1.  Treatment kits containing up to 30 mg of 
RTA 408 will include three bottles, each containing 30 count of either active or placebo 
capsules.  Treatment kits containing greater than 30 mg of RTA 408 will be comprised of four 
bottles, each containing 30 count of either active or placebo capsules.  To maintain the study 
blind, treatment kits used in Part 2 will all include the same number of bottles.  The Sponsor will 
provide sufficient quantities of study drug to allow for completion of the study. 
9.2. 
Prior and Concomitant Medications 
9.2.1. 
Excluded Medications 
Patients who have taken any of the following drugs within 30 days prior to Study Day 1 will be 
excluded from the study: 
• Any other investigational drug 
• Systemic corticosteroids 
Patients who have taken any of the following drugs within 14 days prior to Study Day 1 will be 
excluded from the study: 
• Antioxidant supplements, including but not limited to idebenone, coenzyme Q10, 
nicotinamide, and dosages exceeding the recommended daily allowance of vitamin E 
Patients who have taken any of the following drugs within 7 days prior to Study Day 1 will be 
excluded from the study: 
• Herbal preparations, minerals, or over-the-counter medication, except as identified in 
Section 9.2.2  
• Sensitive substrates for cytochrome P450 2C8 or 3A4 (e.g., repaglinide, midazolam, 
sildenafil) 
• Moderate or strong inhibitors or inducers of cytochrome P450 3A4 
(e.g., carbamazepine, phenytoin, ciprofloxacin, grapefruit juice) 
• Substrates for p-glycoprotein transporter (e.g., ambrisentan, digoxin) 
The following medications and medication classes are not permitted during this study, except as 
noted in Section 9.2.2: 
• Any other investigational drug 
• Systemic corticosteroids 
• Antioxidant supplements, including but not limited to idebenone, coenzyme Q10, 
nicotinamide, and dosages exceeding the recommended daily allowance of vitamin E  


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• Herbal preparations, vitamins, minerals, or over-the-counter medication, except as 
identified in Section 9.2.2 
• Sensitive substrates for cytochrome P450 2C8 or 3A4 (e.g., repaglinide, midazolam, 
sildenafil) 
• Moderate or strong inhibitors or inducers of cytochrome P450 3A4 
(e.g., carbamazepine, phenytoin, ciprofloxacin, grapefruit juice) 
• Substrates for p-glycoprotein transporter (e.g., ambrisentan, digoxin) 
• Any interventional therapy intended to treat the mitochondrial myopathy disease 
condition, with the exception of a constant exercise regimen 
9.2.2. 
Permitted Medications 
The following concomitant medications are permitted, as authorized by the treating physician: 
• Antibiotics, except as noted above (Section 9.2.1) 
• Daily multivitamin 
• Pain medication, except as noted above (Section 9.2.1) 
• Other medications intended to manage concurrent diseases, except as noted above 
(Section 9.2.1) 
• Oral, implantable, or injectable contraceptives 
Patients taking medication chronically should be maintained on those same doses and dose 
schedules throughout the study period, as medically feasible.  Patients taking medications with 
intermittent or as-needed schedules should try to avoid taking the concomitant medication on 
days when PK samples will be collected (i.e., Visits 4, 6, 8, and 11), as medically feasible. 
9.3. 
Compliance With Study Drug 
The investigator or designee will only dispense study drug to patients randomized to study 
treatment in accordance with the protocol.  The study drug must not be used for reasons other 
than that described in the protocol. 
All patients will return all bottles and unused capsules at the Weeks 4, 8 and 12 visits and will be 
dispensed a new kit of study drug at the Weeks 4 and 8 visits.  In addition, patients in the first 
cohort of Part 1 will return all unused capsules at the Week 2 visit and will be dispensed a new 
kit of study drug at that time.  Compliance will be measured by counting capsules to determine 
the number of missed doses from one visit to the next.  Patients will also be provided a dosing 
diary to document that capsules were taken as instructed as well as the date and time of dosing 
(Section 9.9.20).  To be considered compliant with study drug, patients can miss no more than 
25% of the total planned doses (i.e., 21 doses) during the study.  Patients who exceed the number 
of allowed missed doses will be considered noncompliant with dosing.  Patients will not be 
discontinued from the study drug nor terminated from the study for noncompliance, but protocol 
deviations should be recorded for dosing noncompliance. 


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9.4. 
Randomization  
Patients enrolled in Part 1 cohorts will be randomized 3:1 to RTA 408 at the cohort specific dose 
level or placebo.  Patients enrolled in Part 2 will be randomized 1:1:1 to RTA 408 low dose, high 
dose,  or placebo.  Randomization for both Part 1 and Part 2 will be generated using a centralized 
IWRS.  Randomization for Part 2 will be stratified by peak work at baseline (>0.8 W/kg vs. 
≤0.8 W/kg). 
9.5. 
Blinding 
To maintain the study blind, all study drug kits will be packaged with blinded labels.  
Investigators will distribute the blinded study drug kits by kit number to patients as assigned by 
the IWRS.  All patients, investigators, site personnel, and laboratories with direct involvement in 
the conduct of the study or their designees will be blinded to treatment assignments and 
appropriate measures will be taken to ensure the blind is maintained to reduce potential bias.  
Some Sponsor personnel may have access to treatment assignments during dose escalation 
(Part 1), but during Part 2, all Sponsor personnel will be blinded to treatment assignment. 
The only people with access to treatment assignments for Part 2 will be those individuals who 
maintain the IWRS, the DSMB, the unblinded statistical team providing data to and analyzing 
data for the DSMB, and safety personnel without direct involvement in the conduct of the study 
who are assigned to report unblinded data to regulatory authorities as required. 
9.5.1. 
Patient Unblinding 
Although there is no known antidote to RTA 408, under rare circumstances, unblinding may be 
considered medically necessary for safety reasons.  Unless faced with a life-threatening medical 
situation, the investigator should contact the medical monitor to discuss if there is a medically 
compelling reason to unblind the patient’s treatment assignment.  After the discussion, the 
investigator may proceed to unblind the patient, as appropriate.  If unblinding is required, the 
investigator will utilize the IWRS to perform the unblinding.  If a study drug assignment is 
unblinded, a description of the event that required unblinding must be documented by the 
investigator in the patient’s source documents.  Patients must discontinue taking study drug if 
their treatment assignment has been unblinded to the investigator (or designee), but they should 
remain blinded and continue attending all study visits and should undergo all study assessments.  
Patient treatment assignments must not be unblinded in the case of an AE or SAE, except as 
described above. 
9.5.2. 
Unblinding for Regulatory Submission 
In situations where a regulatory body requires unblinding and reporting of a particular SAE, the 
appropriate bodies (e.g., ethics committees, IRBs) must be provided with unblinded information 
according to the applicable regulatory requirement.  This information must not be conveyed to 
the investigator, site personnel, or patient; therefore, this type of unblinding does not necessitate 
that the patient discontinue taking study drug.  


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9.6. 
Unscheduled Visits 
Unscheduled visits are allowed for the following reasons: 
• Patient rescreening 
• Management of an AE or SAE 
• Performance of additional laboratory tests for clinically abnormal test values or to 
confirm a possible pregnancy 
• If the investigator feels that it is clinically appropriate for patient safety 
9.7. 
Pregnancy 
9.7.1. 
Women of Childbearing Potential 
Women of childbearing potential (WOCBP) are female patients who are not surgically sterile (no 
history of bilateral tubal ligation, hysterectomy, or bilateral salpingo-oophorectomy), do not have 
fallopian inserts with confirmed blockage, have not had reproductive potential terminated by 
radiation or chemotherapy, and are not postmenopausal for at least 1 year. 
9.7.2. 
Methods of Birth Control 
9.7.2.1. 
Methods of Birth Control for Patients Enrolled in the United States: 
From the Screening Visit, while taking study drug, and until 3 months after taking the final dose 
of study drug, WOCBP must agree to practice one of the following methods of birth control: 
• Use of a double-barrier contraception method, defined as male use of a condom and 
female use of a barrier method (e.g., contraceptive sponge, spermicidal jelly or cream 
with or without a diaphragm) 
• Use of hormonal contraceptives (oral, parenteral, vaginal, or transdermal) for at least 
3 months prior to study drug administration 
• Use of an intrauterine device 
• Complete abstinence from sexual intercourse 
• Male sterilization (with the appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate.)  The vasectomized partner should be the sole partner for 
that subject. 
From the Screening Visit, while taking study drug, and until 3 months after taking the final dose 
of study drug, males who have female partners of childbearing potential must agree to practice 
one of the following methods of birth control: 
• Have had a vasectomy (at least 6 months earlier) 
• Use of a double-barrier contraception method, defined as male use of a condom and 
female use of a barrier method (e.g., contraceptive sponge, spermicidal jelly or cream 
with or without a diaphragm) 


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• Partner use of hormonal contraceptives (oral, parenteral, vaginal, or transdermal) for 
at least 3 months prior to study drug administration 
• Partner use of an intrauterine device 
• Complete abstinence from sexual intercourse 
Male patients must also agree to not donate sperm starting on the first day of treatment until 
approximately 3 months after last dose of study drug. 
9.7.2.2. 
Methods of Birth Control for Patients Enrolled in the European Union: 
From the Screening Visit, while taking study drug, and until 3 months after taking the final dose 
of study drug, WOCBP must agree to practice one of the following highly effective methods of 
birth control: 
• Use of hormonal contraceptives (contraceptive pills, implants, transdermal patches, 
hormonal vaginal devices or injections with prolonged release) for at least 3 months 
prior to study drug administration 
• Use of an intrauterine device 
• Complete abstinence from sexual intercourse if part of the subject’s preferred lifestyle  
• Male sterilization (with the appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate).  The vasectomized partner should be the sole partner for 
that subject. 
From the Screening Visit, while taking study drug, and until 3 months after taking the final dose 
of study drug, males who have female partners of childbearing potential must agree to practice 
one of the following methods of birth control: 
• Have had a vasectomy (at least 6 months earlier) 
• Partner use of hormonal contraceptives (contraceptive pills, implants, transdermal 
patches, hormonal vaginal devices or injections with prolonged release) for at least 
3 months prior to study drug administration 
• Partner use of an intrauterine device 
• Complete abstinence from sexual intercourse if part of the subject’s preferred 
lifestyle. 
Male patients must also agree to not donate sperm starting on the first day of treatment until 
approximately 3 months after last dose of study drug. 
9.7.3. 
Suspected Pregnancy 
During the study, all WOCBP must be instructed to contact the investigator immediately if they 
suspect they might be pregnant (e.g., late or missed menstrual period).  Male patients must be 
instructed to contact the investigator if a sexual partner suspects she may be pregnant. 
If a patient or investigator suspects that the patient may be pregnant, the study drug must be 
withheld until the results of a serum pregnancy test are available.  If pregnancy is confirmed with 
a serum pregnancy test, the patient must discontinue taking study drug but continue to attend all 


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study visits and undergo all study assessments.  The investigator must immediately report a 
pregnancy associated with study drug exposure and record the event.   
Pregnancy is not considered an AE; however, the investigator must follow a pregnant patient or 
the pregnant female partner of a male patient (if consenting) and report follow-up information 
regarding the course of the pregnancy, including perinatal and neonatal outcome.  Infants 
resulting from such pregnancies should be followed for a minimum of 8 weeks.  The Sponsor or 
its designee may contact the investigator to request additional information throughout the course 
of the pregnancy. 
The following pregnancy outcomes must be considered SAEs and will require additional 
reporting in the case report form (CRF) and on an SAE form: 
• Congenital anomaly/birth defect 
• Stillbirth 
• Spontaneous miscarriage 
9.8. 
Treatment Interruption 
In the case of serious toxicities, the investigator may choose to interrupt treatment with study 
drug.  If study drug treatment interruption exceeds 21 total days, a protocol deviation should be 
noted.  Dose reductions are not permitted.  Patients who are permanently discontinued from 
study drug for any reason should still complete all study visits and undergo all scheduled study 
assessments, if possible.  If the toxicity has resolved such that the investigator does not consider 
continued drug treatment to be an additional risk to the patient, the investigator may restart study 
drug treatment. 
9.9. 
Study Procedures  
To avoid inter-observer variability, every effort should be made to ensure that the same 
individual who made the initial baseline determination completes all subsequent assessments.  
All assessments occur in the study center clinic, with the exception of those assessments for 
Visits 3 (all patients) and 4 (patients in Part 2 only), which may be performed by a home health 
visit nurse (at appropriate locations and approved by Sponsor), and those assessments for 
Visits 7 and 9, which will be performed via telephone contact.  
9.9.1. 
Informed Consent 
Written informed consent (Section 17.3) must be obtained from the patient before any 
study-related procedures are performed, and if there is a change in the study procedures that 
could affect the patient’s willingness to participate. 
9.9.2. 
Inclusion/Exclusion Criteria 
Inclusion and exclusion criteria should be reviewed at the times indicated in Table 3.  Patients 
must meet all of the inclusion criteria and none of the exclusion criteria for entry into the study.  


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9.9.3. 
Demographics and Baseline Disease Characteristics 
Demographic data, including sex, age, race, and ethnicity, and baseline disease characteristics, 
including documentation of evidence of mitochondrial myopathy, will be collected at the times 
indicated in Table 3.  Documentation of mitochondrial myopathy includes genetic profiling of 
mtDNA or nuclear DNA mutations that underlie each patient’s mitochondrial dysfunction.  
9.9.4. 
Prior and Concomitant Medications 
Information on prior and concomitant medications will be collected at the times indicated in 
Table 3.  The name, dose, and frequency of all medications that the patient is taking or has taken 
within 30 days prior to informed consent must be recorded during the study and until the final 
visit.  All allowed and excluded medications should be recorded, including all prescription drugs, 
herbal products, vitamins, minerals, and over-the-counter medications.  Trade or generic drug 
names should be used whenever possible.   
9.9.5. 
Medical History 
A complete medical history (e.g., per patient report) that includes all medical history within the 
past 5 years will be collected and recorded at the time indicated in Table 3.  
9.9.6. 
Height 
Height should be measured without footwear, head coverings, or prosthetics at the time indicated 
in Table 3. 
9.9.7. 
Weight and Body Mass Index 
Weight in kilograms should be measured at the times indicated in Table 3.  Body mass index 
(BMI) will be calculated within the eCRF each time the weight is recorded.  If patients are 
weighed at the Screening Visit with additional leg braces, walkers, or shoes, all subsequent 
weight assessments must be conducted with the same appendages.  
9.9.8. 
Echocardiogram 
An echocardiogram will be recorded at the times indicated in Table 3 after the patient has rested 
for approximately 10 minutes in a supine position.  For patients with echocardiograms collected 
within 30 days prior to Screening Visit, the most recent echocardiogram can be used to assess 
cardiac function and patient eligibility.  Patients are ineligible to participate in the study if they 
have pericardial constriction or restrictive or congestive cardiomyopathy. 
9.9.9. 
Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be recorded at the times indicated in Table 3 after the 
patient has rested for approximately 10 minutes in a supine position.  The heart rate from the 
ECG machine should not be used as part of the vital sign measurements.  For patients with 
electrocardiograms collected within 30 days prior to Screening Visit, the most recent 
electrocardiogram can be used to assess cardiac function and patient eligibility. 


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9.9.10. 
Vital Sign Measurements  
Vital sign measurements should be taken at the times indicated in Table 3 and include the 
patient’s heart rate (beats/minute), blood pressure (mm Hg), and body temperature (°C or °F).  
Blood pressure should be taken after the patient has rested in a sitting position for approximately 
5 minutes.  The same arm (usually the non-dominant arm) and the appropriate size cuff should 
be used for each measurement.   
9.9.11. 
Physical Examination 
A comprehensive physical examination must be performed by a physician, physician assistant, or 
registered nurse practitioner at the times indicated in Table 3.  If possible, the same individual 
should perform each physical examination on a patient during the study.  The examination must 
include the following organ or body system assessments: general appearance, head, eyes, ears, 
nose, throat, neck, musculoskeletal, cardiovascular, lymphatic, respiratory, abdomen, 
dermatologic, extremities, and neurological.  Assessments of any specific signs or symptoms 
reported by the patient must also be performed and documented along with any other findings of 
note.  Each body system finding must be assessed for clinical significance.  Clinically significant 
findings at the Screening Visit must be included in the patient’s medical history.  New clinically 
significant findings after first dose must be included as AEs.  Subsequent assessments beyond 
screening should be characterized as new, worsening, improved, or unchanged relative to the 
previous assessment. 
9.9.12. 
Adverse Event Collection 
Patients should be observed for general appearance, presence of illness or injury, or signs 
indicative of a concurrent illness at the times indicated in Table 3.  Patients should be instructed 
to volunteer any information regarding AEs at any time during the study.  The study physician or 
the study staff should also query patients with an open question regarding any AEs they may be 
experiencing (e.g., “How do you feel?” or “How have you been feeling since your last visit?”).  
Any findings are to be documented. 
9.9.13. 
Clinical Chemistry 
Blood samples will be collected for clinical chemistry analyses at the times indicated in Table 3.  
Clinical chemistry analyses are listed in Table 4.  For calculation of the eGFR, the 4-variable 
MDRD equation must be used.  The equation is as follows: 
eGFR = 175 x standardized serum creatinine –1 154 x age –0 203 x 1.212 [if black] x 0.742 [if female] 






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9.9.18. 
Pregnancy Test 
WOCBP (Section 9.7.3) will provide a blood or urine sample for a pregnancy test at the times 
indicated in Table 3.  Negative serum test results are required at the Screening Visit before study 
enrollment, and negative urine test results are required at all other times indicated in Table 3 for 
continued participation in the study.  Any patient who becomes pregnant during the study must 
discontinue taking study drug immediately.  See Section 9.7 for a description of procedures to be 
followed in case of pregnancy. 
9.9.19. 
Study Drug Dispensation  
Enough study drug will be dispensed to the patient at the times indicated in Table 3 to last at 
least until the next study visit, along with instructions for use.   
9.9.20. 
Study Drug Return and Pill Count  
Study drug will be collected from the patient and capsules will be counted by the principal 
investigator or the study staff at the times indicated in Table 3 to determine treatment 
compliance.  Criteria for noncompliance and instructions for recording compliance on the CRF 
are included in Section 9.3.  
Patients will be provided a dosing diary to track all doses administered, including the date and 
time of each dose.  The patient will bring the dosing diary to the clinic to be reviewed by the site 
staff for study drug accountability. 
9.9.21. 
Study Drug Administration 
As outlined in Section 9.1, study drug treatment kits will contain either three or four 30-count 
bottles of RTA 408 or placebo capsules.  Patients should take 1 capsule from each bottle daily.  
Patients should self-administer study drug orally once daily in the morning on an empty stomach 
(approximately 1 hour before or 2 hours after eating).  Study drug should be taken with water at 
the times indicated in Table 3, except on Days 1, 14, 28 (Part 2 only), 56 (Cohort 1; Part 1 only), 
and 84 when study staff will administer study drug at the clinic following all assessments on 
Day 1, and after the pre-dose blood sample for PK on Days 14, 28 (Part 2 only), 56 (Cohort 1; 
Part 1 only), and 84.  The date and time of the most recent 2 doses of study medication prior to 
Days 14, 28 (Part 2 only), 56 (Cohort 1; Part 1 only), and 84 will be recorded for PK analysis.  
The date and time of the last study drug administration (Day 84) should be recorded.   
A vomited dose should not be replaced.  Missed doses may be taken in the afternoon or evening 
of the same day approximately 1 hour before or 2 hours after a meal.  A double dose 
(e.g., missed dose from previous day and dose for current day) should not be taken. 
9.9.22. 
Telephone Contact 
Sites should complete a telephone visit contact with the patient to assess AEs and concomitant 
medications at the times indicated in Table 3.  Sites should make at least 3 attempts to contact 
the patient within the visit window if contact attempts are unsuccessful. 


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9.9.23. 
Exercise Regimen Reporting 
Exercise regimen will be recorded at baseline.  Patients will be asked about changes to their 
exercise regimen at the times indicated in Table 3.  Changes to the exercise regimen during the 
study will be recorded as protocol deviations. 
9.9.24. 
Maximal Exercise Test 
Cycle ergometry using a recumbent stationary bicycle will be used to conduct maximal exercise 
testing at the times indicated in Table 3.  Procedures for maximal exercise testing will be 
included in a study manual.  Cardiac output measurements will only be done at select sites 
during maximal exercise testing.  Maximal exercise testing assessments include but are not 
limited to peak work, peak oxygen utilization, and cardiac output.  As part of the maximal 
exercise test, additional blood samples to measure serum lactate will be collected at rest, at the 
completion of the test, and at 5 and 10-minutes following the test.  At Sponsor-qualified sites, 
blood samples to measure serum pyruvate, potassium, and glucose will also be collected at the 
same time points noted above. 
9.9.25. 
Submaximal Exercise Test 
Cycle ergometry will be used to conduct submaximal exercise tests at the times indicated in 
Table 3.  Patients will perform the submaximal exercise testing at the subset of sites selected by 
the Sponsor, and submaximal exercise testing assessments will be required for all patients 
enrolling at these selected sites.  Specific instructions will be provided in a study manual.  
Submaximal exercise test assessment may include but are not limited to submaximal work, peak 
serum lactate and pyruvate (optional), peak heart rate, and peak rating of perceived exertion.  As 
part of the submaximal exercise test, additional blood samples to measure serum lactate will be 
collected at rest and at 10-minute intervals throughout the test.  At Sponsor-qualified sites, blood 
samples to measure serum pyruvate, potassium, and glucose will be collected at rest and at 10-
minute intervals throughout the test. 
9.9.26. 
Six-Minute Walk Test 
Patients will be instructed to walk as far as they can along a marked path in 6 minutes at the 
times indicated in Table 3.  Distance walked will be measured.  If patients use a cane or walking 
assist device at Screening, the same walking assist device must be used for all 6MWT 
assessments.  
The 6MWT is a non-encouraged test that measures the distance walked over 6 minutes.  The 
6MWT must be performed consistently across all patients and sites.  Therefore, each test must be 
performed in strict accordance with the instructions and script provided in Appendix 2, which are 
based on American Thoracic Society guidelines (ATS Statement, 2002).  
 
 
 
 
 
 
   


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9.9.32. 
Home Health Visits 
Patients at approved sites will have the option of having a home health visit at the Screening 
Visit and Visit 3.  If patients are enrolled in Part 2 of the study, Visit 4 assessments may be 
collected by a home health nurse.  If a screening home health visit occurs, it will be used to 
collect all required lab samples for screening to help determine eligibility before the patient 
comes to the study clinic to complete all remaining screening activity.  Once the patient has been 
enrolled in the study, the patient has the option of having a home health visit at Visit 3 and Visit 
4 (for patients enrolled in Part 2 only) to complete the required lab collection, to have the home 
health nurse collect vital signs and weight, and to review any updates to AE information and 
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• FOR ORAL USE ONLY 
• Lot number (Non-US countries) 
• Expiration date (Non-US countries) 
• Study contact (Non-US countries) 
• EudraCT number: 2014-003501-15 (European Union countries) 
Additionally, expiry information will be provided on treatment kits intended for use in the EU.   
10.3. 
Study Drug Storage 
The stability of the drug product is being evaluated in ongoing studies. 
Investigative sites must store the investigational product in a secure location under controlled 
room temperature conditions of 20°C to 25°C (68°F to 77°F), with excursions allowed between 
15°C and 30°C (59°F to 86°F).  Sites must maintain documentation of appropriate storage 
conditions.  If a temperature within the storage location at the site is noted to be outside the 
excursion range for 24 hours or more or exceeds 40°C, the Sponsor must be notified.  
10.4. 
Study Drug Administration 
Please refer to Section 9.9.21 for details on study drug administration.  Patients will receive 
enough capsules for continuous dosing once daily at least until the next study visit.  Clear 
instructions will be provided to the patient regarding study drug administration for each study 
drug administration time point listed in Table 3. 
10.5. 
Study Drug Accountability 
The investigator or designee will maintain a record of all study drug received, dispensed, and 
returned to the Sponsor or its designee.  No study drug shall be destroyed by the clinical site 
unless directed to do so by the Sponsor or its designee.  Study drug bottles and any unused 
capsules should be returned by the patient to the study staff. 
10.6. 
Study Drug Handling and Disposal 
The Sponsor or its designee will direct the site regarding the final disposition of any remaining 
study drug. 


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11. 
EFFICACY ASSESSMENTS 
11.1. 
Maximal Exercise Test 
The following parameters will be collected during the maximal exercise test and analyzed from 
Baseline to Weeks 4 and 12: change in peak work, peak oxygen utilization, and cardiac output at 
selected sites.   
11.2. 
Submaximal Exercise Test 
The following parameters will be collected during the submaximal exercise test and analyzed 
from Baseline to Weeks 4 and 12: change in peak serum lactate, change in peak serum pyruvate, 
change in peak heart rate, and change in the rating of perceived exertion.   
11.3. 
Six-Minute Walk Test 
The change in 6MWT distance from Baseline to Weeks 4, 8, and 12 will be analyzed.   
 
 
 
   
 
 
 
   


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12. 
SAFETY ASSESSMENTS 
12.1. 
Safety Parameters 
Safety parameters include results of echocardiogram, ECG, vital sign measurements, weight, 
BMI, physical examination, AEs, SAEs, concomitant medications, and laboratory tests (clinical 
chemistry, hematology, urinalysis, microscopy, and pregnancy tests [as indicated]).  
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event 
An AE is defined as any untoward medical occurrence in a patient regardless of its causal 
relationship to study treatment.  An AE can be any unfavorable and unintended sign (including 
any clinically significant abnormal laboratory test result), symptom, or disease temporally 
associated with the use of the study drug, whether or not it is considered to be study drug related.  
Included in this definition is any newly occurring event or previous condition that has increased 
in severity or frequency since the administration of study drug.   
All AEs that are observed or reported by the patient during the study (from the time of the first 
dose of study drug until the final visit or 30 days following final study dose for patients who 
terminate early) must be reported, regardless of their relationship to study drug or their clinical 
significance. 
12.2.1.2. Serious Adverse Event 
An SAE is any AE occurring at any dose and regardless of causality that: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Is a congenital anomaly or birth defect in an offspring of a patient taking study drug 
• Is an important medical event  
The term "life-threatening" refers to an event in which the patient was at immediate risk of death 
at the time of the event.  It does not refer to an event that hypothetically might have caused death 
if it were more severe. 
Important medical events are those that may not meet any of the criteria defined above; however, 
they may be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
other outcomes listed in the SAE definition. 


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Pregnancy is not considered an AE; however, information will be collected for any pregnancies 
that occur during the study (from the time of first dose of study drug until the final visit).  Certain 
pregnancy outcomes will require submission as an SAE (Section 9.7.3). 
The investigator is responsible for reporting to the Sponsor or its designee all AEs and SAEs that 
are observed or reported by the patient during the study (from the time of first dose of study drug 
until the final visit), regardless of their relationship to study drug or their clinical significance.  
All SAEs reported or observed during the study must be followed to resolution or until the 
investigator deems the event to be chronic or the patient to be stable.  The Sponsor or its 
designee may contact the investigator to obtain additional information on any SAE that has not 
resolved at the time the patient completes the study. 
12.3. 
Eliciting Adverse Event Information  
At every study visit, patients must be asked a standard, non-directed question, such as, “How do 
you feel?” or “How have you been feeling since your last visit?”, to elicit any medically related 
changes in their well-being.  They will also be asked if they have been hospitalized, had any 
accidents, used any new medications, or changed concomitant medication regimens (including 
prescription drugs, over-the-counter medications, vitamins, herbal products, and minerals).  
Responses should be recorded in the source documents. 
In addition to patient observations, AEs must be documented for any clinically significant 
diagnosis resulting from abnormal laboratory test values, physical examination findings, ECG 
abnormalities, or other documents that are relevant to patient safety. 
12.4. 
Assessment of Causality  
The investigator must use the following classifications and criteria to characterize the 
relationship or association of the study drug in causing or contributing to the AE: 
• Unrelated: This relationship suggests that there is no association between the study 
drug and the reported event. 
• Unlikely: This relationship suggests that the temporal sequence of the event with 
study drug administration makes a causal relationship improbable and/or other factors 
also provide plausible explanations. 
• Possible: This relationship suggests that treatment with the study drug caused or 
contributed to the AE.  That is, the event follows a reasonable temporal sequence 
from the time of study drug administration and/or follows a known response pattern 
to the study drug but could have been produced by other factors. 
• Probable: This relationship suggests that a reasonable temporal sequence of the event 
with study drug administration exists and, based upon the known pharmacological 
action of the drug, known or previously reported adverse reactions to the drug or class 
of drugs, or judgment based on the investigator’s clinical experience, the association 
of the event with study drug administration seems likely. 


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12.5. 
Assessment of Severity 
The investigator will grade the severity of the AEs as mild, moderate, or severe using the 
following definitions: 
• Mild: Symptoms causing no or minimal interference with usual social and functional 
activities 
• Moderate: Symptoms causing greater than minimal interference with usual social and 
functional activities 
• Severe: Symptoms causing inability to perform usual social and functional activities 
12.6. 
Recording Adverse Events 
All conditions present prior to the first dose of study drug should be documented as medical 
history.  All drug-related (characterized as possibly or probably related; Section 12.4) AEs and 
abnormal laboratory test results reported or observed during the study must be followed to 
resolution (either return to baseline or within normal limits).  All other AEs or non‒drug-related 
abnormal laboratory results will be followed through the final visit (i.e., end of study or early 
termination).  Information to be collected includes type of event, date of onset, date of resolution, 
investigator-specified assessment of severity and relationship to study drug, seriousness, as well 
as any action taken.  
While an AE is ongoing, changes in the severity (e.g., worsening or improving) should be noted 
in the source documents but when documenting the AE, only the total duration and greatest 
severity should be recorded in the CRF.  AEs characterized as intermittent require documentation 
of onset and duration. 
AEs resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent 
medications, or progression of disease states must also be reported.  Pre-existing conditions 
(present before the start of the AE collection period) are considered concurrent medical 
conditions and should NOT be recorded as AEs.  However, if the patient experiences a 
worsening or complication of such a concurrent condition, the worsening or complication 
(except disease progression) should be recorded as an AE.  Investigators should ensure that the 
AE term recorded captures the change in the condition (e.g., “worsening of…”). 
Each AE should be recorded to represent a single diagnosis.  Accompanying signs (including 
abnormal laboratory test values or ECG findings) or symptoms should NOT be recorded as 
additional AEs.  If a diagnosis is unknown, sign(s) or symptom(s) should be recorded as an 
AE(s).  Changes in laboratory test values or ECG parameters are only considered to be AEs if 
they are judged to be clinically significant (i.e., if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiological fluctuation).  If 
abnormal laboratory test values or ECG findings are the result of pathology for which there is an 
overall diagnosis (e.g., increased creatinine levels in renal failure), only the diagnosis should be 
reported as an AE. 
Elective procedures (surgeries or therapies) that were scheduled prior to the start of AE 
collection are not considered AEs.  These elective procedures should not be recorded as AEs but 
should be documented in the patient’s source documents as elective (e.g., elective periodontal 


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surgery).  However, if a preplanned procedure is performed early (e.g., as an emergency) 
because of a worsening of the pre-existing condition, the worsening of the condition should be 
captured as an AE. 
12.7. 
Reporting Serious Adverse Events 
Any AE that meets the criteria of serious according to the previously described criteria must be 
reported within 24 hours from the time when site personnel first learn about the event.  To report 
the SAE, fax the completed SAE form to Medpace (fax number listed below in Table 8) within 
24 hours of awareness. 
Table 8: 
Serious Adverse Event Reporting Contact Information 
 
 
 
 
 
 
 
 
For questions regarding SAE reporting, contact your study manager, monitor, or medical 
monitor: 
 
 
 
 
 
The investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
patient dies.  Within 24 hours of receipt of new information, the updated follow-up SAE form, 
along with any supporting documentation (e.g., patient discharge summary or autopsy reports), 
should be faxed to Medpace Clinical Safety (Table 8). 
The Sponsor or its designee will notify regulatory agencies of any fatal or life-threatening 
unexpected events associated with the use of the study drug as soon as possible but no later than 
7 calendar days after the initial receipt of the information.  Initial notification will be followed by 
a written report within the timeframe established by the appropriate regulatory agency.  For other 
SAEs that do not meet the fatal or life-threatening unexpected criteria but are reported to be 
associated with the use of the study drug (that is, “possible” or “probable” in causality 
assessment), the Sponsor or its designee will notify the appropriate regulatory agencies in writing 
within the timeframe established by those regulatory agencies.  The Sponsor or its designee will 
provide copies of any reports to regulatory agencies regarding serious and unexpected SAEs to 
the investigators for their information and submission to their IRB/EC, as appropriate.  


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Principal investigators are responsible for informing their IRB/EC of any SAEs at their site, as 
appropriate.  The DSMB will review all safety data in an unblinded manner throughout the study 
and make recommendations as appropriate.  SAE correspondence with regulatory authorities or 
IRBs/ECs must be submitted to the Sponsor or its designee for recording in the study file. 


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14. 
STATISTICS 
14.1. 
Sample Size 
The sample size for Part 1 is based on a dose-escalation scheme to evaluate initial safety, PK, 
and PD activity of RTA 408 in this patient population.  The small number of patients at each 
dose in Part 1 is not expected to fully characterize safety, efficacy, or PD, but rather inform the 
DSMB and Sponsor of the appropriate doses to select for Part 2.  With 24 patients enrolled in 
Part 2 (8 patients per treatment cohort), this study has approximately 80% power to detect an 
improvement of 0.28 W/kg in the peak work of pooled RTA 408 (n=16) versus placebo (n=8) 
assuming a two-sided Type I error rate of 0.05, a common within-group standard deviation (SD) 
of 0.28 W/kg, and a drop-out rate of no more than 1 in the placebo group and no more than 2 in 
the pooled RTA 408 group.  The analysis will use repeated measures methodology, assuming 
compound symmetry for the within-subject covariance structure (ρ=0.20). 
14.1.1. 
Sample Size Recalculation 
A sample size recalculation will be performed in Part 2 after all 24 patients have been 
randomized to evaluate the pooled distribution of baseline peak work.  If the SD for pooled, 
baseline peak work is greater than 0.28 W/kg or the distribution is not approximately normal, 
then an additional 12 patients will be enrolled in Part 2.  With 36 patients enrolled in Part 2 
(i.e., 12 patients per randomized treatment cohort), the 80% power is retained to detect the same 
difference of 0.28 W/kg if the SD is up to 0.35 W/kg, under the same assumptions of a two-sided 
Type I error rate of 0.05, and a drop-out rate of no more than 1 in the placebo group and no more 
than 2 in the pooled RTA 408 group, assuming compound symmetry for the within-subject 
covariance structure (ρ=0.20). 
14.2. 
Study Variables 
 
 
 
 
 
 
 
 
 
 
14.2.3. 
Efficacy Variables 
Efficacy variables include parameters collected during maximal exercise testing (including peak 
work) and submaximal exercise testing; 6MWT distance; Fatigue Severity Scale results; and SF-
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14.2.4. 
Safety Variables 
The safety variables include results of echocardiograms, ECGs, vital sign measurements, weight, 
BMI, physical examinations, AEs, SAEs, concomitant medications, and laboratory test results 
(clinical chemistry, hematology, urinalysis, microscopy, and pregnancy tests [as indicated]).  All 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
analyses of the AE data will be detailed in the SAP. 
14.3. 
Statistical Analyses 
A SAP detailing the analyses to be performed will be developed prior to the database lock.  The 
SAP, which will describe in detail the methods used for the primary and secondary endpoints, 
will serve as the final arbiter of all statistical analyses.   
Data will be summarized using descriptive statistics.  Continuous data will be summarized with 
number of patients (n), mean, median, minimum, maximum, SD, coefficient of variation, and 
geometric mean (where applicable).  Categorical data will be summarized using frequency 
counts and percentages.   
14.3.1. 
Analysis Sets 
The following analysis sets will be defined: 
• The intent-to-treat (ITT) population includes all enrolled patients in both study parts 
(i.e., Part 1 and Part 2) categorized by their assigned treatment group (whether or not they 
received study drug).   
• The modified ITT (mITT) population includes all patients enrolled in Part 2 of the study 
categorized by their assigned treatment group (whether or not they received study drug).  
Efficacy analyses will be performed using the mITT population. 
• The safety population includes all patients who received at least 1 dose of study drug.  
Patients who receive at least 1 dose of RTA 408 will be classified in the RTA 408 group 
at the highest dose level received. 
• Additional analysis sets may be defined in the SAP as appropriate. 
14.3.2. 
Primary Efficacy Analysis 
Primary analysis of the efficacy data will be based on the mITT population, which will include 
all patients randomized in Part 2 of the study.  Peak work from Part 2 for the pooled patients 
treated with RTA 408 will be compared with placebo after 12 weeks of treatment by repeated 
measures analysis of covariance, with treatment group, time, and the interaction between 
treatment and time as fixed factors and baseline peak work as a covariate.  The difference 
between RTA 408 and placebo in change from baseline of mean peak work will be estimated 
along with the 95% confidence interval of the difference.  The SAP will describe the strategy 
used to control the Type I error rate when comparing each dose of RTA 408 with placebo$ 
 


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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
The study monitor, as a representative of the Sponsor, has the obligation to follow the study 
conduct closely.  In doing so, the monitor will visit the principal investigator and study facilities 
periodically, in addition to maintaining necessary telephone and letter contact.  The monitor will 
maintain current knowledge of the study activity of the investigator and his/her staff through 
observation, review of study records and source documentation, and discussion of the conduct of 
the study with the investigators and staff. 
The Sponsor or its designee will monitor all aspects of the study for compliance with applicable 
government regulation with respect to the International Conference on Harmonisation 
Harmonised Tripartite Guideline for Good Clinical Practice (GCP) E6(R1), abbreviated as ICH 
E6(R1), and current standard operating procedures. 
Each principal investigator is expected to make a reasonable effort to accommodate the monitor 
when monitoring visits are necessary and to be available during the site visit.  Furthermore, the 
monitor should be provided direct access to source data and documents for study-related 
monitoring and to the internet during the visit. 
15.2. 
Audits and Inspections 
Principal investigators and institutions involved in the study will permit study-related 
monitoring, audits, IRB/EC review, and regulatory inspection(s) by providing direct access to all 
study records.  In the event of an audit, the principal investigator agrees to allow the Sponsor, 
representatives of the Sponsor, the US Food and Drug Administration (FDA), or other relevant 
regulatory authorities access to all study records. 
The principal investigator or designee should promptly notify the Sponsor or designee of any 
audits scheduled by any regulatory authorities and promptly forward copies of any audit reports 
received to the Sponsor or its designee. 


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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
16.1. 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor may 
conduct a quality assurance audit.  Please see Section 15.2 for more details regarding the audit 
process. 
16.2. 
Financial Disclosure  
Principal investigators and sub-investigators are required to provide financial disclosure 
information prior to starting the study.  In addition, the principal investigator and sub-
investigators must provide the Sponsor or its designee with updated information, if any relevant 
changes occur during the course of the investigation and for 1 year following the completion of 
the study. 
Any potential investigator who has a vested financial interest in the success of this study may not 
participate in this study. 
16.3. 
Sponsor Obligations  
The Sponsor or its designee is not financially responsible for further testing/treatment of any 
medical condition that may be detected during the screening process.  In addition, in the absence 
of specific arrangements, the Sponsor or its designee is not financially responsible for treatment 
of non–study-related fatalities, physical injuries, or damage to health that may occur during the 
clinical study, as well as the patient’s underlying disease. 
16.4. 
Investigator Documentation 
Before beginning the study, the principal investigator will be asked to comply with ICH E6(R1), 
Section 8.2 and Title 21 of the US Code of Federal Regulations (CFR), abbreviated as US CFR 
Title 21, by providing the essential documents to the Sponsor or its designee, which include but 
are not limited to the following: 
• An original investigator-signed investigator agreement page of the protocol 
• The IRB or EC approval of the protocol 
• The IRB- or EC-approved informed consent, samples of site advertisements for 
recruitment for this study, and any other written information regarding this study that 
is to be provided to the patient or legal guardians 
• A Form FDA 1572, fully executed, and all updates on a new fully executed Form 
FDA 1572 
• Curriculum vitae for the principal investigator and each sub-investigator listed on 
Form FDA 1572.  A curriculum vitae and current licensure, as applicable, must be 
provided.  The curriculum vitae must have been signed and dated by the principal 
investigators and sub-investigators within 2 years before study start-up to indicate the 
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• Completed financial disclosure forms (Section 16.2) to allow the Sponsor or its 
designee to submit complete and accurate certification or disclosure statements 
required under US CFR Title 21, Part 54.  In addition, the investigators must provide 
to the Sponsor or its designee a commitment to update this information promptly if 
any relevant changes occur during the course of the investigation and for 1 year 
following the completion of the study 
• Laboratory certifications and normal ranges for any laboratories used by the site for 
the conduct of this study 
16.5. 
Clinical Study Insurance 
In accordance with the respective national drug laws, the Sponsor has taken out patient liability 
insurance for all patients who give their consent and enroll in this study.  This insurance covers 
potential study-related fatalities, physical injuries, or damage to health that may occur during the 
clinical study. 
16.6. 
Use of Information  
All information regarding RTA 408 supplied by the Sponsor to the investigator is privileged and 
confidential.  The investigator agrees to use this information to accomplish the study and will not 
use it for other purposes without consent from the Sponsor.  Furthermore, the investigator is 
obligated to provide the Sponsor with complete data obtained during the study.  The information 
obtained from the clinical study will be used towards the development of RTA 408 Capsules and 
may be disclosed to regulatory authority(ies), other investigators, corporate partners, or 
consultants, as required. 


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17. 
 ETHICS 
17.1. 
Institutional Review Board Review 
The protocol and the proposed informed consent form (ICF) must be reviewed and approved by 
a properly constituted IRB/EC before study start.  Each site must provide the Sponsor or its 
designee a signed and dated statement that the protocol and ICF have been approved by the 
IRB/EC before consenting patients.  Prior to study initiation, the investigator is required to sign a 
protocol signature page confirming agreement to conduct the study in accordance with this 
protocol and to give access to all relevant data and records to the Sponsor, its designee, and 
regulatory authorities, as required. 
The IRB/EC chairperson or designee must sign all IRB/EC approvals and must identify the 
IRB/EC by name and address, the clinical protocol, and the date approval and/or favorable 
opinion was granted. 
The principal investigator is responsible for obtaining reviews of the clinical research at intervals 
specified by the IRB/EC, but not exceeding 1 year.  The principal investigator must supply the 
Sponsor or its designee with written documentation of reviews of the clinical research. 
17.2. 
Ethical Conduct of the Study 
This clinical study was designed and shall be implemented and reported in accordance with the 
ICH E6(R1), with applicable local regulations (e.g., US CFR Title 21, European Directive 
2001/20/EC), and with the ethical principles of the Declaration of Helsinki.  
The principal investigator agrees to conduct the study in accordance with the ICH E6(R1) and 
the principles of the Declaration of Helsinki.  The principal investigator must conduct all aspects 
of this study in accordance with all national, state, and local laws or regulations. 
17.3. 
Written Informed Consent 
Because the study will be conducted under a US Investigational New Drug Application, a signed 
ICF, in compliance with US CFR Title 21, Part 50, will be obtained from each patient before the 
patient enters the study.  An informed consent template may be provided by the Sponsor or its 
designee to the investigators.  The consent must be reviewed by the Sponsor or its designee 
before IRB/EC submission.  Once reviewed, the consent will be submitted by the principal 
investigator to his or her IRB/EC for review and approval before the start of the study.  If the ICF 
is revised during the course of the study, all participants affected by the revision must sign the 
revised IRB- or EC-approved consent form in order to continue on the study. 
Procedures that are to be performed as part of the practice of medicine and which would be done 
whether or not study entry was contemplated, such as for diagnosis or treatment of a disease or 
medical condition, may be performed and the results subsequently used for determining study 
eligibility without first obtaining consent (US FDA, 2014).  Before enrollment, each prospective 
patient will be given a full explanation of the study and be allowed to read the approved ICF.  
Once the principal investigator or designee is assured that the patient understands the 


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implications of participating in the study, the patient will be asked to give consent to participate 
in the study by signing the ICF.  
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB- or EC-approved informed consent.  Informed consent must 
be obtained before conducting any study-specific procedures (i.e., all of the procedures described 
in the protocol).  The process of obtaining informed consent must be documented in the patient 
source documents. 
Any changes to the proposed consent form suggested by the investigator must be agreed to by 
the Sponsor before submission to the IRB/EC, and a copy of the approved version and the notice 
of approval must be provided to the Sponsor’s designated monitor after IRB or EC approval. 
The principal investigator or designee will provide a copy of the ICF (signed copy to be provided 
per applicable law) to the patient and/or legal guardian.  The original form will be maintained in 
the patient’s medical records at the site. 
17.4. 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality.  All records will be kept in a secure storage 
area with limited access.  Clinical information will not be released without the written 
permission of the patient (or the patient’s guardian), except as necessary for monitoring and 
auditing by the Sponsor, its designee, the FDA or applicable regulatory authorities, or the IRB. 
The principal investigator and all employees and coworkers involved with this study may not 
disclose or use for any purpose other than performance of the study, any data, record, or other 
unpublished confidential information disclosed to them for the purpose of the study.  Prior 
written agreement from the Sponsor or its designee must be obtained for the disclosure of any 
said confidential information to other parties. 
17.5. 
Modification of the Protocol 
Any changes that arise after the approval of the protocol must be documented as protocol 
amendments.  FDA must be notified of protocol amendments.  The changes will become 
effective only after approval of the Sponsor, the principal investigator, and the IRB.  In cases 
where the protocol is modified to enhance patient safety, changes may be implemented and the 
amendment must be immediately submitted to the IRB. 
The principal investigator is responsible for informing the IRB of all problems involving risks to 
patients according to national legislation.  In case of urgent safety measures, the Sponsor will 
immediately notify FDA in accord with US CFR Title 21, Part 312, Section 32. 
All substantial protocol amendments must also be submitted to the Danish Health and Medicines 
Authority (DHMA) and the Ethics Committee in Denmark and will become effective for sites in 
Denmark after approval of DHMA and the Ethics Committee. 


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17.6. 
Protocol Deviations 
The principal investigator or designee must document any protocol deviations.  The IRB/EC 
must be notified of all protocol deviations in a timely manner by the investigator as appropriate.  
Protocol deviations will be documented by the site personnel and reviewed by the responsible 
monitor during monitoring visits, and those observations will be communicated to the 
investigator. 
If there is an immediate hazard to a patient, the principal investigator may deviate from the 
protocol without prior Sponsor and IRB/EC approval.  The Sponsor and IRB/EC must be 
notified of the deviation. 


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18. 
DATA HANDLING AND RECORDKEEPING 
18.1. 
Retention of Records 
The investigator will maintain all study records according to ICH E6(R1) and applicable 
regulatory requirement(s).  Records will be retained for at least 2 years after the last marketing 
application is approved or 2 years after formal discontinuation of the clinical development of the 
investigational product.  If the investigator withdraws from the responsibility of keeping the 
study records, custody must be transferred to a person willing to accept the responsibility.  The 
Sponsor must be notified in writing if a custodial change occurs.  
18.2. 
Case Report Forms 
All CRF data will be entered in electronic forms at the investigational site.  The electronic data 
capture (EDC) system used to capture data electronically for all patients who signed informed 
consent will be US CFR Title 21, Part 11 compliant. 


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19. 
PUBLICATION POLICY 
The Sponsor reserves the right to review all planned communications and manuscripts based on 
the results of this study.  This reservation of the right is not intended to restrict or hinder 
publication or any other dissemination of study results, but to allow the Sponsor to confirm the 
accuracy of the data, to protect proprietary information, and to provide comments based on 
information that may not yet be available to the study investigators.  The Sponsor supports 
communication and publication of study results whatever the findings of the study.  The Sponsor 
also encourages disclosure of any conflict of interest from all authors or investigators when 
manuscripts are submitted for publication.  
Those individuals who have contributed greatly to this study, as determined by the Sponsor, may 
serve on any publications committee for the study. 


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LIST OF REFERENCES 
Adhihetty PJ, Taivassalo T, Haller RG, et al. The effect of training on the expression of 
mitochondrial biogenesis- and apoptosis-related proteins in skeletal muscle of patients with 
mtDNA defects. Am J Physiol Endocrinol Metab 2007;293:672-680. 
[No authors listed]. ATS Statement: guidelines for the six-minute walk test. Am J Respir Crit 
Care Med 2002;166:111-117.  
Cejudo P, Bautista J, Montemayor T, et al. Exercise training in mitochondrial myopathy: a 
randomized controlled trial. Muscle Nerve 2005;32:342-350.  
George L, Asghar M, Lokhandwala MF. Exercise stimulates transcription factors (Nrf2 & 
NFkB), increases antioxidant defenses, decreases oxidative stress, and restores renal dopamine 
D1 receptor function in aging. FASEB 2008;22:1159.6.  
Goldstein A, Wolfe LA. The elusive magic pill: finding effective therapies for mitochondrial 
disorders. Neurotherapeutics 2013;10:320-328. 
Holmström KM, Baird L, Zhang Y, et al. Nrf2 impacts cellular bioenergetics by controlling 
substrate availability for mitochondrial respiration. Biol Open 2013;2:761-770.  
Honda T, Rounds BV, Bore L, et al. Novel synthetic oleanane triterpenoids: a series of highly 
active inhibitors of nitric oxide production in mouse macrophages. Bioorg Med Chem Lett 
1999;9:3429-3434. 
Jenkinson C, Stewart-Brown S, Petersen S, Paice C. Assessment of the SF-36 version 2 in the 
United Kingdom. J Epidemiol Community Health 1999;53:36-50. 
Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The Fatigue Severity Scale: Application to 
patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989;46:1121-
1123. 
Irving BA, Lanza I, Henderson G, et al. Effect of exercise training modality on skeletal muscle 
mitochondrial biogenesis in young and older adults. FASEB 2011;25:1107-1120.  
Liu J. Pharmacology of oleanolic acid and ursolic acid. J Ethnopharmacol 1995;49:57-68. 
Ludtmann MHR, Angelova PR, Zhang Y, et al. Nrf2 impacts the efficiency of mitochondrial 
fatty acid oxidation. Biochem J 2014;457:415-424.  
Muthusamy VR, Kannan S, Sadhaasivam K, et al. Acute exercise stress activates Nrf2/ARE 
signaling and promotes antioxidant mechanisms in the myocardium. Free Rad Biol Med 
2012;52:366-376.  
Neymotin A, Calingasan NY, Wille E, et al. Neuroprotective effect of Nrf2/ARE activators, 
CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral 
sclerosis. Free Rad Biol Med 2011;51:88-96.  
Saha PK, Reddy VT, Konopleva M, et al. The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-
28-oic-acid methyl ester has potent anti-diabetic effects in diet-induced diabetic mice and 
Lepr(db/db) mice. J Biol Chem 2010;285:40581-40592. 


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Shin S, Wakabayashi J, Yates MS, Wakabayashi N, et al. Role of Nrf2 in prevention of high-fat 
diet-induced obesity by synthetic triterpenoid CDDO-imidazolide. Eur J Pharmcol 
2009;620:138-144.  
Taivassalo T, Shoubridge EA, Chen J, et al. Aerobic conditioning in patients with mitochondrial 
myopathies: physiological, biochemical, and genetic effects. Ann Neurol 2001;50;133-141.  
Taivassalo T1, Gardner JL, Taylor RW, et al. Endurance training and detraining in mitochondrial 
myopathies due to single large-scale mtDNA deletions. Brain 2006;129(Pt 12):3391-3401. 
Uruno A, Furusawa Y, Yagishita Y, et al. The Keap1-Nrf2 system prevents onset of diabetes 
mellitus. Mol Cell Biol 2013;33:2996-3010. 
United States Food and Drug Administration [Web site]. Guidance for Industry Drug-Induced 
Liver Injury: Premarketing Clinical Evaluation. Accessed July 21, 2014.  Available at: 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf 
United States Food and Drug Administration [Web site]. Screening Tests Prior to Study 
Enrollment - Information Sheet. Guidance for Institutional Review Boards and Clinical 
Investigators. Accessed July 21, 2014. Available at: 
http://www.fda.gov/RegulatoryInformation/Guidances/ucm126430.htm  
Wenz T, Diaz F, Spiegelman BM, et al. Activation of the PPAR/PGC-1α pathway prevents a 
bioenergetic deficit and effectively improves a mitochondrial myopathy phenotype. Cell Metab 
2008;8:249-256. 


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APPENDICES 




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a These procedures should be performed for early termination. 
b Screening procedures for each patient should occur over the course of a few days and must finish at least 1 day prior to randomization.  Study Day -1 is the day prior to first 
dose of study drug. 
c All Day 1 procedures should be performed prior to administration of first dose of study drug. 
d Assessments for Visit 3 may be collected at a home health nurse visit (at appropriate locations and approved by Sponsor) or at the study center clinic.  
e Assessments for Visit 4 must be collected at the study center if patients are enrolled in Part 1 of the study.   
f Visit 6 should be conducted within 18 hours to 48 hours of Visit 5, and Visit 11 should be conducted within 18 hours to 48 hours of Visit 10. 
g For patients with echocardiograms and electrocardiograms collected within 30 days prior to the Screening Visit, the most recent echocardiogram and electrocardiogram can 
be used to assess cardiac function and patient eligibility. 
h At Week 2, electrocardiogram is only required for patients in Part 1 of the study. 
i A home health nurse visit may be used to collect all lab samples required at the Screening Visit. 
j Patients must be allowed to rest for a minimum period of 1 hour following maximal or submaximal exercise testing before this blood sample is collected (at the same time as 
all of the central lab blood collection).  This sample must be taken prior to the 6MWT.  This sample should be taken with the patient in the same position (e.g., sitting or semi-
recumbent) at all appropriate visits 
k Blood samples will be collected to analyze for hepatitis B and C and HIV antibodies only in patients lacking evidence of a negative titer in the past year. 
l Negative serum pregnancy test results are required at the Screening Visit before study enrollment, and negative urine pregnancy test results are required at all other times 
indicated for continued participation in the study. 
m At Week 2, study drug dispensation is only required for patients in the first cohort of Part 1 of the study. 
n A dosing diary check must be performed at study drug return and pill count. 
o At Week 2, study drug return, pill count, and diary check are only required for patients in the first cohort of Part 1 of the study. 
p Study drug should be administered in the presence of study staff in the clinic on Day 1 after all Day 1 assessments have been completed.  Study drug should also be 
administered in the clinic on Day 14, Day 56 (Cohort 1; Part 1 only) and Day 84 after the blood collection for predose PK analysis.  All other doses can be administered at 
home.  RTA 408 should be administered once daily through Day 84.  
q On study days where multiple assessments are to be completed, the maximal exercise test will be the first functional assessment performed.  Blood samples will be collected 
at rest, at the completion of the test, and at 5 and 10 minutes after the test.  Maximal exercise testing should be repeated prior to randomization if the original Screening 
assessment was performed >30 days prior to Day 1. 
r As part of the submaximal exercise test, blood samples will be collected at rest and at 10-minute intervals throughout the test.   
s Muscle needle biopsy, which is optional, should be collected after all study visit assessments are performed, except on Day 1, in which muscle needle biopsy should be the 
second to last procedure performed, collected prior to study drug administration. 
t For patients enrolled in cohort 1 of Part 1 of the study, blood samples for PK analysis at Visit 4 and Visit 8 should be collected prior to study drug administration as well as 1, 2, 
4, and 8 hours after study drug administration.  
u For patients enrolled in cohort 2 and subsequent cohorts of Part 1 of the study, blood samples for PK analysis at Visit 4 should be collected prior to study drug administration 
as well as 1, 2, 4, and 8 hours after study drug administration.  
v Blood samples for PK analysis at Visit 11 should be collected prior to study drug administration  
w Blood collection for biomarkers will be optional. On Day 1, blood collection for blood biomarkers must occur prior to study drug administration.  
 
Abbreviations: 6MWT=6-minute walk test; BMI=body mass index; BNP= B-type natriuretic peptide; HIV=human immunodeficiency virus; NT-proBNP=N-terminal prohormone of 
B-type natriuretic peptide; PK=pharmacokinetic; WOCBP=women of childbearing potential




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a These procedures should be performed for early termination. 
b Screening procedures for each patient should occur over the course of a few days and must finish at least 1 day prior to randomization.  Study Day -1 is the day prior to first 
dose of study drug. 
c All Day 1 procedures should be performed prior to administration of first dose of study drug. 
d Assessments for Visit 3 may be collected at a home health nurse visit (at appropriate locations and approved by Sponsor) or at the study center clinic.  
e If patients are enrolled in Part 2 of the study, Visit 4 assessments may be collected by a home health nurse. 
f Visit 6 should be conducted within 18 hours to 48 hours of Visit 5, and Visit 11 should be conducted within 18 hours to 48 hours of Visit 10. 
g For patients with echocardiograms and electrocardiograms collected within 30 days prior to the Screening Visit, the most recent echocardiogram and electrocardiogram can 
be used to assess cardiac function and patient eligibility. 
h A home health nurse visit may be used to collect all lab samples required at the Screening Visit. 
i Patients must be allowed to rest for a minimum period of 1 hour following maximal or submaximal exercise testing before this blood sample is collected (at the same time as 
all of the central lab blood collection).  This sample must be taken prior to the 6MWT.  This sample should be taken with the patient in the same position (e.g., sitting or semi-
recumbent) at all appropriate visits 
j Blood samples will be collected to analyze for hepatitis B and C and HIV antibodies only in patients lacking evidence of a negative titer in the past year. 
k Negative serum pregnancy test results are required at the Screening Visit before study enrollment, and negative urine pregnancy test results are required at all other times 
indicated for continued participation in the study. 
l A dosing diary check must be performed at study drug return and pill count. 
m Study drug should be administered in the presence of study staff in the clinic on Day 1 after all Day 1 assessments have been completed.  Study drug should also be 
administered in the clinic on Day 28 and Day 84 after the blood collection for predose PK analysis.  All other doses can be administered at home.  RTA 408 should be 
administered once daily through Day 84.  
n On study days where multiple assessments are to be completed, the maximal exercise test will be the first functional assessment performed. Blood samples will be collected 
at rest, at the completion of the test, and at 5 and 10 minutes after the test.  Maximal exercise testing should be repeated prior to randomization if the original Screening 
assessment was performed >30 days prior to Day 1. 
o As part of the submaximal exercise test, blood samples will be collected at rest and at 10-minute intervals throughout the test.   
p Muscle needle biopsy, which is optional, should be collected after all study visit assessments are performed, except on Day 1, in which muscle needle biopsy should be the 
second to last procedure performed, collected prior to study drug administration. 
q Blood samples for PK analysis should be collected prior to study drug administration. 
r Blood collection for biomarkers will be optional. On Day 1, blood collection for blood biomarkers must occur prior to study drug administration.  
 
Abbreviations: 6MWT=6-minute walk test; BMI=body mass index; BNP= B-type natriuretic peptide; HIV=human immunodeficiency virus; NT-proBNP=N-terminal prohormone of 
B-type natriuretic peptide; PK=pharmacokinetic; WOCBP=women of childbearing potential 
 
 
 
 


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APPENDIX 2. SIX-MINUTE WALK TEST INSTRUCTIONS 
(Modified from American Thoracic Society (ATS) Statement: Guidelines for the Six-Minute 
Walk Test. [ATS Statement, 2002])  
PURPOSE AND SCOPE  
This statement provides practical guidelines for the 6-minute walk test (6MWT).  Specifically, it 
reviews indications, details factors that influence results, presents a brief step-by-step protocol, 
outlines safety measures, describes proper patient preparation and procedures, and offers 
guidelines for clinical interpretation of results.  
STUDY-SPECIFIC REQUIREMENTS 
The assessor of the 6MWT must not provide the patient with the results of the assessment once 
complete. 
BACKGROUND  
The 6MWT is a practical simple test that requires a 100-ft (30-meter) hallway but no exercise 
equipment or advanced training for technicians.  Walking is an activity performed daily by all 
but the most severely impaired patients.  This test measures the distance that a patient can walk 
on a flat, hard surface in a period of 6 minutes.  It evaluates the global and integrated responses 
of all the systems involved during exercise, including the pulmonary and cardiovascular systems, 
systemic circulation, peripheral circulation, blood, neuromuscular units, and muscle metabolism.  
It does not provide specific information on the function of each of the different organs and 
systems involved in exercise or the mechanism of exercise limitation, as is possible with maximal 
cardiopulmonary exercise testing.  The self-paced 6MWT assesses the submaximal level of 
functional capacity.  Most patients do not achieve maximal exercise capacity during the 6MWT; 
instead, they choose their own intensity of exercise and are allowed to stop and rest during the 
test.  However, because most activities of daily living are performed at submaximal levels of 
exertion, the 6MWT may better reflect the functional exercise level for daily physical activities.  
CONTRAINDICATIONS  
Absolute contraindications for the 6MWT include the following: unstable angina during the 
previous month and myocardial infarction during the previous month.  Relative contraindications 
include a resting heart rate of more than 120, a systolic blood pressure of more than 180 mm Hg, 
and a diastolic blood pressure of more than 100 mm Hg.  
Patients with any of these findings should be referred to the physician ordering or supervising the 
test for individual clinical assessment and a decision about the conduct of the test.  The results 
from a resting electrocardiogram (ECG) done during the previous 6 months should also be 
reviewed before testing.  Stable exertional angina is not an absolute contraindication for a 
6MWT, but patients with these symptoms should perform the test after using their antiangina 
medication, and rescue nitrate medication should be readily available.  
RATIONALE 
Patients with the previously mentioned risk factors may be at increased risk for arrhythmias or 
cardiovascular collapse during testing.  However, each patient determines the intensity of their 


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exercise, and the test (without ECG monitoring) has been performed in thousands of older 
persons and thousands of patients with heart failure or cardiomyopathy without serious adverse 
events.  The contraindications listed previously here were used by study investigators based on 
their impressions of the general safety of the 6MWT and their desire to be prudent, but it is 
unknown whether adverse events would occur if such patients performed a 6MWT; they are, 
therefore, listed as relative contraindications.  
SAFETY ISSUES  
1. Testing should be performed in a location where a rapid, appropriate response to an 
emergency is possible.  The appropriate location of a crash cart should be determined by 
the physician supervising the facility.  
2. Supplies that must be available include oxygen, sublingual nitroglycerine, aspirin, and 
albuterol (metered dose inhaler or nebulizer).  
3. A telephone or other means should be in place to enable a call for help.  
4. The technician should be certified in cardiopulmonary resuscitation with a minimum of 
Basic Life Support by an American Health Association–approved cardiopulmonary 
resuscitation course.  Advanced cardiac life support certification is desirable.  Training, 
experience, and certification in related health care fields (registered nurse, registered 
respiratory therapist, certified pulmonary function technician, etc.) are also desirable.  A 
certified individual should be readily available to respond if needed.  
5. Physicians are not required to be present during all tests.  The physician ordering the test 
or a supervising laboratory physician may decide whether physician attendance at a 
specific test is required.  
6. If a patient is on chronic oxygen therapy, oxygen should be given at their standard rate or 
as directed by a physician or a protocol.  
Reasons for immediately stopping a 6MWT include the following: (1) chest pain, (2) intolerable 
dyspnea, (3) leg cramps, (4) staggering, (5) diaphoresis, and (6) pale or ashen appearance.  
Technicians must be trained to recognize these problems and the appropriate responses.  If a test 
is stopped for any of these reasons, the patient should sit or lie supine as appropriate depending 
on the severity or the event and the technician's assessment of the severity of the event and the 
risk of syncope.  The following should be obtained based on the judgment of the technician:  
blood pressure, pulse rate, oxygen saturation, and a physician evaluation.  Oxygen should be 
administered as appropriate.  
TECHNICAL ASPECTS OF THE 6MWT  
Location 
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 15-30 meters in length.  An 
approximately 49- to 98-ft hallway is, therefore, required.  The length of the corridor should be 
marked every 3 meters.  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 lap, should be marked 
on the floor using brightly colored tape.  


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Rationale 
A shorter corridor requires patients to take more time to reverse directions more often, reducing 
the 6MWT.  
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  
PATIENT PREPARATION  
1. Comfortable clothing should be worn.  
2. Appropriate shoes for walking should be worn.  A notation should be made in the 
patient’s source documentation of which shoes the patient wore for the first test.  Prior to 
each clinic visit the patient should be called/reminded to ensure they wear this same pair 
of shoes. 
3. Patients should use their usual walking aids during the test (cane, walker, etc.).  NOTE – 
if a patient uses a walking aid for the first test, this same aid should be used during all 
subsequent test whether needed or not.  
4. The patient's usual medical regimen should be continued.  The patient should continue to 
take doses of study drug prior to the test. 
5. A light meal is acceptable before early morning or early afternoon tests.  
6. Patients should not have exercised vigorously within 2 hours of beginning the test.  
MEASUREMENTS  
1. Repeat testing should be performed about the same time of day to minimize intraday 
variability.  
2. A "warm-up" period before the test should not be performed.  
3. The patient should sit at rest in a chair, located at 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.  Also, 
note the patient’s general conditions and ailments (i.e., physical or mental) on this day 
that may potentially influence the results of the test.  Complete the first portion of the 
course document worksheet.   


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4. Pulse oximetry is optional.  If it is performed, measure and record baseline heart rate and 
pulse oximetry oxygen saturation (SpO2) and follow manufacturer's instructions to 
maximize the signal and to minimize motion artifact.  Make sure the readings are stable 
before recording.  Note pulse regularity and whether the oximeter signal quality is 
acceptable.  
The rationale for measuring oxygen saturation is that although the distance is the primary 
outcome measure, improvement during serial evaluations may be manifest either by an increased 
distance or by reduced symptoms with the same distance walked.  The SpO2 should not be used 
for constant monitoring during the exercise.  The technician must not walk with the patient to 
observe the SpO2.  If worn during the walk, the pulse oximeter must be lightweight (less than 2 
pounds), battery powered, and held in place (perhaps by a "fanny pack") so that the patient does 
not have to hold or stabilize it and so that stride is not affected.  Many pulse oximeters have 
considerable motion artifact that prevents accurate readings during the walk.  
1. Set the lap counter to zero and the timer to 6 minutes.  Assemble all necessary equipment 
(lap counter, timer, clipboard, Borg Scale, worksheet) and move to the starting point.  
2. Instruct the patient as follows:  
"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."  
1. 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.  
2. Do not talk to anyone 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 participant returns to the starting line, click the lap counter 
once (or mark the lap on the worksheet).  Let the participant see you do it.  Exaggerate the 
click using body language, like using a stopwatch 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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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 patient the following: "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 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.  
1. Post-test: Record the post-walk Borg dyspnea and fatigue levels and ask this: "What, if 
anything, kept you from walking farther?"  
2. If using a pulse oximeter, measure SpO2 and pulse rate from the oximeter and then 
remove the sensor.  
3. Record the number of laps from the counter (or tick marks on the worksheet).  
4. Record the additional distance covered (the number of meters in the final, partial lap) 
using the markers on the wall as distance guides.  
5. Calculate the total distance walked, rounding to the nearest meter (i.e., 251.3 meters is 
251 meters or 251.5 meters is 252 meters), and record it on the worksheet.  
6. Congratulate the patient on good effort and offer a drink of water.  
QUALITY ASSURANCE  
Sources of Variability 
There are many sources of 6MWT variability.  The sources of variability caused by the test 
procedure itself should be controlled as much as possible.  This is done by following the 
standards found in this document and by using a quality assurance program.  
Technician Training and Experience 
Technicians who perform 6MWT should be trained using the standard protocol and then 
supervised for several tests before performing them alone.  They should also have completed 
cardiopulmonary resuscitation training.  


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Encouragement 
Only standardized phrases for encouragement (as outlined above) must be used during the 
test.  
Rationale 
Encouragement significantly increases the distance walked.  Reproducibility for tests with and 
without encouragement is similar.  We have chosen every minute and standard phrases.  
Supplemental Oxygen 
If oxygen supplementation is utilized chronically, then it should be utilized during the walks and 
if 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.  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 6MWT.  The type of 
oxygen delivery device should also be noted on the report: for instance, the patient carried liquid 
oxygen or pushed or pulled an oxygen tank, the delivery was pulsed or continuous, or a 
technician walked behind the patient with the oxygen source (not recommended).  Measurements 
of pulse and SpO2 should be made after waiting at least 10 minutes after any change in oxygen 
delivery.  
 




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SAP_000.pdf: 
 
 
 
 
S T A TI S TI C A L  A N A L Y SI S  P L A N  
S T U D Y  P A R T  1   
4 0 8- C- 1 4 0 3 
N C T 0 2 2 5 5 4 2 2 
 
A  P h as e  2  St u d y  of t h e  S af et y,  Effi c a c y,  a n d  P h ar m a c o d y n a mi cs  of  R T A  4 0 8 i n t h e 
Tr e at m e nt  of  Mit o c h o n dri al  M y o p at h y 
 
 
 
 
A n al ysis  Pl a n  V ersi o n / D at e:  
V ersi o n  1 . 0 ( P art  1)/0 3 -1 2 -2 0 1 8   
 
 
T h e i nf or m ati o n  c o nt ai n e d  h er ei n is  c o nfi d e nti al  a n d t h e  pr o pri et ar y  pr o p ert y  of  R e at a 
P h ar m a c e uti c als, I n c.  a n d  a n y  u n a ut h ori z e d  us e  or  dis cl os ur e  of s u c h i nf or m ati o n  wit h o ut 
t h e  pri or  writt e n  a ut h ori z ati o n  of  R e at a  P h ar m a c e uti c als, I n c. is  e x pr essl y  pr o hi bit e d. 
 


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als, I n c.   
V ersi o n  1  D at e:  1 2 M ar 2 0 1 8  
P a g e  2  of  3 8  
 
 
 
 
A p p r o v al  a n d  Si g n at u r e  P a g e  
 
 
 
 
. 
  
D at e  
 
 
 
 
  
 
 
 
  
D at e  
 
 
 
  
 
 
 
  
D at e  


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als, I n c.   
V ersi o n  1  D at e:  1 2 M ar 2 0 1 8  
P a g e  3  of  3 8  
 
 
 
T A B L E  O F  C O N T E N T S  
1.  
I N T R O D U C TI O N ......................................................................................................................................... 7 
1. 1  
St u d y  O bj e cti v es  ............................................................................................................................... 7 
1. 1. 1  
Pri m ar y  O bj e cti v es  .......................................................................................................... 7 
1. 1. 2  
S e c o n d ar y  O bj e cti v e  ....................................................................................................... 7 
1. 1. 3  
E x pl or at or y  O bj e cti v es  .................................................................................................... 7 
1. 2  
P art  1  St u d y  D esi g n  ........................................................................................................................... 8 
1. 2. 1  
St u d y  Visits  a n d  Ass ess m e nts  ......................................................................................... 8 
1. 2. 2  
D at a  S af et y  M o nit ori n g  B o ar d  ...................................................................................... 1 1  
1. 2. 3  
Dis c o nti n u ati o n  of  Tr e at m e nt  ........................................................................................ 1 1  
1. 2. 4  
P ati e nt  T er mi n ati o n  ....................................................................................................... 1 1  
1. 2. 5  
R a n d o mi z ati o n  a n d  U n bli n di n g  ..................................................................................... 1 1  
1. 3  
S a m pl e  Si z e  a n d  P o w er  ................................................................................................................... 1 2  
2.  
P L A N N E D  A N A L Y SI S  O F  P A R T  1  .......................................................................................................... 1 3  
2. 1  
I nt eri m  A n al ysis .............................................................................................................................. 1 3  
2. 2  
Ti mi n g  of  A n al ysis  .......................................................................................................................... 1 3  
2. 3  
E n d p oi nt  M e as ur es  .......................................................................................................................... 1 3  
2. 3. 1  
Effi c a c y  E n d p oi nts  ........................................................................................................ 1 3  
2. 3. 2  
S af et y  E n d p oi nts  ........................................................................................................... 1 3  
 
 
 
 
2. 4  
C h a n g es fr o m  Pr ot o c ol -S p e cifi e d  A n al ysis ..................................................................................... 1 4  
3.  
G E N E R A L  C O N SI D E R A TI O N S  F O R  D A T A  A N A L Y SI S  ...................................................................... 1 5  
3. 1  
A n al ysis  C o nsi d er ati o ns  .................................................................................................................. 1 5  
3. 2  
A n al ysis  S ets  ................................................................................................................................... 1 5  
3. 2. 1  
F ull  A n al ysis  S et  ........................................................................................................... 1 5  
3. 2. 2  
S af et y  A n al ysis  S et  ........................................................................................................ 1 5  
3. 2. 3  
P h ar m a c o ki n eti c  ............................................................................................................ 1 5  
3. 3  
Str at a  a n d  C o v ari at es  ....................................................................................................................... 1 5  
3. 4  
E x a mi n ati o n  of  P ati e nt  S u bs ets  ....................................................................................................... 1 5  
3. 5  
M ulti pl e  C o m p aris o ns  ..................................................................................................................... 1 6  
3. 6  
Missi n g  D at a  ................................................................................................................................... 1 6  
3. 7  
Visit  Wi n d o ws  ................................................................................................................................. 1 6  
3. 7. 1  
D efi niti o n  of  St u d y  D a y  ................................................................................................ 1 6  
3. 7. 2  
D efi niti o n  of  St u d y  B as eli n e  ......................................................................................... 1 6  
3. 7. 3  
A n al ysis  Visits ............................................................................................................... 1 6  


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als, I n c.   
V ersi o n  1  D at e:  1 2 M ar 2 0 1 8  
P a g e  4  of  3 8  
 
 
 
3. 7. 4  
A n al ysis  Wi n d o ws f or  U ns c h e d ul e d  Visits  ................................................................... 1 7  
3. 7. 5  
S el e cti o n  of  D at a i n t h e  E v e nt  of  M ulti pl e  R e c or ds i n  a  Visit  ...................................... 1 7  
3. 8  
R o u n di n g  ......................................................................................................................................... 1 7  
4.  
S T U D Y  P O P U L A TI O N  .............................................................................................................................. 1 8  
4. 1  
Dis p ositi o n  of  P ati e nts  .................................................................................................................... 1 8  
4. 2  
Pr ot o c ol  D e vi ati o ns  ......................................................................................................................... 1 8  
4. 3  
D e m o gr a p hi cs  a n d  B as eli n e  C h ar a ct eristi cs  ................................................................................... 1 8  
4. 4  
M e di c al  Hist or y  ............................................................................................................................... 1 9  
5.  
S T U D Y  D R U G  A N D  O T H E R  M E DI C A TI O N S  ........................................................................................ 2 0  
5. 1  
Pri or  a n d  C o n c o mit a nt  M e di c ati o ns  ................................................................................................ 2 0  
5. 2  
D ur ati o n  of  St u d y  Tr e at m e nt  a n d  E x p os ur e t o  St u d y  Dr u g  ............................................................ 2 0  
6.  
E F FI C A C Y  A N A L Y SI S  .............................................................................................................................. 2 1  
6. 1  
Pri m ar y  Effi c a c y  A n al ysis  .............................................................................................................. 2 1  
6. 1. 1  
St atisti c al  H y p ot h esis  .................................................................................................... 2 1  
6. 1. 2  
St atisti c al  M o d el  ............................................................................................................ 2 1  
6. 1. 3  
R e p orti n g  R es ults  .......................................................................................................... 2 2  
6. 2  
S e c o n d ar y  Effi c a c y  ......................................................................................................................... 2 2  
6. 3  
E x pl or at or y  Effi c a c y  ....................................................................................................................... 2 2  
6. 3. 1  
Ot h er  M a xi m al  E x er cis e  T esti n g  M e as ur es (i n cl u di n g  O x y g e n 
Utili z ati o n)  .................................................................................................................... 2 4  
6. 3. 2  
M a xi m al  E x er cis e  T esti n g  L a b or at or y  P ar a m et ers  ........................................................ 2 5  
6. 3. 3  
S u b m a xi m al  E x er cis e  T esti n g  P ar a m et ers  .................................................................... 2 6  
6. 3. 4  
S u b m a xi m al  E x er cis e  T esti n g  L a b or at or y  P ar a m et ers  .................................................. 2 7  
 
 
 
 
7.  
S A F E T Y  A N A L Y SI S  .................................................................................................................................. 2 9  
7. 1  
A d v ers e  E v e nts  a n d  S eri o us  A d v ers e  E v e nts  .................................................................................. 2 9  
7. 1. 1  
G e n er al  C o nsi d er ati o ns f or  A n al ysis  of  A d v ers e  E v e nts  .............................................. 2 9  
7. 1. 2  
Tr e at m e nt -E m er g e nt  A d v ers e  E v e nts  ............................................................................ 2 9  
7. 1. 3  
R el at e d  A d v ers e  E v e nts ................................................................................................. 2 9  
7. 1. 4  
S u m m ar y  of  Tr e at m e nt -E m er g e nt  A d v ers e  E v e nts  a n d  S eri o us  A d v ers e 
E v e nts  ............................................................................................................................ 3 0  
7. 2  
Cli ni c al  L a b or at or y  E v al u ati o ns  ...................................................................................................... 3 0  
7. 3  
Vit a l  Si g ns ....................................................................................................................................... 3 1  
7. 4  
B o d y  W ei g ht  ................................................................................................................................... 3 1  
7. 5  
E c h o c ar di o gr a m  .............................................................................................................................. 3 1  
7. 6  
El e ctr o c ar di o gr a m  ........................................................................................................................... 3 1  
7. 7  
P h ysi c al  E x a mi n ati o n  ...................................................................................................................... 3 2  


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als, I n c.   
V ersi o n  1  D at e:  1 2 M ar 2 0 1 8  
P a g e  5  of  3 8  
 
 
 
7. 8  
Pr e g n a n c y  ........................................................................................................................................ 3 2  
 
 
 
 
 
 
1 0.  R E F E R E N C E S  ............................................................................................................................................ 3 5  
1 1.  A P P E N DI C E S  ............................................................................................................................................. 3 6  
 


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als, I n c.   
V ersi o n  1  D at e:  1 2 M ar 2 0 1 8  
P a g e  6  of  3 8  
 
 
 
R ati o n al e f o r  V e rsi o n  2. 0 
 
T h e  c h a n g es fr o m  V ersi o n  1. 0 t o  V ersi o n  2. 0  of t h e  St atisti c al  A n al ysis  Pl a n  w er e  m oti v at e d  b y 
pr ot o c ol  a m e n d m e nts s u bs e q u e nt t o t h e fi n ali z ati o n  of  V ersi o n  1  of t h e  S A P.  V ersi o n  1  w as 
fi n ali z e d 2 9 A pr 2 0 1 5  u n d er  pr ot o c ol  v ersi o n  3 ( O ct o b er  1 3,  2 0 1 4).  T h e  pr ot o c ol  w as  a m e n d e d 
t w o ti m es si n c e  V ersi o n  1  of t h e  S A P ( Pr ot o c ol  V ersi o n  4,  2 3J u n 2 0 1 5;  Pr ot o c ol  V ersi o n  5, 
2 9 O ct 2 0 1 5).   T h e  c urr e nt  pr ot o c ol  all o ws f or  u p t o  a p pr o xi m at el y  8  c o h orts  of  p ati e nts i n t h e 
d os e-r a n gi n g  p orti o n  of t h e st u d y ( P art  1) .   A d diti o n al  m o difi c ati o ns  w er e  m a d e t o  pr o vi d e 
cl arit y t o t h e st atisti c al  m et h o ds  us e d i n t h e  pl a n n e d  a n al ysis.  
T h e  V ersi o n  2  of t h e  S A P  als o s p e cifi es s e p ar at e  a n al ysis  pl a ns f or  P art  1  a n d  P art  2  of t his 
st u d y.  H a vi n g s e p ar at e  a n al ysis  pl a ns f or  e a c h st u d y  p art  wi ll  all o w f or i nf or m ati o n l e ar n e d i n 
P art  1 t o  b e  a p pli e d t o t h e  a n al ysis  of  P art  2. 
Ot h er   n ot a bl e  m o difi c ati o ns i n cl u d e: 
 
•   N u m b er  of  p ati e nts i n cr e as e d  wit h t h e  a d diti o n  of  m or e  c o h orts i n  P art  1 
•   Cl arif y t h at s e p ar at e  a n al ysis s ets  will  b e  d efi n e d f or  e a c h  P art  
•   R ef or m att e d t o  c urr e nt t e m pl at e  








S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als, I n c.   
V ersi o n  1  D at e:  1 2 M ar 2 0 1 8  
P a g e  1 0  of  3 8  
 
 
 
e Ass ess m e nts f or  Visit  4  m ust  b e  c oll e ct e d  at t h e st u d y  c e nt er if  p ati e nts  ar e  e nr oll e d i n  P art  1  of t h e st u d y.  If  p ati e nts  a r e  e nr oll e d i n  P art  2  of t h e st u d y,  Visit  4  ass ess m e nts  m a y  b e  c oll e ct e d  b y  a 
h o m e  h e alt h  n urs e.  
f Visit  6 s h o ul d  b e  c o n d u ct e d  wit hi n  1 8  h o urs t o  4 8  h o urs  of  Visit  5,  a n d  Visit  1 1 s h o ul d  b e  c o n d u ct e d  wit hi n  1 8  h o urs t o  4 8  h o urs  of  Visit  1 0.  
g F or  p ati e nts  wit h  e c h o c ar di o gr a ms  a n d  el e ctr o c ar di o gr a ms  c oll e ct e d  wit hi n  3 0  d a ys  pri or t o t h e  S cr e e ni n g  Visit, t h e  m ost r e c e nt  e c h o c ar di o gr a m  a n d  el e ctr o c ar di o gr a m  c a n  b e  us e d t o  ass ess  c ar di a c 
f u n cti o n  a n d  p ati e nt  eli gi bilit y. 
h At  W e e k  2,  el e ctr o c ar di o gr a m  is  o nl y r e q uir e d f or  p ati e nts i n  P art  1  of t h e st u d y. 
i A  h o m e  h e alt h  n urs e  visit  m a y  b e  us e d t o  c oll e ct  all l a b s a m pl es r e q uir e d  at t h e  S cr e e ni n g  Visit.  
j P ati e nts  m ust  b e  all o w e d t o r est f or  a  mi ni m u m  p eri o d  of  1  h o ur f oll o wi n g  m a xi m al  or s u b m a xi m al  e x e r cis e t esti n g  b ef or e t his  bl o o d s a m pl e is  c oll e ct e d ( at t h e s a m e ti m e  as  all  of t h e  c e ntr al l a b 
bl o o d  c oll e cti o n).   T his s a m pl e  m ust  b e t a k e n  pri or t o t h e  6 M W T.   T his s a m pl e s h o ul d  b e t a k e n  wit h t h e  p ati e nt i n t h e s a m e  p o siti o n ( e. g., sitti n g  or s e mi -r e c u mb e nt)  at  all  a p pr o pri at e  visits  
k Bl o o d s a m pl es  will  b e  c oll e ct e d t o  a n al y z e f or  h e p atitis  B  a n d  C  a n d  HI V  a nti b o di es  o nl y i n  p ati e nts l a c ki n g  e vi d e n c e  of  a  n e g ati v e tit er i n t h e  p ast  y e ar.  
l N e g ati v e s er u m  pr e g n a n c y t est r es ults  ar e r e q uir e d  at t h e  S cr e e ni n g  Visit  b ef or e st u d y  e nr oll m e nt,  a n d  n e g ati v e  uri n e  pr e g n a n c y t est r es ults  ar e r e q uir e d  at  all  ot h er ti m es i n di c at e d f or  c o nti n u e d 
p arti ci p ati o n i n t h e st u d y.  
m At  W e e k  2, st u d y  dr u g  dis p e ns ati o n is  o nl y r e q uir e d f or  p ati e nts i n t h e first  c o h ort  of  P art  1  of t h e st u d y.  
n A  d osi n g  di ar y  c h e c k  m ust  b e  p erf or m e d  at st u d y  dr u g r et ur n  a n d  pill  c o u nt.  
o At  W e e k  2, st u d y  dr u g r et ur n,  pill  c o u nt,  a n d  di ar y  c h e c k  ar e  o nl y r e q uir e d f or  p ati e nts i n t h e first  c o h ort  of  P art  1  of t h e  st u d y. 
p St u d y  dr u g s h o ul d  b e  a d mi nist er e d i n t h e  pr es e n c e  of st u d y st aff i n t h e  cli ni c  o n  D a y  1  aft er  all  D a y  1  ass ess m e nts  h a v e  b e e n  c o m pl et e d.   St u d y  dr u g s h o ul d  als o  b e  a d mi nist er e d i n t h e  cli ni c  o n  D a ys 
1 4,  2 8 ( P art  2  o nl y),  5 6 ( C o h ort  1;  P art  1  o nl y)  a n d  8 4  aft er t h e  bl o o d  c oll e cti o n f or  pr e d os e  P K  a n al ysis.   All  ot h er  d os es  c a n  b e  a d mi nist er e d  at  h o m e.   R T A  4 0 8 s h o ul d  b e  a d mi nist er e d  o n c e  d ail y 
t hr o u g h  D a y  8 4.  
q O n st u d y  d a ys  w h er e  m ulti pl e  ass ess m e nts  ar e t o  b e  c o m pl et e d, t h e  m a xi m al  e x er cis e t est  will  b e t h e first f u n cti o n al  ass ess m e nt  p erf or m e d.   Bl o o d s a m pl es  will  b e  c oll e ct e d  at r est,  at t h e  c o m pl eti o n 
of t h e t est,  a n d  at  5  a n d  1 0  mi n ut es  aft er t h e t est.   M a xi m al  e x er cis e t esti n g s h o ul d  b e r e p e at e d  pri or t o r a n d o mi z ati o n if t h e  ori gi n al  S cr e e ni n g  ass ess m e nt  w as  p erf or m e d  > 3 0  d a ys  pri or t o  D a y  1.  
r As  p art  of t h e s u b m a xi m al  e x er cis e t est,  bl o o d s a m pl es  will  b e  c oll e ct e d  at r est  a n d  at  1 0 -mi n ut e i nt er v als t hr o u g h o ut t h e t est.    
s M us cl e  n e e dl e  bi o ps y,  w hi c h is  o pti o n al, s h o ul d  b e  c oll e ct e d  aft er  all st u d y  visit  ass ess m e nts  ar e  p erf or m e d,  e x c e pt  o n  D a y  1, i n  w hi c h  m us cl e  n e e dl e  bi o ps y s h o ul d  b e t h e s e c o n d t o l ast  pr o c e d ur e 
p erf or m e d,  c oll e ct e d  pri or t o st u d y  dr u g  a d mi nistr ati o n.  
t F or  p ati e nts  e nr oll e d i n t h e first  c o h ort  of  P art  1  of t h e st u d y,  bl o o d s a m pl es f or  P K  a n al ysis  at  Visit  4  a n d  Visit  8 s h o ul d  b e  c oll e ct e d  pri or t o  st u d y  dr u g  a d mi nistr ati o n  as  w ell  as  1,  2,  4,  a n d  8  h o urs 
aft er st u d y  dr u g  a d mi nistr ati o n.   A si n gl e  bl o o d s a m pl e f or  P K  a n al ysis  at  Visit  1 1 s h o ul d  b e  c oll e ct e d  pri or t o st u d y  dr u g  a d mi nistr ati o n.   
u F or  p a ti e nts  e nr oll e d i n t h e s e c o n d  a n d s u bs e q u e nt  c o h orts  of  P art  1  of t h e st u d y,  bl o o d s a m pl es f or  P K  a n al ysis  at  Visit  4 s h o ul d  b e  c oll e ct e d  pri or t o st u d y  dr u g  a d mi nistr ati o n  as  w ell  as  1,  2,  4,  a n d 
8  h o urs  aft er  st u d y  dr u g  a d mi nistr ati o n.   A  si n gl e  bl o o d  s a m pl e f or  P K  a n al ysis  at  Visit  1 1 s h o ul d  b e  c oll e ct e d  pri or t o st u d y  dr u g  a d mi nistr ati o n.  
v F or  p ati e nts  e nr oll e d i n  P art  2  of t h e st u d y,  bl o o d s a m pl es f or  P K  a n al ysis  at  Visit  6  a n d  Visit  1 1 s h o ul d  b e  c oll e ct e d  pri or  t o st u d y  dr u g  a d mi nistr ati o n.   
w Bl o o d  c oll e cti o n f or  bi o m ar k ers  will  b e  o pti o n al.  O n  D a y  1,  bl o o d  c oll e cti o n f or  bl o o d  bi o m ar k ers  m ust  o c c ur  pri or t o  st u d y  dr u g  a d mi nistr ati o n.   
 
A b br e vi ati o ns:  V = Visit;  W k = W e e k;  6 M W T = 6 -mi n ut e  w al k t est;  B MI = b o d y  m ass i n d e x;  B N P =  B -t y p e  n atri ur eti c  p e pti d e;  HIV = h u m a n i m m u n o d efi ci e n c y  vir us;  N T -pr o B N P = N -t er mi n al  pr o h or m o n e 
of  B -t y p e  n atri ur eti c  p e pti d e;  P K = p h ar m a c o ki n eti c;  W O C B P = w o m e n  of  c hil d b e ari n g  p ot e nti al 


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  1 1  of  3 8  
 
1. 2. 2   D at a  S af et y  M o nit o ri n g  B o a r d 
A n i n d e p e n d e nt  D at a  S af et y  M o nit ori n g  B o ar d ( D S M B )  will b e  m o nit ori n g  d at a fr o m t h e st u d y 
o n  a  m o nt hl y  b asis t hr o u g h o ut  P art  1 t o  e ns ur e  t h e s af et y  of t h e p ati e nts  in t h e tri al . 
A n  i n d e p e n d e nt st atisti c al  gr o u p,  St atisti cs  C oll a b or ati v e, I n c.,  will  pr e p ar e  u n bli n d e d  a n al ys es 
f or t h e  D S M B  a n d  will  n ot  h a v e  a r ol e i n t h e st atisti c al  a n al ysis  pl a n  ( S A P)  or  d a y-t o- d a y 
s u p p ort  of t h e st u d y.   
1. 2. 3   Dis c o nti n u ati o n  of  T r e at m e nt 
Dis c o nti n u ati o n r ef ers t o  a  p ati e nt st o p pi n g  a d mi nistr ati o n  of st u d y  dr u g.  R e as o ns f or st u d y  dr u g 
dis c o nti n u ati o n  m a y i n cl u d e t h e f oll o wi n g: 
•   O c c urr e n c e  of  a n  a d v ers e  e v e nt  or  c h a n g e i n  m e di c al st at us t h at l e a ds t h e i n v esti g at or 
t o  b e  c o n c er n e d  a b o ut t h e  p ati e nt’s  w elf ar e 
•   Pr ot o c ol  vi ol ati o ns 
•   A d mi nistr ati v e r e as o ns ( e. g., i n a bilit y t o  c o nti n u e) 
•   S p o ns or t er mi n ati o n  of t h e st u d y 
•   V ol u nt ar y  wit h dr a w al 
•   Pr e g n a n c y   d uri n g t h e st u d y 
•   I n v esti g at or  u n bli n di n g 
•   Ot h er  
P ati e nts  w h o  ar e  dis c o nti n u e d fr o m st u d y  dr u g s h o ul d still  c o m pl et e  all st u d y  visits  a n d  u n d er g o 
all s c h e d ul e d st u d y  ass ess m e nts, if  p ossi bl e. 
1. 2. 4   P ati e nt  T e r mi n ati o n  
T er mi n ati o n r ef ers t o  a  p ati e nt st o p pi n g st u d y  dr u g  a n d  all st u d y  ass ess m e nts  a n d  visits.  R e as o ns 
f or st u d y t er mi n ati o n i n cl u d e t h e f oll o wi n g: 
•   A d mi nistr ati v e r e as o ns ( e. g., i n a bilit y t o  c o nti n u e, l ost t o f oll o w- u p) 
•   D e at h  
•   W it h dr a w al of  c o ns e nt  
P ati e nts  w h o t er mi n at e t h e st u d y f or  a n y r e as o n  m a y  n ot r e- i niti at e st u d y  dr ug  or st u d y 
ass ess m e nts  at  a n y ti m e.  
1. 2. 5   R a n d o mi z ati o n  a n d  U n bli n di n g  
T h e first  c o h ort  e nr oll e d i n  P art  1  will  b e r a n d o mi z e d  3: 1 t o  R T A  4 0 8  2. 5  m g  or  pl a c e b o.   Aft er 
t h e  W e e k  2  visit,  e a c h  p ati e nt i n t h e first  c o h ort  will  d os e  es c al at e t o  5  m g ( or r e m ai n  o n  pl a c e b o) 
a n d r e m ai n  o n  5  m g t hr o u g h t h e r e m ai ni n g  1 0  w e e ks  of tr e at m e nt.   B e gi n ni n g  wit h t h e s e c o n d 
c o h ort  e nr oll e d i n  P art  1 ,  p ati e nts  will  b e r a n d o mi z e d  3: 1 t o a s p e cifi c  d os e  of  R T A  4 0 8  or 
pl a c e b o  as r e c o m m e n d e d  b y t h e  D S M B .  P ati e nts  will r e m ai n  at t h eir r a n d o mi z e d  d os e t hr o u g h 
t h e  e ntir e  1 2  w e e ks  of tr e at m e nt. 
T o  m ai nt ai n t h e st u d y  bli n d,  all st u d y  dr u g  kits  will  b e  p a c k a g e d  wit h  bli n d e d l a b els.  
I n v esti g at ors  will  distri b ut e t h e  bli n d e d st u d y  dr u g  kits  b y  kit  n u m b er t o  p ati e nts  as  assi g n e d  b y 
t h e I W R S.   All  p ati e nts, i n v esti g at ors, sit e  p ers o n n el,  a n d l a b or at ori es  wit h  dir e ct i n v ol v e m e nt i n 
t h e  c o n d u ct  of t h e st u d y  or t h eir  d esi g n e es  will  b e  bli n d e d t o tr e at m e nt  assi g n m e nts  a n d 


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  1 2  of  3 8  
 
a p pr o pri at e  m e as ur es  will  b e t a k e n t o  e ns ur e t h e  bli n d is  m ai nt ai n e d t o r e d u c e  p ot e nti al  bi as.  
S o m e  S p o ns or  p ers o n n el  m a y  h a v e  a c c ess t o tr e at m e nt  assi g n m e nts  d uri n g  d os e  es c al ati o n 
( P art 1).  
1. 3   S a m pl e  Si z e  a n d  P o w e r  
T h e s a m pl e si z e f o r  P art  1 (i. e.,  8  p er  c o h ort f or 6 4  t ot al  p ati e nts i n  P art  1) is  b as e d  o n  a  d os e-
es c al ati o n s c h e m e t o  e v al u at e i niti al s af et y  a n d  P D  a cti vit y  of  R T A  4 0 8 i n t his  p ati e nt 
p o p ul ati o n.   T h e s m all  n u m b er  of  p ati e nts  at  e a c h  d os e i n  P art  1 is  n ot  e x p e ct e d t o f ull y 
c h ar a ct eri z e s af et y,  effi c a c y,  or  P D,  b ut r at h er i nf or m t h e  D S M B  a n d  S p o ns or  of t h e  a p pr o pri at e 
d os es t o s el e ct f or  P art  2.   






S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  1 5  of  3 8  
 
3.   G E N E R A L  C O N SI D E R A TI O N S  F O R  D A T A  A N A L Y SI S  
3. 1   A n al ysis  C o nsi d e r ati o ns 
All i n di vi d u al  d at a  will  b e list e d  as  r e c or d e d i n t h e  d at a b as e.  All st atisti c al s u m m ari es  a n d 
a n al ys es  will  b e  p erf or m e d  usi n g  S A S ® s oft w ar e ( S A S I n stit ut e,  C ar y,  N ort h  C ar oli n a,  U S A).  
O nl y  p ati e nts  i n t h e a p pr o pri at e  a n al ysis s et  will  b e i n cl u d e d i n s u m m ar y st atisti cs.   F or 
e n d p oi nts  dis c uss e d i n t his  S A P,  a ll  a v ail a bl e  d at a f or  e a c h  p ati e nt  will  b e i n cl u d e d i n 
s u m m ari es.  
P ati e nts r a n d o mi z e d  t o  R T A  4 0 8 i n  c o h ort  1  will  es c al at e fr o m  2. 5  m g t o  5  m g  at  W e e k  2.   T h es e 
p ati e nts  will  b e  c at e g ori z e d  as t h e  5 - m g tr e at m e nt  gr o u p f or  d at a  pr es e nt ati o ns.   P ati e nts  e nr oll e d 
i n  all  ot h er  c o h orts  will r e m ai n  o n t h eir r a n d o mi z e d  d os e f or  all  1 2  w e e ks  of tr eat m e nt,  a n d  will 
b e  c at e g ori z e d  a c c or di n g t o t h eir r a n d o mi z e d tr e at m e nt f or  d at a  pr es e nt ati o ns.   P ati e nts 
r a n d o mi z e d t o  pl a c e b o  wit hi n  e a c h  c o h ort  will  b e  p o ol e d f or  d at a  pr es e nt ati o ns i nt o  a si n gl e 
pl a c e b o tr e at m e nt  gr o u p. 
All r a w  p ati e nt  d at a  will  b e  c o n v ert e d t o  S D T M f or s u b missi o n t o  F D A,  h o w e v er,  o nl y t h e 
a n al ysis  d at a  will  b e  pr es e nt e d i n i n di vi d u al- p ati e nt  d at a listi n gs.    
C o nti n u o us  d at a  will  b e s u m m ari z e d  b y tr e at m e nt  usi n g  d es cri pti v e st atisti cs ( n u m b er,  m e a n, 
st a n d ar d  d e vi ati o n [ S D],  mi ni m u m,  m e di a n,  q u artil es  ( Q 1,  Q 3),  a n d  m a xi m u m).   C at e g ori c al 
d at a  will  b e s u m m ari z e d  b y tr e at m e nt  usi n g fr e q u e n c y t a bl es ( n u m b er  a n d  p er c e nt a g e).  
3. 2   A n al ysis  S ets 
F or  P art   1  of t h e st u d y, t h e f oll o wi n g  a n al ysis s ets  will  b e  d efi n e d. 
3. 2. 1   F ull  A n al ysis  S et   
T h e  f ull  a n al ysis s et ( F A S) i n cl u d es  all  e nr oll e d  p ati e nts i n P art  1 , w h et h er  or  n ot t h e y r e c ei v e d 
st u d y  dr u g.  T h e  F A S  will  b e  us e d t o  ass ess   p ati e nt  dis p ositi o n  a n d effi c a c y  e n d p oi nts.   P ati e nts 
will  b e s u m m ari z e d  a c c or di n g t o t h e tr e at m e nt t o  w hi c h t h e y  w er e r a n d o mi z e d.    
3. 2. 2   S af et y  A n al ysis  S et 
T h e s af et y  a n al ysis s et  i n cl u d es  all  p ati e nts  w h o r e c ei v e d  at l e ast  1  d os e  of st u d y  dr u g.  T h e 
s af et y  a n al ysis s et   will  b e  us e d t o  ass ess s af et y  e n d p oi nts.  P ati e nts  w h o r e c ei v e  at l e ast  1  d os e  of 
R T A  4 0 8  will  b e  cl assifi e d i n t h e  R T A  4 0 8  gr o u p  at t h e  hi g h est  d os e l e v el r e c ei v e d. 
3. 2. 3   P h a r m a c o ki n eti c  
T h e  P h ar m a c o ki n eti c  a n al ysis s et  will  b e  a st a n d - al o n e  a n al ysis. 
3. 3   St r at a  a n d  C o v a ri at es  
R a n d o mi z ati o n i n  P art  1  of  t his st u d y is  n ot str atifi e d.   Si n c e s a m pl e si z e  p er  d os e l e v el  will  b e 
s m all,  n o  c o v ari at es  will  b e  c o nsi d er e d f or t h e  pri m ar y  a n al ysis  of  P art  1. 
3. 4   E x a mi n ati o n  of  P ati e nt  S u bs ets  
E m er gi n g  d at a  h a v e i d e ntifi e d  p ati e nts  wit h  b as eli n e  bl o o d l a ct at e  l e v els  ≤  2. 0  m M  at r est  d uri n g 
t h e s u b m a xi m al  e x er cis e t est a n d  p ati e nts  wit h  b as eli n e r esti n g  h e art r at e  ≤ 8 0  b p m  d uri n g t h e 
s u b m a xi m al  e x er cis e t est  as  p arti c ul ar s u b gr o u ps  of i nt er est . A n al ys es  of s u b m a xi m al  e x er cis e 
t esti n g  p ar a m et ers  d at a m a y  b e  p erf or m e d  o n  t hes e  s u b gr o u ps of i nt er est.   


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  1 6  of  3 8  
 
3. 5   M ulti pl e  C o m p a ris o ns  
N o  a dj ust m e nts f or  m ulti pli cit y  will  b e  c o nsi d er e d f or  a n al ysis  of  P art  1  d at a.    
3. 6   Missi n g  D at a  
Missi n g  d at a  will  n ot  b e i m p ut e d f or  t h e  pri m ar y  a n al ysis  of s af et y,  P K,  P D,  or  e x pl or at or y 
effi c a c y  e n d p oi nts.   T h e  pl a n n e d  st atisti c al  m et h o ds  us e  all  a v ail a bl e  d at a , t h er ef or e  n o 
i m p ut ati o n is  pl a n n e d f or t h e  pri m ar y  a n al ysis  of t h e pri m ar y  a n d s e c o n d ar y  effi c a c y  e n d p oi nts 
(i. e.,  p e a k  w or k  a n d 6 M W D ).   S e nsiti vit y  a n al ys es  m a y  b e  p erf or m e d  as  a p pr o pri at e t o  ass ess t h e 
i m p a ct  of  missi n g  d at a.    
3. 7   Visit  Wi n d o ws  
3. 7. 1   D efi niti o n  of  St u d y  D a y  
St u d y  d a y is t h e  d a y r el ati v e t o t h e first  d os e  of st u d y  dr u g  a d mi nistr ati o n.   St u d y  d a y f or  e v e nts 
o n  or  aft er t h e  d at e  of t h e first  d os e  will  b e  d efi n e d  as t h e  n u m b er  of  d a ys fr o m t h e  d at e  of t h e 
first  d os e  of st u d y  dr u g,  pl us  1  d a y, s o t h at t h e  d at e  of t h e first  d os e  will  b e  defi n e d  as  D a y  1.  
F or  e v e nts  b ef or e t h e  d at e  of t h e f irst  d os e, st u d y  d a y  will  b e  c al c ul at e d  as t h e  diff er e n c e i n  d a ys 
b et w e e n t h e  d at e  of t h e first  d os e  a n d t h e  d at e  of i nt er est.   T h us, t h e  d a y  b ef or e t h e  d at e  of t h e 
first d os e  will  b e  d efi n e d  as  D a y  - 1. 
3. 7. 2   D efi niti o n  of  St u d y  B as eli n e  
T h e  a v er a g e  of  S cr e e ni n g  a n d  D a y  1  ass ess m e nts  will  b e  us e d  as  b as eli n e f or  6 M W T .   F or  all 
ot h er  p ar a m et ers , st u d y  b as eli n e is  d efi n e d  as t h e l ast  n o n-missi n g   o bs er v ati o n  o bt ai n e d  pri or t o 
a d mi nistr ati o n   of t h e first  d os e  o n  St u d y  D a y  1.  B as eli n e  will  b e  d efi n e d  as  a n al ysis  visit  0.  
3. 7. 3   A n al ysis  Visits  
T h e  C R F  n o mi n al st u d y  visits  will  b e  us e d f or  all s af et y  a n al ys es.  F or  effi c a c y  a n al ys es  or  w h e n  
ot h er wis e s p e cifi e d, s u m m ari es  b y  visit  will  b e  d o n e  usi n g  a n al ysis  visits  d efi n e d  b el o w. 
A n al ysis  Visit  
N u m b er  
L a b el   
Pr ot o c ol  Visit 
N u m b er  
T ar g et  St u d y  D a y  
0   
B as eli n e   
1,  2  
≤ 1  
4   
W e e k  4   
5 ,  6 
2 8  
8   
W e e k  8   
8  
5 6  
1 2   
W e e k  1 2   
1 0,  1 1  
8 4  
 


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  1 7  of  3 8  
 
3. 7. 4   A n al ysis  Wi n d o ws f o r  U ns c h e d ul e d  Visits  
U ns c h e d ul e d  visits  will  b e r efl e ct e d i n s u m m ari z ati o n  of  c h a n g es t o  w orst  p ost- b as eli n e 
m e as ur es.  
A d diti o n all y ,  u ns c h e d ul e d  ass ess m e nts  will  b e  us e d i n t h e  pl a c e  of  missi n g s c h e d ul e d  effi c a c y 
a n d s af et y  ass ess m e nts, if t h e  u ns c h e d ul e d  ass ess m e nt  w as  c oll e ct e d  wit hi n  ± 7  d a ys  of t h e 
s c h e d ul e d  ass ess m e nt .  St u d y  d a y  will  b e  c al c ul at e d f or  e a c h  u ns c h e d ul e d ass ess m e nt  a n d 
c o m p ar e d t o t h e  pr ot o c ol  d efi n e d st u d y  d a y f or  e a c h  visit.  I n  g e n er al,  a n al ysis  wi n d o ws f or 
u ns c h e d ul e d  visits  will  b e  d efi n e d  as f oll o ws: 
A n al ysis  Visit  
T ar g et  St u d y 
D a y  
A n al ysis  Wi n d o w 
0  
1  
St u d y  D a y  ≤ 1  
1   
( S af et y  O nl y) 
7  
2  ≤  St u d y  D a y  ≤  1 0  
2   
( S af et y  O nl y) 
1 4  
1 1  ≤  St u d y  D a y  ≤  2 0  
4  
2 8   
2 1  ≤  St u d y  D a y  ≤  3 5  
8  
5 6   
4 9  ≤  St u d y  D a y  ≤  6 3  
1 2  
8 4   
7 7  ≤  St u d y  D a y  ≤  9 1  
R e c or ds  fr o m  u ns c h e d ul e d  visits t h at  d o  n ot f all  wit hi n  a n  a n al ysis  wi n d o w  will  b e list e d,  b ut 
will  n ot  b e  a n al y z e d. 
3. 7. 5   S el e cti o n  of  D at a i n t h e  E v e nt  of  M ulti pl e  R e c o r ds i n  a  Visit  
If  m ulti pl e  ass ess m e nts f all  wit hi n t h e s a m e  a n al ysis  visit, t h e  ass ess m e nt  cl os est t o t h e t ar g et 
visit  d a y s p e cifi e d i n t h e  pr ot o c ol st u d y  pr o c e d ur es  will  b e  us e d.  If t w o  ass e ss m e nts  ar e 
e q ui dist a nt fr o m  a  p ost- b as eli n e  t ar g et  visit  d a y, t h e  e arli er  ass ess m e nt  will  b e  us e d.  
3. 8   R o u n di n g  
T h e  m et h o d  of r o u n di n g f or  d at a  pr es e nt ati o n is  pr o vi d e d i n  A p p e n di x  2 . 


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  1 8  of  3 8  
 
4.   S T U D Y  P O P U L A TI O N  
4. 1   Dis p ositi o n  of  P ati e nt s 
E nr oll m e nt  a n d  d is p ositi o n  will  b e s u m m ari z e d.   A  p ati e nt  will  b e  d efi n e d  as  e nr oll e d if t h e y 
si g n t h e i nf or m e d  c o ns e nt f or m.   A  d is p ositi o n s u m m ar y  wil l i n cl u d e t h e  n u m b er  a n d  p er c e nt a g e 
of  p ati e nts  w h o: 
•   E nr oll e d i n t h e st u d y 
•   Ar e i n t h e s af et y  a n al ysis s et  
•   Ar e i n t h e f ull  a n al ysis s et  
•   N u m b er  of  p ati e nt s  d os e  es c al at e d ( C o h ort  1  o nl y) 
•   C o m pl et e d tr e at m e nt t hr o u g h  W e e k  1 2 
•   Pr e m at ur el y  dis c o nti n u e d fr o m st u d y tr e at m e nt 
•   C o m pl et e d t h e st u d y 
•   Pr e m at ur el y t er mi n at e d fr o m t h e st u d y.  
T h e  dis p ositi o n s u m m ar y  will  als o i n cl u d e t h e  pri m ar y r e as o n f or  dis c o nti n u ati o n fr o m st u d y 
tr e at m e nt  or t er mi n ati o n fr o m t h e st u d y.    
Dis p ositi o n s u m m ari es  will  b e  pr es e nt e d  b y r a n d o mi z e d tr e at m e nt.   P er c e nt a g es  will  b e  b as e d  o n 
t h e  n u m b er  of r a n d o mi z e d p ati e nt s. 
A listi n g  of  p ati e nt  dis p ositi o n  will i n cl u d e  t h e d at e  of first  d os e  of st u d y  dr u g,  d at e  of l ast  d os e 
of st u d y  dr u g,  t ot al  w e e ks  of tr e at m e nt, st u d y tr e at m e nt  c o m pl eti o n st at us, st u d y  c o m pl eti o n 
st at us,  a n d r e as o n (s) f or st u d y  dr u g  dis c o nti n u ati o n  a n d/ or st u d y  t er mi n ati o n. 
4. 2   P r ot o c ol  D e vi ati o ns 
W h er e  a v ail a bl e,  pr ot o c ol  d e vi ati o ns  will  b e list e d  b y  d e vi ati o n  c at e g or y ( e. g.,  eli gi bilit y  crit eri a, 
o ut  of  wi n d o w  visit, s eri o us  a d v ers e  e v e nt ( S A E) r e p orti n g, st u d y  pr o c e d ur es, tr e at m e nt 
pr o c e d ur es).   All  d e vi ati o ns, i n cl u di n g  m aj or  pr ot o c ol  d e vi ati o ns t h at  c o ul d  p ot e nti all y  aff e ct t h e 
effi c a c y  or s af et y  c o n cl usi o ns  of t h e st u d y,  will  b e i d e ntifi e d  pri or t o  d at a b as e l o c k.   Pr ot o c ol 
d e vi ati o ns  will  b e list e d i n  a  d at a listi n g  a n d s u m m ari z e d  b y  d e vi ati o n  c at e g or y. 
4. 3   D e m o g r a p hi cs  a n d  B as eli n e  C h a r a ct e risti cs  
D e m o gr a p hi c  a n d  b as eli n e  c h ar a ct eristi cs s u m m ari es, f or  p ati e nts i n t h e s af et y  a n al ysis s et,  will 
i n cl u d e: 
•   A g e ( y e ars  at  st u d y b as eli n e)  
•   S e x  
•   R a c e  
•   Et h ni cit y  
•   W ei g ht ( k g) 


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  1 9  of  3 8  
 
•   H ei g ht  ( c m) 
•   B as eli n e  p e a k  w or k   
•   B as eli n e r esti n g  h e art r at e  d uri n g t h e s u b m a xi m al  e x er cis e t est  
•   B as eli n e s er u m  cr e ati n e  ki n as e  ( C K) 
D u e t o t h e  n u m b er  of  m e as ur es,  b as eli n e  c h ar a ct eristi cs  will  b e  pr o vi d e d i n  a s e p ar at e s u m m ar y.  
C o nti n u o us st atisti cs  will  b e  pr o vi d e d f or: 
•   A g e  at  mit o c h o n dri al  m y o p at h y  o ns et 
•   Y e ars  si n c e  mit o c h o n dri al  m y o p at h y  o ns et ( at st u d y  b as eli n e) 
Fr e q u e n c y t a bl es ( n u m b er  a n d  p er c e nt a g e)  will  b e  pr o vi d e d  f or  dis cr et e  m e as ur es: 
•   C li ni c al  di a g n osis 
•   Str o k e- li k e e pis o d es i n t h e  p ast  y e ar  
•   O p ht h al m o pl e gi a i n t h e  p ast  y e ar   
•   P ol y n e ur o p at h y i n t h e  p ast  y e ar   
•   S ei z ur es i n t h e  p ast  y e ar  
D e m o gr a p hi c  a n d  b as eli n e  c h ar a ct eristi cs  will  b e s u m m ari z e d  b y r a n d o mi z e d tr e at m e nt   gr o u p. 
4. 4   M e di c al  Hist o r y  
M e di c al  hist or y  will  b e  m a p p e d t o  pr ef err e d t er ms  ( P T) a n d s yst e m  or g a n  cl ass es  ( S O C)  usi n g 
t h e M e di c al  Di cti o n ar y f or  R e g ul at or y  A cti viti es  ( M e d D R A® )  Di cti o n ar y ( v ersi o n  1 4. 1).  
M e di c al  hist or y it e ms  will  b e s u m m ari z e d  b y  M e d D R A  S O C  a n d  P T  a n d  p ati e nt listi n g  will  b e 
pr o vi d e d. 


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  2 0  of  3 8  
 
5.   S T U D Y  D R U G  A N D  O T H E R  M E DI C A TI O N S  
5. 1   P ri o r  a n d  C o n c o mit a nt  M e di c ati o ns 
Pri or  a n d  c o n c o mit a nt  m e di c ati o ns  will  b e  c o d e d  usi n g t h e  W orl d  H e alt h  Or g a ni z ati o n ( W H O) 
dr u g  di cti o n ar y ( B 2 _ D D E _ H D _ S e p 2 0 1 1- Wit h  P er f T er m) f or  a n at o mi c al t h er a p e uti c  c h e mi c al 
cl assifi c ati o n ( A T C)  a n d  pr ef err e d  dr u g  n a m e.   
A  p ri or  m e di c ati o n is  a n y  m e di c ati o n t h at is t a k e n  pri or t o t h e first  d os e  of st u d y  dr u g.  A 
c o n c o mit a nt  m e di c ati o n  is a n y  m e di c ati o n t a k e n  at t h e  ti m e  of first st u d y tr e at m e nt or  a 
m e di c ati o n t h at  w as st art e d  aft er  t h e st art  of st u d y  dr u g  d osi n g.  S p e cifi c all y,  c o n c o mit a nt 
m e di c ati o ns  ar e  m e di c ati o ns  
•   t h at  ar e  c o nti n u e d fr o m s cr e e ni n g  a n d  c o nti n u e d  aft er t h e first st u d y  dr u g  d osi n g,  or 
•   t h at  h a v e st art  d at es  or st o p  d at es  wit hi n t h e tr e at m e nt  p eri o d. 
A  m e di c ati o n  c a n  b e  cl assifi e d  as  b ot h  pri or  a n d  c o n c o mit a nt if it  w as st art e d  pri or t o st u d y 
tr e at m e nt  a n d  c o nti n u e d  d uri n g t h e tr e at m e nt  p eri o d.   
Pri or  a n d  c o n c o mit a nt  m e di c ati o ns  will  b e s u m m ari z e d f or  e a c h tr e at m e nt  gr o u p  b y  W H O  D D 
A T C  cl ass  a n d  pr ef err e d  n a m e.    T h es e s u m m ari es  will  pr es e nt t h e  n u m b er  a n d  p er c e nt a g e  of 
p ati e nt s  usi n g  e a c h  m e di c ati o n.   P ati e nts  m a y  h a v e  m or e t h a n  o n e  m e di c ati o n  p er  A T C  cl ass  a n d 
pr ef err e d  n a m e.   At  e a c h l e v el  of  p ati e nt  s u m m ari z ati o n,  a  p ati e nt  is  c o u nt e d  o n c e if  h e/s h e 
r e p ort e d  o n e  or  m or e  m e di c ati o ns  at t h at l e v el.   E a c h s u m m ar y  will  b e  or d er e d  b y  d es c e n di n g 
or d er  of i n ci d e n c e  of  A T C  cl ass  a n d  pr ef err e d  n a m e  wit hi n  e a c h  A T C  cl ass.   
I n  a d diti o n,  p ati e nts  w h o t a k e  e x cl u d e d  m e di c ati o ns s e nsiti v e s u bstr at es f or  c yt o c hr o m e  P 4 5 0 
2 C 8  or  3 A 4,  m o d er at e  or str o n g i n hi bit ors  or i n d u c ers  of  c yt o c hr o m e  P 4 5 0  3 A 4,  or s u bstr at es f or 
p- gl y c o pr ot ei n tr a ns p ort er ( d efi n e d i n t h e  Pr ot o c ol  S e cti o n  9. 2. 1)  d uri n g t h e st u d y  will  b e list e d. 
5. 2   D u r ati o n  of  St u d y  T r e at m e nt  a n d  E x p os u r e t o  St u d y  D r u g  
T h e  d ur ati o n  of st u d y  dr u g  e x p os ur e is  d efi n e d  as t h e  n u m b er  of  d a ys  o n tr e at m e nt fr o m t h e first 
d os e  of st u d y  dr u g  u ntil t h e l ast  d os e  of st u d y  dr u g (l ast  d os e  –  first  d os e  +  1).   St u d y  dr u g 
e x p os ur e  will  b e s u m m ari z e d  b y  d es cri pti v e st atisti cs.   S u m m ari es  will i n cl u d e t h e  n u m b er  of 
d os es r e c ei v e d ( or  dis p e ns e d), t ot al  d os e ( m g) r e c ei v e d ( or  dis p e ns e d),  a v er a g e  d ail y  d os e ( m g), 
st u d y  dr u g  c o m pli a n c e,  a n d  d ur ati o n ( d a ys)  of  e x p os ur e  d uri n g t h e st u d y tr e at m e nt  p eri o d.   
T ot al  n u m b er  of  d os es  dis p e ns e d  a n d t ot al  d os e ( m g)  dis p e ns e d  will  b e  c al c ul at e d fr o m t ot al 
n u m b er  of  kits ( b ottl es) r e c or d e d  o n t h e  St u d y  Dr u g  Dis p e ns ati o n  e C R F.   T ot al  n u m b er  of  d os es 
r e c ei v e d  will  b e  c alc ul at e d fr o m i nf or m ati o n  o n t h e  e C R F  of  St u d y  Dr u g  R et ur n  a n d  St u d y  Dr u g 
Dis p e ns ati o n,  as t h e t ot al  n u m b er  of  d os es  dis p e ns e d  – t ot al  n u m b er  of  d os es r et ur n e d.   T h e t ot al 
d os e ( m g) r e c ei v e d  c a n  b e  c al c ul at e d i n si mil ar  w a y.   T h e  a v er a g e  d ail y  d os e ( m g)  will  b e 
c al c ul at e d  as t ot al  d os e ( m g) / (t ot al  n u m b er  of  d a ys  of  e x p os ur e).   
St u d y  dr u g  c o m pli a n c e ( %)  will  b e  c al c ul at e d  as  1 0 0  × t ot al  n u m b er  of  d os es r e c ei v e d / t ot al 
n u m b er  of  d os es  e x p e ct e d.   P ati e nts  ar e  e x p e ct e d t o  d os e  d ail y, t h er ef or e  8 4  d os es  e x p e c t e d  at 
W e e k  1 2.   
All st u d y  dr u g  dis p e ns e  a n d  a c c o u nt a bilit y  d at a  will  b e list e d i n  p ati e nt listi n g. 


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  2 1  of  3 8  
 
6.   E F FI C A C Y  A N A L Y SI S  
Pri m ar y  a n al ysis  of t h e  effi c a c y  d at a  will  b e  b as e d  o n t h e  f ull  a n al ysis s et,  w hi c h  will i n cl u d e  all 
p ati e nts  e nr oll e d  i n  Part   1  of t h e st u d y.  A n al ys es  will  b e  p erf or m e d f or  e a c h  R T A  4 0 8  d os e 
l e v el. S u m m ar y st atisti cs  f or  o bs er v e d  v al u es,  c h a n g e fr o m  b as eli n e,  a n d  p er c e nt  c h a n g e fr o m 
b as eli n e (i n cl u di n g  9 5 %  CI  a n d  q u artil es)  will   b e  pr es e nt e d  b y r a n d o mi z e d tr e at m e nt  gr o u p. 
6. 1   P ri m a r y  Effi c a c y   A n al ysis 
P e a k  w or k ( w/ k g) is  c al c ul at e d  as t h e  m a xi m u m  w or kl o a d ( w)  at  e a c h  visit  di vi d e d  b y  b as eli n e 
w ei g ht ( k g) f or  e a c h  p ati e nt.   P e a k  w or k s h o ul d  b e r o u n d e d t o t h e  n e ar est  0. 0 0 0 1  di git.   A  m i x e d-
m o d el f or r e p e at e d  m e as ur es ( M M R M ) a n al ysis  will  b e  us e d t o  a n al y z e  t h e  pri m ar y effi c a c y 
v ari a bl e.    All s c h e d ul e d  p e a k  w or k  v al u es  c oll e ct e d t hr o u g h t h e  W e e k  1 2  visit  will  c o ntri b ut e t o 
t h e  pri m ar y  a n al ysis.  T h e  pri m ar y  effi c a c y  v ari a bl e,  t h e  c h a n g e fr o m  b as eli n e i n  p e a k  w or k 
v al u e,  will  b e  c al c ul at e d f or  e a c h  p ost first  d os e ti m e  p oi nt  t hr o u g h  W e e k  1 2  visit (i. e.,  W e e ks  4 
a n d  1 2).   Missi n g  d at a f or t h e  P h as e  2  p orti o n  will  n ot  b e i m p ut e d f or t h e  pri m ar y  a n al ysis.   T h e 
pri m ar y i nf er e n c e  will  b e t h e t est  of  L S  m e a n  at  e a c h ti m e  p oi nt.   T h e  pri m ar y  e n d p oi nt is t h e 
m e a n  c h a n g e fr o m  b as eli n e i n  p e a k  w or k  at  W e e k  1 2.  
P ati e nts  m ust  c o m pl et e t h e  m a xi m al  e x er cis e t est f or  at l e ast  4  mi n u t es t o  b e  c o nsi d er e d  a  v ali d 
t est.  M a xi m al  e x er cis e t est tri als  w hi c h  w er e  4  mi n ut es  or l ess i n  d ur ati o n  will  n ot  b e  us e d i n t h e 
pri m ar y  effi c a c y  a n al ysis.   
6. 1. 1   St atisti c al  H y p ot h esis  
F or t h e  pri m ar y  effi c a c y  e n d p oi nt, t h e  n ull  h y p ot h esis is t h e  W e e k  1 2  m e a n ([ μ O M A V ] - [μ P B O ]) 
c h a n g e fr o m  b as eli n e i n  p e a k  w or k  =  0  w/ k g .   T h e  alt er n ati v e  h y p ot h esis is t h e  W e e k  1 2  m e a n 
([μ O M A V ] - [μ P B O ]) c h a n g e fr o m  b as eli n e i n  p e a k  w or k  ≠  0  w/ k g . 
A  p ositi v e  c h a n g e fr o m  b as eli n e s u g g ests  a n i m pr o v e m e nt. 
6. 1. 2   St atisti c al  M o d el  
T h e  M M R M   m o d el  will i n cl u d e  c h a n g e fr o m  b as eli n e i n  p e a k  w or k  as t h e  d e p e n d e nt  v ari a bl e, 
tr e at m e nt  gr o u p,  pr ot o c ol s c h e d ul e d ti m e  p oi nt ( a n al ysis  visit),  a n d t h e i nt er a cti o n  b et w e e n 
tr e at m e nt  a n d ti m e  as fi x e d  eff e cts,  p ati e nt  as  a r a n d o m  eff e ct. A n a l ysis  visits 0,  4,  a n d  1 2  will  b e 
us e d.  Wit hi n - p ati e nt  c orr el ati o ns  will  b e  m o d el e d  usi n g  a n  u nstr u ct ur e d  c o v ari a n c e str u ct ur e.  
T i m e  or d eri n g is  a r e p e at e d  m e as ur e  wit hi n  p ati e nts.  It is  ass u m e d t h at  err ors f or  diff er e nt 
p ati e nt s  ar e i n d e p e n d e nt  wit h  a n  u nstr u ct ur e d  c o v ari a n c e str u ct ur e.   T h e  esti m ati o n  m et h o d f or 
t h e  m o d el  will  b e r estri ct e d  m a xi m u m li k eli h o o d ( R E M L).  T h e  S A S  ps e u d o- c o d e is  as f oll o ws:   
p r o c   M i x e d   d a t a = e f f i c a c y   m e t h o d = r e m l ;  
    C l a s s   u s u b j i d   t r t   a v i s i t ;  
    m o d e l   r e s p = t r t   a v i s i t   t r t * a v i s i t   / s ;  
    r e p e a t e d   a v i s i t   /   s u b j e c t = u s u b j i d   t y p e = u n   r c o r r ;  
    l s m e a n s   t r t * w e e k   /   d i f f   c l   a l p h a = 0 . 0 5 ;  
r u n ;  
I n t h e  e v e nt t h e  M M R M  m o d el  wit h  a n  u nstr u ct ur e d  c o v ari a n c e str u ct ur e  d o es  n ot  c o n v er g e, t h e 
f oll o wi n g  c o v ari a n c e str u ct ur es  will  b e  as s u bstit uti o n i n t h e f oll o wi n g  or d er.   E a c h s u bs e q u e nt 
c o v ari a n c e str u ct ur e  will  b e  us e d  o nl y if  all  pr e vi o us  c o v ari a n c e str u ct ur e(s) is ( ar e)  us e d  a n d t h e 
m o d el(s)  di d  n ot  c o n v er g e. 


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  2 2  of  3 8  
 
1.   T o e plit z  c o v ari a n c e str u ct ur e ( ass u mi n g  m e as ur e m e nts fr o m s a m pl es t a k e n  cl os er 
t o g et h er i n ti m e  ar e  m or e  hi g hl y  c orr el at e d t h a n t h os e fr o m s a m pl es t a k e n f art h er  a p art). 
2.   First  or d er  of  a ut o -r e gr essi v e [ A R( 1)] c o v ari a n c e  str u ct ur e ( ass u mi n g  m e as ur e m e nts fr o m 
s a m pl es t a k e n  cl os er t o g et h er i n ti m e  ar e  m or e  hi g hl y  c orr el at e d t h a n t h os e fr o m s a m pl es 
t a k e n f art h er  a p art). 
3.   C o m p o u n d s y m m etr y  c o v ari a n c e  str u ct ur e ( ass u mi n g  e q u al  c orr el ati o n f or  m e as ur e m e nts 
fr o m  a  p ati e nt, r e g ar dl ess  of  h o w f ar  a p art i n ti m e  w h e n t h e y w er e t a k e n).   
6. 1. 3   R e p o rti n g  R es ults  
T h e l e ast s q u ar es ( L S)  m e a n, st a n d ar d  err or ( S E)  of t h e  L S  m e a n,  a n d t w o-si d e d  9 5 %  c o nfi d e n c e 
i nt er v al ( CI)  of t h e  L S  m e a n  a n d  p-v al u e  will  b e r e p ort e d  at  e a c h ti m e  p oi nt f or ( 1)  e a c h  d os e 
l e v el  of  R T A  4 0 8 a n d ( 2) t h e  diff er e n c e  b et w e e n  e a c h  d os e  a n d  pl a c e b o.   F or  p art  1  of t h e st u d y, 
st atisti c al t esti n g  will  b e  p erf or m e d  at  e v er y ti m e  p oi nt t h at  p e a k  w or k is  m e as ur e d.   T h e 
diff er e n c e  b et w e e n  R T A  4 0 8  a n d  pl a c e b o i n  c h a n g e fr o m  b as eli n e i n  p e a k  w or k  at  W e e k  1 2 t est 
is t h e  pri m ar y  e n d p oi nt.   T h e  m e a n  c h a n g e fr o m  b as eli n e i n p e a k  w or k  at  all  ot h er ti m e  p oi nts 
will  b e  c o nsi d er e d  e x pl or at or y, s o t ests  at t h es e ti m e  p oi nts  will  b e  p erf or m e d  wit h  n o 
a dj ust m e nts f or  m ulti pl e  c o m p aris o ns.   
A  pl ot  of t h e  L S  m e a n  diff er e n c e s  wit h  9 5 %  CIs  of  c h a n g e fr o m  b as eli n e i n  e G F R  v al u e  o v er 
ti m e  will  b e  pr es e nt e d f or s el e ct e d  d os es.  
6. 2   S e c o n d a r y  Effi c a c y  
T h e s e c o n d ar y  e n d p oi nt  of t his st u d y is t h e  m o difi e d  c h a n g e i n  6- mi n ut e  w al k t est ( 6 M W T) 
dist a n c e  s c or e.  
T h e  b as eli n e  6 M W D  r es ult is t h e  a v er a g e  of  S cr e e ni n g  a n d  D a y  1  6 M W T  v al u es.  
P uls e  o xi m etr y  at r esti n g  a n d t h e  e n d  of t h e  6 M W T  will  b e s u m m ari z e d  usi n g s u m m ar y 
st atisti cs,  at  d es cri b e d i n  S e cti o n  3. 1 . 
T h e  c h a n g e fr o m  b as eli n e i n  6 M W T  wil l  b e  a n al y z e d  usi n g t h e s a m e  M M R M  m o d el  us e d f or t h e 
pri m ar y  effi c a c y  e n d p oi nt.   A n al ysis  visits  0,  4,  8  a n d  1 2  will  b e  us e d.   T h e  p air wis e  d os e  gr o u p 
c o m p aris o ns  wit h  pl a c e b o  will  b e  esti m at e d  usi n g t h e  diff er e n c e i n  a dj ust e d  m e a ns  a n d  9 5 %  CI 
f or t h e diff er e n c e i n  c h a n g es fr o m  b as eli n e t o  W e e k   1 2.  
 
6. 3   E x pl o r at o r y  Effi c a c y  
S u m m ar y st atisti cs  a n d  9 5 %  c o nfi d e n c e i nt er v als f or tr e at m e nt  diff er e n c es  i n  m e a n  c h a n g e fr o m 
b as eli n e ,  usi n g t h e s a m e M M R M   m o d el  us e d f or t h e  pri m ar y  a n d s e c o n d ar y  e n d p oi nts, will  b e 
pr o vi d e d f or  all  e x pl or at or y  e n d p oi nts  u nl ess  ot h er wis e  n ot e d.   P- v al u es  will  b e  pr o vi d e d f or 
d es cri pti v e  p ur p os es  o nl y. 
F or  p ar a m et ers  h a vi n g r e p e at e d  m e as ur e m e nts  wit hi n  a n  a n al ysis  visit  d uri n g t h e  m a xi m al  a n d 
s u b m a xi m al  e x er cis e t est, t h e  M M R M  c o d e s h o ul d i n c or p or at e t h e  a n al ysis  visit  a n d  ass ess m e nt 
ti m e ( d uri n g t h e  e x er cis e t est) i n t h e  a n al ysis: 
P r o c   M i x e d   d a t a = x   o r d e r = d a t a ;  
    C l a s s   p a t n o   t r t   w e e k ;  
    m o d e l   r e s p   =     t r t * t i m e * w e e k   / s ;  
    R e p e a t e d   t i m e * w e e k   /   s u b   =   p a t n o   t y p e   =   u n ;  


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  2 3  of  3 8  
 
    l s m e a n s   t r t * t i m e * w e e k   /   d i f f   c l   a l p h a = 0 . 0 5 ;  
    R u n ;  
 
F or  bl o o d l a ct at e  m e as ur e m e nts  d uri n g t h e s u b m a xi m al  e x er cis e t est, t h e r e p e at e d  m e as ur es 
m o d el  will i n c or p or at e  b as eli n e r esti n g  bl o o d l a ct at e  as  a  c o v ari at e:  
P r o c   M i x e d   d a t a = x   o r d e r = d a t a ;  
    C l a s s   p a t n o   t r t   w e e k ;  
    m o d e l   r e s p   =     t r t * t i m e * w e e k   b a s e l i n e _ r e s t i n g _ l a c t a t e   / s ;  
    R e p e a t e d   t i m e * w e e k   /   s u b   =   p a t n o   t y p e   =   u n ;  
    l s m e a n s   t r t * t i m e * w e e k   /   d i f f   c l   a l p h a = 0 . 0 5 ;  
    R u n ;  
As  wit h t h e  pri m ar y  a n d s e c o n d ar y  e n d p oi nts,  e x pl or at or y  e n d p oi nts  will  b e  a n al y z e d  usi n g 
i n di vi d ual   d os es  of  R T A  4 0 8  v ers us  pl a c e b o  p o ol e d.   A s e p ar at e  m o d el t h at  d o es  n ot  p o ol t h e 
R T A  4 0 8  d os es  will  b e  us e d t o  o bt ai n  p air wis e  diff er e n c es  f or  e a c h  d os e l e v el  v ers us  p o ol e d 
pl a c e b o . 
F or  p ar a m et ers  h a vi n g r e p e at e d  m e as ur e m e nts  wit hi n  a n  a n al ysis  visit  d uri n g t h e  m a xi m al  a n d 
s u b m a xi m al  e x er cis e t est,  t h e  c h a n g e fr o m r esti n g ( d elt a) f or  p ar a m et ers  m e as ur e d  at r esti n g  a n d 
a  c ert ai n ti m e p oi nt  d uri n g t h e  m a xi m al  or s u b m a xi m al  e x er cis e t est  will  b e r e p ort e d  as:  
•  
D elt a  = [ P ar a m et er  at  Y  mi n ] –  [ P ar a m et er  at r esti n g] 
I n t h e  m a xi m al  e x er cis e t est, l a b or at or y  m e as ur e m e nts  m a y  b e  m e as ur e d  at r esti n g,  at t h e  e n d  of 
t h e  m a xi m al  e x er cis e t est,  5  mi n  aft er t h e  e n d  of t h e  m a xi m al  e x er cis e t est,  a n d  1 0  mi n  aft er t h e 
e n d  of t h e  m a xi m al  e x er cis e t est.  
I n t h e s u b m a xi m al  e x er cis e t est,  effi c a c y  a n d l a b or at or y  m e as ur e m e nts  ar e r e c or d e d  at r esti n g,  at 
1 0  mi n,  2 0  mi n,  a n d  3 0  mi n.  
T h e  c h a n g e fr o m  b as eli n e is  d efi n e d f or  p ar a m et ers  m e as ur e d  at r esti n g  a n d  a  c ert ai n ti m e p oi nt 
d uri n g t h e  m a xi m al  of s u b m a xi m al  e x er cis e t est is  d efi n e d  as:  
•  
C h a n g e fr o m  B as eli n e i n  D elt a = [ P ar a m et er  at  Y ( At  Visit  X)  - P ar a m et er  at r esti n g( At 
Visit  X)]  - [ P ar a m et er  at  Y  mi n ( At  B as eli n e) - P ar a m et er  at r esti n g( At  B as eli n e)]  
 
 


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  2 4  of  3 8  
 
6. 3. 1   Ot h e r  M a xi m al  E x e r cis e  T esti n g  M e as u r es (i n cl u di n g  O x y g e n  Utili z ati o n ) 
V ari o us  p ar a m et ers i n  a d diti o n t o  p e a k  w or k  ar e  ass ess e d  d uri n g  m a xi m al  e x er cis e t esti n g,  as 
list e d  b el o w i n T a bl e  2 .  
T a bl e  2 :  M a xi m al  E x e r cis e  T esti n g  M e as u r es 
P a r a m et e r 
At  R est ( P ri o r 
t o  T est) 
At  M a xi m al 
W o r k ( E n d  of 
T est)  
E x pir e d  Air  G as  V ol u m e ( V e B T P S)  (  L/ mi n ) a 
X 
X 
C ar di a c  O ut p ut (  L/ mi n ) a 
X 
X 
H e art  R at e (  b p m ) a 
X 
X 
O x y g e n  S at ur ati o n ( S p O 2) ( %)  
X 
X 
Di ast oli c  Bl o o d  Pr ess ur e (  m m H g ) a 
X 
X 
S yst oli c  Bl o o d  Pr ess ur e (  m m H g ) a 
X 
X 
C ar b o n  Di o xi d e  Pr o d u cti o n ( V C O 2) (  m L/ k g/ mi n )a,  b 
X 
X 
O x y g e n  C o ns u m pti o n ( V O 2) (  m L/ k g/ mi n )a,  b 
X 
X 
Art eri o v e n o us  O x y g e n  Diff er e n c e ( a- V O 2 diff)  (  m L O 2/ dl Q ) a  
X 
X 
R es pir at or y  E x c h a n g e  R ati o  
X 
X 
B or g  
  
X 
L e g  Eff ort  R ati n g  of  P er c ei v e d  E x erti o n   
  
X 
E x er cis e  D ur ati o n (  mi n ) 
  
X 
M a xi m al  w or k (  W/ k g ) 
  
X 
M a xi m al  w or kl o a d (  W )  
  
X 
O 2  p uls e (  % ) c 
  
X 
aO bs er v e d  v al u es  a n d  diff er e n c e  b et w e e n r esti n g  a n d  p e a k  p erf or m a n c e f or t h es e  p ar a m et ers  will  b e s u m m ari z e d  at 
b as eli n e  a n d  at  e a c h ti m e p oi nt.   
b A n al ysis  of  V O 2 a n d  V C O 2 will  b e  p erf or m e d  usi n g  a dj ust m e nts f or  w ei g ht  at t h e  visit  w e e k i n  w hi c h t h e  m a xi m al 
e x er cis e t est  w as  p erf or m e d , s u c h t h at V O 2 a n d  V C O 2 ar e i n  u nits  of  m L/ k g/ mi n  
c  O 2 p uls e  will  b e  c al c ul at e d f or  a n al ysis:   O 2 p uls e  = ( M a xi m al _ V O 2 (i n  u nits  of  m L/ mi n) * 1 0 0 0)/ M a xi m al _ H R) 
 
F or  p ar a m et ers  m e as ur e d  at r esti n g  a n d  at t h e  e n d  of t h e  m a xi m al  e x er cis e t est, t h e  c h a n g e fr o m 
r esti n g  a n d t h e  c h a n g e fr o m  b as eli n e s h o ul d  b e  c al c ul at e d.  
T h e  c h a n g e fr o m r esti n g ( d elt a) f or  p ar a m et ers  m e as ur e d  at r esti n g  a n d  at t h e  e n d  of t h e  m a xi m al 
e x er cis e t est is  d efi n e d  as:  
•   D elt a  =  P ar a m et er  at  m a xi m al  w or k  - P ar a m et er  at  r esti n g 
 
T h e  c h a n g e fr o m  b as eli n e is  d efi n e d f or  p ar a m et ers  m e as ur e d  at r esti n g  a n d  at t h e  e n d  of t h e 
m a xi m al  e x er cis e t est is  d efi n e d  as:  


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  2 5  of  3 8  
 
•   C h a n g e fr o m  b as eli n e i n  D elt a = [ P ar a m et er  at  m a xi m al  w or k( At  Visit  X)  - P ar a m et er  at 
r esti n g( At  Visit  X)] - [ P ar a m et er  at  m a xi m al  w or k( At  B as eli n e) - P ar a m et er  at r esti n g( At 
B as eli n e)]  
O bs er v e d  v al u es  a n d  diff er e n c e  b et w e e n  r esti n g  a n d p e a k  p erf or m a n c e f or t h es e  p ar a m et ers  will 
b e s u m m ari z e d  at  b as eli n e  a n d  at  e a c h ti m e p oi nt.  F or  all  ass ess m e nts,  e a c h  p ar a m et er  will  b e  
s u m m ari z e d  at  b as eli n e  a n d  at  e a c h ti m e  p oi nt  al o n g  wit h t h e  c h a n g e fr o m  b as eli n e  b y tr e at m e nt. 
F or  p ar a m et ers  m e as ur e d  at r esti n g  a n d  at t h e  e n d  of t h e  m a xi m al  e x er cis e t est [ V e B T P S,  c ar di a c 
o ut p ut,  h e art r at e,  V O 2 ( L/ mi n)  a n d  V O2 ( ml/ m g/ mi n), V C O 2 ( L/ mi n)  a n d  V C O2 ( ml/ m g/ mi n), 
di ast oli c  bl o o d  pr ess ur e, s yst oli c  bl o o d  pr ess ur e,  a- V O 2diff ,  a n d  S P O2  ( %)], t h e  c h a n g e fr o m 
r esti n g  a n d t h e  c h a n g e fr o m  b as eli n e s h o ul d  b e  c al c ul at e d.  
T h e  c h a n g e fr o m r esti n g  ( d elt a) for  p ar a m et ers  m e as ur e d  at r esti n g  a n d  at t h e  e n d  of t h e  m a xi m al 
e x er cis e t est is  d efi n e d  as:  
•   D elt a  =  P ar a m et er  at  m a xi m al  w or k  - P ar a m et er  at r esti n g  
T h e  c h a n g e fr o m  b as eli n e is  d efi n e d f or  p ar a m et ers  m e as ur e d  at r esti n g  a n d  at t h e  e n d  of t h e 
m a xi m al  e x er cis e t est is  d efi n e d  as:  
•   C h a n g e fr o m  b as eli n e  i n  D elt a = [ P ar a m et er  at  m a xi m al  w or k( At  Visit  X) - P ar a m et er  at 
r esti n g( At  Visit  X)] - [ P ar a m et er  at  m a xi m al  w or k( At  B aseli n e)  - P ar a m et er  at r esti n g( At 
B as eli n e)]  
O nl y s u m m ar y st atisti cs  will  b e  pr o vi d e d.   
6. 3. 2   M a xi m al  E x e r cis e  T esti n g  L a b o r at o r y  P a r a m et e rs  
T h e f oll o wi n g  s eri al l a b or at or y p ar a m et ers  ar e  ass ess e d  at r esti n g,  at  p e a k  w or k,  5  mi n ut es  aft er 
r e a c hi n g  p e a k  w or k,  a n d  1 0  mi n ut es  aft er r e a c hi n g  p e a k  w or k.  Th e  M M R M  a n al ysis  s h o ul d 
i n c or p or at e t h e  visit  a n d ti m e ( d uri n g t h e  e x er cis e t est) i nt er a cti o n f or  m a xi m al  e x er cis e t esti n g 
l a b or at or y  p ar a m et ers,  as  d es cri b e d i n  S e cti o n 6. 3 . 
T a bl e  3 :  L a b o r at o r y  P a r a m et e rs  C oll e ct e d  D u ri n g  M a xi m al  E x e r cis e  T esti n g 
P a r a m et e r 
At  R est 
( P ri o r t o 
T est)  
At  M a xi m al 
W o r k ( E n d 
of  T est)  
5  mi n 
Aft e r  E n d 
of  T est  
1 0  mi n 
Aft e r  E n d 
of  T est  
Bl o o d  Gl u c os e (  m g/ d L )  
X  
X  
X   
X  
Bl o o d  L a ct at e (  m M )  
X  
X  
X   
X  
Bl o o d  P yr u v at e (  m M )  
X  
X  
X   
X  
Bl o o d  P ot assi u m (  m M/ L )  
X  
X  
X   
X  
 
O bs er v e d  v al u es  a n d  diff er e n c e  b et w e e n r esti n g  a n d  0,  5,  or  1 0  mi n ut es  aft er  p e a k  p erf or m a n c e 
f or t h es e  p ar a m et ers  will  b e s u m m ari z e d  at  b as eli n e  a n d  at  e a c h ti m e p oi nt.  F or  p ar a m et ers 
m e as ur e d  at r esti n g  a n d  0,  5,  or  1 0  mi n ut es  aft er t h e  e n d  of t h e  m a xi m al  e x er cis e t est, t h e  c h a n g e 
fr o m r esti n g  a n d t h e  c h a n g e fr o m  b as eli n e s h o ul d  b e  c al c ul at e d.  
T h e  c h a n g e fr o m r esti n g ( d elt a) f or  p ar a m et ers  m e as ur e d  at r esti n g  a n d  1 0  mi n  aft er t h e  e n d  of 
t h e  m a xi m al  e x er cis e t est is  d efi n e d  as: 
•   D elt a  =  [P ar a m et er  at  0,  5,  or  1 0  mi n  aft er  e n d  of  e x er cis e t esti n g ]  – [P ar a m et er  at 
r estin g] 


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  2 6  of  3 8  
 
T h e  c h a n g e fr o m  b as eli n e is  d efi n e d f or  p ar a m et ers  m e as ur e d  at r esti n g  a n d  0,  5,  or  1 0   mi n  aft er 
t h e  e n d  of t h e  m a xi m al  e x er cis e t est is  d efi n e d  as: 
•   C h a n g e fr o m  B as eli n e i n  D elt a = [ P ar a m et er  at  Y  mi n  aft er  e n d  of  e x er cis e t esti n g( At 
Visit  X)  - P ar a m et er  at r esti n g( At  Visit  X)]  - [ P ar a m et er  at Y  mi n  aft er  e n d  of  e x er cis e 
t esti n g( At  B as eli n e) - P ar a m et er  at r esti n g( At  B as eli n e)]  
S u m m ar y st atisti cs  at r esti n g,  at  t h e  c o m pl eti o n  of t h e m a xi m al  e x er cis e t est,  5  mi n ut es  aft er 
e x er cis e t est,  a n d  1 0  mi n ut es  aft er  e x er cis e t est  will  b e  pr o vi d e d.   
6. 3. 3   S u b m a xi m al  E x e r cis e  T esti n g  P a r a m et e rs  
T h e f oll o wi n g  p ar a m et ers  ar e  ass ess e d  at r esti n g,  at  1 0  mi n ut es,  2 0  mi n ut es,  a n d  3 0  mi n ut es 
d uri n g t h e s u b m a xi m al  e x er cis e t est.  
T a bl e  4 :  S u b m a xi m al  E x e r cis e  T esti n g  P a r a m et e rs  
P a r a m et e r 
At  R est 
( P ri o r t o 
T est)  
1 0 
mi n ut es  
2 0 
mi n ut es  
3 0 
mi n ut es 
( E n d  of 
T est)  
B or g  
   
X   
X   
X  
L e g  Eff ort  R ati n g  of  P er c ei v e d  E x erti o n   
   
X   
X   
X  
H e art  R at e (  b p m ) a 
X   
X   
X   
X  
 C ar b o n  Di o xi d e  Pr o d u cti o n ( V C O 2) (  m L/ k g/ mi n )a, b 
X   
X   
X   
X  
O x y g e n  C o ms u m pti o n ( V O 2) (  m L/ k g/ mi n )a, b 
X   
X   
X   
X  
E x pir e d  Air  G as  V ol u m e ( V e B T P S) (  L/ mi n ) a 
X   
   
   
X  
C ar di a c  O ut p ut (  L/ mi n ) a 
X   
   
   
X  
Art eri o v e n o us  O x y g e n  Diff er e n c e ( a -V O 2 diff) (  m L O 2/ dl Q )a  
X   
   
   
X  
R es pir at or y  E x c h a n g e  R ati o a 
X   
   
  
X  
St arti n g  W or kl o a d (  W )  
X   
   
   
  
E x er cis e  D ur ati o n (  mi n )  
   
   
  
X  
Fi n al  W or kl o a d (  W )  
   
   
  
X  
aO bs er v e d  v al u es  a n d  diff er e n c e  b et w e e n r esti n g  a n d  3 0  mi n ut es f or t h es e  p ar a m et ers  will  b e s u m m ari z e d  at 
b as eli n e  a n d  at  e a c h ti m e p oi nt.  F or  p ar a m et ers  m e as ur e d  at r esti n g  a n d  at t h e  e n d  of t h e s u b m a xi m al  e x er cis e t est 
(f or  p ati e nts  w h o  c o m pl et e  3 0  mi n ut es  of t h e t est), t h e  c h a n g e fr o m r esti n g  a n d t h e  c h a n g e fr o m  b as eli n e s h o ul d  b e 
c al c ul at e d.   
b A n al ysis  of  V O 2 a n d  V C O 2 will  b e  p erf or m e d  usi n g  a dj ust m e nts f or  w ei g ht  at t h e  visit  w e e k i n  w hi c h t h e 
s u b m a xi m al  e x er cis e t est  w as  p erf or m e d  
 
T h e  c h a n g e fr o m r esti n g ( d elt a) f or  p ar a m et ers  m e as ur e d  at r esti n g  a n d  at t h e  e n d  of t h e 
s u b m a xi m al  e x er cis e t est is  d efi n e d  as:  
•   D elt a  =  P ar a m et er  at  1 0,  2 0,  or  3 0  mi n  - P ar a m et er  at r esti n g  
T h e  c h a n g e fr o m  b as eli n e is  d efi n e d f or  p ar a m et ers  m e as ur e d  at r esti n g  a n d  at t h e   e n d  of t h e 
s u b m a xi m al  e x er cis e t est is  d efi n e d  as:  
•   C h a n g e fr o m  b as eli n e i n  D elt a = [ P ar a m et er  at  Y  mi n ( At  Visit  X)  - P ar a m et er  at 
r esti n g( At  Visit  X)] - [ P ar a m et er  at Y  mi n ( At  B as eli n e)  - P ar a m et er  at r esti n g( At 
B as eli n e)]  
S u m m ar y st atisti cs  at r esti n g,  at  1 0  mi n ut es,  2 0  mi n ut es,  a n d  3 0  mi n ut es  will  b e  pr o vi d e d.  


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  2 7  of  3 8  
 
T h e  M M R M  a n al ysis  s h o ul d i n c or p or at e t h e  visit  a n d ti m e ( d uri n g t h e  e x er cis e t est) i nt er a cti o n 
f or  c h a n g e fr o m  b as eli n e  h e art r at e,  as  d es cri b e d i n  S e cti o n 6. 3  .  
T h e  c h a n g e fr o m  b as eli n e r esti n g  h e art r at e is  d efi n e d  as:  
•   C h a n g e fr o m  b as eli n e i n  H e art  R at e = [ H e art  R at e  at  Y  mi n ( At  Visit  X)  - H e art  R at e  at 
r esti n g( At  Visit  X)] - [H e art  R at e  at  Y  mi n ( At  B as eli n e)  - H e art  R at e  at r esti n g( At 
B as eli n e)]  
A n al ysis  visits  0,  4,  8  a n d  1 2  will  b e  us e d.   T h e  p air wis e  d os e  gr o u p  c o m p aris o ns  wit h  pl a c e b o 
will  b e  esti m at e d  usi n g t h e  diff er e n c e i n  a dj ust e d  m e a ns  a n d  9 5 %  CI f or t h e  diff er e n c e i n 
c h a n g es fr o m  b as eli n e t o  W e e k  1 2.  
6. 3. 4   S u b m a xi m al  E x e r cis e  T esti n g  L a b o r at o r y  P a r a m et e rs  
T h e f oll o wi n g l a b or at or y  p ar a m et ers  ar e  ass ess e d  at r esti n g,  at  1 0  mi n ut es,  2 0  mi n ut es,  a n d  3 0 
mi n ut es  d uri n g t h e s u b m a xi m al  e x er cis e t est. 
P a r a m et e r 
At  R est 
( P ri o r t o 
T est)  
1 0  mi n ut es   
2 0  mi n ut es  
3 0  mi n ut es 
( E n d  of  T est) 
Bl o o d  Gl u c os e (  m g/ d L ) a 
X  
X  
X  
X  
Bl o o d  L a ct at e (  m M ) a 
X  
X  
X  
X  
Bl o o d  P yr u v at e (  m M ) a 
X  
X  
X  
X  
aO bs er v e d  v al u es  a n d  diff er e n c e  b et w e e n r esti n g  a n d  3 0  mi n ut es f or t h es e  p ar a m et ers  will  b e 
s u m m ari z e d  at  b as eli n e  a n d  at  e a c h ti m e p oi nt.  F or  p ar a m et ers  m e as ur e d  at r esti n g  a n d  at t h e  e n d 
of t h e s u b m a xi m al  e x er cis e t est (f or  p ati e nts  w h o  c o m pl et e  3 0  mi n ut es  of t h e  t est), t h e  c h a n g e 
fr o m r esti n g  a n d t h e  c h a n g e fr o m  b as eli n e s h o ul d  b e  c al c ul at e d.  
T h e  c h a n g e fr o m r esti n g ( d elt a) f or  p ar a m et ers  m e as ur e d  at r esti n g  a n d  at t h e  e n d  of t h e 
s u b m a xi m al  e x er cis e t est is  d efi n e d  as:  
•   D elt a  =  P ar a m et er  at  1 0,  2 0,  or  3 0  mi n  - P ar a m et er  at r esti n g  
T h e  c h a n g e fr o m  b as eli n e is  d efi n e d f or  p ar a m et ers  m e as ur e d  at r esti n g  a n d  at t h e  e n d  of t h e 
s u b m a xi m al  e x er cis e t est is  d efi n e d  as:  
•   C h a n g e fr o m  b as eli n e i n  D elt a = [ P ar a m et er  at  Y  mi n ( At  Visit  X)  - P ar a m et er  at 
r esti n g( At  Visit  X)] - [ P ar a m et er  at Y  mi n ( At  B as eli n e)  - P ar a m et er  at r esti n g( At 
B as eli n e)]  
S u m m ar y st atisti cs  at r esti n g,  at  1 0  mi n ut es,  2 0  mi n ut es,  a n d  3 0  mi n ut es  will  b e  pr o vi d e d.  
T h e  M M R M  a n al ysis  of  c h a n g e fr o m  b as eli n e  bl o o d l a ct at e  s h o ul d i n c or p or at e t h e  visit  a n d ti m e 
( d uri n g t h e  e x er cis e t est) i nt er a cti o n f or s u bm a xi m al  e x er cis e t esti n g l a b or at or y  p ar a m et ers,  as 
d es cri b e d i n  S e cti o n  6. 3  .  
T h e  c h a n g e fr o m r esti n g  bl o o d l a ct at e  is  d efi n e d  as: 
•   C h a n g e fr o m  b as eli n e i n  Bl o o d  L a ct at e = [ Bl o o d  L a ct at e  at  Y  mi n ( At  Visit  X)  -  Bl o o d 
L a ct at e  at r esti n g( At  Visit  X)]  - [ Bl o o d  L a ct at e  at Y  mi n ( At  B as eli n e)  -  Bl o o d  La ct at e  at 
r esti n g( At  B as eli n e)] 




S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  2 9  of  3 8  
 
7.   S A F E T Y  A N A L Y SI S  
S af et y  a n d t ol er a bilit y  ar e  e v al u at e d  b y  A E s, S A Es,  cli ni c al  l a b or at or y t est r es ults,  b o d y  w ei g ht, 
vit al si g n,   1 2-l e a d  el e ctr o c ar di o gr a m [E C G ],  e c h o c ar di o gr a m,  a n d  p h ysi c al e x a mi n ati o n  
ass ess m e nts.   All  a n al ys es  of t h e s af et y  d at a  will  b e  p erf or m e d  usi n g t h e  s af et y  a n al ysis s et.  
D es cri pti v e st atisti cs ( d es cri b e d i n  S e cti o n  3)  will  b e  pr es e nt e d  b y tr e at m e nt  gr o u p  assi g n m e nt i n 
t h e s af et y  a n al ysis s et. 
7. 1   A d v e rs e  E v e nts  a n d  S e ri o us  A d v e rs e  E v e nts  
All  a d v ers e  e v e nt  v er b ati m t er ms  o n  e C R Fs  will  b e  m a p p e d t o  pr ef err e d t er ms  a n d s yst e m  or g a n 
cl ass es  usi n g  t h e M e di c al  Di cti o n ar y f or  R e g ul at or y  A cti viti es  ( M e d D R A® )  Di cti o n ar y ( v ersi o n 
1 4. 0 ).  All r e p ort e d  A Es,  S A Es,  a n d  d e at hs  will  b e list e d  i n s e p ar at e  p ati e nt listi n gs. 
7. 1. 1   G e n e r al   C o nsi d e r ati o ns f o r  A n al ysis  of  A d v e rs e  E v e nts 
G e n er al  c o nsi d er ati o ns f or  A E s u m m ari es  a n d  c al c ul ati o ns  ar e:  
•   M ulti pl e  e v e nts  b y  pr ef err e d t er m ( P T ) a n d  s yst e m  or g a n  cl ass (S O C)  will  b e  c o u nt e d  o n c e 
o nl y  p er  p ati e nt  f or e a c h  tr e at m e nt. 
•   F or s u m m ari es  b y s e v erit y,  o nl y  t h e  m ost s e v er e  e v e nt  will  b e c o u nt e d  p er  p ati e nt  f or  e a c h 
tr e at m e nt. 
•   F or s u m m ari es  b y r el ati o ns hi p ,  o nl y t h e  m ost r el at e d e v e nt  will  b e  c o u nt e d  p er  p ati e nt  f or 
e a c h tr e at m e n t. 
•   A n  A E  wit h  a  missi n g r es ol uti o n  d at e  or i n c o m pl et e  d at e t h at is  n ot i d e ntifi e d  as  c o nti n ui n g 
will  b e  ass u m e d t o  b e  c o nti n ui n g  a n d  n o  d ur ati o n  will  b e  c al c ul at e d. 
•   A Es  will  b e s u m m ari z e d  b y t h e  hi g h est  d os e r e c ei v e d. 
•   O nl y tr e at m e nt -e m er g e nt  a d v ers e  e v e nts  ( T E A Es)  will  b e i n cl u d e d i n s u m m ari es. 
7. 1. 2   T r e at m e nt -E m e r g e nt  A d v e rs e  E v e nts  
T r e at m e nt- e m er g e nt  A Es ( T E A Es)  ar e  d efi n e d  as  a n y  A Es, r e g ar dl ess  of r el ati o ns hi p t o st u d y 
dr u g, t h at  h a v e  a n  o ns et  or  w ors e n i n s e v erit y  o n  or  aft er t h e first  d os e  of st u d y  dr u g.  If it  c a n n ot 
b e  d et er mi n e d  w h et h er t h e  A E is tr e at m e nt -e m er g e nt  d u e t o  a  p arti al  o ns et  d at e, t h e n it  will  b e 
c o u nt e d  as  a  T E A E.   A d v ers e  e v e nts  wit h i n c o m pl et e st art  d at es  will  b e  c o nsi d er e d  T E A E s, if: 
•   O ns et ti m e is  missi n g  b ut t h e  o ns et  d at e is  o n  St u d y  D a y  1. 
•   D a y  a n d  m o nt h  ar e  missi n g  a n d t h e  y e ar is  e q u al t o  or  aft er t h e  y e ar  of t h e first  d at e  of 
st u d y  dr u g  d osi n g;  
•   D a y is  missi n g  a n d t h e  y e ar is  aft er t h e  y e ar  of t h e first  d at e  of st u d y  dr u g  d osi n g;  
•   D a y is  missi n g  a n d t h e  y e ar is  e q u al t o t h e  y e ar  of t h e first  d at e  of st u d y  dr u g  d osi n g  a n d 
t h e  m o nt h is  e q u al t o  or  aft er t h e  m o nt h  of t h e first  d at e  of st u d y  dr u g  d osi n g;  or 
•   Ye ar is  missi n g.  
7. 1. 3   R el at e d  A d v e rs e  E v e nts  
R el at e d  A Es  ar e t h os e  wit h r el ati o ns hi p t o st u d y  dr u g r e p ort e d  as  “ p ossi bl y r el at e d ”,  “ pr o b a bl y 
r el at e d ”,  or  “ d efi nit el y r el at e d ”.  If s e v erit y (r el ati o ns hi p)  of  a n  A E t o st u d y  dr u g is  n ot r e c or d e d, 
t h e s e v erit y (r el ati o ns hi p)  will  b e i m p ut e d  as ‘s e v er e’ (‘d efi nit el y r el at e d ’). 


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  3 0  of  3 8  
 
7. 1. 4   S u m m a r y  of  T r e at m e nt -E m e r g e nt  A d v e rs e  E v e nts  a n d  S e ri o us  A d v e rs e  E v e nts  
All  T E A E s u m m ar y t a bl es  will  i n cl u d e t h e  n u m b er  a n d  p er c e nt a g es  of p ati e nt s r e p orti n g  T E A Es.  
A s u m m ar y  of  T E A Es  b y s e v erit y, s eri o us n ess,  a n d r el ati o n t o st u d y  dr u g  will  b e t a b ul at e d.  I n 
a d diti o n,  T E A Es  will  b e s u m m ari z e d  b y  M e d D R A  s yst e m  or g a n  cl ass  a n d  pr ef err e d t er m .  
P ati e nt s c a n   h a v e  m or e t h a n  o n e T E A E  p er s yst e m  or g a n  cl ass  a n d  pr ef err e d t er m .  T h es e 
s u m m ari es  will i n cl u d e t h e f oll o wi n g:  
•   All  T E A Es  
•   T E A Es  b y  w orst s e v erit y  
•   R el at e d  T E A Es  
•   T E A Es  l e a di n g t o st u d y  dr u g i nt err u pti o n (if  a n y) 
•   T E A Es  l e a di n g t o st u d y  dr u g  dis c o nti n u ati o n (if  a n y) 
•   All tr e at m e nt -e m er g e nt  S A Es  
•   Tr e at m e nt -e m er g e nt  S A Es   b y  w orst s e v erit y 
•   R el at e d tr e at m e nt -e m er g e nt  S A Es.  
At  e a c h l e v el  of  p ati e nt  s u m m ari z ati o n,  a  p ati e nt  is  c o u nt e d  o n c e if  h e/s h e r e p ort e d  o n e  or  m or e 
T E A E  at t h at l e v el.   If  a p ati e nt  r e p ort e d t h e s a m e T E A E   o n  m ulti pl e  o c c asi o ns, t h e  hi g h est 
s e v erit y (s e v er e  >  m o d er at e  >  mil d )  or st u d y  dr u g r el ati o ns hi p ( r el at e d  >  pr o b a bl e  >  p ossi bl e > 
u nli k el y  >  u nr el at e d) r e c or d e d f or t h e  e v e nt  will  b e  s u m m ari z ed.   E a c h s u m m ar y  will  b e  or d er e d 
b y  d es c e n di n g  or d er  of i n ci d e n c e  of  s yst e m  or g a n  cl ass  a n d  pr ef err e d t er m  wit hi n  e a c h s yst e m 
or g a n  cl as s.  
7. 2   Cli ni c al  L a b o r at o r y  E v al u ati o ns 
Cli ni c al l a b or at or y  r es ults (i n cl u di n g  c h e mistr y,  h e m at ol o g y,  uri n e  p H,  a n d  uri n e s p e cifi c 
gr a vit y)  fr o m t h e  c e ntr al l a b or at or y a n d  c h a n g e fr o m  b as eli n e  will  b e s u m m ari z e d  usi n g 
d es cri pti v e st atisti cs  at  e a c h s c h e d ul e d ti m e  p oi nt.   P ost- b as eli n e l a b or at or y  ass ess m e nts  missi n g 
or  b el o w  L L D  will  n ot  b e i m p ut e d,  u nl ess  ot h er wis e s p e cifi e d i n  S e cti o n  3.  B o x  pl ot  gr a p hs  a n d 
li n e  gr a p hs  m a y  b e  g e n er at e d f or s el e ct e d l a b or at or y t ests, s u c h  as  A L T,  A S T,  G G T, cr e ati n e 
ki n as e ( C K) ,  a n d f erriti n.   Li n e  gr a p hs  will i n cl u d e  m e a n  ±  S E  o v er ti m e f or  b ot h t h e  o bs er v e d 
v al u es  a n d f or t h e  c h a n g e fr o m  b as eli n e  v al u es. 
I n  a d diti o n,  a s u m m ar y t a bl e  will  b e  pr o vi d e d f or  n u m b er  a n d  p er c e nt a g e  of  p ati e nts  m e eti n g t h e 
f oll o wi n g  pr e-s p e cifi e d t hr es h ol d l e v el  at  a n y ti m e  d uri n g t h e st u d y.  
T a bl e  5:  P r e -S p e cifi e d  T h r es h ol d  L e v els f o r  C at e g o ri c al  L a b o r at o r y  S u m m a ri es  
L a b  P a r a m et e r   
P r e -S p e cifi e d  L e v el  
M a g n esi u m   
<  1. 3  m E q/ L ( 0. 6 5  m m ol/ L)  
B N P  
>  2 0 0  p g/ m L  
A L T,  A S T   
>  3  ×  u p p er li mit  of  n or m al ( U L N)  
A L T,  A S T   
>  8  ×  U L N  
A L T,  A S T   
>  5  ×  U L N f or  m or e t h a n  2  w e e ks  
A L T,  A S T,  T B L   
>  3  ×  U L N  a n d ( T B L  >  2  ×  U L N  ×  U L N ) 
 
Uri n al ysis  r es ults ( ot h er t h a n  p H  a n d s p e cifi c  gr a vit y) will  n ot  b e s u m m ari z e d .   


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  3 1  of  3 8  
 
All l a b or at or y r es ults (i n cl u di n g  pr e g n a n c y t est r es ults)  will  b e list e d .   L a b or at or y r es ults t h at ar e 
a b o v e  or  b el o w  n or m al li mits  will  b e fl a g g e d  i n t h e listi n gs.   
7. 3   Vit al  Si g ns  
D es cri pti v e st atisti cs f or  bl o o d  pr ess ur e,  h e art r at e, r es pir at or y r at e,  a n d t e m p er at ur e i n cl u di n g 
b as eli n e  v al u es  a n d  c h a n g e fr o m  b as eli n e  v al u es,  will  b e s u m m ari z e d  b y ti m e  p oi nt.   All  vit al 
si g ns  p ar a m et ers  will  b e list e d.    
7. 4   B o d y  W ei g ht 
D es cri pti v e st atisti cs f or  b o d y  w ei g ht t h at  ar e  c oll e ct e d  o n t h e  e C R F  a n d  c h a n g e fr o m  b as eli n e 
v al u es  will  b e  will  b e s u m m ari z e d  a n d list e d  b y ti m e  p oi nt.   B o x pl ot  a n d li n e  gr a p hs  of  c h a n g e 
fr o m  b as eli n e  o v er ti m e f or  w ei g ht  will  b e  pl ott e d. 
7. 5   E c h o c a r di o g r a m 
E c h o c ar di o gr a m  ( E C H O) d at a , s u c h  as  car di a c f u n cti o n [ ej e cti o n fr a cti o n  ( %), l eft  v e ntri c ul ar 
e n d - di ast oli c  p ost eri or  w all t hi c k n ess ( P W T d), left  v e ntri c ul ar  e n d -di ast oli c s e pt al t hi c k n ess 
( L V S T d), left  v e ntri c ul ar  e n d - di ast oli c i nt er n al  di m e nsi o n ( L VI D d), l eft  v e ntri c ul ar  e n d-s yst oli c 
i nt er n al  di m e nsi o n ( L VI Ds), left  atri al  a nt er o - p ost eri or  di m e nsi o n, Ri g ht  V e ntri c ul ar  W all 
T hi c k n ess i n  di ast ol e ( R V W T d), l eft  v e ntri cl e  m ass (i n d e x) ]  m e as ur e m e nts ar e  c oll e ct e d  o n t h e 
e C R F.   D es cri pti v e st atisti cs f or  o bs er v e d  v al u es  a n d  c h a n g e fr o m  b as eli n e  will  b e  pr es e nt e d f or 
e a c h  E C H O  ass ess m e nt.   
All  E C H O  p ar a m et ers  will  b e list e d.  
7. 6   El e ct r o c a r di o g r a m  
El e ctr o c ar di o gr a m ( E C G ) d at a, s u c h  as   ve ntri c ul ar r at e  ( b p m), P R  int er v al  ( ms), Q R S  d ur ati o n 
( ms), Q T  ( ms),  a n d Q T c ( ms ) ar e  c oll e ct e d  o n t h e  e C R F . D es cri pti v e st atisti cs f or  o bs er v e d 
v al u es  a n d  c h a n g e fr o m  b as eli n e  will  b e  pr es e nt e d f or  e a c h  E C G  ass ess m e nt.  
I n  a d diti o n, n u m b er  a n d  p er c e nt a g e  of  p ati e nts  wit h  a n y  a b n or m al  v al u es (i. e.,  a b o v e  a  pr e-
s p e cifi e d t hr es h ol d)  will  b e s u m m ari z e d   b y ti m e  p oi nt  a n d  o v er all  w hil e  o n st u d y  dr u g.   T h e  pr e-
s p e cifi e d l e v els  of  E C G  Q T c t hr es h ol ds  ar e  c o nsist e nt  wit h  F D A  g ui d a n c e ( S e e  T a bl e  6  b el o w ).   
T a bl e  6:  P r e -S p e cifi e d  T h r es h ol d  L e v els f o r  E C G  P a r a m et e rs  
E C G 
P a r a m et e r  
P r e -S p e cifi e d  L e v el  
P R  
> 2 0 0  ms e c  
Q T c F  
> 4 5 0,  > 4 8 0  or  > 5 0 0  ms e c,  > 3 0  or  > 6 0  ms e c i n cr e as e fr o m 
b as eli n e  
H e art r at e   
< 4 0,  > 1 0 0  b e ats/ mi n  
 
All  E C G  p ar a m et ers  will  b e list e d.   A n y  r es ults t h at  e x c e e d t h e  a b o v e l e v els ( pr o vi d e d i n t h e 
a b o v e  t a bl e) will  b e fl a g g e d  i n t h e listi n g. 


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  3 2  of  3 8  
 
7. 7   P h ysi c al  E x a mi n ati o n 
A b n or m al  cli ni c all y si g nifi c a nt fi n di n gs  will  b e r e p ort e d  as  M e di c al  Hist or y  or  A d v ers e  E v e nts 
d e p e n di n g  o n  d a y  of  o ns et.  A b n or m al  n o n- cli ni c all y si g nifi c a nt fi n di n gs fr o m  p h ysi c al 
e x a mi n ati o ns  will  b e list e d.   
7. 8   P r e g n a n c y  
A listi n g  will  b e  pr o vi d e d s er u m  a n d  uri n e  pr e g n a n c y r es ults  of  all  o n-st u d y  pr e g n a n ci es , if 
a p pli c a bl e . 
 






S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  3 5  of  3 8  
 
1 0.  R E F E R E N C E S   
Kr u p p  L B,  L a R o c c a  N G,  M uir- N as h J,  St ei n b er g  A D.  T h e  F ati g u e  S e v erit y  S c al e : A p pli c ati o n t o  p ati e nts 
w it h  m ulti pl e scl er osis  a n d  syst e mi c  l u p us  er yt h e m at os us.  Ar c h  N e ur ol  1 9 8 9; 4 6: 1 1 2 1- 1 1 2 3 
R atit c h  B,  O’ K ell y  M,  T osi ell o  R.  Missi n g  d at a i n  cli ni c al tri als: fr o m  cli ni c al  ass u m pti o ns t o st atisti c al 
a n al ysis  usi n g  p att er n  mi xt ur e  m o d els.   P h ar m  St at  2 0 1 3; 1 2: 3 3 7- 4 7. 


S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  3 6  of  3 8  
 
1 1.  A P P E N DI C E S  
 
A p p e n di x  1.     
List  of  L a b o r at o r y T ests  
A p p e n di x  2.     
P r o g r a m mi n g  S p e cifi c ati o ns 
 
  
 
  
 
 




 
S A P f or  P art  1  of  4 0 8 - C-1 4 0 3   
R e at a  P h ar m a c e uti c als , I n c.  
V ersi o n  1  D at e:  0 3 M ar 2 0 1 8  
P a g e  3 8  of  3 8  
 
A p p e n di x  2.    
P r o g r a m mi n g  S p e cifi c ati o ns 
C o nti n u o us  d at a  will  b e list e d  c orr es p o n di n g t o t h e  pr e cisi o n  m e as ur e d  or  c al c ul at e d. 
M e as ur es  of  c e ntr al t e n d e n c y  will  b e  pr es e nt e d  usi n g  o n e  a d diti o n al  d e ci m al  pl a c e t h a n t h e 
pr e cisi o n  of t h e  d at a.   V ari a bilit y s u m m ari es  will  b e   pr es e nt e d  usi n g t w o  a d diti o n al 
si g nifi c a nt  di gits r el ati v e t o t h e  pr e cisi o n  of t h e  u n d erl yi n g  d at a.  Q u artil es, t h e  mi ni m u m,  a n d 
t h e  m a xi m u m  will  b e  pr es e nt e d  usi n g t h e  pr e cisi o n  of t h e  d at a.  R o u n di n g f or  d eri v e d  v al u es 
s h o ul d  b e  o n e  a d diti o n al  d e ci m al  pl a c e  t o  w hi c h t h e r a w  d at a  w er e  e nt er e d.  F or i nst a n c e, if 
t h e r a w  d at a  ar e r o u n d e d t o t h e  0. 0 0 1  d e ci m al  pl a c e, t h e  d eri v e d  v al u es  m ust  b e r o u n d e d t o 
t h e  0. 0 0 0 1  d e ci m al  pl a c e.  
All  p er c e nt a g es  ar e t o  b e  e x pr ess e d  as i nt e g ers  wit h  o n e  d e ci m al  pl a c e.  T h e  c o n v e nti o n f or 
r o u n di n g  p er c e nt ag es is  as f oll o ws:  
•   V al u es  gr e at er t h a n  o r  e q u al t o  x. x 5 %  ar e r o u n d e d  u p 
•   V al u es  b et w e e n  0  a n d  x. x 5 %  ar e r o u n d e d  d o w n