Clinical trial NCT04102501
Conditions: Friedreich's Ataxia
Sponsor: Biojiva LLC
Start date: 2019-10-30; Completion date: 2021-08-23
Enrollment: 65 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the Efficacy, Long Term Safety and Tolerability of RT001 in subjects with Friedreich's Ataxia

Detailed description:
This is a randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, tolerability, in subjects with FRDA following the oral administration of study drug (active or placebo capsules). Sixty eligible patients will undergo various assessments at different time points during the the study. The study duration is 13 months which includes screening, treatment and safety follow up phone call.

Arms: arm 1: * 9 capsules daily (8.64 g total dose) given as 3 capsules three times a day (TID) with meals for the first month of treatment.
* Six capsules daily (5.76 g total dose) given as 3 capsules (BID) with breakfast, and 3 capsules with dinner after the first month of treatment arm 2: * 9 capsules daily (8.64 g total dose) given as 3 capsules three times a day (TID) with meals for the first month of treatment.
* Six capsules daily (5.76 g total dose) given as 3 capsules (BID) with breakfast, and 3 capsules with dinner after the first month of treatment
Interventions: intervention 1: RT001 intervention 2: Placebo
Intervention descriptions: intervention 1: RT001 is encapsulated 9-cis, 12-cis-11,11-D2-linoleic acid ethyl ester, which is a site specific (C11) di-deutero synthetic homologue of LA ethyl ester. Each capsule contains 960 mg of RT001. intervention 2: The placebo product is composed of encapsulated USP safflower oil. The placebo capsules are identical in appearance and size to RT001.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
A RANDOMIZED, DOUBLE-BLIND, CONTROLLED, PHASE 2/3 STUDY 
TO ASSESS EFFICACY, LONG TERM SAFETY AND TOLERABILITY 
OF RT001 IN SUBJECTS WITH FRIEDREICH’S ATAXIA 
 
PROTOCOL NUMBER: RT001-006 
 
 
 
 
 
 
 
 
 
 
 
 
Version 8.0 
Protocol Date: 03 Nov 2021 
 
 
 
 
Confidentiality Statement 
This information contained within this document is confidential and is provided to you as an Investigator or 
consultant for review by you, your staff, and the applicable Institutional Review Board. Acceptance of this 
document constitutes agreement that you will not disclose the information contained herein to others without written 
authorization from the Sponsor. 




Page 3  
Protocol RT001-006: A Randomized, Double-Blind, Controlled, Phase 2/3 Study to Assess Efficacy, Long Term 
Safety and Tolerability of RT001 in Subjects with Friedreich’s Ataxia 
 
Retrotope, Inc. 
Version 8.0 - Date: 03 Nov 2021 
2. 
STUDY SYNOPSIS 
Sponsor: 
Retrotope, Inc. 
4300 El Camino Real, Suite 201 
Los Altos, CA 94022 
Title: 
A Randomized, Double-Blind, Controlled, Phase 2/3 Study to Assess Efficacy, 
Long Term Safety and Tolerability of RT001 in Subjects with Friedreich’s Ataxia 
Protocol No: 
RT001-006 
Study Drugs:  
Active: RT001, 960 mg soft gelatin capsules (9-cis, 12-cis-11,11-D2-linoleic acid 
ethyl ester [deuterated ethyl linoleate, or D2-LA])  
Placebo: Soft gelatin capsule of USP safflower oil (Placebo or H2-LA) 
Study 
Population: 
Friedreich’s ataxia (FRDA) patients who meet all entry criteria.  
Number of 
Subjects 
The planned enrollment is 60 subjects randomized 1:1 (active: placebo).  
Randomization will be stratified by Friedreich Ataxia Rating Scale (FARS) 
Neurological score: ≤45 and >45 
Enrollment of patients with age > 25 will be capped at 25 % of the total enrollment 
Dosing 
Schedule  
Subjects will receive the content of nine capsules daily (8.64 g total dose) given as 3 
capsules three times a day (TID) with meals for the first month of treatment. After 
this initial loading period, the dose will be reduced to six capsules daily (5.76 g total 
dose) given as 3 capsules with breakfast, and 3 capsules with dinner for the 
remainder of the trial, while on study drug. 
If a subject is unable to tolerate study drug because of adverse events during the 
initial loading period, the dose may be reduced to six capsules daily (5.76 g total 
dose) given as 3 capsules with breakfast, and 3 capsules with dinner.  
If a subject is unable to tolerate study drug because of adverse events after the dose 
reduction to six capsules daily (5.76 g total dose), the dose may be spread over three 
meals (2 capsules at breakfast, 2 capsules with lunch, and 2 capsules with dinner). If 
the subject is still unable to tolerate study drug after spreading it over three meals, 
the total dose may be reduced by 1-2 capsules/day, preferably by reducing the dose 
for a meal from 2 to 1 capsule(s) as needed. After 2 weeks of taking a dose of less 
than 6 caps/day, the subject should try to increase the dose to 6 capsules/day given 
as 2 capsules TID given with meals. If 6 caps/day is not tolerable, the subject can 
take the drug at the dose of less than 6 caps/day that was tolerable. 
Route of 
Administration: Oral 
Study Centers: 
up to 10 study centers 
Phase of 
Development 
Phase 2/3 
 
 


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Protocol RT001-006: A Randomized, Double-Blind, Controlled, Phase 2/3 Study to Assess Efficacy, Long Term 
Safety and Tolerability of RT001 in Subjects with Friedreich’s Ataxia 
 
Retrotope, Inc. 
Version 8.0 - Date: 03 Nov 2021 
Objectives 
 
Primary endpoints: 
1. To demonstrate the efficacy of RT001 compared to placebo on the change of 
MVO2 in patients with FA through change from baseline to 11 months 
Key secondary endpoint: 
1. To demonstrate the efficacy of RT001 compared to placebo on an overall 
performance score based on a Global Statistical Test (GST) change from 
baseline to 11 months. The GST will be a combination of three endpoints 
(timed 1 minute walk test [T1MW], peak workload, and maximum rate of 
oxygen consumption [MVO2]).   
Secondary endpoints: 
1. To demonstrate the efficacy of RT001 compared to placebo on T1MW with 
change from baseline to 11 months 
2. To demonstrate the efficacy of RT001 compared to placebo on the change of 
peak workload measured by CPET through change from baseline to 11 
months. 
Exploratory endpoints: 
To demonstrate the efficacy of RT001 on change from baseline at 11 months in 
clinical symptoms as measured by: 
1. Modified Friedreich’s Ataxia Scale (mFARS)  
2. Fatigue Symptom Scale (items 2. 4. 7.9 of the total fatigue scale) 
3. Clinician-rated Clinical Global Impression of Change (CGI-C) 
4. Activities of daily living (ADL) elements of fatigue scale (items 5,6, 8, 10, 
and 11) 
5. Patient Global Impression of Change (PGI-C) 
 
• 
To evaluate the effects of RT001 on Visual Analogue Scale [VAS] 
• 
To evaluate the effects of RT001 on speech measurements and Speech 
Assessment questionnaire 
• 
To evaluate the effect of RT001 on a timed 25-feet walk (T25FW)  
• 
To evaluate the effects of RT001 on the neurological examination of the 
Friedreich Ataxia Rating Scale (FARS-Neuro) 
• 
To evaluate the effects of RT001 on the activities of daily living of the 
Friedreich Ataxia Rating Scale (FARS-ADL) 
• 
To evaluate the effects of RT001 on SF-36 
• 
To evaluate the effects of RT001 on the Neuro-QoL scales (Upper 
Extremity Function and Lower Extremity Function) 
• 
To evaluate the effects of RT001 on the frequency of falls as reported in a 
fall diary and subject’s fear of falling 
• 
To evaluate the effects of RT001 on the Patient Global Impression of 
Change (PGI-C) Scale 
• 
To evaluate the effects of RT001 on efficacy assessments after 4 months of 
treatment 
• 
To evaluate the effects of RT001 on efficacy assessments after 8 months of 
treatment 
• 
To evaluate the effects of RT001 on ejection fraction as reported in the 
Echocardiogram 
• 
To evaluate the effects of RT001 on hypertrophy as reported in the 
Echocardiogram 
Optional PK Profile Sub-Study Objective: 


Page 5  
Protocol RT001-006: A Randomized, Double-Blind, Controlled, Phase 2/3 Study to Assess Efficacy, Long Term 
Safety and Tolerability of RT001 in Subjects with Friedreich’s Ataxia 
 
Retrotope, Inc. 
Version 8.0 - Date: 03 Nov 2021 
The objective of the study is to evaluate the pharmacokinetic (PK) profile of 
RT001 at steady state.   
Optional PK Washout Sub-Study Objective: 
The objective of the study is to evaluate the washout blood levels of RT001 after 
treatment in RT001-006 is completed. 
Study 
Methodology 
 
This is a randomized, double-blind, placebo-controlled study to evaluate the 
efficacy, safety, tolerability, in subjects with FRDA following the oral 
administration of study drug (active or placebo capsules). Subjects will self-
administer the study drug orally with meals. While on study drug, subjects are 
recommended to avoid eating foods high in PUFAs.  Subjects will keep food 
journals from screening through the completion of month 1 on study drug. After 
month 1, subjects will keep 2-week food journals prior to the next scheduled onsite 
visit. Subjects (or parents/caregivers, as applicable) will have an initial call and as 
needed with the diet coach to discuss food journal completion requirements. 
 
CPET and the T1MW/T25FW should be separated in time to allow the subject to 
recover sufficiently before doing the next test. CPET should occur in the morning 
after fasting for a minimum of 2 hours (if the subject has had a meal/snack), with 
neither caffeine nor nicotine for at least 12 hours before testing. All tests should be 
done at approximately the same time and order each day.  
Study Duration 
Participation is anticipated to require 13 months.  
• Screening: Up to 30 days from start of treatment 
• Treatment Period: treatment for a 12-month period 
For patients who consent to the Optional Washout Sub-Study Objective, the study 
duration will be 19 months. 
Study Design  
The planned enrollment is 60 subjects randomized 1:1 active: placebo. There are 
two optional PK sub-studies. Subjects will have the opportunity to consent to these 
studies at the Day 330 visit or at the time of the first draw. 
 
Safety 
Assessments 
Safety assessments include physical and neurologic examinations, vital signs, 12-
lead electrocardiogram (ECG) tracing, and clinical laboratory tests (hematology, 
clinical chemistry, lipid profile, coagulation, and urinalysis) to identify adverse 
events (AEs). Adverse events will be evaluated for incidence, severity, and 
relationship to study drug. Any AE ongoing at the End of Treatment (EOT) phone 
call will be followed to conclusion or until stabilized. 


Page 6  
Protocol RT001-006: A Randomized, Double-Blind, Controlled, Phase 2/3 Study to Assess Efficacy, Long Term 
Safety and Tolerability of RT001 in Subjects with Friedreich’s Ataxia 
 
Retrotope, Inc. 
Version 8.0 - Date: 03 Nov 2021 
PK/Biomarker 
Analysis 
Bioanalytical measurements will be performed to determine the concentration of 
D2-LA, deuterated arachidonic acid (D2-ARA), H2-LA and nondeuterated 
arachidonic acid (H2-ARA) in plasma, and D2-LA, D2-ARA H2-LA, and H2-ARA 
in red blood cells.  
 
Blood samples will be collected for the plasma measurements as follows: 
Month 4 (Day 120 ± 30 days): Pre-dose (prior to breakfast) 
Month 8 (Day 240 ± 30 days): Pre-dose (prior to breakfast) 
Month 11 (Day 330 ± 30 days): Pre-dose (prior to breakfast) 
 
Blood samples for the assessments in red blood cells will be collected as follows:  
Month 4 (Day 120 ± 30 days): Pre-dose (prior to breakfast) 
Month 8 (Day 240 ± 30 days): Pre-dose (prior to breakfast) 
Month 11 (Day 330 ± 30 days): Pre-dose (prior to breakfast) 
 
Additional blood samples will be collected and stored for future biomarker analysis 
as follows: 
Day 1: Pre-dose (prior to breakfast) 
Month 4 (Day 120 ± 30 days): Pre-dose (prior to breakfast) 
Month 8 (Day 240 ± 30 days): Pre-dose (prior to breakfast) 
Month 11 (Day 330 ± 30 days): Pre-dose (prior to breakfast) 
 
Two additional optional PK sub-studies are offered. The first study is a 24hr PK 
Profile at steady state that will occur immediately before or after the Day 330 visit. 
Blood samples for this study will be collected as follows: 
Day 1: Hour -1.0 to -0.5 (pre-breakfast, pre-dose), 0.5 (± 5 min), 1 (± 5 min), 2 
(± 10 min), 4 (± 15 min) (pre-lunch), 8 (± 15 min) (pre-dinner), and 12 (± 60 min)  
Day 2: 24 hours following dosing on Day 1 (± 60 min; pre-breakfast, pre-dose)  
The second optional sub-study is a 6-month study to evaluate the washout blood 
levels of RT001 after treatment in RT001-006 is completed. Depending on the 
timing of entry into the sub-study, blood samples for this study will be collected as 
follows: 
7 days (± 1 day) 
4 weeks (± 7 days) 
12 weeks (± 7 days) 
24 weeks (± 7 days) 
Efficacy 
Assessments 
Subjects will perform CPET using a recumbent exercise bike at Screening, on Day 
1, Day 120 (± 30 days), Day 240 (± 30 days), and Day 330 (± 30 days). Peak oxygen 
consumption and peak work rate will be measured during incremental exercise 
testing. CPET should occur after fasting (if the subject has had a meal/ snack) for a 
minimum of 2 hours, with neither caffeine nor nicotine for at least 12 hours before 
testing. 


Page 7  
Protocol RT001-006: A Randomized, Double-Blind, Controlled, Phase 2/3 Study to Assess Efficacy, Long Term 
Safety and Tolerability of RT001 in Subjects with Friedreich’s Ataxia 
 
Retrotope, Inc. 
Version 8.0 - Date: 03 Nov 2021 
Subjects (with or without assistive device) will perform a T1MW and T25FW at 
Screening, on Day 1, Day 120 (± 30 days), Day 240 (± 30 days), and Day 330 (± 30 
days). 
CPET and the T1MW/T25FW should be separated in time to allow the subject to 
recover sufficiently before doing the next test. All tests should be done at 
approximately the same time and order for each visit. 
The FARS-Neuro and clinician-rated CGI scale will be performed at Screening, on 
Day 1, Day 120 (± 30 days), Day 240 (± 30 days), and Day 330 (± 30 days) by a 
qualified physician or health professional who is trained on the use of the tool. The 
CPET examination should always precede the FARS-Neuro evaluation at all visits. 
A trained health professional will also work with the subject to perform the speech 
measurement recording at Screening, on Day 1, Day 240 (± 30 days), and Day 330 
(± 30 days). 
The FARS-ADL, SF-36, VAS (for Fatigue), Fatigue scale, Neuro-QoL scales (lower 
extremity function and upper extremity function) and Fall Questionnaire will be 
completed by the subjects at screening and at the visits on Day 1, Day 120 
(± 30 days), Day 240 (± 30 days), and Day 330 (± 30 days). The Patient Global 
Impression of Change (PGI-C) scale and VAS (for Improvement of FA symptoms) 
will be completed by all subjects at Day 120 (± 30 days), Day 240 (± 30 days), and 
Day 330 (± 30 days). In between the clinic visits, subjects will also be contacted by 
phone by a study site staff member and asked questions relating to the PGI-C scale, 
Fatigue scale, Neuro-QoL scales (lower extremity function, and upper extremity 
function), and questions 8 and 9 of the Fall Questionnaire. These phone ‘visits’ will 
take place monthly. A Speech Assessment Questionnaire will also be completed by 
the subject and parents/caregiver (as applicable) at Screening, on Day 1, Day 240 
(± 30 days), and Day 330 (± 30 days). 
Between clinic visits subjects will be asked to keep a daily log (diary) documenting 
falls, near-falls, stumbles, and fear of falling. 
Inclusion 
Criteria 
 
 
 
 
 
 
 
 
 
To be enrolled into the study, subjects must meet the following requirements: 
1. Male or female 12 to 50 years of age 
2. Medical history consistent with the symptoms of FRDA at ≤ 25 years of age 
3. Detection of biallelic pathogenic variants in frataxin gene (FXN) (i.e. biallelic 
repeat expansions of GAA in the disease-causing range, or compound 
heterozygous for a repeat expansion of GAA in the disease-causing range + an 
intragenic pathogenic variant, etc.) 
4. Ambulatory (with or without assistive device) and capable of performing other 
assessments/evaluations 
5. Must be able to walk 25 feet during the timed 1-minute walk 
6. Agree to receive calls from a diet coach regarding completion of electronic food 
journal 
7. Sign the informed consent form prior to entry into the study 
8. Agree to stay locally for the required visit days  
9. Able to provide the necessary repeated blood samples 


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Protocol RT001-006: A Randomized, Double-Blind, Controlled, Phase 2/3 Study to Assess Efficacy, Long Term 
Safety and Tolerability of RT001 in Subjects with Friedreich’s Ataxia 
 
Retrotope, Inc. 
Version 8.0 - Date: 03 Nov 2021 
Exclusion 
Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects meeting one or more of the following may not enter the study:  
1. Received treatment with other experimental therapies within the last 30 days 
prior to the first dose 
2. Previously participated in the RT001 trial 
3. Refusal to discontinue fish oils or other oil-based supplements for the duration of 
the study (Screening until last study procedure completed) 
4. History of malignancies (other than basal cell carcinomas) 
5. Inability to complete CPET protocol, as, for example, unable to move the pedals 
on the exercise bicycle, inability to maintain sufficient RPMs to finish the study, 
or as judged by the exercise physiologist supervising the testing 
6. Female who is breastfeeding or has a positive pregnancy test 
7. Male participant or female participant of childbearing potential, who is sexually 
active and unwilling/unable to use a medically acceptable and effective double 
barrier birth control method throughout the study 
8. Unwilling or unable to comply with the requirements of this protocol, including 
the presence of any condition (physical, mental, or social) that is likely to affect 
the subject’s ability to return for visits as scheduled 
9. Clinically significant cardiac abnormalities (e.g., left ventricular ejection fraction 
[LVEF] < 40% on a recent echocardiogram [obtained within 12 months prior to 
screening] or clinically unstable arrhythmia) at screening that, in the opinion of 
the Investigator, would make the subject unsuitable for enrollment 
10. History of uncontrolled diabetes mellitus (Type 1 or 2) 
11. Suicidal ideation within the last 12 months as determined by the Columbia-
Suicide Severity Rating Scale (C-SSRS) 
12. History, within the last 2 years, of alcohol abuse, significant mental illness, or 
physical opioid dependence 
Food Journal 
requirement 
While on study drug, subjects are recommended to avoid eating foods high in 
PUFAs. Subjects will keep food journals from screening through the completion of 
month 1 on study drug. After month 1, subjects will keep 2-week food journals prior 
to next scheduled onsite visit. Subjects (or parents/caregivers, as applicable) will 
have an initial call and as needed with the diet coach to discuss food journal 
completion requirements. 
Prohibited 
Medications 
Supplements that contain EPA or DHA are prohibited. Oil-based supplements like 
Fish oil, Cod Liver oil, Edible algae oil and Flax oil are also prohibited. 
Statistical 
methods 
Demographic data will be presented using descriptive statistics (e.g., mean, standard 
deviation, median, and range). Exposure to study drug and reasons for 
discontinuation will be tabulated. Safety variables will be tabulated and presented 
for all subjects who receive study drug or placebo capsules. Adverse events will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA). The 
incidence of treatment-emergent AEs will be presented by system organ class and 
preferred term. Adverse events will be presented by severity and relationship to 


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Protocol RT001-006: A Randomized, Double-Blind, Controlled, Phase 2/3 Study to Assess Efficacy, Long Term 
Safety and Tolerability of RT001 in Subjects with Friedreich’s Ataxia 
 
Retrotope, Inc. 
Version 8.0 - Date: 03 Nov 2021 
study drug. Changes from Baseline in clinical laboratory parameters and vital signs 
will be summarized across time. Shift tables will be provided for selected laboratory 
parameters. Physical examination results will be presented in listings. 
Change from baseline (CFB) will be analyzed by comparing the change between 
treatment groups using a mixed model with repeated measures (MMRM). The 
MMRM will compare the estimated change from baseline between treatments for 
the primary endpoint. This analysis will assess whether there is a difference in 
estimated CFB between active and placebo groups at 11 months.  
The primary analysis of percent change from baseline to 11 months in MVO2 as 
measured by CPET will use the ITT methodology and an MMRM methodology with 
a random slope and intercept for each individual.  
  
All secondary and exploratory endpoints CFB values will be analyzed using 
the MMRM Responder analyses will be run on MVO2 (primary), GST, 
T1MW, Peak Workload, mFARS, and CGI-C (functional assessment). The 
PK of D2-LA, D2-ARA, H2-LA, and H2-ARA will be characterized in terms of 
minimum and maximum exposure at steady state.  
For the primary analysis of peak workload, group sample sizes of 30 and 30 achieve 
over 99% power to reject the null hypothesis of equal means when the population 
mean difference is μ1 - μ2 = 7.5 - -8.3 = 15.8 with a standard deviation for both 
groups of 11.1 and with a significance level (alpha) of 0.05 using a two-sided two-
sample equal-variance t-test. 
 
Safety 
Monitoring 
The blinded safety and efficacy data will be reviewed by the medical monitor on an 
ongoing basis. A Data Safety and Monitoring Board (DSMB) will be established to 
evaluate events according to the DSMB Charter. The safety and efficacy review data 
will not be made available to the Principal Investigators unless changes need to be 
made to the protocol for safety reasons. 
 


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Protocol RT001-006: A Randomized, Double-Blind, Controlled, Phase 2/3 Study to Assess Efficacy, Long Term Safety and Tolerability of RT001 in Subjects 
with Friedreich’s Ataxia 
 
Retrotope, Inc. 
Version 8.0 - Date 03 Nov 2021 
Table 1: Schedule of Events 
Assessments 
Study 
Period 
Screening 
 
Study Drug Administration 
 
Clinic Visit 
No.  
1 
2 
Phone Call 
3 
Phone Call 
4 
Phone Call 
5 
End of 
Treatment 
Phone Call 
Study Day 
Up to 30  
Days 
Day 1 
Days 30,60, 90 
(± 7 days) 
Day 120 
(± 30 days) 
Days 150, 180, 210 
(± 7 days) 
Day 240 
(±30 days) 
Days 270, 300 
(± 7 days) 
Day 330 
(±30 days) 
4 weeks after 
Day 330 visit 
(+ 7 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
Demographics/Medical History 
X 
X 
 
 
 
 
 
 
 
Columbia-Suicide Severity 
Rating Scale 
X 
 
 
 
 
 
 
 
 
Echocardiograma 
X 
 
 
 
 
 
 
X 
 
Serum Pregnancy Testb  
X 
 
 
 
 
 
 
 
 
Cardio-Pulmonary Exercise Test 
(CPET)c 
X 
X 
 
X 
 
X 
 
X 
 
T1MW and T25FW  
X 
X 
 
X 
 
X 
 
X 
 
Physical Exam  
X 
X 
 
X 
 
X 
 
X 
 
FARS-Neuro and clinician-rated 
CGId 
Xd 
Xd 
 
X 
 
X 
 
X 
 
Speech Measurement Recording  
X 
X 
 
 
 
X 
 
X 
 
Subject completed Speech 
Assessment Questionnaire 
X 
X 
 
 
 
X 
 
X 
 
FARS ADL, SF36, VASe 
Xe 
Xe 
 
X 
 
X 
 
X 
 
Subject completed PGI-Cf, 
Fatigue scale, and Neuro-QoL 
scales 
Xf 
Xf 
X 
X 
X 
X 
X 
X 
 
Fall Questionnaire 
X 
X 
Xg 
X 
Xg 
X 
Xg 
X 
 
Vital Signs (including weight) 
Xh 
X 
 
X 
 
X 
 
Xh 
 
12-Lead ECGi  
X 
Xi 
 
X 
 
X 
 
X 
 
Urine Pregnancy Testb,l  
 
X 
 
X 
 
X 
 
X 
Xl 
Urinalysis 
X 
 
 
 
 
 
 
X 
 
Safety Laboratory Testsi,j,k 
X 
Xi 
 
X 
 
X 
 
X 
 


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Protocol RT001-006: A Randomized, Double-Blind, Controlled, Phase 2/3 Study to Assess Efficacy, Long Term Safety and Tolerability of RT001 in Subjects 
with Friedreich’s Ataxia 
 
Retrotope, Inc. 
Version 8.0 - Date 03 Nov 2021 
Lipid Profilei,k 
X 
Xi 
 
X 
 
X 
 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
 
In-Clinic Drug Administration 
 
X 
 
X 
 
X 
 
X 
 
Study Drug Dispensingm 
 
X 
 
X 
 
X 
 
X 
 
Perform Drug Accountabilityn 
 
 
 
X 
 
X 
 
X 
Xn 
PK Sampling 
 
 
 
X 
 
X 
 
X 
 
Biomarker Sampling 
 
X 
 
X 
 
X 
 
X 
 
Monitor AE/Concomitant 
Medication 
 
X 
X 
X 
X 
X 
X 
X 
Xo 
Fall diary 
 
 
 
 
 
 
 
 
 
Food Journal 
Xp 
Xq 
 
Xp 
 
Xp 
 
Xp 
 
 
a Does not need to be performed in subjects who had echocardiogram done in the last 12 months before screening. 
b   Serum and Urine Pregnancy Tests to be performed on all females, unless there is documented evidence confirming they are not of childbearing potential. 
c The cardio-pulmonary exercise test (CPET) should occur in the morning after fasting for a minimum of 2 hours, with neither caffeine nor nicotine for at least 12 hours before 
testing. All tests should be done at approximately the same time and order for each visit. The CPET should always precede the FARS-Neuro evaluation at all visits. 
d For Clinician Rated CGI, only question 1 will be answered at Screening and Day 1 
e Only VAS (for Fatigue) will be performed at Screening and Day 1. VAS (for Improvement of FA Symptoms) will not be performed at Screening or Day 1. 
f Patient Global Impression of Change (PGI-C) to be performed Day 30 and onwards only. Not to be performed at Screening and Day 1. 
g Only questions 8 and 9 of the Fall Questionnaire will be answered over phone visits 
h At Screening and Day 330, height will be collected, and body mass index (BMI) will be calculated. 
i   Safety labs, Lipid Profile and ECG do not have to be repeated at Day 1 if the screening and Day 1 visit is within 7 days (or less) of each other. 
j Safety laboratory tests include chemistry, hematology, and coagulation. 
k Safety laboratory tests and lipid profile should be performed in a fasting state. 
l Urine Pregnancy test to be performed by subject at home on the day of the EOT phone call (before the call and after the last dose).  
m The study drug for the first 4 weeks of dosing will be dispensed at the study sites. Study Drug for the subsequent dosing months may be shipped to the subject or site from a drug 
depot or site, depending on the dispensing schedule. 
n Site to perform drug accountability with subject on the EOT call. Subject to return unused study drug/bottles to the site. 
o Any AE ongoing at EOT will be followed to conclusion or until stabilized. 
p  The Diet Coach will have an initial call and as needed with the subjects (or parents/ caregivers as applicable) to discuss food journal requirement.  
q  The food journal has to be completed through end of month 1, and every 2 weeks prior to next onsite visit. 
 
 
 


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Protocol RT001-006: A Randomized, Double-Blind, Controlled, Phase 2/3 Study to Assess Efficacy, Long Term Safety and Tolerability of RT001 in Subjects 
with Friedreich’s Ataxia 
 
Retrotope, Inc. 
Version 8.0 - Date 03 Nov 2021 
Table 1.1: Optional PK Profile Sub-Study PK Schedule of Events 
Assessments 
Pharmacokinetic Profile of RT001 at Steady State in Subjects with Friedreich’s Ataxia Who Participated in Study RT001-006 
 
Study 
Time 
-1 Hour to -
30 Minutes 
(± 5 min) 
30 Minutes  
(± 5 min) 
1 Hour 
(± 5 min) 
2 Hours 
(± 10 min) 
 
4 Hours 
 Before 
lunch 
(± 15 min) 
 
8 Hour 
Before 
dinner 
(± 15 min) 
12 Hour 
Post dinner 
(± 60 min) 
24 Hour 
Day 2 
(± 60 min) 
Notes 
Pre-
breakfast, 
pre-dose  
Post-
breakfast, 
post-dose 
Post-
breakfast, 
post-dose 
Post-
breakfast, 
post-dose 
Pre-lunch, 
post-dose 
Post-lunch, 
post-dose 
Post-dinner, 
skip evening 
dose 
Pre-breakfast, 
pre-dose 
PK Sampling 
X 
X 
X 
X 
X 
X 
X 
X 
 
Table 1.2: Optional Washout Sub-Study Schedule of Events 
Assessments 
Washout Blood Levels of Subjects Who Have Completed Treatment in RT001-006 
 
Study 
Day 
Day 7 
(± 1 day) 
Week 4 
(± 7 days) 
Week 12 
(± 7 days) 
Week 24 
(± 7 days) 
PK Sampling 
Xa,b 
Xa,b 
Xa,b 
Xa,b 
a Draw can be performed onsite or remotely by a mobile phlebotomist 
b Subjects who complete RT001-006 are eligible to participate in any part of the PK sub-study. 
 


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Protocol RT001-006: A Randomized, Double-Blind, Controlled, Phase 2/3 Study to Assess Efficacy, Long Term Safety and Tolerability of RT001 in Subjects 
with Friedreich’s Ataxia 
 
Retrotope, Inc. 
Version 8.0 - Date 03 Nov 2021 
3. 
TABLE 2: 
STUDY SCHEMATIC 
 
 
 
 
 
 
 


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4. 
TABLE OF CONTENTS AND LIST OF TABLES  
TABLE 4: TABLE OF CONTENTS 
1. 
SIGNATURE PAGE ....................................................................................................2 
1.1. 
Sponsor Approval .........................................................................................................2 
1.2. 
Investigator Agreement ................................................................................................2 
2. 
STUDY SYNOPSIS .....................................................................................................3 
3. 
TABLE 2: STUDY SCHEMATIC .............................................................................13 
4. 
TABLE OF CONTENTS AND LIST OF TABLES ..................................................14 
TABLE 4: TABLE OF CONTENTS ...........................................................................................14 
5. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................21 
6. 
INTRODUCTION ......................................................................................................24 
6.1. 
Friedreich’s Ataxia .....................................................................................................24 
6.2. 
Oxidative Stress and Neurodegenerative Disease ......................................................24 
6.3. 
Non-Clinical Rationale Supporting RT001 Development for FRDA ........................25 
6.4. 
Clinical Rationale Supporting RT001 Development for FRDA .................................26 
6.5. 
Non-Clinical Safety Summary ....................................................................................29 
6.6. 
Clinical Safety Summary ............................................................................................29 
6.7. 
Inclusion of Pediatric Subjects of 12 Years and Older in the Current Protocol .........32 
6.8. 
Potential Risks and Benefits to Human Subjects ........................................................33 
6.9. 
Description and Justification for the Dosing Regimens to Be Studied ......................35 
7. 
STUDY OBJECTIVES ..............................................................................................36 
7.1. 
Primary endpoint ........................................................................................................36 
7.2. 
Key secondary endpoint .............................................................................................36 
7.3. 
Secondary endpoints ...................................................................................................36 
7.4. 
Exploratory endpoints .................................................................................................36 
7.5. 
Optional Sub-Study Objectives ..................................................................................37 
7.5.1. 
Optional PK Profile Sub-Study ..................................................................................37 
7.5.2. 
Optional PK Washout Sub-Study ...............................................................................37 
8. 
INVESTIGATIONAL PLAN .....................................................................................38 
8.1. 
Study Design ...............................................................................................................38 


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8.2. 
Randomization ............................................................................................................40 
8.3. 
Blinding ......................................................................................................................40 
8.4. 
Safety Monitoring .......................................................................................................41 
8.4.1. 
Safety Monitoring .......................................................................................................41 
8.4.2. 
Sponsor Safety Monitoring .........................................................................................41 
8.4.3. 
Data Safety and Monitoring Board .............................................................................41 
9. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................42 
9.1. 
Inclusion Criteria ........................................................................................................42 
9.1.1. 
Inclusion Criteria for Optional PK Profile Sub-Study ................................................42 
9.1.2. 
Inclusion Criteria for Optional PK Washout Sub-Study ............................................42 
9.2. 
Exclusion Criteria .......................................................................................................42 
9.2.1. 
Exclusion Criteria for Sub-Studies .............................................................................43 
9.3. 
Withdrawal .................................................................................................................43 
9.3.1. 
Withdrawal Criteria ....................................................................................................43 
9.3.2. 
Withdrawal Procedures ...............................................................................................44 
9.3.3. 
Documentation of Withdrawal ...................................................................................44 
9.3.4. 
Replacement of Subjects .............................................................................................44 
9.3.5. 
Termination of Study by Sponsor ...............................................................................44 
9.4. 
Pregnancy ...................................................................................................................45 
10. 
INVESTIGATIONAL PRODUCT ............................................................................46 
10.1. 
Identity of Investigational Product .............................................................................46 
10.2. 
Packaging and Labeling of Clinical Supplies .............................................................46 
10.3. 
Storage of Clinical Supplies .......................................................................................46 
10.4. 
Study Drug Dispensation ............................................................................................46 
10.5. 
Drug Accountability ...................................................................................................46 
11. 
STUDY DRUGS AND OTHER MEDICATIONS, SUPPLEMENTS ......................47 
11.1. 
Study Drug Administration .........................................................................................47 
11.2. 
Prior and Concomitant Medications ...........................................................................47 
11.3. 
Subject Compliance ....................................................................................................47 
12. 
EFFICACY ENDPOINTS, SAFETY, PHARMACOKINETIC, AND 
OTHER ASSESSMENTS ..........................................................................................48 
12.1. 
Efficacy Endpoints ......................................................................................................48 


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12.2. 
Exercise Testing Using CPET ....................................................................................48 
12.3. 
Timed Walk ................................................................................................................49 
12.3.1. 
Timed 1-Minute Walk (T1MW) .................................................................................49 
12.3.2 
Timed 25-Feet Walk (T25FW) ...................................................................................49 
12.4. 
Speech Measurement Recording ................................................................................49 
12.5. 
Clinician-rated Scales .................................................................................................49 
12.5.1. 
FARS-Neuro ...............................................................................................................49 
12.5.2. 
Clinician-rated Clinical Global Impression (CGI) .....................................................50 
12.6. 
Questionnaires and scales completed by the subject ..................................................50 
12.6.1. 
FARS -Activities of Daily Living (FARS-ADL) .......................................................50 
12.6.2. 
SF-36 ...........................................................................................................................50 
12.6.3. 
Patient Global Impression of Change (PGI-C) Scale .................................................50 
12.6.4. 
Visual Analogue Scale (VAS) ....................................................................................51 
12.6.5. 
Fatigue Scale ...............................................................................................................51 
12.6.6. 
Neuro-QoL scales .......................................................................................................51 
12.6.7. 
Fall Questionnaire .......................................................................................................51 
12.6.8. 
Fall Diary ....................................................................................................................51 
12.6.9. 
Speech Assessment Questionnaire .............................................................................52 
12.7. 
Safety ..........................................................................................................................52 
12.7.1. 
Adverse Events ...........................................................................................................52 
12.7.2. 
Physical Examination .................................................................................................52 
12.7.3. 
Vital Signs ..................................................................................................................52 
12.7.4. 
12-Lead Electrocardiogram ........................................................................................52 
12.7.5. 
Clinical Laboratory Tests ...........................................................................................53 
12.7.6. 
Columbia-Suicide Severity Rating Scale ....................................................................54 
12.7.7. 
Echocardiogram ..........................................................................................................54 
12.8. 
Pharmacokinetics ........................................................................................................54 
12.8.1. 
Sample Collection .......................................................................................................54 
12.9. 
Biomarker Assessment ...............................................................................................55 
12.10. 
Other ...........................................................................................................................55 
12.10.1. 
Food Journal Requirement ..........................................................................................55 


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13. 
STUDY PROCEDURES AND SCHEDULE ............................................................56 
13.1. 
Visit 1: Screening (Up to 30 Days) .............................................................................56 
13.2. 
Visit 2: Study Day 1 ...................................................................................................57 
13.3. 
Days 30 (± 7 days), 60 (± 7 days), and 90 (± 7 days) .................................................58 
13.4. 
Visit 3: Day 120 (± 30 days) .......................................................................................58 
13.5. 
Day 150 (± 7 days), Day 180 (± 7 days) and Day 210 (± 7 days) ..............................59 
13.6. 
Visit 4: Day 240 (± 30 days) .......................................................................................59 
13.7. 
Day 270 (± 7 days) and Day 300 (± 7 days) ...............................................................60 
13.8. 
Visit 5: Day 330 (± 30 Days) ......................................................................................60 
13.9. 
Optional PK Profile Sub-Study ..................................................................................61 
13.10. 
End of Treatment call (4 weeks from Day 330 + 7 days) ...........................................62 
13.11. 
Optional PK Washout Sub-Study ...............................................................................62 
13.12. 
Unscheduled Visits .....................................................................................................62 
13.13. 
Early Termination Visit ..............................................................................................62 
14. 
STATISTICS ..............................................................................................................64 
14.1. 
Statistical Plan ............................................................................................................64 
14.2. 
Determination of Sample Size ....................................................................................66 
14.3. 
Interim Analysis ..........................................................................................................66 
14.4. 
Deviation from Original Analysis Plan ......................................................................67 
15. 
ADVERSE EVENTS ..................................................................................................68 
15.1. 
Adverse Event Definitions ..........................................................................................68 
15.1.1. 
Adverse Event .............................................................................................................68 
15.1.2. 
Suspected Adverse Reaction .......................................................................................68 
15.1.3. 
Life-Threatening Adverse Event or Life-Threatening Suspected Adverse 
Reaction ......................................................................................................................69 
15.1.4. 
Serious Adverse Event or Serious Suspected Adverse Reaction ................................69 
15.1.5. 
Unexpected Adverse Event or Unexpected Suspected Adverse Reaction .................69 
15.2. 
Adverse Event Classification ......................................................................................70 
15.2.1. 
Relationship to Investigational Drug ..........................................................................70 
15.2.2. 
Severity .......................................................................................................................71 
15.3. 
Exposure in Utero .......................................................................................................71 
15.4. 
Monitoring of Adverse Event Data .............................................................................71 


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15.5. 
Documentation of Adverse Events by Investigator ....................................................72 
15.6. 
Notification about Serious Adverse Events and Serious and Unexpected 
Suspected Adverse Reactions .....................................................................................73 
15.6.1. 
Investigator Reporting to Sponsor ..............................................................................73 
15.6.2. 
Reporting to Regulatory Agencies and Institutional Review Boards .........................74 
15.7. 
Emergency Identification of Study Medication ..........................................................74 
15.8. 
Optional Sub-Study Adverse Event Monitoring .........................................................74 
15.9. 
Emergency Sponsor Contact .......................................................................................75 
16. 
ETHICS ......................................................................................................................76 
16.1. 
Institutional Review Board .........................................................................................76 
16.2. 
Ethical Conduct of the Study ......................................................................................76 
16.3. 
Subject Information and Informed Consent ...............................................................76 
17. 
STUDY ADMINISTRATION ...................................................................................77 
17.1. 
Administrative Structure .............................................................................................77 
17.2. 
Quality Control and Quality Assurance ......................................................................77 
17.2.1. 
Overview .....................................................................................................................77 
17.2.2. 
Monitoring ..................................................................................................................77 
17.2.3. 
Data Management/Coding ..........................................................................................78 
17.2.4. 
Quality Assurance Audit .............................................................................................78 
17.3. 
Data Handling and Recordkeeping .............................................................................78 
17.3.1. 
Electronic Data ...........................................................................................................78 
17.3.2. 
Case Report Form Completion ...................................................................................79 
17.3.3. 
Data Handling .............................................................................................................79 
17.3.4. 
Retention of Study Records ........................................................................................79 
17.4. 
Financing and Insurance .............................................................................................79 
17.5. 
Confidentiality ............................................................................................................80 
17.6. 
Publication Policy .......................................................................................................80 
17.7. 
Direct Access to Source Data .....................................................................................80 
17.8. 
Protocol Amendments ................................................................................................81 
18. 
REFERENCES ...........................................................................................................82 
19. 
APPENDICES ............................................................................................................89 


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19.1. 
Cardiopulmonary Exercise Testing as a Primary Endpoint in Mitochondrial 
Diseases ......................................................................................................................89 
19.1.1. 
Background .................................................................................................................89 
19.1.2. 
What is cardiopulmonary exercise testing (CPET)? ...................................................89 
19.1.3. 
Conditions in which it is used clinically .....................................................................90 
19.1.4. 
Association with morbidity/mortality .........................................................................91 
19.1.5. 
Conditions for which it has been used as an endpoint in clinical trials ......................91 
19.2. 
FARS-Neuro Scale .....................................................................................................93 
19.3. 
Clinician-rated Clinical Global Impression (CGI) ...................................................102 
19.4. 
FARS -Activities of Daily Living (FARS-ADL) .....................................................103 
19.5. 
SF-36 .........................................................................................................................105 
19.6. 
Patient Global Impression of Change Scale (PGI-C) ...............................................109 
19.7. 
Visual Analogue Scale (VAS) ..................................................................................110 
19.8. 
Fatigue Scale .............................................................................................................111 
19.9. 
Neuro-QoL scales .....................................................................................................112 
19.10. 
Fall Questionnaire .....................................................................................................114 
19.11. 
Speech Assessment Questionnaire ...........................................................................116 
19.12. 
Optional PK Profile Sub-Study: Pharmacokinetic Profile of RT001 at Steady 
State in Subjects with Friedreich’s Ataxia Who Participated in Study RT001-
006 ............................................................................................................................117 
19.12.1. 
Study Objectives .......................................................................................................117 
19.12.2. 
Study Design .............................................................................................................117 
19.12.3. 
Randomization ..........................................................................................................117 
19.12.4. 
Blinding ....................................................................................................................117 
19.12.5. 
Inclusion Criteria ......................................................................................................117 
19.12.6. 
Sample Size ..............................................................................................................117 
19.12.7. 
Sample Collection .....................................................................................................118 
19.12.8. 
Timing of Meals and Study Drug .............................................................................118 
19.12.9. 
Data Analysis ............................................................................................................118 
19.13. 
Optional Washout Sub-Study: Washout Blood Levels of Subjects Who Have 
Completed Treatment in RT001-006 ........................................................................119 
19.13.1. 
Study Objectives .......................................................................................................119 
19.13.2. 
Study Design .............................................................................................................119 


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19.13.3. 
Randomization ..........................................................................................................119 
19.13.4. 
Blinding ....................................................................................................................119 
19.13.5. 
Inclusion Criteria ......................................................................................................119 
19.13.6. 
Sample Size ..............................................................................................................119 
19.13.7. 
Sample Collection .....................................................................................................119 
19.13.8. 
Data Analysis ............................................................................................................120 
 


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5. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 5: 
Abbreviations and Specialist Terms 
Abbreviation or 
Specialist Term 
Explanation 
ADL 
Activities of Daily Living 
AE 
Adverse event 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
BID 
Twice a day 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CDC 
Centers for Disease Control 
CGI 
Clinical Global Impression 
CO2 
Carbon dioxide 
CPET 
Cardio-Pulmonary Exercise Testing 
CRF 
Case Report Form 
CRO 
Clinical research organization 
CSR 
Clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
D-PUFAs 
Deuterated polyunsaturated fatty acids 
D2-ARA 
Deuterated arachidonic acid 
D2-LA 
Deuterated linoleic acid  
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
FARS 
Friedreich’s ataxia rating scale 
FARS-ADL 
Activities of daily living of the Friedreich Ataxia Rating Scale 
FARS-Neuro 
Neurological examination of the Friedreich Ataxia Rating Scale 
FDA 
Food and Drug Administration 
FeS 
Iron sulfur 
FRDA 
Friedreich’s ataxia  
FXN 
Frataxin gene 
GCP 
Good Clinical Practice 


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GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
GRAS 
Generally recognized as safe 
GST 
Global Statistical Test 
H2-ARA 
Nondeuterated arachidonic acid 
H2-LA 
Nondeuterated linoleic acid 
HBsAg 
Hepatitis B surface antigen 
HDL 
High density lipoprotein 
HED 
Human equivalent dose  
HIPAA 
Health Insurance Portability Assurance Act 
HIV 
Human immunodeficiency virus 
HNE 
4-hydroxynonenal 
HSP60 
Heat shock protein 60 
ICF 
Informed consent form 
ICH 
International Conference for Harmonization  
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
IV 
Intravenous 
KIE 
Kinetic isotope effect 
LA 
Linoleic acid 
LDL 
Low density lipoprotein 
LVEF 
Left ventricular ejection fraction 
MedDRA 
mFARS 
Medical Dictionary for Regulatory Activities 
Modified Friedreich’s Ataxia Scale 
mITT 
modified Intent-To-Treat 
mRNA 
Messenger RNA 
MVO2 
Maximum rate of oxygen consumption 
NOAEL 
No observed adverse effect level 
PBMC 
Peripheral blood mononuclear cell 
PD 
PGI-C 
Pharmacodynamic 
Patient Global Impression of Change 


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PK 
Pharmacokinetic 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
PUFAs 
Polyunsaturated fatty acids 
QA 
Quality Assurance 
QC 
Quality Control 
QD 
Once a day 
RBC 
Red blood cell 
ROS 
Reactive oxygen species 
SAE 
Serious adverse event 
SOC 
System organ class 
SOP 
Standard operating procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
T25FW 
Timed 25-foot walk 
T1MW 
Timed 1-minute walk 
TEAE 
Treatment-emergent adverse event 
TID 
Three times a day 
TMF 
Trial Master File 
ULN 
Upper limit of normal 
US 
United States 
VAS 
Visual Analogue Scale 
VO2 MAX 
Maximum rate of oxygen consumption 
WBC 
White blood cell 
WHODD 
World Health Organization Drug Dictionary 
WOCBP 
Women of childbearing potential 
 


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6. 
INTRODUCTION 
6.1. 
Friedreich’s Ataxia 
Friedreich’s ataxia (FRDA), a syndrome of ataxia in all 4 limbs with an onset of symptoms 
between late childhood and early adolescence, is a model of significant mitochondrial 
dysfunction with excess chronic oxidative damage leading to selective cell death and significant 
neurologic damage (Santos et al., 2010; Armstrong et al., 2010). It is characterized by 
neurodegeneration of the dorsal root ganglia with loss of large sensory neurons and the posterior 
columns, and by degeneration in the spinocerebellar and corticospinal tracts in the spinal cord 
with cerebellar involvement (Santos et al., 2010). While relatively rare, it is the most common of 
the inherited ataxias with prevalence of 1:50,000 in the United States (US) (Armstrong et al., 
2010; Santos et al., 2010). Other disease findings may include scoliosis, diabetes, incontinence, 
cardiomyopathy, optic atrophy, and hypoacusis with median life expectancy of 35 years. 
Physiologically, FRDA is characterized by mitochondrial dysfunction and inefficient oxidative 
metabolism with three particular findings: intracellular iron deposits; a deficit in the 
mitochondrial iron-sulfur (FeS) cluster containing enzymes such as aconitase and respiratory 
chain Complexes I-III; and the presence of markers of oxidative damage in the blood and urine 
(Martelli et al., 2012). 
The genetic basis of FRDA is a recessive GAA trinucleotide expansion mutation of the first 
intron in the frataxin gene (FXN). The normal frataxin gene has ≤ 40 GAA repeats, while FRDA 
subjects have increasing and varying GAA repeats. This expansion leads to significantly 
decreased protein expression levels (5% to 30% of normal) of the frataxin protein (Santos et al., 
2010; Martelli et al., 2012). The low levels of frataxin cause dysregulation of normal iron levels 
resulting in an insufficient supply of iron to the FeS complexes, the primary cause of inefficient 
mitochondrial energy generation. The suboptimal delivery of iron to the FeS complexes results in 
a number of secondary potentially toxic reflexive mechanisms such as an excess of free Fe+2, 
which in turn catalyzes HO• (hydroxy radical) production from H2O2 that leads to widespread 
lipid peroxidation (Foury & Cazzalini, 1997; Qian & Buettner, 1999). The chronic reactive 
oxygen species (ROS) generation overwhelms the intramitochondrial and intracellular ROS 
quenching systems leading to significant oxidative damage, inefficient power generation, 
widespread cellular dysfunction, and premature cell death (Armstrong et al., 2010; Guéraud et 
al., 2010). 
6.2. 
Oxidative Stress and Neurodegenerative Disease 
A great deal of evidence exists that demonstrates the involvement of oxidative stress in the 
pathology of neurological disorders. Moreover, the vulnerability of the central nervous system to 
ROS-mediated injury is well established since neurons consume large amounts of oxygen, the 
brain has many areas containing high iron content, and neuronal mitochondria generate large 


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amounts of hydrogen peroxide. Furthermore, neuronal membranes are rich in polyunsaturated 
fatty acids, which are particularly susceptible to oxidative stress. The biological roles of products 
produced by lipid peroxidation have received much attention, not only for their pathological 
mechanisms associated with neurological disorders, but also for their practical clinical 
applications as biomarkers. Reactive oxygen species are likely to play a pathophysiological role 
in many neurological disorders, including Alzheimer’s disease, Down syndrome, Parkinson’s 
disease, and stroke. 
The brain is extremely sensitive to oxidative damage for several reasons. The brain consumes an 
inordinate amount of oxygen (around 20%), particularly when considering the fact that the brain 
accounts for only 2% of body weight (Halliwell, 2006). A major reason for the high O2 uptake is 
the vast amounts of ATP needed to maintain neuronal intracellular ion homeostasis in the face of 
ion channels need for action potentials and neurosecretion. Additionally, several brain areas, 
including the substantia nigra, caudate nucleus, putamen, and globus pallidus, are rich in iron 
content (Zecca et al., 2004). It is generally accepted that iron accumulates in the brain of older 
individuals, and iron ions that are released following brain damage can catalyze free radical 
reactions. The brain is a source of ROS. Complex I-dependent hydrogen peroxide generation in 
brain mitochondria is greater than that in skeletal muscle mitochondria (Malinska et al., 2009). 
Lastly, neuronal membranes are rich in polyunsaturated fatty acids (PUFAs), particularly 
arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) (Chen et 
al., 2008). These PUFAs are particularly vulnerable to oxidative stress due to their degree of 
unsaturation (multiple double bonds). For these reasons, neural cells are more susceptible to 
oxidative damage when compared to other body tissues. 
The mechanism of ROS production differs in each neurological disorder; excess amounts of 
oxidized lipids causing neurological degeneration may be the result of excessive generation of 
these compounds, reduced clearance, or some combination of the two processes. These 
differences provide multiple targets for therapeutic intervention. However, any intervention that 
results in less lipid peroxidation is likely to exhibit some therapeutic benefit in neurological 
degeneration. In FA, the cause of excessive ROS is the excess production that accompanies low 
levels of expression of the iron chaperon protein frataxin, causing oxidation stress from Fenton 
reaction catalysis of free-iron induced lipid peroxidation. 
6.3. 
Non-Clinical Rationale Supporting RT001 Development for FRDA 
RT001 is a site-specific (C11) di-deutero synthetic homologue of linoleic acid (LA) ethyl ester. 
It has been established that substitution of hydrogen with deuterium at specific bis-allylic sites, 
as in RT001, decreases the production of lipid peroxidation products in yeast models of oxidative 
stress (Hill et al., 2011; Hill et al., 2012; Grazia Cotticelli et al., 2013; Abeti et al., 2015; 
Andreyev et al., 2015). In vitro yeast, murine, and human models of FRDA also indicated that 
RT001 free acid managed the oxidative stress associated with increased iron (Grazia Cotticelli et 


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al., 2013; Abeti et al., 2015). The significance of the results with FRDA model systems is 3-fold. 
First, oxidative stress in FRDA has been difficult to measure, and the protective effects of 
deuterated polyunsaturated fatty acids (D-PUFAs) in the FRDA cell models indicate not only 
that there is oxidative stress in these models, but also emphasize the importance of lipid 
peroxidation damage. Second, results further support the proposal that reinforcing essential 
PUFAs with isotopic replacement decreases lipid peroxidation and decelerates toxic cellular 
cascades. Third, the results suggest that dietary dosed D-PUFAs such as RT001, which are easily 
distributed to all the target tissues, might be an effective therapeutic strategy for the treatment of 
FRDA. The chemical basis for this decrease in lipid peroxidation is the kinetic isotope effect 
(KIE). KIE is related to the difference in molecular weight, substitution of deuterium for 
hydrogen (with a 100% in increase in molecular weight) exhibits one of the largest KIEs 
observed. The KIE of RT001 vs. LA has been well documented (Hill et al., 2012, Lamberson et 
al., 2014). 
Given the deleterious effects of frataxin mutations on the mitochondrial electron transport chain, 
and the presence of mitochondrial iron accumulation in FRDA, the PUFA-rich inner 
mitochondrial membranes are the primary sites of autoxidative damage. In H9C2 myoblasts, 
treatment with t-ButOOH caused both respiratory inhibition and increased membrane leak. 
RT001 free acid protected mitochondrial function from stress caused by t-ButOOH; maximal 
respiration was preserved and membrane leakage was diminished (Andreyev et al., 2015).  
6.4. 
Clinical Rationale Supporting RT001 Development for FRDA 
RT001-002 was a randomized, double blind, comparator controlled, 28-day clinical study with 2 
cohorts of 9 subjects each randomized 2:1 to RT001 or linoleic acid control in identical gel 
capsules. Cohort 1 received 1.8 g/day (2 capsules) and Cohort 2 received 9.0 g/day (10 capsules) 
with meals. All subjects were followed for 28 days with a 30-day safety follow up. The primary 
endpoint was safety, tolerability, and pharmacokinetics. The secondary endpoints were timed 25-
foot walk (T25FW) test and Friedreich Ataxia Rating Scale (FARS) neurologic scale measurement 
comparing baseline to test results on Day 28. Exploratory endpoints included changes in 
pharmacodynamic biomarkers, multi-axis movement measurement of the lower extremity during 
the T25FW test, and measurement of exercise capacity using a Cardio-Pulmonary Exercise 
Testing (CPET) protocol to measure peak workload and maximum rate of oxygen consumption 
(VO2 MAX) when performed on a recumbent bicycle with full pulmonary metabolic 
measurements. 
A total of 19 subjects were enrolled in RT001-002 (13 subjects in the RT001 group and 
6 subjects in the comparator group). Of the 19 enrolled subjects, 17 subjects completed the study. 
The two subjects who withdrew from the study were in the RT001 group. 


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Plasma deuterated linoleic acid (D2-LA) concentrations rose over the course of the 28-day study 
in both cohorts and appeared to be approaching a steady state by the Day 28 dosing interval. 
Mean plasma D2-LA concentrations on Day 28 fluctuated slightly (less than 2-fold) during the 12 
or 24 h dosing interval, and then fell slowly, with a mean terminal half-life of 42.3 ± 9.8 h in 
Cohort 1 and 30.3 ± 18.3 h in Cohort 2 (Table 6, Table 7). When the daily dose was increased 
5-fold from 1.8 g to 9.0 g, the AUC0-24h on Day 28 rose from 1527 ± 445 ug•h/mL to 6800 ± 
918 ug•h/mL (approx. 4-fold). 
Table 6. Summary of D2-LA PK Parameters in Plasma on Day 1 
 
 
Cohort 1 
1.8 g QD 
Cohort 2 
4.5g BID 
Parameter 
units 
n 
Mean 
SD 
n 
Mean 
SD 
Cmax 
ug/mL 
6 
35.9 
9.8 
7 
58.6 
16 
Tmax 
h 
6 
6.1 
- 
7 
8.0 
-- 
AUClast 
ug h/mL 
6 
520 
86 
7 
912 
251 
Median shown for Tmax. On Day 1 AUClast was 24h 


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Table 7. Summary of D2-LA PK Parameters in Plasma on Day 28 
 
 
Cohort 1 
1.8 g QD 
Cohort 2 
4.5g BID 
Parameter 
units 
n 
Mean 
SD 
n 
Mean 
SD 
Cmax 
ug/mL 
6 
80.8 
24.6 
5 
359.9 
31.6 
Tmax 
h 
6 
7.9 
- 
5 
6.0 
- 
Cmin 
ug/mL 
6 
26.0 
10.1 
5 
86.2 
43.7 
Tmin 
h 
6 
71.8 
- 
5 
72.0 
- 
AUC0-12h 
ug h/mL 
6 
809 
269 
5 
3400 
459 
AUC0-24h 
ug h/mL 
6 
1527 
445 
5 
6800a 
918 
AUClastb 
ug h/mL 
6 
3345 
950 
5 
13854 
2899 
t1/2 
h 
5 
42.3 
9.77 
4 
30.3 
18.30 
Medians shown for Tmax, Tmin 
a – For comparison of the two dosing regimens, the AUC0-24h shown here is the AUC0-24h at  
steady state (= 2 * AUC0-12) for the BID regimen 
b – AUClast was 72 h after the last dose in all subjects 
The CPET testing change between baseline and Day 28 showed an improvement in peak 
workload of +0.16 watts/kg (25.7%) in the subjects on all doses of study drug (n=10) vs. 
comparator (n=6). The reported p value in post hoc analysis was p=0.008 (Mann-Whitney Rank 
Sum test). This modified Intent-To-Treat (mITT) analysis excluded 2 subjects unable to either 
start or complete the test, and full Intent-To-Treat (ITT) analysis including the two subjects, had 
a p= 0.021. Similarly, the study showed a strong trend from baseline to Day 28 of therapy in 
peak oxygen consumption (VO2 MAX). The median change from baseline for comparator vs. 
RT001 was -0.02 L/min vs. 0.14 L/min; respectively, p=0.116. Assessment on the neurological 
examination of the Friedreich Ataxia Rating Scale (FARS-Neuro) scoring showed a trend in 
improvement between baseline and Day 28 of treated vs. placebo patients (a decrease of 1.95 
FARS points, p= 0.348 ITT). This result was on top of a decrease of 2.8 FARS points in the 
placebo group, (i.e. a 4.75 FARS point decrease from baseline for the treated group), 
highlighting the robust placebo effect in the FARS-Neuro measure that has been documented 
elsewhere (Zesiewicz, 2017). Expected change in FARS-Neuro for one month of dosing based 
on extensive natural history data (Patel et. al., 2016) would be ~ +0.25 FARS points. The 
average stride speed (stride time)-1 during the T25FW, measured with an electronic motion 
sensor, improved 7% (p=0.15 ITT). Traditionally measured T25FW-1 (via stopwatch) showed no 
signal of significance (p=0.88). 
The relatively small size and short duration of the trial necessitates caution in over-interpretation 
of efficacy results. Nevertheless, clear correlations between the various parameters measured 


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cross-sectionally across all patient encounters can be seen in RT001-002.  Comparisons of peak 
workload, VO2 MAX, FARS-Neuro Score, and T25FW show consistent correlation. This 
indicates that these are all legitimate measures of disease severity, and correlative to traditional 
measures such as FARS neuro, which may be less consistent and predictable than CPET-
determined peak workload and VO2 MAX. 
6.5. 
Non-Clinical Safety Summary 
Refer to the Investigator Brochure for a summary of the nonclinical studies conducted with 
RT001. There was no adverse finding in any parameter in Good Laboratory Practice (GLP) 
dietary toxicity rat studies of RT001 up to 26-weeks at the highest doses tested, averaging 
452 mg/kg (401 and 502 mg/kg in males and females; respectively).  
Long-term increased intake of dietary fats, including LA, can lead to obesity when consumed 
above normal ranges. As a result, obese rats are no longer normal, and this state of physiological 
dysregulation has a confounding effect on the interpretation of direct toxicological effects 
(Heden et al., 2014). To avoid the confounding effects of obesity, the LA content in rat studies 
were based on physiologic levels of PUFAs. Further dose escalation of RT001 in rat studies 
poses a challenge as higher doses result in polyunsaturated fat intake in excess of accepted 
healthy diet values. This would lead to a study in elevated fat intake, elevated PUFA intake, and 
altered caloric density, rather than a clear study of RT001 effects. In our studies at the highest 
dose tested, the total fat made up 14% of the subject dietary calories, the recommended 
maximum level for rats (National Academy of Sciences, 1995), and RT001 made up 100% of the 
LA component.  
In animal studies, RT001 was found to be equivalent to, and biologically interchangeable with 
normal dietary LA as a sole source (100% replacement) of LA, indicating that the substitution of 
hydrogen with deuterium does not interfere with the normal biology of the fat. If this was not the 
case, essential lipid deficiency diseases (Burr & Burr, 1929 and 1930) would be observed in the 
treated populations. In addition, LA is recognized by the Food and Drug Administration (FDA) 
as generally recognized as safe (GRAS), and has no upper limit under the GRAS designation. 
Additionally, IntraLipid® is approved as an IV drug at doses up to 93 g/day LA (2.5 g/kg/day) 
based on a 60-kg person (IntraLipid Prescribing Information, 2006) representing a 16.3-fold 
safety margin over the dose of 5.7 g/day. 
6.6. 
Clinical Safety Summary 
In clinical study RT001-002, one subject in cohort 2 (9g/day dose group) dropped from the study 
on Day 3 after experiencing severe oily diarrhea (steatorrhea). The subject was hospitalized for 
overnight observation. The symptoms resolved spontaneously within several hours and there 
were no signs of gastrointestinal (GI) malabsorption. The subject had a remarkably low body 
mass at 38.9 kg, suggesting that care must be observed at the highest dose in low body mass 


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subjects. The subject did not continue with the trial and another subject was recruited. This event 
was judged to be severe and probably related to study drug. Another subject withdrew due to an 
AE of depression. Diarrhea was reported in 3 additional subjects in the RT001 treatment group 
and 1 subject in the comparator treatment group of cohort 2. These events were assessed by the 
investigators as mild and possibly related to study drug. The other treatment-emergent adverse 
events (TEAEs) were assessed by the Investigators as mild (grade 1) or moderate (grade 2) in 
severity and unrelated to study drug. The TEAEs are shown by System Organ Class (SOC) and 
Preferred Term in Table 8. 
Table 8 
TEAEs by System Organ Class and Preferred Term (Safety Population) 
System Organ Class / 
Preferred Term 
Cohort 1 
Cohort 2 
RT001 
(N=6) 
n(%) 
Comparator 
(N=3)  
n(%) 
RT001 
(N=7)  
n(%) 
Comparator 
(N=3)  
n(%) 
Subjects Reporting at Least One TEAE 
5 (83.3%) 
2 (66.7%) 
5 (71.4%) 
2 (66.7%) 
Gastrointestinal disorders 
2 (33.3%) 
0 (0.0%) 
5 (71.4%) 
1 (33.3%) 
Diarrhea 
0 (0.0%) 
0 (0.0%) 
4 (57.1%) 
1 (33.3%) 
Abdominal discomfort 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Abdominal distension 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Abdominal pain 
0 (0.0%) 
0 (0.0%) 
1 (14.3%) 
0 (0.0%) 
Constipation 
0 (0.0%) 
0 (0.0%) 
1 (14.3%) 
0 (0.0%) 
Feces discolored 
0 (0.0%) 
0 (0.0%) 
1 (14.3%) 
0 (0.0%) 
Nausea 
0 (0.0%) 
0 (0.0%) 
1 (14.3%) 
0 (0.0%) 
Steatorrhea 
0 (0.0%) 
0 (0.0%) 
1 (14.3%) 
0 (0.0%) 
Infections and infestations 
1 (16.7%) 
2 (66.7%) 
0 (0.0%) 
0 (0.0%) 
Conjunctivitis viral 
0 (0.0%) 
1 (33.3%) 
0 (0.0%) 
0 (0.0%) 
Sinusitis 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Upper respiratory tract infection 
0 (0.0%) 
1 (33.3%) 
0 (0.0%) 
0 (0.0%) 
Nervous system disorders 
2 (33.3%) 
1 (33.3%) 
0 (0.0%) 
0 (0.0%) 
Dysgeusia 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Sciatica 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Tremor 
0 (0.0%) 
1 (33.3%) 
0 (0.0%) 
0 (0.0%) 
Injury, poisoning and procedural 
complications 
1 (16.7%) 
1 (33.3%) 
0 (0.0%) 
0 (0.0%) 
Facial bones fracture 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Muscle strain 
0 (0.0%) 
1 (33.3%) 
0 (0.0%) 
0 (0.0%) 


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System Organ Class / 
Preferred Term 
Cohort 1 
Cohort 2 
RT001 
(N=6) 
n(%) 
Comparator 
(N=3)  
n(%) 
RT001 
(N=7)  
n(%) 
Comparator 
(N=3)  
n(%) 
Respiratory, thoracic and mediastinal 
disorders 
1 (16.7%) 
0 (0.0%) 
1 (14.3%) 
0 (0.0%) 
Nasal discomfort 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Oropharyngeal pain 
0 (0.0%) 
0 (0.0%) 
1 (14.3%) 
0 (0.0%) 
Rhinorrhea 
0 (0.0%) 
0 (0.0%) 
1 (14.3%) 
0 (0.0%) 
Blood and lymphatic system disorders 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Anemia 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Cardiac disorders 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (33.3%) 
Palpitations 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (33.3%) 
Psychiatric disorders 
0 (0.0%) 
0 (0.0%) 
1 (14.3%) 
0 (0.0%) 
Depression 
0 (0.0%) 
0 (0.0%) 
1 (14.3%) 
0 (0.0%) 
Skin and subcutaneous tissue disorders 
0 (0.0%) 
0 (0.0%) 
1 (14.3%) 
0 (0.0%) 
Pruritus 
0 (0.0%) 
0 (0.0%) 
1 (14.3%) 
0 (0.0%) 
In addition to RT001-002, RT001 is currently in use in 19 subjects with infantile neuroaxonal 
dystrophy in the U.S.  The study enrollment is complete, and subjects continue to participate in 
the extension trial.  No serious adverse or unexpected drug-related events have been reported in 
the study thus far. 
RT001 is also being administered in several Expanded Access studies. These Expanded Access 
studies have been implemented when a plausible mechanism for RT001 therapeutic benefit is 
considered. The Expanded Access studies have served to support PK, efficacy, and safety data 
while generating experience in neurodegenerative conditions that might later warrant a formal 
study in a treatment protocol. Refer to the Investigator Brochure, for additional information of 
RT001 Sponsor clinical studies and Expanded Access studies. 
At the present stage of development, the risk of RT001 seems acceptable considering the 
potential benefit of RT001 treatment for patients diagnosed with Friedreich’s ataxia. Based on 
these observed gastrointestinal disorder adverse events, we believe that a maximal tolerated dose 
of 9.0 g/d may have been reached and steps are being taken in the current protocol to address this 
issue by reducing the dose to 5.76 g/d and dividing the dose between 2 or 3 meals. Additional 
adjustment possibilities have been added to the protocol to correct for diarrhea-related adverse 
events for low body mass adults and children. 


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6.7. 
Inclusion of Pediatric Subjects of 12 Years and Older in the Current 
Protocol 
The decision to include pediatric subjects with FRDA in a clinical trial requires per the 
regulations a careful analysis of the risks and potential benefits to the subjects. Inclusion of 
pediatric subjects also involves an analysis of whether or not the subjects would be 
representative of the population of subjects under study, and whether or not the pediatric subjects 
would be able to comply with the protocol requirements. 
RT001 is a deuterated formulation of linoleic acid, the predominant fatty acid in several 
approved drug products for IV nutritional supplementation, including the widely used 
IntraLipidTM. Pediatric subjects in the clinical trials that led to the approval of the nutritional 
supplementation drugs containing linoleic acid constituted more than half of all enrolled patients. 
Most adverse reactions were related to the route of administration than to the drug itself; the 
warning for use in pediatric patients limiting use to less than 3g/kg/day was related to a side 
effect that was clearly linked to IV administration. RT001 is planned for oral administration 
only, and the maximum daily dosage will be 8.64 g/day for 30 days followed by 5.76g/day. The 
average weight of a 12 to 14-year old patient is approximately 40 kg. Therefore, the maximum 
dosage administered orally in our clinical trial will be 0.216 g/kg/day, far less than the maximum 
recommended IV dosage for pediatric patients using IntraLipid.  The use of RT001 in pediatric 
patients is likely to be safe, as evidenced by the many years of safe use of the nutritional 
supplements in this age group. In the clinical trials of RT001 in adults, steatorrhea has been the 
only significant adverse reaction, and this appears to be easily manageable with dose adjustment. 
The chief benefit of including pediatric patients in clinical trials with FA include the potential for 
halting or reversing disease progression. The early age of onset of FA, its most rapid progression 
in the first years after diagnosis, and its tendency to produce most severe disability in patients 
who present earliest in life, all necessitate the development of an effective treatment that is 
applicable to pediatric patients.  If RT001 is shown to be beneficial in treating FA, pediatric 
patients are likely to be the greatest beneficiaries of this therapy. 
RT001 is currently in use in a pediatric study with 19 patients with infantile neuroaxonal 
dystrophy aged between 18 months and 10 years of age. Each patient is receiving RT001 at a 
dose of 1 capsule TID (2.88 g/day). At present, no adverse drug effects have been identified or 
reported. 
In previous clinical trials of FA patients, pediatric age subjects have been found to be 
cooperative and important contributors to observational studies (Sival et al. 2011, Patel et al. 
2016). The requirement for cardiopulmonary exercise testing (CPET) for determination of the 
primary endpoint in the clinical trial with RT001 will require subject cooperation which exceeds 
the capacity of pediatric patients of younger age. Previous observational studies of pediatric 
patients with FA that required the performance of CPET have limited the use of CPET in the 


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younger patients for this reason. Pharmacological trials have had lower age limits of 11 years 
(Artuch et al. 2002), or 16 years (NCT02367014, NCT02255435). Retrotope believes that the 
enrollment of FA patients 12 years old and above strikes the optimal balance between risk, 
benefits, and practicality for the present clinical trial. 
6.8. 
Potential Risks and Benefits to Human Subjects 
FA is a rare, inherited recessive disorder characterized by progressive degenerative changes, in 
particular to mitochondria, which lead to morbidity and mortality at a young age. There is 
currently no approved therapy for this condition. RT001 offers a novel yet specific approach to 
mitigation of the harmful oxidative attack on lipids of mitochondrial membranes, which has 
potential benefit if the hypothesis is proven in this and subsequent efficacy studies. RT001 is 
based on a common, essential dietary sourced fatty acid, LA. The slight modification to the 
chemical structure of LA, the site-specific replacement of 2 hydrogen atoms with 2 deuterium 
atoms, does not impact any of the key properties and fate of the lipid, yet remains functionally 
active against unwanted, pathological oxidative attack. The deuterium presents low risk (see 
below) in that it is stably incorporated in covalent bonds, and the amount dosed is relatively low. 
Thus, the risk-benefit profile is thought to be favorable and suggests a future potential benefit of 
RT001 treatment in this intractable condition. 
In models of neurodegenerative diseases, possible triggers such as an aberrant protein (e.g., beta 
amyloid or synuclein), the low expression of frataxin in FA, chemical or environmental toxins, 
or redox imbalances, induce a stress in the cell that is first manifested in lipid peroxidation inside 
mitochondria where several factors combine to make the cells most susceptible. Those factors 
include: 1) the high concentration of ROS generated by cellular energy generation; 2) the 
concentrated accumulation of highly susceptible PUFAs in the mitochondrial inner membrane; 
and 3) inadequate protection by antioxidants due to the hydrophobic nature of the inner 
membrane that limits antioxidant solubility and diffusion into the susceptible domains. Most 
important to our mechanism of action is the recognition that the accelerated free radical chain 
reaction that results from disease amplifies damage massively through an autocatalytic process 
that propagates recurring damage from a single initiating event. The initiating event is a slow, 
rate determining step that is self-propagating in its damage to membranes. Stabilizing the bonds 
most susceptible to oxidation in the initiating event can shut down an entire cascade of 
accelerating damage in a non-stoichiometric fashion and can provide a new treatment modality 
for disorders of lipid peroxidation. 
RT001 is a site-specific deuterated analogue of LA ethyl ester. LA is designated by the FDA as 
GRAS with no upper limit set by toxicity. The exposure to LA in the typical Western diet ranges 
from 5 to 20 g/day. Intralipid® 20%, a product approved by FDA for intravenous (IV) parenteral 
nutrition, can be administered at doses which provide up to 93 g/day of LA (2.5 g/kg of Intralipid 
which is up to 2/3 LA). As demonstrated in nonclinical and in vitro studies, there were no 


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demonstrable adverse metabolic effects of deuterating LA. Likewise, the amount of deuterium to 
be administered at the highest dose proposed for use in this clinical study is approximately four-
orders of magnitude lower than the safety threshold described by the International Atomic 
Energy Agency (IAEA, 2009). 
Linoleic acid is the predominant fatty acid in two emulsions approved by the FDA as a source of 
calories and essential fatty acids. Intralipid 10% (Cutter Pharmaceuticals, IND 17-643) was 
submitted as an NDA on August 9, 1974. Also, around this time, Liposyn 10% (Abbott 
Laboratories, IND 18-203) also was filed. These intravenous formulations were developed to 
provide nutrition to patients who had conditions which precluded effective enteral feeding. 
Subsequent to these approvals, some changes have been made to the concentration and plant 
source for the various products, but the component fatty acids have remained consistent. 
Intralipid is predominantly soybean oil in concentrations of 10%, 20% and 30%. Egg yolk 
phospholipids are added in a concentration of about 1.2%. Liposyn includes both soybean and 
safflower oil in the identical concentrations. The approximate major component fatty acids 
include linoleic (65%), oleic (20%), palmitic (5%), linolenic (5%), and stearic (5%). Intralipid 
was approved based on the results of 67 studies conducted before approval. These included 4 
studies in 22 human volunteers, and 63 studies in 298 patients. Of the patients included in the 
studies, 128 were adults, and 170 were pediatric patients (mostly infants). The studies showed 
that the product was pharmacologically inactive and relatively well-tolerated. Most adverse drug 
reactions were related to the route of administration rather than to the systemic effects of the 
product itself. These reactions included: local vein reaction, sepsis, allergic reactions, 
hyperlipidemia, fever, sleepiness, headache, nausea, vomiting, flushing, hypercoagulability, 
thrombophlebitis, thrombocytopenia, leukopenia, tachycardia, dyspnea, splenomegaly, and 
shock. 
Post approval, deaths were reported in association with Intralipid use in pre-term infants. This 
was thought due to fat accumulation in the lungs in these infants. The maximum dose used in 
pediatric patients was reduced to 3 g/kg/day, and a warning placed on the label for use in 
pediatric patients. 
Deuterated LA and other deuterated PUFAs have been used safely and extensively in 
biochemistry and nutrition research for several decades to elucidate the metabolic pathways for 
fatty acid metabolism, cell membrane integrity and prostaglandin synthesis (Brenna, 1997). 
Single and multiple doses of deuterated PUFAs (up to 10-18 g) have been used in clinical studies 
without adverse reactions. A wide variety of deuteration positions on LA have been used for 
those studies, and some, including perdeuterated LA, included deuterium at the C11 position. For 
example, Emken and colleagues investigated the desaturation of 18:0 and 16:0 and 18:2n-6 and 
18:3n-3 elongation/desaturation in four healthy adults, who received oral doses of about 3-3.5 g 
of d2-18:2n-6, d4,-18:3n-3, and d6-18:n-9 fatty acids (Emken et al., 1990). Salem and colleagues 


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have safely administered d5-18:2n-6 and d5-18:3n-3 doses of 50-10 mg/kg body weight to 
premature infants and showed that infants as small as 1,980 g and 32 weeks gestation elongate 
and desaturate both precursors within 24 hours (Salem et al., 1996). 
Based on the initial analysis of data from RT001-002, RT001 remains very safe. The maximal 
tolerated adult dose studied is approximately 9.0 g/d above which steatorrhea/diarrhea may 
occur. In the initial 28-day study, signs of clinical activity may have been demonstrated. These 
changes in clinical activity markers were not expected in this 28-day study, but they form the 
basis for Study RT001-006 where RT001 will be dosed for 11 months. 
6.9. 
Description and Justification for the Dosing Regimens to Be Studied 
LA cannot be synthesized by mammals and is an essential component of the human diet. LA is 
the most common dietary source of polyunsaturated fat for humans and is a source of metabolic 
energy (9 Calories/g) and longer chain omega-6 fatty acids. LA is also the starting compound for 
other desaturated and elongated fatty acids that are normal physiological lipid components 
(e.g., arachidonic acid 20:4n-6), an important fatty acid in membrane phospholipids. Nonclinical 
studies have shown that RT001 recapitulates LA biochemistry in normal physiological lipid 
processing. 
The amount of deuterium contained in the high dose proposed for the clinical study is below 
doses commonly used for isotope labeling studies. The dose of RT001 will contribute 
approximately 80 Calories and is within the range of daily fat intake recommended by the 
Centers for Disease Control (CDC). 
RT001 has been administered in humans at a higher level than the current study proposed dosing 
regimen and was found to be safe in Study RT001-002. There was one treatment emergent 
adverse event report characterized as serious – steatorrhea associated with the use of study drug.  
The event resolved after 6 hours. The subject was hospitalized for overnight observation.  The 
subject had no other symptoms and did not receive specific treatment. Upon questioning, a few 
other subjects in the high dose cohort also reported occasional diarrhea that was mild and not 
worrisome. The dose for this study is 8.64 g/d for 30 days followed by 5.76 g/day, which is well 
below the highest tested dose of 9.0 g/day in Study RT001-002. 


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7. 
STUDY OBJECTIVES 
This study is designed to evaluate the effect of RT001 in subjects with FRDA:  
7.1. 
Primary endpoint 
1. To demonstrate the efficacy of RT001 compared to placebo on the change of MVO2 in 
patients with FA through change from baseline to 11 months 
7.2. 
Key secondary endpoint 
1. To demonstrate the efficacy of RT001 compared to placebo on an overall performance 
score based on a GST change from baseline to 11 months. The GST will be a 
combination of three endpoints (timed 1 minute walk test [T1MW], peak workload, and 
MVO2).   
7.3. 
Secondary endpoints 
1. To demonstrate the efficacy of RT001 compared to placebo on T1MW with change from 
baseline to 11 months 
2. To demonstrate the efficacy of RT001 compared to placebo on the change of peak 
workload measured by CPET through change from baseline to 11 months 
7.4. 
Exploratory endpoints 
To demonstrate the efficacy of RT001 on change from baseline at 11 months in clinical 
symptoms as measured by: 
1. Modified Friedreich’s Ataxia Scale (mFARS)  
2. Fatigue Symptom Scale (items 2. 4. 7.9 of the total fatigue scale) 
3. Clinician-rated Clinical Global Impression of Change (CGI-C) 
4. Activities of daily living (ADL) elements of fatigue scale (items 5,6, 8, 10, and 11) 
5. Patient Global Impression of Change (PGI-C) 
 
• To evaluate the effects of RT001 on Visual Analogue Scale [VAS] 
• To evaluate the effects of RT001 on speech measurements and Speech Assessment 
questionnaire 
• To evaluate the effect of RT001 on T25FW  
• To evaluate the effects of RT001 on FARS-Neuro 
• To evaluate the effects of RT001 on FARS-ADL 


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• To evaluate the effects of RT001 on SF-36 
• To evaluate the effects of RT001 on the Neuro-QoL scales (Upper Extremity Function 
and Lower Extremity Function) 
• To evaluate the effects of RT001 on the frequency of falls as reported in a fall diary and 
subject’s fear of falling 
• To evaluate the effects of RT001 on the Patient Global Impression of Change (PGI-C) 
Scale 
• To evaluate the effects of RT001 on efficacy assessments after 4 months of treatment 
• To evaluate the effects of RT001 on efficacy assessments after 8 months of treatment 
• To evaluate the effects of RT001 on ejection fraction as reported in the Echocardiogram 
• To evaluate the effects of RT001 on hypertrophy as reported in the Echocardiogram 
 
7.5. 
Optional Sub-Study Objectives 
7.5.1. 
Optional PK Profile Sub-Study 
The objective of the study is to evaluate the pharmacokinetic (PK) profile of RT001 at steady 
state.   
7.5.2. 
Optional PK Washout Sub-Study 
The objective of the study is to evaluate the washout blood levels of RT001 after treatment in 
RT001-006 is completed. 


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8. 
INVESTIGATIONAL PLAN 
8.1. 
Study Design 
This is a randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and 
tolerability in subjects with FRDA following the oral administration of study drug (active or 
placebo capsules).  
Subjects will self-administer the study drug orally with meals. While on study drug, subjects are 
recommended to avoid eating foods high in PUFAs. Subjects will keep food journals from 
screening through the completion of month 1 on study drug. After month 1, subjects will keep 
2-week food journals prior to next scheduled onsite visit. Subjects (or parents/caregivers, as 
applicable) will have an initial call and as needed with the diet coach to discuss food journal 
completion requirements. 
A total 60 FRDA subjects will be enrolled. Subjects will be randomized to active [9 capsules of 
RT001 (8.64 g/day) for the first month, followed by 6 capsules of RT001 (5.76 g/day)] or 
placebo in a 1:1 ratio. Randomization will be stratified by FARS Neurological score: ≤45 and 
>45. Enrollment of patients with age > 25 will be capped at 25 % of the total enrollment. 
Subjects will self-administer orally 9 capsules daily for the first month with a meal: 3 capsules 
with breakfast, 3 capsules with lunch, and 3 capsules with dinner for the first month.  After this 
initial period the dose will be reduced to 6 capsules daily with a meal: 3 capsules with breakfast, 
and 3 capsules with dinner for the remainder of the trial, while on study drug. If a subject is 
unable to tolerate study drug because of adverse events during the initial loading period, the dose 
may be reduced to six capsules daily (5.76 g total dose) given as 3 capsules with breakfast, and 
3 capsules with dinner. If a subject is unable to tolerate study drug because of adverse events 
after the dose reduction to six capsules daily (5.76 g total dose), the dose may be spread over 
three meals (2 capsules at breakfast, 2 capsules with lunch, and 2 capsules with dinner). If the 
subject is still unable to tolerate study drug after spreading it over three meals, the total dose may 
be reduced by 1-2 capsules/day, preferably by reducing the dose for a meal from 2 to 1 
capsule(s) as needed. After 2 weeks of taking a dose of less than 6 caps/day, the subject should 
try to increase the dose to 6 capsules/day given as 2 capsules TID given with meals. If 6 caps/day 
is not tolerable, the subject can take the drug at the dose of less than 6 caps/day that was 
tolerable. The last dose of study drug will be taken at 4 weeks from Day 330 visit. 
Participation is anticipated to require 13 months. 
• Screening: Up to 30 days from start of treatment  
• Treatment Period: treatment for a 12-month period 
Safety assessments include physical and neurologic examinations, vital signs, 12-lead 
electrocardiogram (ECG) tracing, and clinical laboratory tests (hematology, clinical chemistry, 


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lipid profile, coagulation, and urinalysis) to identify adverse events (AEs). Adverse events will 
be evaluated for incidence, severity, and relationship to study drug.   
The first dose of the study drug will be taken on Day 1. Bioanalytical measurements will be 
performed to determine the concentration of D2-LA, deuterated arachidonic acid (D2-ARA), 
nondeuterated linoleic acid (H2-LA) and nondeuterated arachidonic acid (H2-ARA) in plasma 
and red blood cells. Blood samples will be collected at month 4 (Day 120 ± 30 days), at month 8 
(Day 240 ± 30 days), and at month 11 (Day 330 ± 30 days). All samples are to be obtained prior 
to dosing and prior to breakfast.  
Subjects will perform CPET on a stationary recumbent bike at Screening, on Day 1, Day 120 
(± 30 days), Day 240 (± 30 days), and Day 330 (± 30 days). Peak work rate and VO2 MAX will 
be measured during incremental exercise testing. CPET should occur after fasting (if the subject 
has had a meal/snack) for a minimum of 2 hours, with neither caffeine nor nicotine for at least 
12 hours before testing. 
Subjects (with or without assistive device) will perform a T1MW and electronically measured 
T25FW at Screening, on Day 1, Day 120 (± 30 days), Day 240 (± 30 days), and Day 330 
(± 30 days). 
CPET and the T1MW/T25FW should be separated in time to allow the subject to recover 
sufficiently before doing the next test. All tests should be done at approximately the same time 
and order for each visit.  
The FARS-Neuro and clinician-rated CGI scale will be performed at Screening, on Day 1, 
Day 120 (± 30 days), Day 240 (± 30 days), and Day 330 (± 30 days) by a qualified physician or 
health professional who is trained on the use of the tool. The CPET examination should always 
precede the FARS-Neuro evaluation at all visits. 
A trained health professional will also work with the subject to perform the speech measurement 
recording at Screening, on Day 1, Day 240 (± 30 days), and Day 330 (± 30 days). 
The FARS-ADL, SF-36, VAS (for Fatigue), Fatigue scale, Neuro-QoL scales (lower extremity 
function and upper extremity function) and Fall Questionnaire will be completed by the subjects 
at screening and at the visits on Day 1, Day 120 (± 30 days), Day 240 (± 30 days), and Day 330 
(± 30 days). The PGI-C scale and VAS (for Improvement of FA symptoms) will be completed 
by all subjects at Day 120 (± 30 days), Day 240 (± 30 days), and Day 330 (± 30 days).  
In between the clinic visits, subjects will also be contacted by phone by a study site staff member 
and asked questions relating to the PGI-C, Fatigue scale, Neuro-QoL Scales (lower extremity 
function and upper extremity function), and questions 8 and 9 of the fall questionnaire. These 
phone ‘visits’ will take place monthly. A Speech Assessment Questionnaire will be completed by 
the subject and parents/caregiver (as applicable) at Screening, on Day 1, Day 240 (± 30 days), 
and Day 330 (± 30 days). 


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Between clinic visits, subjects will be asked to keep a daily log (diary) documenting falls, near-
falls, stumbles, and fear of falling (Screening through Day 330). 
Additional blood samples will be collected and stored for future biomarker analysis on Day 1, on 
Day 120 (± 30 days), Day 240 (± 30 days), and Day 330 (± 30 days). These samples are to be 
obtained prior to dosing and prior to breakfast.  
A final phone call will occur 4 weeks (+ 7 days) from the Day 330 visit to confirm date of last 
dose and accountability of final bottles. The site will also collect AE information and confirm 
any change in concomitant medication since the last visit. Any ongoing AEs at EOT will be 
followed to conclusion or until stabilized. 
Two additional optional sub-studies will be offered. The first is a 24hr PK Profile at steady state 
that will occur before or after the Day 330 visit. Immediately before or after the Day 330 visit in 
RT001-006, PK samples will be obtained 30 minutes to 1 hour before the morning dose; and 30 
min, 1, 2, 4, 8, 12 and 24 hours after the morning dose.  
The second optional sub-study is a 6-month study to evaluate the washout blood levels of RT001 
after treatment in RT001-006 is completed. Depending on the timing of entry into the sub-study, 
washout pharmacokinetic (PK) samples will be obtained at 7 days, 4, 12, and 24 weeks after the 
last dose to determine the trough concentration of deuterated linoleic acid (D2-LA), deuterated 
arachidonic acid (D2-ARA), nondeuterated linoleic acid (H2-LA) and nondeuterated arachidonic 
acid (H2-ARA) in plasma, and D2-LA, D2-ARA H2-LA, and H2-ARA in red blood cells. 
8.2. 
Randomization 
The randomized, double-blind design of the study is intended to minimize bias on the part of 
subjects, investigators, and analysts. Subjects who meet all enrollment criteria and from whom 
consent has been obtained will be randomly assigned to receive one of two treatments (RT001 or 
placebo capsules) following a 1:1 ratio. Randomization will be stratified as much as possible 
according to the FARS Neurological score (baseline FARS score of ≤45 and >45).  Enrollment 
of patients with age > 25 will be capped at 25 % of the total enrollment. 
8.3. 
Blinding 
Subjects and study personnel, including but not limited to investigators, study coordinators, 
nursing staff, clinical monitors, the Sponsor, and the Sponsor’s representatives, will remain 
blinded to the study treatment assignments (RT001 or placebo). 
If there is a need to unblind the study drug assignment for a subject, the Principal Investigator 
will discuss with the sponsor’s Medical Monitor. A separate unblinding plan will document the 
specific processes related to emergency unblinding. Refer to Section 15.7 for a description of 
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The reason for unblinding must be documented in the source document for the subject. If a 
subject’s study drug assignment is unblinded, the subject should remain in the study and 
continue the protocol-specified follow-up evaluations.  
8.4. 
Safety Monitoring  
8.4.1. 
Safety Monitoring 
The study site investigators assess each subject and record findings obtained during each visit. 
Subjects will be queried to report any observations, concerns or symptomatology, and a clinical 
assessment will also be made. This includes any evidence of disease exacerbation and/or 
progression. Safety reports made during the study (see Section 15) will be promptly reviewed by 
the Sponsor’s Medical Monitor and processed. This includes reporting to the FDA according to 
21 CFR 312.32, “IND Safety Reporting,” and taking any action necessary to protect subject 
safety. 
8.4.2. 
Sponsor Safety Monitoring 
The blinded safety and efficacy data will be reviewed by the study monitor on an ongoing basis.  
This data will not be made available to the Principal Investigators unless changes need to be 
made to the protocol for safety reasons. 
8.4.3. 
Data Safety and Monitoring Board 
A Data Safety and Monitoring Board (DSMB) will be established to review this study and 
provide recommendations per the DSMB Charter.   


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9. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
9.1. 
Inclusion Criteria 
To be enrolled into the study subjects must meet the following requirements: 
1. Male or female 12 to 50 years of age 
2. Medical history consistent with the symptoms of FRDA at ≤ 25 years of age 
3. Detection of biallelic pathogenic variants in frataxin gene (FXN) (i.e. biallelic repeat 
expansions of GAA in the disease-causing range, or compound heterozygous for a repeat 
expansion of GAA in the disease-causing range + an intragenic pathogenic variant, etc.) 
4. Ambulatory (with or without assistive device) and capable of performing other 
assessments/evaluations 
5. Must be able to walk 25 feet during the timed 1-minute walk 
6. Agree to receive calls from a diet coach regarding completion of electronic food journal 
7. Sign the informed consent form prior to entry into the study 
8. Agree to stay locally for the required visit days  
9. Able to provide the necessary repeated blood samples 
9.1.1. 
Inclusion Criteria for Optional PK Profile Sub-Study 
1. At selected sites, subjects who are enrolled in RT001-006 will be invited to participate in this 
study.   
2. All participating subjects will be required to sign an informed consent prior to the collection 
of the blood draws.   
3. Subjects must be willing to stay overnight close to the study site and able to provide the 
necessary repeated blood samples. 
9.1.2. 
Inclusion Criteria for Optional PK Washout Sub-Study 
1. Subjects who have successfully completed treatment in RT001-006 will be invited to 
participate in the washout PK sub-study.   
2. All participating subjects will be required to sign an informed consent prior to any blood 
draws.   
3. Subjects must be willing and able to provide the necessary repeated blood samples. 
9.2. 
Exclusion Criteria 
Subjects meeting one or more of the following may not enter the study: 


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1. Received treatment with other experimental therapies within the last 30 days prior to the first 
dose 
2. Previously participated in the RT001 trial 
3. Refusal to discontinue fish oils or other oil-based supplements for the duration of the study 
(Screening till last study procedure completed) 
4. History of malignancies (other than basal cell carcinomas) 
5. Inability to complete CPET protocol, as, for example, unable to move the pedals on the 
exercise bicycle, inability to maintain sufficient RPMs to finish the study, or as judged by the 
exercise physiologist supervising the testing 
6. Female who is breastfeeding or has a positive pregnancy test 
7. Male participant or female participant of childbearing potential, who is sexually active and 
unwilling/unable to use a medically acceptable and effective double barrier birth control 
method throughout the study 
8. Unwilling or unable to comply with the requirements of this protocol, including the presence 
of any condition (physical, mental, or social) that is likely to affect the subject’s ability to 
return for visits as scheduled 
9. Clinically significant cardiac abnormalities (e.g., left ventricular ejection fraction [LVEF] 
<40% on a recent echocardiogram [obtained within 12 months prior to screening] or 
clinically unstable arrhythmia) at screening that, in the opinion of the Investigator, would 
make the subject unsuitable for enrollment 
10. History of or currently uncontrolled diabetes mellitus (Type 1 or 2) 
11. Suicidal ideation within the last 12 months as determined by the Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
12. History, within the last 2 years, of alcohol abuse, significant mental illness, or physical 
opioid dependence 
9.2.1. 
Exclusion Criteria for Sub-Studies 
There are no exclusion criteria for the two additional sub-studies. 
9.3. 
Withdrawal  
9.3.1. 
Withdrawal Criteria 
Subjects may choose to withdraw from the study at any time for any reason. In addition, subjects 
may be withdrawn from the study by the Investigator for any of the following reasons:  
• The subject is unwilling or unable to adhere to the protocol. 


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• During the course of the study, the subject develops symptoms or conditions listed in the 
exclusion criteria.  
• Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent illness, or 
other medical condition that indicates to the Investigator that continued participation is 
not in the best interest of the subject.  
• Other medical reason, at the discretion of the Investigator and/or the Medical Monitor. 
9.3.2. 
Withdrawal Procedures 
• If it is necessary for a subject to discontinue the study drug/study earlier than planned, 
subjects should complete Early Termination procedures (see Section 13.13) and return 
the study drug, as applicable. Date of last dose should be recorded. 
• The Investigator must notify the Sponsor and the Medical Monitor within 24 hours when 
a subject has been withdrawn from the study. Any subject withdrawn because of a related 
AE (whether serious or non-serious), including clinically significant abnormal laboratory 
test values, will be evaluated by the Investigator or a designee and be treated and/or 
followed until the symptoms resolve or values return to normal or acceptable levels, as 
judged by the Investigator. 
• If a subject does not return for a scheduled visit, every effort should be made to contact 
the subject. If a subject withdraws from the study, the Investigator or designee should 
inquire about the reason for withdrawal, and follow-up with the subject by phone as 
scheduled to collect AE information. 
• If the subject withdraws from the study and also withdraws consent for disclosure of 
future information, no further evaluations will be performed, and no additional data will 
be collected. The Sponsor may retain and continue to use any data collected before such 
withdrawal of consent; these data will be included in the safety database. 
9.3.3. 
Documentation of Withdrawal 
The reason(s) for withdrawal from the study drug/study must be recorded in the subject's medical 
record and case report forms (CRF). 
9.3.4. 
Replacement of Subjects 
Subjects who discontinue before enrollment is complete may be replaced in the study. 
Replacement subjects will be assigned unique subject numbers.  
9.3.5. 
Termination of Study by Sponsor 
Although the Sponsor has every intention of completing the study, the Sponsor reserves the right 
to discontinue the study at any time for clinical or administrative reasons, or if required by the 


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FDA or other regulatory authorities. Both the Sponsor and the Medical Monitor will review the 
safety of RT001 throughout the study. The study may be halted at any time for safety concerns. 
9.4. 
Pregnancy 
Pregnant women are not eligible for inclusion in the study. Before enrolling women of 
childbearing potential (WOCBP) in this clinical trial, Investigators must advise WOCBP of the 
importance of avoiding pregnancy during trial participation and the potential risk factors for an 
unintentional pregnancy. WOCBP must agree to use a medically acceptable and effective barrier 
method of contraception (e.g., condom with spermicide, birth control pill) prior to study entry 
and for the duration of study participation to avoid pregnancy throughout the study and for a 
period of at least 30 days after all study procedures are completed. Male subjects must also agree 
to use an accepted method of contraception for the duration of the study and for a period of at 
least 30 days after all study procedures are completed. This should be covered during the 
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10. 
INVESTIGATIONAL PRODUCT 
10.1. 
Identity of Investigational Product 
The investigational product is RT001. RT001 is encapsulated 9-cis, 12-cis-11,11-D2-linoleic acid 
ethyl ester, which is a site-specific (C11) di-deutero synthetic homologue of LA ethyl ester. Each 
capsule contains 960 mg of RT001. The placebo product is composed of encapsulated USP 
safflower oil. The placebo capsules are identical in appearance and size to the investigational 
drug product. The study drug and placebo are indistinguishable. Both are described as opaque 
brown oblong soft-gel capsules. 
10.2. 
Packaging and Labeling of Clinical Supplies 
RT001 and placebo are supplied as soft-gelatin (softgel) capsules. RT001 and placebo capsules 
are provided in identical glass bottles each containing 42 softgel capsules. 
10.3. 
Storage of Clinical Supplies 
Study drug should be stored by the study site in a controlled refrigerated temperature of 2 to 8℃ 
(35.6 to 46.4 °F). If the temperature exceeds or falls below this range, please report it to the 
Sponsor as outlined in the Pharmacy Manual. Study drug should be refrigerated by the subject 
once dispensed from the site. Please refer to Pharmacy manual for further details.  
10.4. 
Study Drug Dispensation 
The study drug for the first 4 weeks of dosing will be dispensed at the study sites. Study drug for 
the subsequent dosing may be shipped directly to the subject or site from a drug depot or site, 
depending on the dispensing schedule.   
10.5. 
Drug Accountability 
Subjects will be asked to return the used and unused study bottles to the study site or send it back 
to the depot. It is the responsibility of the Investigator or his/her designee to maintain drug 
accountability at the clinical trial site and ensure that a current record of investigational product 
disposition is maintained. It is the responsibility of the Investigator or his/her designee to ensure 
that the investigational product is used only in accordance with the approved protocol. All 
records or logs must comply with applicable regulations and guidelines. The Sponsor will 
provide forms to facilitate accountability if the staff at the investigational site does not have an 
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11. 
STUDY DRUGS AND OTHER MEDICATIONS, SUPPLEMENTS  
11.1. 
Study Drug Administration 
Subjects will receive instructions on taking the study drug with meals. RT001 should be 
administered with food, preferably at mealtime.  On clinic visit days all subjects will receive the 
morning dose of study drug in the clinic.  
Subjects will self-administer orally 9 capsules daily for the first month with a meal: 3 capsules 
with breakfast, 3 capsules with lunch, and 3 capsules with dinner for the first month.  After this 
initial period the dose will be reduced to 6 capsules daily with a meal: 3 capsules with breakfast, 
and 3 capsules with dinner for the remainder of the trial, while on study drug. If a subject is 
unable to tolerate study drug because of adverse events during the initial loading period, the dose 
may be reduced to six capsules daily (5.76 g total dose) given as 3 capsules with breakfast, and 
3 capsules with dinner. If a subject is unable to tolerate study drug because of adverse events 
after the dose reduction to six capsules daily (5.76 g total dose), the dose may be spread over 
three meals (2 capsules at breakfast, 2 capsules with lunch, and 2 capsules with dinner). If the 
subject is still unable to tolerate study drug after spreading it over three meals, the total dose may 
be reduced by 1-2 capsules/day, preferably by reducing the dose for a meal from 2 to 1 
capsule(s) as needed. After 2 weeks of taking a dose of less than 6 caps/day, the subject should 
try to increase the dose again to 6 capsules/day given as 2 capsules TID given with meals. If 
6 caps/day is not tolerable, the subject can take the drug at the dose of less than 6 caps/day that 
was tolerable. The last dose of study drug (3 capsules) will be taken 4 weeks from the Day 330 
visit. 
11.2. 
Prior and Concomitant Medications 
Stable, ongoing therapies will be permitted during this study. Any drug therapy initiated during 
the study should be discussed with the Medical Monitor prior to administration, if possible. Data 
on concomitant medications will be collected at each visit.  
Fish oils or other oil-based supplements should not be taken for the duration of the study. In 
addition, if subjects have participated in prior therapeutic trials, they will need to have been off 
therapy for at least 30 days prior to receiving the first dose of study drug. Changes in herbal 
remedies and changes in prescription medications are strongly discouraged during the trial.  
11.3. 
Subject Compliance 
Compliance will be assessed through counting the number of bottles/capsules returned to the 
investigational site by the subject. The site will contact the subject to confirm date of last study 
dose as well as to perform final drug accountability during the EOT call. The subject will be 
given instructions on how to return any unused study drug/bottles to the site.  


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12. 
EFFICACY ENDPOINTS, SAFETY, PHARMACOKINETIC, AND 
OTHER ASSESSMENTS 
12.1. 
Efficacy Endpoints 
Efficacy endpoints include the following:   
• Exercise testing using CPET (peak workload and VO2MAX) 
• T1MW and T25FW  
• Speech measurement recording 
• Clinician-rated Scales 
o FARS-Neuro 
o Clinician-rated CGI 
• Questionnaires and scales completed by the subject 
o FARS-ADL 
o SF-36 
o Patient Global Impression of Change (PGI-C) 
o VAS 
o Fatigue scale 
o Neuro-QoL scale (lower extremity function and upper extremity function) 
o Fall Questionnaire 
o Speech Assessment Questionnaire 
• Frequency of falls, near falls, and stumbles as reported in a fall diary 
12.2. 
Exercise Testing Using CPET 
Subjects will perform exercise testing using the CPET protocol at Screening, on Day 1, Day 120 
(± 30 days), Day 240 (± 30 days), and Day 330 (± 30 days). Peak work rate and VO2 MAX will 
be measured during incremental exercise testing on a recumbent bike. All tests should be done at 
approximately the same time for each visit. CPET should occur after fasting (if the subject has 
had a meal/snack) for a minimum of 2 hours, with neither caffeine nor nicotine for at least 12 
hours before testing. Fluid consumption during the fasting period is limited to water, preferably 
at room temperature. Physical activity during the 24 hours prior to testing should be minimized. 
Routines followed for the initial laboratory assessments with respect to diet and physical activity 
should be duplicated for each subsequent visit. Subjects may take as much resting time as they 


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need between the bike test and the T1MW/T25FW. Detailed testing instructions will be provided 
in a separate manual. 
12.3. 
Timed Walk 
12.3.1. Timed 1-Minute Walk (T1MW)  
The T1MW is a quantitative measure of lower extremity function. The subject is instructed to 
walk for 1 minute as quickly and safely as possible on a clearly marked course. The distance 
walked over 1 minute is measured. The T1MW will be performed on subjects who are 
ambulatory (with or without assistive device). This will be evaluated at Screening, on Day 1, 
Day 120 (± 30 days), Day 240 (± 30 days), and Day 330 (± 30 days). 
12.3.2 
Timed 25-Feet Walk (T25FW) 
The T25FW is a quantitative measure of lower extremity function. The subject is instructed to 
walk 25 feet as quickly and safely as possible. The time to walk 25 feet will be measured 
electronically. The T25FW will be performed on subjects who are ambulatory (with or without 
assistive device). This will be evaluated at Screening, on Day 1, Day 120 (± 30 days), Day 240 
(± 30 days), and Day 330 (± 30 days). Detailed testing instructions will be provided in a separate 
manual. 
12.4. 
Speech Measurement Recording 
The subject will have to undergo a speech recording for about 10 minutes at Screening, on Day 
1, Day 240 (± 30 days), and Day 330 (± 30 days). This recording will include (but not limited to) 
(1) reading a brief passage, (2) responding to a task: e.g. days of the week (3) syllable repetition: 
e.g. saying PATAKA as quickly and as clearly as possible; (e) monologue: on a topic of choice. 
Details will be included in a separate manual.
12.5. 
Clinician-rated Scales 
12.5.1. FARS-Neuro 
The FARS-Neuro scale includes evaluations of the neurological signs that specifically reflect 
neural substrates affected in subjects with FRDA. Based on a neurological examination, bulbar, 
upper limb coordination, lower limb coordination, peripheral nervous system, and upright 
stability functions are assessed for individual sub-scores (11, 36, 16, 26, and 36) with a 
maximum score of 125 (Friedreich’s Ataxia Study Group, Subramony et al., 2005, Lynch et al., 
2006). FARS-Neurologic examinations will be conducted by a qualified physician or health 
professional listed on the Form FDA 1572 who is trained on use of the FARS-Neurologic scale 
format. This scale will be evaluated at Screening, on Day 1, Day 120 (± 30 days), Day 240 
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(± 30 days), and Day 330 (± 30 days). The CPET examination should always precede the 
FARS-Neuro evaluation at all visits. Refer to Section 19.2 for the specific items assessed. 
12.5.2. 
Clinician-rated Clinical Global Impression (CGI) 
The CGI is a 3-item observer-rated scale that measures illness severity, global improvement and 
therapeutic response. The illness severity is rated on a 7-point scale, with the severity of illness 
scale using a range of responses from 1 (normal) through 7 (amongst the most severely ill 
patients). The global improvement scores range from 1 (very much improved) through to 7 (very 
much worse). Treatment response ratings should take account of both therapeutic efficacy and 
treatment-related adverse events and range from 0 (marked improvement and no side-effects) 
and 4 (unchanged or worse and side-effects outweigh the therapeutic effects). Each component 
of the CGI is rated separately; the instrument does not yield a global score. This scale will be 
evaluated at Screening, on Day 1, Day 120 (± 30 days), Day 240 (± 30 days), and Day 330 
(± 30 days). At screening and Day 1, only the severity of illness (question 1) needs to be 
assessed. From Day 120 onwards, all 3 items (severity of illness, global improvement, and 
therapeutic response) will be assessed.  Refer to Section 19.3 for the specific items assessed. 
12.6. 
Questionnaires and scales completed by the subject 
12.6.1. FARS -Activities of Daily Living (FARS-ADL) 
The subject self-administered FARS-ADL is a sub-scale of the FARS. There are nine questions 
regarding activities of daily living. The ADL is scored from 0 to 36, with higher score 
representing more severe progression. The FARS-ADL will be collected at Screening, on Day 1, 
Day 120 (± 30 days), Day 240 (± 30 days), and Day 330 (± 30 days). Refer to Section 19.4 for 
the specific items assessed. 
12.6.2. 
SF-36 
The SF-36 is a well validated 36-item subject self-administered Short Form Health Survey and is 
a set of generic, coherent and easily administered quality-of-life measures. The SF-36 will be 
collected at Screening, on Day 1, Day 120 (± 30 days), Day 240 (± 30 days), and Day 330 
(± 30 days). Refer to Section 19.5 for the specific items assessed. 
12.6.3. 
Patient Global Impression of Change (PGI-C) Scale 
The Patient Global Impression of Change (PGI-C) Scale is a qualitative assessment of change 
completed by the subject using a 7-item scale ranging from “very much worse” to “very much 
improved”. The PGI-C will be collected at Day 120 (± 30 days), Day 240 (± 30 days), and 
Day 330 (± 30 days). In between the clinic visits the subject will be contacted by phone by a 
study site staff member and asked to complete the PGI-C. This will be done after 30, 60, 90, 150, 
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180, 210, 270 and 300 days of dosing. All calls have a window of ± 7 days. Refer to Section 19.6 
for the specific items assessed. 
12.6.4. 
Visual Analogue Scale (VAS) 
The subject will complete a VAS for Improvement of FA Symptoms and a VAS for fatigue. The 
VAS for Fatigue will be completed at Screening, on Day 1, Day 120 (± 30 days), Day 240 
(± 30 days), and Day 330 (± 30 days). VAS for Improvement of FA Symptoms will be 
completed on Day 120 (± 30 days), Day 240 (± 30 days), and Day 330 (± 30 days). Refer to 
Section 19.7 for the VAS. 
12.6.5. 
Fatigue Scale 
The subject will complete a Fatigue scale at Screening, on Day 1, Day 120 (± 30 days), Day 240 
(± 30 days), and Day 330 (± 30 days). In between the clinic visits the subject will be contacted 
by phone by a study site staff member and asked to complete the Fatigue scale. This will be done 
after 30, 60, 90, 150, 180, 210, 270 and 300 days of dosing. All calls have a window of ± 7 days. 
Refer to Section 19.8 for the specific items assessed. 
12.6.6. 
Neuro-QoL scales 
The subject will complete the Neuro-QoL scale for upper extremity function and lower extremity 
function. These scales will be collected at Screening, on Day 1, Day 120 (± 30 days), Day 240 
(± 30 days), and Day 330 (± 30 days). In between the clinic visits the subject will be contacted 
by phone by a study site staff member and asked to complete the Neuro-QoL scales. This will be 
done after 30, 60, 90, 150, 180, 210, 270 and 300 days of dosing. All calls have a window of 
± 7 days. Refer to Section 19.9 for the specific items assessed. 
12.6.7. 
Fall Questionnaire 
The subject will complete a Fall questionnaire at Screening, on Day 1, Day 120 (± 30 days), 
Day 240 (± 30 days), and Day 330 (± 30 days). In between the clinic visits the subject will be 
contacted by phone by a study site staff member and asked to complete questions 8 and 9 of the 
fall questionnaire. This will be done after 30, 60, 90, 150, 180, 210, 270 and 300 days of dosing. 
All calls have a window of ± 7 days. Refer to Section 19.10 for the specific items assessed. 
12.6.8. 
Fall Diary 
The subjects will be asked to keep a daily log (diary) documenting falls, near-falls, stumbles, and 
fear of falling from screening until the end of treatment. Falls are defined as any event that 
results in unintentionally falling to the ground. Near-falls are defined as losing balance with no 
fall to the ground (e.g. hold on to something/somebody, or fall onto a chair, bed, or other soft 
landing). Stumbles are defined as losing balance momentarily with regaining of footing and no 
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12.6.9. 
Speech Assessment Questionnaire 
The subject will complete a Speech Assessment Questionnaire to evaluate his/ her speech pattern 
and communication style at Screening, on Day 1, Day 240 (± 30 days), and Day 330 (± 30 days). 
Parent/caregiver/travel companion will also have to complete one question on this questionnaire. 
Refer to Section 19.11 for the specific items assessed. 
12.7. 
Safety 
Safety assessments include AEs, physical and neurologic examinations, vital signs, 12-lead 
electrocardiogram (ECG), and clinical laboratory tests (hematology, clinical chemistry, lipid 
profile, coagulation, and urinalysis). Safety signals must be promptly communicated to the 
Medical Monitor. 
12.7.1. 
Adverse Events 
Subjects will be assessed for AEs at each study visit after the informed consent is obtained 
through the end of the study. Adverse events will be evaluated for incidence, severity, and 
relationship to study drug. The safety evaluation will include an assessment of all AEs, SAEs, 
and dose discontinuations due to adverse event. Monitoring and grading of AEs will be done in 
accordance with Medical Dictionary for Regulatory Activity (MedDRA) during the study. See 
Section 15 for additional information. 
12.7.2. 
Physical Examination 
Complete physical examinations will be conducted at Screening, Day 1, Day 120 (± 30 days), 
Day 240 (± 30 days), and Day 330 (± 30 days). Physical examinations include skin, HEENT, 
respiratory, cardiovascular, gastrointestinal, endocrine/metabolic, neurological, blood/lymphatic, 
musculoskeletal, hepatic, allergies and psychological/psychiatric examinations. 
12.7.3. 
Vital Signs 
Vital signs (systolic and diastolic blood pressure, heart rate, respiration rate, temperature) and 
weight will be measured at each site visit. All measurements should be performed in the 
supine/semi-supine or seated position after the subject has rested in that position for at least 
3 minutes. Blood pressure will be obtained with an automated or manual blood pressure 
apparatus in the same position. Blood pressure and pulse should be performed on the same 
extremity throughout the study and documented as such. Height and BMI will be measured at 
Screening and at Day 330. 
12.7.4. 
12-Lead Electrocardiogram 
A single ECG reading will be obtained at each site visit [Screening, Day 1, Day 120 (± 30 days), 
Day 240 (± 30 days), and Day 330 (± 30 days)]. If the Screening and Day 1 visit are within 


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7 days (or less) of each other, the ECG does not have to be repeated, unless to rule out any 
clinically significant findings. A copy of the tracing should be retained as a source document. 
The Investigator will review each ECG and provide an interpretation of the ECG as to whether 
the ECG is: (1) within normal limits compared with Baseline and within normal limits for a 
FRDA population, (2) or abnormal with any clinically significant findings noted. Clinically 
significant changes will be recorded as AEs. 
Individuals with FRDA show substantial variance in ECG readings; typical ECG changes in 
subjects with FRDA may be assessed as clinically significant in other populations. Underlying 
disease must be considered when evaluating ECG changes. 
12.7.5. 
Clinical Laboratory Tests 
The following clinical laboratory tests will be performed at each site visit [Screening, Day 1, 
Day 120 (± 30 days), Day 240 (± 30 days), and Day 330 (± 30 days)] at a local approved 
laboratory. If the Screening and Day 1 visit are within 7 days (or less) of each other, the 
laboratory tests do not have to be repeated, unless to rule out any clinically significant findings. 
The safety laboratory tests, and lipid profile should be performed in a fasting state: 
• Hematology: hematocrit, hemoglobin, mean corpuscular hemoglobin, mean 
corpuscular volume, mean platelet volume, platelet count, red blood cell (RBC) 
count, and white blood cell (WBC) count with differential (absolute). 
• Coagulation: prothrombin time (PT), international normalized ratio (INR), and partial 
thromboplastin time (PTT). 
• Clinical chemistry: ALT, AST, alkaline phosphatase, total bilirubin, amylase, lipase, 
calcium, magnesium, glucose, sodium, potassium, carbon dioxide (CO2), chloride, 
blood urea nitrogen (BUN), and creatinine.  
• Urinalysis (only at screening and Day 330): dipstick test and a microscopic 
examination if clinically indicated. 
• Lipid profile: total cholesterol, high density lipoprotein (HDL), low density 
lipoprotein (LDL) and triglycerides. 
Women will be tested for pregnancy by serum pregnancy test at Screening and by a urine 
pregnancy test at subsequent visits (including EOT), unless there is documented evidence 
confirming they are not of childbearing potential. Subjects should be counseled to avoid 
pregnancy for at least 30 days after all study procedures are completed (see Section 9.4). A Urine 
Pregnancy test is to be performed by the subject at home on the day of the EOT phone call 
(before the call and after the last dose). Subjects taking the Urine Pregnancy Test will 
telephonically confirm the result with the site, scan and email/fax a photo of the result to the site. 


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12.7.6. 
Columbia-Suicide Severity Rating Scale  
This scale will be administered at Screening to identify if the subject has suicidal ideation or 
suicidal behavior. 
12.7.7. 
Echocardiogram 
Subjects will need to get an echocardiogram done at Screening if there has not been an 
echocardiogram obtained in the 12 months prior to screening. An echocardiogram obtained up to 
12 months prior to Screening can be used for the assessment of the eligibility in the study. A 
repeat echocardiogram will be obtained on Day 330 (± 30 days). 
12.8. 
Pharmacokinetics 
12.8.1. 
Sample Collection 
Bioanalytical measurements will be performed to determine the concentration of D2-LA, 
D2-ARA, H2-LA and H2-ARA in plasma and red blood cells. Blood samples will be collected 
for plasma measurements and assessment in red blood cells at month 4 (Day 120 ± 30 days), at 
month 8 (Day 240 ± 30 days), and month 11 (Day 330 ± 30 days). Samples are to be obtained 
prior to dosing and prior to breakfast. Actual collection time points should be recorded and will 
be used for PK analysis. Best efforts to collect the samples at the planned time should be made. 
Protocol-specific instructions will be provided to each site in a Study Lab Manual for the 
collection, handling, storage, and shipping of PK (plasma and RBC) samples. The date and 
actual time each sample is collected will be recorded. Date and time of last dose prior to sample 
collection will also be recorded. 
Two additional optional PK sub-studies will be offered. The first is a 24hr PK Profile at steady 
state that will occur immediately before or after the Day 330 visit. At the time of the Month 11 
visit in RT001-006, PK samples will be obtained 30 minutes to 1 hour before the morning dose 
(pre-breakfast); and 30 min, 1, 2, 4 (pre-lunch), 8 (pre-dinner), 12 (post-dinner) and 24 hours 
after the initial morning dose.  
The second optional sub-study is a 6-month study to evaluate the washout blood levels of RT001 
after treatment in RT001-006 is completed. Depending on the timing of entry into the sub-study, 
washout pharmacokinetic (PK) samples will be obtained at 7 days, 4, 12, and 24 weeks after the 
last dose to determine the trough concentration of deuterated linoleic acid (D2-LA), deuterated 
arachidonic acid (D2-ARA), nondeuterated linoleic acid (H2-LA) and nondeuterated arachidonic 
acid (H2-ARA) in plasma, and D2-LA, D2-ARA H2-LA, and H2-ARA in red blood cells. 


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12.9. 
Biomarker Assessment 
Additional blood samples will be collected and stored for future biomarker analysis on Day 1, on 
Day 120 (± 30 days), on Day 240 (± 30 days), and on Day 330 (± 30 days). These samples are to 
be obtained prior to dosing and prior to breakfast.  
Protocol-specific instructions will be provided to each site in a Study Lab Manual for the 
collection, handling, storage, and shipping of samples. The date and actual time each sample is 
collected will be recorded. Date and time of last dose prior to sample collection will also be 
recorded. 
12.10. 
Other 
12.10.1. 
Food Journal Requirement 
While on study drug, subjects are recommended to avoid eating foods high in PUFAs. Subjects 
will keep food journals from screening through the completion of month 1 on study drug. After 
month 1, subjects will keep 2-week food journals prior to next scheduled onsite visit. Subjects 
(or parents/caregivers, as applicable) will have an initial call and as needed with the diet coach to 
discuss food journal completion requirements. 


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13. 
STUDY PROCEDURES AND SCHEDULE 
All study visits, assessments, and procedures involving study subjects will be performed at a 
Sponsor-approved investigator site, and assessments and procedures will be performed by study 
personnel with the supervision of an Investigator. All measurements and results obtained as part 
of the protocol will be recorded in the CRF. The Schedule of Events is summarized in Table 1. It 
is recommended, but not required that the procedures should be completed in the order that they 
are listed to avoid causing fatigue to the subject. Each site visit can be done over multiple days as 
needed to accommodate for scheduling flexibility. Actual start times of all protocol assessments 
will be recorded. 
13.1. 
Visit 1: Screening (Up to 30 Days) 
Screening procedures can be performed from 30 to 14 days prior to the first dose on Day 1. A 
signed and dated ICF (or assent form) will be obtained from the subject as required by the 
protocol before any screening procedures are conducted. A signed copy of the ICF will be given 
to the subject. Screening procedures include the following: 
• Evaluate eligibility per inclusion/exclusion criteria 
• Perform a serum pregnancy test for all female subjects, unless there is documented 
evidence confirming they are not of childbearing potential 
• Obtain blood samples for hematology, chemistry, coagulation, and lipid profile in a 
fasting state 
• Obtain a urinalysis sample (dipstick test and microscopic examination if clinically 
indicated) 
• Perform the exercise bike test (CPET should occur in the morning after fasting for a 
minimum of 2 hours {if the subject has had a meal/snack}, with neither caffeine nor 
nicotine for at least 12 hours before testing) 
• Perform a FARS-Neuro and clinician-rated CGI (severity of illness question only) 
• Record medical history and demographics 
• Record the C-SSRS  
• Complete the Speech Measurement Recording 
• Perform a physical examination 
• Record vital sign measurements, height, weight, and BMI 
• Subject complete FARS ADL, SF-36, VAS (for Fatigue), Fatigue scale, Neuro-QoL 
scales, Speech Assessment Questionnaire and Fall questionnaire 


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• Obtain T1MW and T25FW  
• Obtain an echocardiogram (LVEF) (To be performed if there has been no 
echocardiogram performed in the last 12 months before screening). 
• Obtain a 12-lead ECG 
• Sites to train subject on completion requirements for the Fall Diary 
• Phone call with the diet coach to review food journal completion requirement 
13.2. 
Visit 2: Study Day 1 
The following procedures will be performed: 
Pre-Dose 
• Reassess inclusion/exclusion criteria 
• Obtain blood samples for hematology, chemistry, coagulation, and lipid profile in a 
fasting state (does not have to be repeated if Screening visit is ≤ 7 days and there are 
no clinically significant findings) 
• Perform a urine pregnancy test for all female subjects unless there is documented 
evidence confirming they are not of childbearing potential 
• Perform the exercise bike test (CPET should occur in the morning after fasting for a 
minimum of 2 hours {if the subject has had a meal/snack}, with neither caffeine nor 
nicotine for at least 12 hours before testing) 
• Perform a FARS-Neuro and clinician-rated CGI (severity of illness question only) 
• Update medical history and demographics 
• Complete the Speech Measurement Recording 
• Record vital sign measurements and weight 
• Obtain blood samples for biomarkers prior to the morning meal and dosing 
• Randomize subject to study treatment group and dispense study drug 
• Perform a physical examination 
• Subject complete FARS ADL, SF-36, VAS (for Fatigue), Fatigue scale, Neuro-QoL 
scales, Speech Assessment questionnaire and Fall questionnaire 
• Obtain T1MW and T25FW  
• Obtain a 12-lead ECG (does not have to be repeated if Screening visit is ≤ 7 days and 
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• Collect fall diary 
Dosing  
Subjects will take, as per the randomization scheme, the first dose of study drug at the 
clinic with a meal after all baseline testing is complete.  
Post-Dose 
• Record concomitant medications 
• Record AEs 
13.3. 
Days 30 (± 7 days), 60 (± 7 days), and 90 (± 7 days) 
Subjects will be contacted by phone by a study site staff member and asked to complete the 
PGI-C, the Fatigue scale, the Neuro-QoL scales (lower extremity function and upper extremity 
function), and questions 8 and 9 of the Fall questionnaire. Subjects can scan and email 
questionnaires to the site. The site is to also confirm if the subject is taking study drug as 
instructed. Adverse events will also be assessed.  
13.4. 
Visit 3: Day 120 (± 30 days) 
The following procedures will be performed: 
• Obtain blood samples for hematology, chemistry, coagulation, and lipid profile in a 
fasting state 
• Perform a urine pregnancy test for all female subjects unless there is documented 
evidence confirming they are not of childbearing potential 
• Record vital sign measurements and weight 
• Obtain blood samples for PK and biomarkers prior to the morning meal and dosing 
• Perform the exercise bike test (CPET should occur in the morning after fasting for a 
minimum of 2 hours, with neither caffeine nor nicotine for at least 12 hours before 
testing) 
• Perform a FARS-Neuro and clinician-rated CGI 
• Perform a physical examination 
• Subject complete FARS ADL, SF-36, PGI-C, VAS, Fatigue scale, Neuro-QoL scales 
and Fall questionnaire 
• Obtain T1MW and T25FW  
• Obtain a 12-lead ECG 


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• Collect fall diary 
• Perform drug accountability 
• Record concomitant medications 
• Record AEs 
Dosing  
• Subjects will take the morning dose of study drug at the clinic with their breakfast. 
13.5. 
Day 150 (± 7 days), Day 180 (± 7 days) and Day 210 (± 7 days)  
Subjects will be contacted by phone by a study site staff member and asked to complete the 
PGI-C, the Fatigue scale, the Neuro-QoL scales (lower extremity function and upper extremity 
function), and questions 8 and 9 of the Fall questionnaire. Subjects can scan and email 
questionnaires to the site. The site is to also confirm if the subject is taking study drug as 
instructed. Adverse events will also be assessed. 
13.6. 
Visit 4: Day 240 (± 30 days)  
The following procedures will be performed: 
• Obtain blood samples for hematology, chemistry, coagulation, and lipid profile in a 
fasting state 
• Perform a urine pregnancy test for all female subjects unless there is documented 
evidence confirming they are not of childbearing potential 
• Record vital sign measurements and weight 
• Obtain blood samples for PK and biomarkers prior to the morning meal and dosing 
• Perform the exercise bike test (CPET should occur in the morning after fasting for a 
minimum of 2 hours, with neither caffeine nor nicotine for at least 12 hours before 
testing) 
• Perform a FARS-Neuro and clinician-rated CGI 
• Perform a physical examination 
• Complete Speech Measurement recording. 
• Subject complete FARS ADL, SF-36, PGI-C, VAS, Fatigue scale, Neuro-QoL scales, 
Speech Assessment questionnaire and Fall questionnaire 
• Obtain T1MW and T25FW  
• Obtain a 12-lead ECG 


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• Collect fall diary 
• Perform drug accountability 
• Record concomitant medications 
• Record AEs 
Dosing  
• Subjects will take the morning dose of study drug at the clinic with their breakfast. 
13.7. 
Day 270 (± 7 days) and Day 300 (± 7 days)  
Subjects will be contacted by phone by a study site staff member and asked to complete the 
PGI-C, the Fatigue scale, the Neuro-QoL scales (lower extremity function and upper extremity 
function), and questions 8 and 9 of the Fall questionnaire. Subjects can scan and email 
questionnaires to the site. The site is to also confirm if the subject is taking study drug as 
instructed. Adverse events will also be assessed. 
13.8. 
Visit 5: Day 330 (± 30 Days) 
The following procedures will be performed.  
• Obtain blood samples for hematology, chemistry, coagulation, and lipid profile in a 
fasting state 
• Obtain a urinalysis sample (dipstick test, microscopic examination) 
• Perform a urine pregnancy test for all female subjects unless there is documented 
evidence confirming they are not of childbearing potential. A Urine Pregnancy test kit 
will be provided to all female subjects (unless there is documented evidence 
confirming they are not of childbearing potential) to take home for the EOT visit. The 
site to instruct the subject that Pregnancy test has to be performed by the subject at 
home on the day of the EOT phone call (before the call and after the last dose) 
• Record vital sign measurements, height, weight, and BMI 
• Obtain blood samples for PK and biomarkers prior to the morning meal 
• Perform the exercise bike test (CPET should occur in the morning after fasting for a 
minimum of 2 hours, with neither caffeine nor nicotine for at least 12 hours before 
testing) 
• Perform a FARS-Neuro and clinician-rated CGI 
• Perform a physical examination 


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• Subject complete FARS ADL, SF-36, PGI-C, VAS, Fatigue scale, Neuro-QoL scales, 
Speech Assessment questionnaire and Fall questionnaire 
• Obtain T1MW and T25FW  
• Obtain a 12-lead ECG 
• Obtain an echocardiogram  
• Collect fall diary 
• Perform drug accountability, if applicable 
• Record concomitant medications 
• Record AEs 
Dosing  
• Subjects will take the morning dose of study drug at the clinic with their breakfast. 
Subjects to be reminded that the last dose of study drug has to be taken 4 weeks from 
the Day 330 visit.  
13.9. 
Optional PK Profile Sub-Study 
The following procedures will be performed on Day 1: 
• A blood sample for PK will be obtained at hour -1.0 to -0.5 (pre-breakfast, pre-dose), 
• Subjects will take the morning dose of study drug at the clinic with their breakfast,  
• A blood sample for PK will be obtained hour 0.5 (± 5 min),  
• A blood sample for PK will be obtained hour 1 (± 5 min),  
• A blood sample for PK will be obtained hour 2 (± 10 min), 
• A blood sample for PK will be obtained hour 4 (± 15 min) (pre-lunch),  
• A blood sample for PK will be obtained hour 8 (± 15 min) (pre-dinner),  
• A blood sample for PK will be obtained hour 12 (± 60 min) (post-dinner) 
The following procedures will be performed on Day 2: 
• A blood sample for PK will be obtained on Hour 24 (pre-dose, pre-breakfast) 
Dosing: 
• The subject will only take the morning dose on the PK collection day. They will skip 
the evening dose.  
• The subject should resume regular dosing schedule after morning PK draw on Day 2.  


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13.10. 
End of Treatment call (4 weeks from Day 330 + 7 days) 
Subjects will be contacted by phone by a study site staff member to make sure they have taken 
their last dose of study drug and to perform final drug accountability. The subject will be 
provided with instructions, so they can ship or return all unused study drug/ bottles to the site. If 
none, the subject can destroy the same.  
Site to confirm a urine pregnancy test for all female subjects (unless there is documented 
evidence confirming they are not of childbearing potential) was performed on the day of the 
EOT call (before the call and after the last dose). The subject to share the result and email a 
scanned photo of the result for site records. Study site staff member to also collect AE 
information and confirm any change in concomitant medication since last visit. For any ongoing 
AEs at EOT, the site will follow up to conclusion or until stabilized. 
13.11. 
Optional PK Washout Sub-Study 
Depending on the timing of entry into the sub-study, the following procedures will be performed 
throughout the Optional Washout PK Sub-Study: 
• A blood sample for PK will be obtained 7 days (± 1 day) after the last dose. 
• A blood sample for PK will be obtained 4 weeks (± 7 day) after the last dose. 
• A blood sample for PK will be obtained 12 weeks (± 7 day) after the last dose. 
• A blood sample for PK will be obtained 24 weeks (± 7 day) after the last dose. 
13.12. 
Unscheduled Visits  
Procedures to be performed at any unscheduled visit are at the discretion of the Investigator, but 
should at least include safety, laboratory, and health examinations necessary for collection of AE 
information. Any procedure can be repeated at an unscheduled visit as needed. 
13.13. 
Early Termination Visit 
If the subject withdraws or is discontinued from the study the following safety procedures should 
be performed:  
• Perform a complete physical examination 
• Record vital sign measurements and weight  
• Obtain a 12-lead ECG 
• Obtain blood samples for hematology, chemistry, coagulation, and lipid profile 
• Obtain a urinalysis sample (dipstick test, microscopic examination) 
• Perform a urine pregnancy test for all female subjects unless there is documented 
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• Record AEs 
• Record concomitant medications 
• Perform drug accountability 


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14. 
STATISTICS 
14.1. 
Statistical Plan 
A complete description of analysis populations and statistical methods will be provided in a 
formal Statistical Analysis Plan that will be finalized prior to unblinding and statistical analysis. 
Analysis populations 
• All Patients Population: Any participant with any record in the database. This 
population includes both screening and randomized subjects. Population will be 
utilized for descriptive patient counts that include screening subjects. 
• Intent-to-Treat (ITT) population: All participants randomized to treatment.  
• Modified Intent-to-Treat (mITT) Population: All randomized subjects with at least 
one post-baseline efficacy evaluation will be included in the mITT population and 
will be analyzed as randomized. The mITT population will be analyzed for efficacy 
evaluations.  
• Per Protocol (PP) Population: For programming purposes, they will be identified as 
having no major protocol violations as identified separately by the study team and the 
Sponsor prior to database lock. Analyses of the PP population will be analyzed as 
treated. 
• Safety population: All participants who receive at least 1 dose of drug or placebo. 
Demographic data will be presented using descriptive statistics (e.g., mean, standard deviation, 
median, and range). Exposure to study drug and reasons for discontinuation will be tabulated. 
Safety analyses will use the Safety population. Safety variables will be tabulated and presented 
for all subjects who receive study drug or placebo capsules. Adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). The incidence of treatment-
emergent AEs will be presented by system organ class and preferred term. Adverse events will 
be presented by severity and relationship to study drug. Changes from Baseline in clinical 
laboratory parameters and vital signs will be summarized across time. Shift tables will be 
provided for selected laboratory parameters. Physical examination results will be presented in 
listings. 
Primary, secondary and exploratory efficacy analyses of the 11-month on-treatment period will 
use the mITT population and the per-protocol population unless otherwise specified. 
Change from baseline (CFB) will be analyzed by comparing the change between treatment 
groups using a mixed model with repeated measures (MMRM). The MMRM will compare the 
estimated change from baseline between treatments for the primary endpoint. This analysis will 
assess whether there is a difference in estimated CFB between active and placebo groups at 11 
months.  


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The primary analysis will use the ITT methodology and an MMRM methodology with a random 
slope and intercept for each individual. Due to the small sample size the model will be optimized 
by implementation of two risk scores (baseline and slope) that account for multiple baseline 
covariates in one variable. The risk scores will be derived from blinded data using the GST 
change from baseline values and generated using the baseline model covariates (excluding 
treatment and visit; baseline risk score) or the baseline model covariates*time interactions (slope 
risk score). The risk scores will be included as covariates in the model.   
To calculate the baseline risk score, the GST change score is regressed on the covariates listed 
below. Individual coefficients for the baseline risk score are multiplied by individual covariate 
values and summed. A separate slope risk score is calculated for baseline covariates interacting 
with time. 
The MMRM with primary outcome CFB value as the response variable will include the 
following covariates and fixed effects: 
• baseline risk score: 
• baseline score for GST 
• age 
• slope risk score: 
• baseline score for GST * time 
• age*time 
• Time (continuous) 
• Time by treatment interaction (time*treatment) 
• baseline score for parameter of interest (if not in GST) 
• site pooled by region (random effect) 
Model assumptions will be evaluated. If the parametric assumptions are evaluated as 
inappropriate or violated, rank analogues will be advanced.  
All secondary and exploratory endpoints CFB values will be analyzed using the MMRM 
described above. This analysis will assess whether or not there is a difference in estimated CFB 
values between treatment group and placebo at the 11-month model estimate using least squares 
means estimates from the MMRM model. 
Speech measurement reporting will be analyzed by a third party vendor. A separate report will be 
provided. 
Responder analyses will be run on MVO2 (primary), GST, T1MW, Peak Workload, mFARS, 
and CGI-C (functional assessment). Responder analyses are performed to illustrate the clinical 
meaningfulness of the relationship between treatment differences and efficacy outcomes on a per 


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person basis. Responder analyses will be assessed at change from baseline cutoffs at the overall 
quartiles for each of the three variables. Patients who die or are unable to perform the test during 
the study will be counted as non-responders. Patients who do not complete will be carried 
forward using the last observation carried forward and the imputed value at the study endpoint 
will be used for the responder analysis.  
In addition to summarizing the results for each relationship between individual clinical responses 
and treatment multiple clinical responses will also be correlated with treatment using the five 
GST component outcomes individually. Those who experienced the following combined clinical 
responses will be summarized in terms of counts and percent: 
• Improvement or stabilization on at least 1, 2, 3, 4, and all of the 5 responder 
endpoints. 
The PK of D2-LA and H2-LA will be characterized in terms of minimum and maximum 
exposure at steady state, based on a validated assay. The PK of D2-LA and H2-LA in RBC, 
D2-ARA, and H2-ARA also will be characterized in terms of minimum and maximum exposure 
at steady state; the validation of the assays to characterize these concentration values has not yet 
been validated. 
Full details of planned analyses will be provided in a separate statistical analysis plan. 
14.2. 
Determination of Sample Size 
For the primary analysis of peak workload, group sample sizes of 30 and 30 achieve over 99% 
power to reject the null hypothesis of equal means when the population mean difference is μ1 - 
μ2 = 7.5 - -8.3 = 15.8 with a standard deviation for both groups of 11.1 and with a significance 
level (alpha) of 0.05 using a two-sided two-sample equal-variance t-test. 
Subjects who discontinue from the study may be replaced. 
14.3. 
Interim Analysis 
One of two interim analyses may be performed. Retrotope will determine which interim, if 
either, to perform. 
Interim analysis 1 using Month 4 data. 
An interim analysis may be performed when all subjects have completed the Month 4 visit. 
The Interim Analysis Committee (IAC) will report the following information to the steering 
committee, which will report the information to Retrotope management. 
• The average within-treatment-group standard deviation of the change from baseline to 
Month 4 in CPET 
• The average within-treatment-group standard deviation of the change from baseline to 
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That is, for CPET and for mFARS, the IAC statistician will calculate the within-treatment-group 
standard deviation of the change from baseline to Month 4 for each treatment group, and then 
calculate the average of the standard deviations of the two treatment groups. 
The IAC will not report the mean change from baseline within treatment group and will not 
report the difference between the treatment groups in the mean change from baseline. 
Retrotope may use this information on average within-treatment-group standard deviation to 
consider stopping the trial for futility or to consider sample size re-estimation. 
The Interim Analysis Committee (IAC) will report the Pearson and Spearman correlation of the 
change in CPET with the change in mFARS at 4 months, and at the last available time point for 
each subject. Retrotope may use this information to re-order the primary and first secondary 
analyses. 
There will be no alpha penalty for this interim analysis for the following reasons. 
1. Only the average within-treatment-group standard deviations will be reported.  
2. Neither mean change from baseline within treatment group nor the difference between 
the treatment groups in the mean change from baseline will be reported to Retrotope. 
3. Retrotope will remain blinded to treatment assignments. 
Interim analysis 2 using Month 11 data. 
An interim analysis may be performed when approximately half the subjects have completed the 
Month 11 visit. 
The Interim Analysis Committee (IAC) will report the following information to the steering 
committee, which will report the information to Retrotope management. 
• The results of a futility analysis for the CPET endpoint 
• The results of a futility analysis for the mFARS endpoint 
Retrotope may use this information to consider stopping the trial for futility, to change the order 
of the primary and secondary endpoint, or to consider sample size re-estimation. 
The Interim Analysis Committee (IAC) will report the Pearson and Spearman correlation of the 
change in CPET with the change in mFARS at 4 months, and at the last available time point for 
each subject. Retrotope may use this information to re-order the primary and first secondary 
analyses. 
There will be no alpha penalty for this interim analysis for the following reasons. 
1. The trial cannot be stopped for efficacy at this interim. It can only be stopped for futility.  
Retrotope will remain blinded to treatment assignments. 
14.4. 
Deviation from Original Analysis Plan 
Deviations from the original statistical or PK analysis plans will be provided in the final clinical 
study report (CSR).  


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15. 
ADVERSE EVENTS 
All subjects in the study will have FRDA and the Investigators will take the subjects’ Baseline 
status into account when reporting AEs. Investigators will also consider the underlying disease 
when designating relationship of AE to study drug, and if AEs are due to the FRDA disease, 
disease progression or symptomatology exacerbation. Common characteristics of FRDA and 
RT001 treatment include the following: 
• loss of coordination (ataxia) in the arms and legs 
• loss of mobility 
• fatigue - energy deprivation and muscle loss 
• vision impairment, hearing loss, and slurred speech 
• severe scoliosis 
• foot deformities such as clubfoot, flexion of the toes, hammer toes, foot inversion 
• diabetes mellitus (insulin-dependent, in most cases) 
• hypertrophic cardiomyopathy 
• chest pain, shortness of breath, and heart palpitations 
• myocardial fibrosis 
• heart rhythm abnormalities 
• steatorrhea, diarrhea, loose stools  
All adverse physical findings/laboratory results identified prior to initiation of study drug will be 
reported on the medical history and/or physical examination CRFs. After initiation of study drug, 
any clinically significant changes in physical findings/laboratory results or any new adverse 
physical findings/laboratory results will be reported as AEs.  
15.1. 
Adverse Event Definitions 
15.1.1. 
Adverse Event 
An AE means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE (also referred to as an adverse experience) can be 
any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a drug and does not imply any judgment about causality. 
15.1.2. 
Suspected Adverse Reaction  
A suspected adverse reaction means any AE for which there is a reasonable possibility that the 
drug caused the AE. For the purposes of Investigational New Drug (IND) safety reporting, 
‘‘reasonable possibility’’ means there is evidence to suggest a causal relationship between the 


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drug and the AE. Suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any AE caused by a drug. 
15.1.3. Life-Threatening Adverse Event or Life-Threatening Suspected Adverse Reaction 
An AE or suspected adverse reaction is considered ‘‘life-threatening’’ if, in the view of either the 
Investigator or Sponsor, its occurrence places the subject at immediate risk of death. It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
15.1.4. Serious Adverse Event or Serious Suspected Adverse Reaction  
An AE or suspected adverse reaction is considered ‘‘serious’’ if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: 
• Death 
• A life-threatening AE - see definition above  
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
15.1.5. Unexpected Adverse Event or Unexpected Suspected Adverse Reaction 
An AE or suspected adverse reaction is considered ‘‘unexpected’’ if it is not listed in the 
Investigator Brochure or is not listed at the specificity or severity that has been observed. 
For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the Investigator Brochure referred only to elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of 
greater specificity) if the Investigator Brochure listed only cerebral vascular accidents.  
‘‘Unexpected,’’ as used in this definition, also refers to AEs or suspected adverse reactions that 
are mentioned in the Investigator Brochure as occurring with a class of drugs or as anticipated 


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from the pharmacological properties of the drug but are not specifically mentioned as occurring 
with the particular drug under investigation. 
15.2. 
Adverse Event Classification 
15.2.1. 
Relationship to Investigational Drug 
The Investigator’s assessment of causality must be provided for all AEs (serious and non-
serious). An Investigator’s causality assessment is the determination of whether or not there 
exists a reasonable possibility that the study drug caused or contributed to an AE, as described 
below: 
• None: No relationship between the experience and the administration of study drug; 
related to other etiologies such as concomitant medications or subject’s clinical state. 
• Unlikely: The current state of knowledge indicates that a relationship is unlikely.  
• Possible: A reaction that follows a plausible temporal sequence from administration 
of the study drug and follows a known response pattern to the suspected study drug. 
The reaction might have been produced by the subject’s clinical state or other modes 
of therapy administered to the subject, but this is not known for sure. 
• Probable: A reaction that follows a plausible temporal sequence from administration 
of the study drug and follows a known response pattern to the suspected study drug. 
The reaction cannot be reasonably explained by the known characteristics of the 
subject’s clinical state or other modes of therapy administered to the subject. 
• Definite: A reaction that follows a plausible temporal sequence from administration 
of the study drug and follows a known response pattern to the suspected study drug 
and can be confirmed with a positive re-challenge test or supporting laboratory data. 
As this is a blinded study, it is assumed the event is related to the active study drug until proven 
otherwise. 


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15.2.2. 
Severity 
All AEs will be graded for severity using the following terms: 
Grade 1 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
Grade 2 
Moderate 
Minimal, local or noninvasive intervention indicated; 
limiting age appropriate instrumental ADLa 
Grade 3 
Severe 
Medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care ADLb 
Grade 4 
Life threatening 
consequences 
Urgent intervention indicated 
Grade 5 
Death 
Death related to an AE 
a Instrumental activities of daily life (ADL) refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b Self-care activities of daily life refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
15.3. Exposure in Utero 
The subject will be instructed to notify the Investigator if the subject or subject’s partner 
becomes pregnant during the study. The Investigator must notify the Sponsor within 24 hours via 
telephone or e-mail and must complete the Pregnancy Notification Form and submit it to the 
Sponsor within 2 working days of being notified. The Investigator should obtain informed 
consent/assent from the subject or subject’s partner allowing the Investigator to obtain 
information regarding the pregnancy and its outcome. If the subject or subject’s partner provides 
informed consent/assent, the Investigator should follow the pregnancy until outcome. A final 
Pregnancy Notification Form should be completed when the outcome of the pregnancy is known. 
15.4. Monitoring of Adverse Event Data 
The Investigator and the Sponsor or its representative will be responsible for the following:  
• Reviewing AE data on an ongoing basis throughout the study. Should any AE report 
suggest that an unexpected Grade 3 or higher, and probably or definite study drug-
related occur, the Investigator and Sponsor will take prompt and appropriate action to 
protect subject safety. These actions may range from no action (proceed with the 
study) to halting the study for safety reasons. The evaluation and action decided upon 
will be documented.  
• Assessing the safety data and providing recommendations if the Sponsor should stop 
or modify the study.  
See Section 8.4 for additional details.  


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15.5. Documentation of Adverse Events by Investigator 
Subjects will be evaluated and questioned generally to identify AEs during the course of the 
study. Any events occurring prior to administration of the first dose will be recorded on the 
Medical History CRF. Events occurring after administration of the first dose of study drug will 
be recorded on the Adverse Event CRF. Adverse events that occur up to and including the 
90 days after the last dose of study drug must be reported.  
Record all AEs spontaneously reported by the subject and/or in response to an open question 
from study personnel or revealed by observation, physical examination, or other diagnostic 
procedures on the Adverse Event Form for that visit. Any clinically relevant deterioration in 
laboratory assessments or other clinical findings is considered an AE and must be recorded on 
the Adverse Event Form. In addition, an abnormal test finding must be classified as an AE if one 
or more of the following criteria are met: 
• The test finding is accompanied by clinical symptoms. 
• The test finding necessitates additional diagnostic evaluation(s) or medical/surgical 
intervention; including significant additional concomitant drug treatment or other 
therapy. (Note: simply repeating a test finding, in the absence of any of the other 
listed criteria, does not constitute an AE.) 
• The test finding leads to a change in study drug dosing or discontinuation of subject 
participation in the clinical research study. 
• The test finding is considered an AE by the Investigator. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified. However, if an observed or reported sign or symptom is not 
considered a component of a specific disease or syndrome by the Investigator, it should be 
recorded as a separate AE. Laboratory data are to be collected as stipulated in this protocol. 
Clinical syndromes associated with laboratory abnormalities are to be recorded as appropriate 
(e.g., diabetes mellitus rather than hyperglycemia). 
For SAEs, a Serious Adverse Event Form must also be completed with as much information as 
possible and submitted in the time frame described below in Section 15.6. When new significant 
information is obtained as well as when the outcome of an event become known, the Investigator 
should record the information on a new Serious Adverse Event Form, indicating that it is a 
follow-up report. If the subject was hospitalized, a copy of the discharge summary and any other 
relevant hospital records (e.g., admission report, laboratory test results) must be included as part 
of the subject medical file.  
All AEs considered to be related (definitely, probably, or possibly related) to study drug and all 
SAEs will be followed until resolved or until a stable status has been achieved. 


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15.6. Notification about Serious Adverse Events and Serious and Unexpected 
Suspected Adverse Reactions 
15.6.1. 
Investigator Reporting to Sponsor 
All SAEs that occur during the course of the study must be reported by the Investigator to the 
Sponsor and to the Medical Monitor within 24 hours by telephone or by text message. 
Additionally, the SAE Form should be faxed/e-mailed within 1 working day from the point in 
time when the Investigator becomes aware of the SAE. In addition, all SAEs that occur up to and 
including 90 days after administration of the last dose of study drug must be reported to the 
Sponsor within 1 working day from when the Investigator becomes aware of the SAE. 
Investigators must report to the Sponsor any SAE, whether or not considered drug related, 
including those listed in the protocol or Investigator Brochure. The report must include an 
assessment of causality.  
For all SAEs, the Investigator is obligated to obtain and provide information to the Sponsor in 
accordance with the timeframes for reporting specified above. In addition, an Investigator may 
be requested by the Sponsor to obtain specific additional follow-up information in an expedited 
fashion. This information may be more detailed than that captured on the Adverse Event eCRF. 
In general, this will include a description of the AE in sufficient detail to allow for a complete 
medical assessment of the case and independent determination of possible causality. Information 
on other possible causes of the event, such as concomitant medications and illnesses must be 
provided. In the case of a subject death, a summary of available autopsy findings must be 
submitted as soon as possible to the Sponsor or its designated representative. 
The Sponsor’s Medical Monitor will review the information submitted and seek further detail if 
deemed medically relevant and ideally concur on the severity and relatedness. However, the 
Medical Monitor may revise the severity and relatedness upward but may not reduce severity 
and/or relatedness. Such revisions will be documented in the Sponsor file and provided to the 
Investigator. 


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Serious Adverse Event Reporting Contact Information: 
Mark Midei, MD  
Medical Monitor 
Retrotope, Inc. 
4300 El Camino Real, Suite 201 
Los Altos, CA 94022 
Tel:  410-371-5357 
mark@retrotope.com 
15.6.2. 
Reporting to Regulatory Agencies and Institutional Review Boards 
If there is a serious and unexpected suspected adverse reaction, the Sponsor will notify the 
appropriate regulatory agency and all appropriate parties on an expedited basis. In addition, 
Sponsor must submit expedited reports of an increased rate of occurrence of serious suspected 
adverse reactions over that listed in the protocol or Investigator Brochure (§ 312.32(c)(1))(iv)). 
It is the responsibility of the Investigator to promptly notify the Institutional Review Board (IRB) 
of all serious and unexpected suspected adverse reactions involving risk to human subjects.  
Provide a copy of this communication to the Sponsor. 
15.7. 
Emergency Identification of Study Medication 
In the event of a medical emergency, when knowledge of the subject’s treatment assignment may 
influence the subject’s clinical care, the Investigator may obtain the treatment assignment of the 
subject experiencing the emergency through the unblinded statistician/designee. However, prior 
to unblinding, the Investigator should make every effort to contact the Medical Monitor. 
If unblinding is necessary, the Investigator must document the reasons for unblinding in the 
subject’s source documents but should not divulge the subject’s treatment assignment to any 
individuals except the Medical Monitor (if required) and those individuals involved in the direct 
care of the subject. The date and the reasons for breaking the blind must be submitted to the 
Sponsor within 24 hours.  
If a subject’s treatment assignment is unblinded, the subject should remain in the study and 
continue the protocol-specified follow-up evaluations. 
15.8. 
Optional Sub-Study Adverse Event Monitoring 
For the Optional PK Profile Sub-Study, there will be adverse event monitoring because this 
study will start and stop within the RT001-006 study dosing window. 
For the Optional PK Washout Sub-Study, there will not be any adverse event monitoring because 
the study occurs after the last dose of study drug. SAEs will still be monitored. 


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15.9. 
Emergency Sponsor Contact 
In a medical emergency (such as an event that requires immediate attention regarding the 
treatment of a subject, operation of the clinical study, and/or the use of investigational drug), 
study site staff will apply appropriate medical intervention according to current standards of care, 
and contact the Medical Monitor and the Sponsor Contact. 
Medical Monitor and Sponsor Contact Information: 
Mark Midei, MD  
Medical Monitor 
Retrotope, Inc. 
4300 El Camino Real, Suite 201 
Los Altos, CA 94022 
Tel:  410-371-5357 
mark@retrotope.com 
 
Frederic Heerinckx 
VP, Clinical Operations 
Retrotope, Inc. 
4300 El Camino Real, Suite 201 
Los Altos, CA 94022 
Tel: 408-834-5729 
frederic@retrotope.com  


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16. 
ETHICS 
16.1. 
Institutional Review Board  
The IRB must comply with FDA requirements governing IRBs (21 CFR Part 56).  
The Investigator will provide the Sponsor (or designee) with documentation of IRB approval of 
the following documents before the study begins at the study site(s): protocol, ICF, and any other 
relevant materials intended for or directed to subjects (e.g., subject diaries, advertisements). The 
Investigator will supply documentation to the Sponsor of IRB requirements regarding continuing 
review and approval of revisions to any of these documents. 
16.2. 
Ethical Conduct of the Study 
This study will be conducted in accordance with the current IRB approved clinical protocol, 
International Conference for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines, and 
relevant policies and requirements of the national regulations and laws, including the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA). 
16.3. 
Subject Information and Informed Consent 
Written informed consent/assent is required from each subject prior to any testing under this 
protocol, including screening tests and evaluations. The ICF, as specified by the clinical site’s 
IRB/IEC, must follow the Protection of Human Subjects regulations listed in 21 CFR Part 50. 
The ICF will be used to explain the risks and benefits of study participation in simple terms 
before the subject will be entered into the study. The ICF will contain a statement that the 
consent is freely given, that the subject is aware of the risks and benefits of entering the study, 
and that the subject is free to withdraw from the study at any time. Written informed consent 
must be given by the subject after the receipt of detailed information on the study and sufficient 
time to read it and have any questions answered. It is the responsibility of the Investigator to 
obtain consent/assent and to provide the subject with a copy of the signed and dated ICF. 
Confirmation of a subject’s informed consent must also be documented in the subject’s medical 
record prior to any testing under this protocol, including screening tests and evaluations. 
All ICFs used in this study must be approved by the appropriate IRB and by the Sponsor or its 
designee. The ICF must not be altered without the prior agreement of the relevant IRB and the 
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17. 
STUDY ADMINISTRATION 
17.1. 
Administrative Structure 
A list of individuals who will have key positions in this study will be saved in the Trial Master 
File (TMF). This list will include names, titles, and roles of selected individuals from the 
Sponsor and/or the contract research organization (CRO) that will contribute to this study. 
17.2. 
Quality Control and Quality Assurance 
17.2.1. 
Overview 
According to the GCP Guidelines, the Sponsor is responsible for implementing and maintaining 
quality assurance and control systems with written standard operating procedures (SOPs).  
Quality Control (QC) will be applied to each stage of data handling. The following steps will be 
taken to ensure the accuracy, consistency, completeness, and reliability of the data: 
• Investigator meeting(s) 
• Site initiation visit 
• Routine site monitoring 
• Ongoing site communication and training 
• Data management quality control checks 
• Continuous data acquisition and cleaning 
• Internal review of data; and 
• QC checks of the final CSR 
In addition, the Sponsor’s (or designee) Clinical Quality Assurance (QA) Department may 
conduct periodic audits of the study processes, including, but not limited to study site, site visits, 
vendors, clinical database, and final CSR. When audits are conducted, access must be authorized 
to Sponsor’s representatives and regulatory authorities for all study-related documents, including 
medical history and concomitant medication documentation. 
17.2.2. 
Monitoring 
Site Monitors will work in accordance with Sponsor SOPs. Monitors will establish and maintain 
regular contact between the Investigator or designee and the Sponsor. 
Monitors will evaluate the competence of each study site, informing the Sponsor about any 
problems relating to facilities, technical equipment or medical staff. During the study, monitors 
will check that written informed consent/assent has been obtained from all subjects correctly and 
that data are recorded correctly and completely on the CRFs. Monitors are also required to 


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compare entries in CRFs with corresponding source data and to inform the Investigator or 
designee of any errors or omissions. Monitors will also review adherence to the protocol and to 
regulatory requirements at the study site and discuss any deviations noted with the Investigator 
or designee. They will arrange for the study site to receive adequate supply of study drug and 
ensure appropriate storage conditions are maintained. 
Monitoring visits will be conducted according to the US CFR Title 21 Parts 50, 56, and 312 and 
ICH Guideline for GCP. The monitor will make written reports to the Sponsor following each 
contact with the Investigator or designee, regardless of whether it is by phone or in person. 
17.2.3. Data Management/Coding 
Study data will be handled according to the relevant SOPs of the data management and 
biostatistics departments of the Sponsor or CRO. 
Adverse events will be coded using MedDRA and medications will be coded using World Health 
Organization Drug Dictionary (WHODD). 
17.2.4. 
Quality Assurance Audit 
Study sites, the study database, and study documentation may be subject to a Quality Assurance 
audit by the Sponsor or designee on behalf of the Sponsor. In addition, inspections may be 
conducted by regulatory bodies at their discretion. 
17.3. 
Data Handling and Recordkeeping 
17.3.1. 
Electronic Data 
When using electronic trial data handling and/or remote electronic trial data systems, the Sponsor 
will: 
• Ensure and document that the electronic data processing system(s) conforms to the 
Sponsor’s established requirements for completeness, accuracy, reliability, and 
consistent intended performance (i.e., validation). 
• Maintain SOPs for using these systems. 
• Ensure that the systems are designed to permit data changes in such a way that the 
data changes are documented and that there is no deletion of entered data (i.e., 
maintain an audit trail, data trail, edit trail). 
• Maintain a security system that prevents unauthorized access to the data. 
• Maintain a list of the individuals who are authorized to make data changes. 
• Maintain adequate backup of the data. 


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• Safeguard the blinding, if any (e.g., maintain the blinding during data entry and 
processing). 
Documentation regarding electronic systems used in this protocol is available upon request from 
the CRO maintaining the electronic trial data system. 
17.3.2. 
Case Report Form Completion 
CRFs will be completed for each study subject. It is the Investigator’s responsibility to ensure the 
accuracy, completeness, legibility, and timeliness of the data reported in the subject’s CRF. 
Source documentation supporting the CRF data should indicate the subject’s participation in the 
study and should document the dates and details of study procedures, AEs, and subject status. 
Electronic data capture will be used for the study. Data will be recorded on source 
documentation at each study location and entered electronically by the study center personnel. 
Data collected on each subject will be documented on the appropriate eCRF. Completed eCRFs 
are to be signed off by the Investigator or his/her designee. 
17.3.3. 
Data Handling 
If data are transformed during processing, records will be maintained so that it will be possible to 
compare the original data and observations with the processed data. 
An unambiguous subject identification code will be used that allows identification of all the data 
reported for each subject. 
17.3.4. 
Retention of Study Records 
The Investigator must maintain essential study documents (protocol and protocol amendments, 
completed CRFs, signed ICFs, relevant correspondence, and all other supporting documentation) 
until at least 2 years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region or at least 2 years 
after the formal discontinuation of clinical development of the investigational product. These 
documents will be retained for a longer period if required by the applicable regulatory 
requirements or the hospital, institution, or private practice in which the study is being 
conducted. Subject identification codes (subject names and corresponding study numbers) will 
be retained for this same period of time. These documents may be transferred to another 
responsible party, acceptable to the Sponsor, who agrees to abide by the retention policies. 
Written notification of transfer must be submitted to the Sponsor. The Investigator or designee 
must contact the Sponsor prior to disposing of any study records. 
17.4. 
Financing and Insurance 
Financing and insurance are addressed in a separate document. 


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17.5. 
Confidentiality 
To maintain subject privacy, all CRFs, study drug accountability records, study reports and 
communications will identify the subject by the assigned subject number. The Investigator will 
grant monitor(s) and auditor(s) from the Sponsor or its designee and regulatory authority(ies) 
access to the subject’s original medical records for verification of data gathered on the CRFs and 
to audit the data collection process. The subject’s confidentiality will be maintained and will not 
be made publicly available to the extent permitted by the applicable laws and regulations. 
Subject will be notified that registration information, results, and other information about this 
study will be submitted to ClinicalTrials.gov, a publicly available trial registry database; 
however, protected health information of individual subjects will not be used. 
All information regarding the investigational product supplied by the Sponsor to the Investigator 
is privileged and confidential information. The Investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from the Sponsor. It 
is understood that there is an obligation to provide the Sponsor with complete data obtained 
during the study. The information obtained from the clinical study will be used toward the 
development of the investigational product and may be disclosed to regulatory authority(ies), 
other Investigators, corporate partners, or consultants as required. 
17.6. 
Publication Policy 
The data generated by this study are considered confidential information and the property of 
Sponsor and shall not be published or disclosed without the prior written consent of Sponsor. 
17.7. 
Direct Access to Source Data 
The Investigators/institutions/clinical sites will permit trial-related monitoring, audits, IRB 
review, and regulatory inspections as requested by FDA, the Sponsor, or the Sponsor designee, 
including direct access to source data/documents (e.g., original medical records, laboratory 
reports, hospital documents, progress reports, signed informed consent forms) in addition to 
CRFs. 
The Investigator or designee will prepare and maintain adequate and accurate source documents 
to support all observations and other pertinent data recorded on the CRFs for each subject 
randomized into the study.  
The Investigator will allow the Sponsor (or designee), and authorized regulatory authorities to 
have direct access to all documents pertaining to the study. 


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17.8. 
Protocol Amendments 
Changes to the conduct of the study should be prepared as a protocol amendment and 
implemented only upon approval of the Sponsor, or a representative of the Sponsor. Protocol 
amendments should also receive written IRB approval prior to implementation, except when 
necessary to eliminate immediate hazards to the subjects or when the changes involve only 
logistical or administrative aspects of the trial (e.g., change of monitor, telephone numbers). In 
this case, the Sponsor will amend and implement the protocol change and subsequently notify 
the regulatory authorities and/or the IRB, as appropriate. 


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18. 
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19. 
APPENDICES 
19.1. 
Cardiopulmonary Exercise Testing as a Primary Endpoint in 
Mitochondrial Diseases 
19.1.1. 
Background 
Assessment of exercise capacity is useful in providing valuable diagnostic, prognostic, and 
therapeutic information in patients in a variety of disease states.  Exercise capacity traditionally 
has been assessed in heart failure by the New York Heart Association criteria.  Such assessment 
is both subjective and insensitive.  The 6-minute walk test (i.e., the distance walked over a period 
of six minutes) is less subjective than the New York Heart Association functional class but still 
can be heavily influenced by the patient’s and/or tester’s motivation.  Additionally, the results of 
the 6-minute walk test cannot estimate how close the patient is to his or her maximal capacity. 
Some form of quantitative exercise testing has been available for more than a half century and, 
like many other cardiovascular procedures, has evolved in its technology and scope.  Information 
regarding a patient’s ECG and vital sign responses to supervised exercise on a treadmill or 
bicycle has long been used for diagnostic purposes in clinical situations.  It has also been used to 
predict prognosis, and on this basis, in the qualification of patients for therapeutic interventions.  
Used after such an intervention, it may be used to assess the resultant effects on symptom status 
or disease progression.  The quantitative assessment a patient’s exercise capacity provides a wide 
array of unique and clinically useful information.  Over time, the type of data collected, and the 
analysis performed during exercise testing has become increasingly complex.  This complexity 
allows the tailoring of the type of exercise protocol used, the method and amount of data 
collection, and its analysis to the condition under study. 
19.1.2. 
What is cardiopulmonary exercise testing (CPET)? 
CPET refers to the addition of gas exchange parameter measurement and analysis to 
conventional supervised exercise testing.  This usually entails a protocol administered stress test 
using either a treadmill or cycle ergometer (for either upper body or lower body exercise).  The 
protocol selected for administration may be tailored for the particular individual or condition 
under examination.  Under such conditions, the peak workload can be measured objectively and 
reproducibly.  Gas exchange analysis at rest, during exercise, and during recovery yields breath-
by-breath measures of oxygen uptake (VO2), carbon dioxide output (VCO2), and ventilation 
(VE).  Such metrics add utility to the peak workload analysis and may provide objective 
evidence of consistent effort when the anaerobic threshold is attained.  These data can be readily 
integrated with standard variables measured during exercise testing, including heart rate, blood 
pressure, work rate, electrocardiography findings, and symptoms to provide a comprehensive 
assessment of exercise tolerance and exercise responses.  
The ability to perform physical exercise is critically related to the cardiovascular system’s 
capacity to supply oxygen (O2) to the muscles and the pulmonary system’s ability to clear 
carbon dioxide (CO2) from the blood via the lungs. The cardiovascular and respiratory systems 
work together to provide both a delivery system (of O2) and a removal system (of CO2) from the 
tissues. There are 4 processes that occur to make this happen: 


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1. Pulmonary ventilation, or the movement of air into and out of the lungs;  
2. Pulmonary diffusion, or the exchange of O2 and CO2 between the lungs and the blood; 
3. Transport of O2 and CO2 in the blood; 
4. Capillary gas exchange, or the exchange of O2 and CO2 between the capillary blood and 
the working muscle. 
The first 2 processes are referred to as external respiration because they involve the movement 
of gases from the ambient air into the lungs and then the blood. The fourth step is commonly 
termed internal respiration because it involves gas exchange between the blood and the tissues. 
These 2 processes are linked by the circulatory system. CPET is valuable because taxing the 
mechanisms responsible for external and internal respiration by exercise can frequently reveal 
abnormalities not apparent at rest. In addition, typical pulmonary and cardiac function tests 
performed at rest cannot reliably determine exercise capacity or the particular mechanisms 
underlying exercise intolerance among individual patients with diseases affecting the heart, the 
lungs or the muscles (Balady et al. 2010). 
Maximal aerobic capacity (VO2MAX) is frequently cited as the single most important derivative 
of the CPET test because it is considered to be the metric that defines the limits of the 
cardiopulmonary system.  Although VO2MAX is measured in liters of oxygen per minute, it is 
usually expressed in milliliters of oxygen per kilogram of body weight per minute to facilitate 
inter-subject comparisons.  The measurement of VO2MAX implies that an individual’s 
physiological limit has been reached (also termed maximal aerobic capacity).  Consistent 
attainment of this limit is dependent on the efforts of the subject and the administrator of any test 
of exercise capacity.  CPET has an advantage over most of these tests in that maximal effort may 
be assured reproducibly when the oxygen consumption curve flattens at the anaerobic threshold.  
This also objectively assures the validity of other performance parameters made during CPET 
such as measurement of total workload. 
19.1.3. 
Conditions in which it is used clinically 
CPET may be useful in clinical conditions where exercise limitation occurs as a result of disease.  
For any appropriate disease in which exercise intolerance is a prominent feature, CPET may help 
to diagnose, identifying degree or stage, detect progression, predict prognosis, and guide 
therapeutic intervention. 
The value of CPET and its attendant data elements including peak workload and VO2MAX has 
been recognized as the most objective method to assess exercise capacity in heart failure patients 
(Balady et al. 2010). It is a useful test to determine the severity of the disease and to help to 
determine whether heart failure is the cause of exercise limitation (American College of 
Cardiology/American Heart Association recommendation Class IIa, Level of Evidence C), 
provide important prognostic information and identify candidates for cardiac transplantation or 
other advanced treatments (American College of Cardiology/American Heart Association 
Recommendation Class IIa, Level of Evidence B); facilitate the exercise prescription (American 
College of Cardiology/American Heart Association Recommendation Class I, Level of Evidence 
C) (Hunt et al. 2001); and assess the effectiveness of new drugs and devices.  VO2MAX has been 


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shown to predict prognosis in patients with heart failure in many studies (Davies et al. 2000, 
Cohn et al 1993). In addition, there may be enhanced prognostic value from CPET testing in 
chronic heart failure by non-linear analysis.  Use of the oxygen uptake efficiency slope may add 
to the utility of the CPET testing (Davies et al. 2006). 
Peak workload and VO2 MAX during CPET are also useful in the assessment of patients with 
hypertrophic cardiomyopathy (HCM).  In a retrospective review of 182 patients with HCM and 
minimal or no symptoms followed for up to four years, multiple parameters of metabolic 
exercise were associated with a risk of death and the development of severe symptoms. On 
multivariate analyses, the independent predictors of death and severe symptoms were the 
severity of the left ventricular outflow tract gradient at rest and the percentage of predicted peak 
myocardial oxygen consumption achieved during exercise.  (Sorajja et al. 2012) In a more recent 
study of 1898 patients with HCM, VO2MAX and several sub-maximal exercise parameters 
measured during CPET were predictors of death or need for cardiac transplantation (Coats et al. 
2015). 
CPET parameters are also used clinically in the evaluation of chronic obstructive pulmonary 
disease. Reductions in VO2MAX, and attainment of anaerobic threshold at lower levels of work 
performed correlate well with the degree of impairment due to emphysema, and with worse 
prognosis (Chen et al. 2012). 
19.1.4. 
Association with morbidity/mortality 
Peak workload measured during exercise testing correlates well with functional capacity.  In 
patients with respiratory disease, peak workload is more closely associated with the distance a 
patient is able to walk over 6 minutes (6MWD-a common endpoint in heart failure and 
respiratory failure clinical trials) than it is with tests of respiratory function (Singh et al. 2014).   
CPET predicts poor outcomes and mortality in a variety of conditions including dilated 
cardiomyopathies (Mudge et al. 1993, Francis et al. 2000, Davies et al. 2000, Kleber et al. 2000), 
HCM (Sorraja et al. 2012, Coats et al. 2015), congenital heart disease (Diller et al. 2010), and 
pulmonary hypertension (Miyamoto et al. 2000). 
19.1.5. 
Conditions for which it has been used as an endpoint in clinical trials 
CPET is useful in a number of different ways when used as part of a clinical trial.  
Determinations of peak workload and VO2MAX have been used to qualify subjects objectively 
for enrollment and assessment of therapeutic effect.  Assessment of patient candidacy for 
enrollment in a clinical trial is fraught with subjectivity among investigators. The use of a 
VO2MAX threshold may be used to qualify patients for enrollment (Abozguia et al. 2010) and 
may assure better uniformity, prevents unnecessary drug exposure to patients unlikely to benefit, 
and would potentially guide later application of perhexiline use clinically.   
CPET parameters are continuous variables which may improve trial efficiency by allowing the 
identification of a significant treatment effect with a smaller number of patients required for 
efficacy analysis in rare diseases. 
In a study of 453 patients with advanced congestive heart failure randomized to control or 
cardiac resynchronization therapy, VO2MAX was used as a secondary endpoint (Abraham et al. 


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2002) and correlated well with 6-minute walk distance (primary endpoint).  Other studies have 
shown good correlation between these two endpoints (Ross et al. 2010). 
Although the majority of literature supporting the value of CPET in patients with heart failure 
has been performed in patients with systolic dysfunction, initial investigations demonstrate that 
CPET also has great promise in the evaluation of patients who have HFNEF—the kind of heart 
failure responsible for symptoms in HCM patient (Phan et al. 2009).  Patients with heart failure 
resulting from either systolic or diastolic dysfunction appear to have the same degree of impaired 
aerobic capacity (Brubaker et al. 2003, Farr et al. 2008).  In subjects diagnosed with HCM, VO2 
MAX and VCO2 MAX at peak exercise are both significantly correlated with resting pulmonary 
hemodynamics (Arena et al. 2008).  An abnormal response effectively identified subjects with 
pulmonary hypertension. Other investigations indicate the VCO2 MAX slope, and VO2 MAX 
may be significant predictors of adverse events in heart failure patients with diastolic dysfunction 
(Arena et al. 2008, Guazzi et al. 2008). 
VO2 MAX has been shown in a pilot clinical trial to serve well as a qualifier for enrollment and 
has been used successfully in determining a significant difference in VO2 MAX (Abozguia et al 
2010).  Forty-six patients with symptomatic HCM and a VO2 MAX <75% of predicted were 
enrolled in a trial comparing perhexiline with placebo.  At the end of 4.6 + 1.8 months, VO2 
MAX increased in the perhexiline group (22.2+0.2 to 24.3+0.2 mL/kg/min) while it declined in 
the placebo group (23.6+0.3 to 22.3+0.2 mL/kg/min; p<0.003).  These changes were associated 
with significant improvement in cardiac energetic status (measured by myocardial ratio of 
phosphocreatine to adenosine triphosphate using 31P magnetic resonance spectroscopy), 
improved diastolic function (measured by left ventricular diastolic filling at rest and during 
exercise using radionuclide ventriculography), and improved quality of life (using NYHA 
Classification).   
Thus, CPET and the parameters extracted from its performance play important roles in 
identifying patients at highest risk.  These metrics serve as continuous variables in the 
assessment of benefit from pharmacologic intervention in patients with heart failure, and have 
recently been shown to serve an identical purpose specifically in HCM.  
 
 


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19.2. 
FARS-Neuro Scale 
 
 
 
A. BULBAR 
Most subjects with FA do not have significant facial or tongue atrophy. If mild facial or tongue atrophy is noted score as per 
instructions. Speech and cough assessment are self-explanatory. For items in Section A, increments of 0.5 may be used if examiner 
feels an item falls between two severities. 
1. Facial Atrophy, Fasciculation, Action Myoclonus, and Weakness 
0 – None  
1 – Fasciculations or action myoclonus, but no atrophy. 
2 – Atrophy present but not profound of complete.  
3 – Profound atrophy and weakness. 
Score 
. 
2. Tongue Atrophy, Fasciculation, Action Myoclonus, and Weakness 
0 – None  
1 – Fasciculations or action myoclonus, but no atrophy. 
2 – Atrophy present but not profound of complete.  
3 – Profound atrophy and weakness. 
Score 
. 
3. Cough (subject asked to cough forcefully 3 times) 
0 – Normal.  
1 – Depressed. 
2 – Totally or nearly absent. 
Score 
. 
4. Speech (ask the patient to read or repeat the sentences: A. “The president lives in the white 
house” and B. “The traffic is heavy today”) 
0 – Normal.  
1 – Mild (all or most words understandable). 
2 – Moderate (most words not understandable). 
3 – Severe (no or almost no useful speech). 
Score 
. 
TOTAL BULBAR SCORE:  . 


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B. UPPER LIMB COORDINATION 
Upper limb coordination: Most of the items are self-explanatory. For items 3-5, ask the subject to count as they do the task.   
Example: “Move your hand back and forth 10 times as fast as you can. Please count each time to yourself”.  
You can time the activity with either a watch or a stopwatch.  For items in Section B, increments of 0.5 may be used if examiner 
feels an item falls between two severities. 
1. Finger to Finger Test (Index fingers are placed in front of each other with flexion at the elbow 
about 25 cm. from the sternum. Observe for 10 seconds. Score amplitude of oscillations) 
0 – Normal.  
1 – Mild oscillations of finger (less than 2 cm). 
2 – Moderate oscillations of finger (2-6 cm). 
3 – Severe oscillations of finger (greater than 6 cm) 
Score (Right) 
 . 
Score (Left) 
. 
2. Nose-Finger Test (Assess kinetic or intention tremor during and towards the end of movement: 
examiner holds index finger at 90% reach of patient; test at least 3 nose-finger-nose trials; 
movement slow greater than 3 sec.) 
0 - None 
1 - Mild (less than 2 cm. amplitude). 
2 - Moderate (2-6 cm. amplitude or persisting through movement). 
3 - Severe (greater than 6 cm. & persisting through movement). 
4 - Too poorly coordinated to perform task. 
Score (Right) 
. 
 
Score (Left) 
. 
3. Dysmetria Test (The subject touches tip of examiner’s finger then subject’s chin 8 times as 
rapidly as possible while the examiner moves his finger to four corners of a one-foot square and at 
about 90% reach of the subject. Assess dysmetria – i.e. inaccuracy of reaching the target- tip of 
examiner’s finger) 
0 - None. 
1 - Mild (misses 2 or fewer times). 
2 - Moderate (misses 3-5 times). 
3 - Severe (misses 6-8 times.). 
4 - Too poorly coordinated to perform task. 
Score (Right) 
. 
 
Score (Left) 
. 
4. Rapid Alternating Movements of Hands (Subject should be seated. Forearm 
pronation/supination 15 cm. above thigh; 10 full cycles as fast as possible; assess rate, rhythm, 
accuracy; practice 10 cycles before rating, if time greater than 7 sec. add 0.5 to score. Use 
stopwatch) 
0 - Normal.                                                                                                Time to Complete (R): 
1 - Mild (slightly irregular or slowed).                                                  ____________ 
2 - Moderate (irregular and slowed). 
3 – Too poorly coordinated to perform task.                                     Time to Complete (L): 
                                                                                                                    ____________ 
Score (Right) 
. 
 
Score (Left) 
. 


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5. Finger Taps (index fingertip-to-thumb crease; 15 reps as fast as possible; practice 15 reps once 
before rating; if time greater than 6 sec., add 1 to rating. Use stopwatch) 
0 - Normal.                                                                                                Time to complete (R): 
1 - Mild (misses 1-3 times).                                                                     ____________ 
2 - Moderate (misses 4-9 times).               
3 - Severe (misses 10-15 times).                                                           Time to complete (L): 
4 - Cannot perform the task.                                                                  ____________ 
Score (Right) 
. 
 
Score (Left) 
. 
TOTAL UPPER LIMB COORDINATION SCORE  . 
C. LOWER LIMB COORDINATION 
Lower limb coordination: The heel shin slide is scored 1 if there is an abnormality but contact is steady along the top of the shin. If 
the heel starts going off the shin to one or other side score 2 or 3 as noted. For heel to shin tap instruct the subject to count 8 
taps with heel raised about 8 " each time. It is preferable to do this section with the patient lying down. If this is not followed for 
a particular subject, it should be done in the same position each time.  For items in Section C, increments of 0.5 may be used if 
examiner feels an item falls between two severities. 
1. Heel Along Shin Slide (Perform while seated or supine, under visual control, slide heel on the 
contralateral tibia from the patella to the ankle up and down with contralateral leg extended, 3 
cycles at moderate speed, one leg at a time.) 
0 - Normal (stay on shin).  
1 - Mild (abnormally slow, tremulous but contact maintained). 
2 - Moderate (goes off shin a total of 3 or fewer times during 3 cycles). 
3 - Severe (goes off shin 4 or more times during 3 cycles). 
4 - Too poorly coordinated to attempt the task. 
 
Position of patient: ___________________ 
Score (Right) 
. 
 
Score (Left) 
. 
2. Heel-to-Shin Tap (Subject taps heel on midpoint of opposite shin 8 times on each side from 
about 6-10", one at a time. Perform seated or supine.) 
0 - Normal (stays on target).  
1 - Mild (misses shin 2 or <less times). 
2- Moderate (misses shin 3-5 times). 
3 - Severe (misses shin greater than times). 
4 - Too poorly coordinated to perform task. 
 
Position of patient: ___________________ 
Score (Right) 
. 
 
Score (Left) 
. 
TOTAL LOWER LIMB COORDINATION SCORE  . 


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D. PERIPHERAL NERVOUS SYSTEM 
Peripheral nervous system: these items are self-explanatory. Check deltoids and intrinsic hand muscles in the upper limbs, iliopsoas and 
tibialis anterior in the lower limbs. Atrophy and weakness are scored on the basis of the worst muscle in this group. One does not have 
to do extensive muscle testing. Vibration sense is recorded as noted in seconds and then given a score depending on the extent of 
impairment. DTR are recorded in the given space as noted and then any hypo/areflexia is given a numerical score as noted. 
1. Muscle Atrophy (score most severe atrophy in either upper or lower limb) 
0 - None. 
1 - Present - mild/moderate 
2 - Severe/total wasting 
If atrophy is present or severe, indicate location of atrophy 
(R):____________________ 
 
If atrophy is present or severe, indicate location of atrophy 
(L):____________________ 
Score (Right) 
 
 
Score (Left) 
 
2. Muscle Weakness (Test deltoids, interossei, iliopsoas and tibialis anterior. Score most severe 
weakness in either upper or lower limb) 
0 - Normal (5/5). 
1 - Mild (movement against resistance but not full power 4/5). 
2 - Moderate (movement against gravity but not with added resistance 3/5) 
3 - Severe (movement of joint but not against gravity 2/5). 
4 - Near paralysis (muscular activity without movement 1/5) 
5 - Total paralysis (0/5) 
Score (Right) 
 
 
Score (Left) 
 
3. Vibratory Sense (Educate patient regarding the sensation at the elbow. Tested with 128 cps 
tuning fork set to near full vibration; eyes closed; test over index finger and top of great toe (most 
distal joint not nail). Abnormal less than 15 seconds for toes and less than 25 seconds for hands) 
 
3a. Time felt for toes (R): _______ 
3b. Time felt for toes (L): _______ 
3c. Time felt for Fingers (R): _______ 
3d. Time felt for Fingers (L): _______ 
3e. RIGHT                                                                3e. LEFT 
0 - Normal.                                                               0 - Normal. 
1 - Impaired at toes or fingers.                             1 - Impaired at toes or fingers 
2 - Impaired at toes and fingers.                          2 - Impaired at toes and fingers. 
Score (Right) 
 
 
Score (Left) 
 


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4. Position Sense (test using minimal random movement of distal interphalangeal joints of index 
finger and big toe)                                                               
0 - Normal.                                                      
1 - Impaired at toes or fingers.                    
2 - Impaired at toes and fingers.                    
Score (Right) 
 
 
Score (Left) 
 
5.  DTR (0 = absent, 1 = hyporeflexia, 2 = normal, 3 = hyperreflexia, 4 = pathologic 
hyperreflexia) 
5a. RIGHT                                5b. LEFT 
Elbow (BJ):    _______            Elbow (BJ):    _______ 
Wrist (BrJ):    _______            Wrist (BrJ):    _______             
Knee (KJ):      _______             Knee (KJ):      _______              
Ankle (AJ):    _______              Ankle (AJ):    _______ 
 
5c. RIGHT 
0 – No areflexia. 
1 – Areflexia or mild hyperreflexia in either upper or lower limbs. 
2 – Generalized areflexia or pathologic hyperreflexia. 
 
5c. LEFT 
0 – No areflexia. 
1 – Areflexia or mild hyperreflexia in either upper or lower limbs. 
2 – Generalized areflexia or pathologic hyperreflexia. 
 
 
Score (Right)  
. 
 
 
 
 
 
Score (Left) 
. 
TOTAL PERIPHERAL NERVOUS SYSTEM SCORE 
 . 


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E. UPRIGHT STABILITY 
For sitting posture patient can sit in a chair or examination table. For standing and walking assessment instruct patient to wear best 
walking shoes and record below if barefoot, footwear or AFOs used. Stance assessment begins with feet 20 cm apart. Place marker 
tapes in the exam room 20 cm apart and the insides of the feet are lined up against these. Subsequent stance tests get more difficult. 
For feet together the entire inside of the feet should be close together as much as possible. For tandem stance, the dominant foot is in 
the back and the heel of the other foot is lined with the toes of the dominant foot but not in front of the toes (because this makes it 
even more difficult). For one-foot stance, the patient is asked to stand on dominant foot and the other leg is elevated by bringing it 
forward with knee extended; this gives some advantage to the patient. If a patient can stand in a particular position for 1 minute or 
longer in trial 1, the trials 2 and 3 are abandoned. Otherwise each of 3 trials is timed and then averaged. Grading scores are then given 
as noted. Tandem walk and gait are performed in a hallway. Preferably no carpet but at least serial examinations should be on the same 
surface. For gait place markers 25 feet apart. Patient walks the distance turns around and comes back and the activity is timed. Note if 
the gait was achieved with or without device and serial examinations should be done with the same device as in the first examination. 
Ea.   Is subject:   
 Barefoot      
 Footwear 
Eb.   Indicate if AFO’s (plastic brace) are used?  
 No  
 Yes 
Ec.   Test performed on Carpet? 
 No  
 Yes 
1. Sitting Posture (Subject seated in chair with thighs together, arms folded across chest, back 
unsupported; observe for 30 sec.) 
0 - Normal. 
1 - Mild oscillations of head/trunk without touching chair back or side. 
2 - Moderate oscillations of head/trunk; needs contact with chair back or side for 
stability. 
3 - Severe oscillations of head/trunk; needs contact with chair back or side for 
stability. 
4 - Support on all 4 sides for stability. 
Score   


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2a.    Stance - feet apart – Eyes open (Inside of feet 20 cm apart marked on floor. Use stopwatch; 
3 attempts; time in seconds. If greater than 60 seconds on trial 1 stop, if less than 60 seconds 
do all three trials.) 
0 - 1 minute or longer.                                                                                Time 1:   _______ 
1 – less than 1 minute, greater than 45 sec. 
2 – less than 45 sec., greater than 30 sec.                                               Time 2:   _______ 
3 – less than 30 sec., greater than 15 sec. 
4 – less than 15 sec. or needs hands held by assistant/device.           Time 3:   _______     
Score 1    
 
Score 2    
 
Score 3    
 
Avg. Score   . 
2b.    Stance - feet apart – Eyes closed (If greater than 60 seconds on trial 1 stop, if less than 60 
seconds do all three trials.) 
0 - 1 minute or longer.                                                                                Time 1:   _______ 
1 – less than 1 minute, greater than 45 sec. 
2 – less than 45 sec., greater than 30 sec.                                               Time 2:   _______ 
3 – less than 30 sec., greater than 15 sec. 
4 – less than 15 sec. or needs hands held by assistant/device.           Time 3:   _______     
 Score 1    
 
Score 2    
 
Score 3    
 
Avg. Score   . 
3a.    Stance - feet together (use stopwatch; 3 attempts; time in seconds.  If greater than 60 
seconds on trial 1 stop, if less than 60 seconds do all three trials.) 
0 - 1 minute or longer.                                                                                Time 1:   _______ 
1 – less than 1 minute, greater than 45 sec. 
2 – less than 45 sec., greater than 30 sec.                                               Time 2:   _______ 
3 – less than 30 sec., greater than 15 sec. 
4 – less than 15 sec. or needs hands held by assistant/device.           Time 3:   _______     
   Score 1    
 
Score 2    
 
Score 3    
 
Avg. Score   . 


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3b.    Stance - feet together – Eyes Closed ( If greater than 60 seconds on trial 1 stop, if less than 
60 seconds do all three trials.) 
0 - 1 minute or longer.                                                                                Time 1:   _______ 
1 – less than 1 minute, greater than 45 sec. 
2 – less than 45 sec., greater than 30 sec.                                               Time 2:   _______ 
3 – less than 30 sec., greater than 15 sec. 
4 – less than 15 sec. or needs hands held by assistant/device.           Time 3:   _______     
  Score 1    
 
Score 2    
 
Score 3    
 
Avg. Score   . 
4. Tandem Stance (dominant foot in front; front foot lined up with great toe of the back foot.  If 
greater than 60 seconds on trial 1 stop, if less than 60 seconds do all three trials.) 
0 - 1 minute or longer.                                                                                Time 1:   _______ 
1 – less than 1 minute, greater than 45 sec. 
2 – less than 45 sec., greater than 30 sec.                                               Time 2:   _______ 
3 – less than 30 sec., greater than 15 sec. 
4 – less than 15 sec. or needs hands held by assistant/device.           Time 3:   _______     
   Score 1    
 
Score 2    
 
Score 3    
 
Avg. Score   . 
5. 
Stance on Dominant Foot (elevate leg straight out in front, use stopwatch; 3 attempts; time 
in seconds.  If greater than 60 seconds on trial 1 stop, if less than 60 seconds do all three trials.) 
0 - 1 minute or longer.                                                                                Time 1:   _______ 
1 – less than 1 minute, greater than 45 sec. 
2 – less than 45 sec., greater than 30 sec.                                               Time 2:   _______ 
3 – less than 30 sec., greater than 15 sec. 
4 – less than 15 sec. or needs hands held by assistant/device.           Time 3:   _______     
  Score 1    
 
Score 2    
 
Score 3    
 
Avg. Score   . 


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6. Tandem Walk (tandem walk 10 steps in straight line; performed in hallway with no furniture 
within reach of 1 m / 3 ft. and no loose carpet) 
0 - Normal (able to tandem walk greater than 8 sequential steps). 
1 - Able to tandem walk in less than perfect manner/can tandem walk greater than 4 
sequential steps, but less than 8. 
2 - Can tandem walk, but fewer than 4 steps before losing balance. 
3 - Too poorly coordinated to attempt task. 
 Score  
7. Gait (observe subject walk at normal pace with assistive device in one direction, turn around 
and return to start; performed in hallway with no furniture within reach of 1 m / 3 ft. and no 
loose carpet) 
0 - Normal. 
1 - Mild ataxia/veering/difficulty in turning; no cane/other support needed to be safe. 
2 - Walks with definite ataxia; may need intermittent support/or examiner needs to 
walk with patient for safety sake. 
3 - Moderate ataxia/veering/difficulty in turning; walking requires cane/holding onto 
examiner with one hand to be safe. 
4 - Severe ataxia/veering; walker or both hands of examiner needed. 
5 - Cannot walk even with assistance (wheelchair bound). 
Score  
TOTAL UPRIGHT STABILITY SCORE 
 . 
TOTAL FARS  
(Add subtotals for sections A, B, C, D, & E)   . 


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19.3. 
Clinician-rated Clinical Global Impression (CGI)  
 
1. Severity of Illness 
Considering your total clinical experience with this particular population, how ill is the patient at this time 
0 = Not assessed  
4 = Moderately ill 
1 = Normal, not at all ill 
5 = Markedly ill 
2 = Borderline ill  
6 = Severely ill 
3 = Mildly ill 
 
7 = Among the most extremely ill patients 
 
2. Global Improvement 
Rate total improvement whether or not, in your judgement, it is due entirely to drug treatment. Compared to 
subject’s condition at admission to the study, how much has the subject changed? 
0 = Not assessed  
4 = No change 
1 = Very much improved 5 = Minimally worse 
2 = Much improved 
6 = Much worse 
3 = Minimally improved 
7 = Very much worse 
 
3. Efficacy index 
Rate this item on the basis of drug effect only. 
Select the terms which best describe the degrees of therapeutic effect and side effects and record the 
number in the box where the two items intersect. 
EXAMPLE: Therapeutic effect is rated as ‘Moderate’ and side effects are judged ‘Do not significantly 
interfere with patient’s functioning.’ 
 
 
 
 
Therapeutic effect 
Side Effects 
 
None 
Do not significantly
interfere with 
patient’s 
functioning 
Significantly interfere
with patient’s 
functioning 
Outweighs 
therapeutic 
effect 
Marked 
Vast improvement. Complete or 
nearly complete remission of all 
symptoms 
01 
02 
 
03 
04 
Moderate Decided improvement. Partial 
remission of symptoms 
05 
06 
07 
08 
Minimal 
Slight Improvement which doesn’t 
alter status of care of patient 
09 
10 
11 
12 
Unchanged or worse 
13 
14 
15 
16 
Not assessed = 00 


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19.4. 
FARS -Activities of Daily Living (FARS-ADL) 
 
 
 


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19.5. 
SF-36 
 


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19.6. 
Patient Global Impression of Change Scale (PGI-C) 
 
 
1. Please indicate how you feel now, compared to how you felt before receiving treatment in 
this study (Choose one) 
 
1 = Very Much Improved 
 
5 = Minimally Worsened 
2 = Much Improved  
 
6 = Much Worsened 
3 = Minimally Improved 
 
7 = Very Much Worsened 
4 = No Change 
 
 
 
 
 


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19.7. 
Visual Analogue Scale (VAS) 
 
Visual Analogue Scale for Improvement of FA Symptoms 
Rate your Friedreich’s Ataxia symptoms compared to baseline (prior to taking study medication) 
whether or not, in your judgement, it is due entirely to drug treatment. Please circle the 
appropriate happy/sad face. You can also circle “no change”. 
0 = Very much improved 
 
2 = Much improved 
4 = Minimally improved 
6 = Minimally worse 
8 = Much worse 
10 = Very much worse 
 
 
 
 
 
 
 
Visual Analogue Scale for Fatigue 
How would you rate your fatigue level over the last week? 
 
 
 
 


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19.8. 
Fatigue Scale 
Below is a list of statements that other people with your illness have said are important. Please circle or mark one 
number per line to indicate your response as it applies to the past 7 days. 
 
Not 
at all 
A little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
HI7 
 
I feel fatigued...................................................................     0 
 
1 
 
2 
 
3 
 
4 
HI12 
I feel weak all over ..........................................................     0 
1 
2 
3 
4 
An1 
I feel listless (“washed out”) ...........................................     0 
1 
2 
3 
4 
An2 
I feel tired ........................................................................     0 
1 
2 
3 
4 
An3 
I have trouble starting things because I am tired .............     0 
1 
2 
3 
4 
An4 
I have trouble finishing things because I am tired ...........     0 
1 
2 
3 
4 
An5 
I have no energy.............................................................    0 
1 
2 
3 
4 
An7 
I have trouble doing my usual activities ..........................     0 
1 
2 
3 
4 
An8 
I need to sleep during the day ..........................................     0 
1 
2 
3 
4 
An12 
I am too tired to eat ..........................................................     0 
1 
2 
3 
4 
An14 
I need help doing my usual activities ..............................     0 
1 
2 
3 
4 
An15 
I am frustrated by being too tired to do the things I want 
to do ..................................................................................... 0 
 
1 
 
2 
 
3 
 
4 
An16 
I have to limit my social activity because I am tired ............ 0 
1 
2 
3 
4 
 
 
 


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19.9. 
Neuro-QoL scales 
 


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19.10. 
Fall Questionnaire 
 
1. How many times in the last year have you: 
Fallen to the ground: ___________________________________________________ 
Had near falls (this means you lose your balance but retain your upright position, for 
instance, by grabbing on to something): _____________________________________ 
_____________________________________________________________________ 
Stumble and catch yourself: ______________________________________________ 
 
 
2. Did you ever hurt yourself because of a fall? 
○   No 
○   Once 
○   More than once 
 
 
3. What kind of injuries have you suffered as a consequence of a fall? 
○   None 
○   A fracture (i.e. A hip): _________________________________________________ 
○   Other wounds (i.e. Bruises, scrapes, cuts): ________________________________ 
○   Loss of consciousness  
○   Other (i.e. Internal bleeding, including the brain): ____________________________ 
 
 
4. When you fall, where does this usually take place? 
○   Outdoors 
○   Indoors 
○   Both 
 
 
5. When you fall, at what time does this usually take place? 
○   Any time of day 
○   Daytime 
○   Evening 
○   Night time (after going to bed) 


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6. In which direction do you fall most often? 
○   Backwards 
○   Forwards 
○   Sideward             right    /     left           (circle the correct answer) 
○   All directions equally 
 
 
7. What do you do to prevent falling? 
○   Nothing 
○   Avoid certain activities (give examples): _________________________________ 
○   The use of aids (i.e. cane, walker, holding on to a person, holding on to furniture): 
_____________________________________________________________________ 
○   Other: ____________________________________________________________ 
 
 
8. Do you experience a fear of falling? 
○   No 
○   Slightly 
○   Very much 
 
 
9. Can you give an indication of your confidence in balance during daily activities on a scale of 0 
up to 100 on the below mentioned scale?  Zero means no confidence and 100 means full 
confidence in performing the activities? 
 
 
 
 
 
 
 
 
 
 
0         10         20         30         40         50         60         70         80         90         
100 


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19.11. 
Speech Assessment Questionnaire 
 
For subject: 
 
How would you rate the overall quality of your speech? 
 
Very Good 
Good 
Fair 
Poor 
Very Poor 
 
How would you rate your verbal communication with your family or friends? 
 
Very Good 
Good 
Fair 
Poor 
Very Poor 
 
For parents, caregiver or travel companion response (not for patients to respond)  
Enter NA, if not present: 
 
How would you rate the subject’s overall quality of verbal communication? 
 
Very Good 
Good 
Fair 
Poor 
Very Poor 
 
 
 


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19.12. 
Optional PK Profile Sub-Study: Pharmacokinetic Profile of RT001 
at Steady State in Subjects with Friedreich’s Ataxia Who 
Participated in Study RT001-006 
19.12.1. 
Study Objectives 
The objective of the study is to evaluate the pharmacokinetic (PK) profile of RT001 at steady 
state.   
19.12.2. 
Study Design  
At selected sites, subjects who are enrolled in RT001-006 will be invited to participate in this 
study. At the time of the Month 11 visit in RT001-006, PK samples will be obtained 30 minutes 
to 1 hour before the morning dose; and 30 min, 1, 2, 4, 8, 12 and 24 hours after the initial 
morning dose. It is recommended that the blood draws are done on a different day than the study 
procedures for the Month 11 visit in RT001-006.   
19.12.3. 
Randomization  
There will be no randomization. All subjects who are volunteering for this sub-study will 
be enrolled.  
19.12.4. 
Blinding 
Subjects and study personnel, including but not limited to investigators, study coordinators, 
nursing staff, clinical monitors, the Sponsor, and the Sponsor’s representatives, will remain 
blinded to the study treatment assignments (RT001 or placebo) in RT001-006.   
19.12.5. 
Inclusion Criteria 
1. At selected sites, subjects who are enrolled in RT001-006 will be invited to participate in 
this study.   
2. All participating subjects will be required to sign an informed consent prior to the 
collection of the blood draws.   
3. Subjects must be willing to stay overnight close to the study site and able to provide the 
necessary repeated blood samples. 
19.12.6. 
Sample Size 
Subjects who are enrolled in RT001-006 will be invited to participate in this study. Because the 
study treatment (active or placebo) in RT001-006 is blinded, a minimum of 10 subjects will be 
enrolled to ensure that at least 5 subjects who are randomized to active are enrolled in this study. 
An unblinded person may be asked to verify that at least 5 of the selected subjects were 
randomized to active. Additional subjects may be added as needed.  


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19.12.7. 
Sample Collection  
Bioanalytical measurements will be performed to determine the concentration profiles of D2-LA, 
D2-ARA, H2-LA and H2-ARA in plasma and red blood cells. Blood samples will be 
collected according to the schedule below:  
Day 1: Hour -1.0 to -0.5 (pre-breakfast, pre-dose), 0.5 (± 5 min), 1 (± 5 min), 2 
(± 10 min), 4 (± 15 min) (pre-lunch), 8 (± 15 min) (pre-dinner), and 12 (± 60 min) (post-
dinner) 
Day 2: 24 hours following dosing on Day 1 (± 60 min; pre-breakfast, pre-dose)  
Actual collection time points should be recorded and will be used for PK analysis. Best efforts to 
collect the samples at the planned time should be made.  
Protocol-specific instructions will be provided for the collection, handling, storage, and shipping 
of PK (plasma and RBC) samples. The date and actual time each sample is collected will be 
recorded. Date and time of the morning dose will also be recorded. The subject will only take the 
morning dose on the PK collection day.  
19.12.8. 
Timing of Meals and Study Drug 
The timing of the meals and study drug needs to be planned in relationship to the timing of the 
sample collection. The subjects will need to consume an in-clinic standardized meal (breakfast) 
which will be administered at Hour -0.5 and should be consumed within 30 minutes. Patients 
will need to take the morning dose in the clinic, 30 minutes after the start of their breakfast, at 
Hour 0.  
Lunch can be eaten after the 4-hour sample is collected. Dinner can be eaten after the 8-hour 
sample is collected, but before the 12-hour sample is collected. The subject will only take the 
morning dose on the PK collection day.  
19.12.9. 
Data Analysis 
Bioanalytical measurements will be performed to determine plasma concentration profiles of 
D2-LA, D2-ARA, H2-LA, and H2-ARA. PK parameters will include area under the 
concentration-time curve (AUC), maximum observed plasma concentration (Cmax), and time to 
reach maximum plasma concentration (Tmax). Full details of planned analyses will be provided in 
a separate PK analysis plan.  
 
 


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19.13. 
Optional Washout Sub-Study: Washout Blood Levels of Subjects 
Who Have Completed Treatment in RT001-006 
19.13.1. 
Study Objectives 
The objective of the study is to evaluate the washout blood levels of RT001 after treatment in 
RT001-006 is completed. 
19.13.2. 
Study Design  
Subjects who completed treatment in RT001-006 will be invited to participate in this sub-study. 
Subjects who complete RT001-006 are eligible to participate in any part of the PK sub-study.  
For example, a subject may enroll 4 months after completing the treatment period of RT001-006.  
For such a subject, only the Month 6 PK washout sample will be obtained and analyzed. 
Depending on the timing of entry into the sub-study, washout pharmacokinetic (PK) samples will 
be obtained at 7 days, 4, 12, and 24 weeks after the last dose to determine the trough 
concentration of deuterated linoleic acid (D2-LA), deuterated arachidonic acid (D2-ARA), 
nondeuterated linoleic acid (H2-LA) and nondeuterated arachidonic acid (H2-ARA) in plasma, 
and D2-LA, D2-ARA H2-LA, and H2-ARA in red blood cells.   
The samples may be obtained at a qualified laboratory local to the subject or at home by an 
approved phlebotomy service provider. 
19.13.3. 
Randomization  
There will be no randomization. All subjects who volunteer for this sub-study will be enrolled.  
19.13.4. 
Blinding 
Subjects and study personnel, including but not limited to investigators, study coordinators, 
nursing staff, clinical monitors, the Sponsor, and the Sponsor’s representatives, will remain 
blinded to the study treatment assignments (RT001 or placebo) in RT001-006. 
19.13.5. 
Inclusion Criteria 
1. Subjects who have successfully completed treatment in RT001-006 will be invited to 
participate in the washout PK sub-study.   
2. All participating subjects will be required to sign an informed consent prior to any blood 
draws.   
3. Subjects must be willing and able to provide the necessary repeated blood samples. 
19.13.6. 
Sample Size 
Subjects who have successfully completed the treatment period in the RT001-006 trial and meet 
all entry criteria will be invited to participate in this sub-study. 
19.13.7. 
Sample Collection  
Bioanalytical measurements will be performed to determine the concentration of D2-LA, D2-
ARA, H2-LA and H2-ARA in plasma and red blood cells. Blood samples will be collected for 


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plasma measurements and assessment in red blood cells at 7 days (± 1 day), at 4 weeks (± 7 
days), at 12 weeks (± 7 days) and at 24 weeks (± 7 days). Collection time points should be 
recorded and will be used for PK analysis. Best efforts to collect the samples at the planned time 
should be made. The sample may be obtained at a qualified laboratory local to the subject or at 
home by an approved phlebotomy service provider. 
Instructions will be provided for the collection, handling, storage, and shipping of PK (plasma 
and RBC) samples in a separate document. The date and actual time each sample is collected 
will be recorded.   
19.13.8. 
Data Analysis 
The PK of D2-LA, D2-ARA, H2-LA, and H2-ARA will be characterized in terms of minimum 
and maximum levels after washout. Full details of planned analyses will be provided in a 
separate PK analysis plan.