A Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of 24 Weeks Treatment With REN001 in Patients With Primary Mitochondrial Myopathy
Phase: PHASE2
Conditions: Primary Mitochondrial Myopathy
Sponsor: Reneo Pharma Ltd

CLINICAL STUDY PROTOCOL
Title: A Double-blind, Placebo-controlled Study to Evaluate the Efficacy 
and Safety of 24 Weeks Treatment With REN001 in Patients With Primary 
Mitochondrial Myopathy  (PMM)
NCTID: NCT04535609
Document Date: 24 June 2022

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CLINICAL STUDY PROTOCOL 
A DOUBLE-BLIND, PLACEBO-CONTROLLED, STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF 24 WEEKS TREATMENT WITH REN001 IN 
PATIENTS WITH PRIMARY MITOCHONDRIAL MYOPATHY (PMM) 
Sponsor: 
Reneo Pharma Ltd. 
Innovation House, Discovery Park 
Ramsgate Road  
Sandwich 
Kent CT13 9FF 
United Kingdom 
Clinical Research 
Organization: 
Orphan-Reach Ltd. 
The Old School, 
Newport Road, 
Woughton Park, 
Milton Keynes MK6 3AP 
United Kingdom 
Chief Investigator: 
 
  
Massachusetts General Hospital 
175 Cambridge St. 
Boston MA 02114 
Sponsor Protocol No.: 
REN001-201 
EudraCT No.: 
2020-002855-40 
IND No.: 
148211 
Study Drug Name: 
REN001 
Development Phase: 
Phase 2b 
Date of Protocol: 
24 June 2022 
Protocol version: 
Final V4.0 Global Amendment 3.0 
The study will be conducted according to the protocol and in compliance with Good 
Clinical Practice (GCP), with the Declaration of Helsinki, and with other applicable 
regulatory requirements. 
This document contains confidential information of Reneo Pharma Ltd. 
Do not copy or distribute without written permission from the Sponsor. 
CONFIDENTIAL 

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SIGNATURE PAGE
Declaration of Sponsor Chief Medical Officer
Title: A double-blind, placebo-controlled, study to evaluate the efficacy and safety of 24 
weeks treatment with REN001 in patients with primary mitochondrial myopathy 
(PMM)
This study protocol was subjected to critical review. The information it contains is consistent 
with current knowledge of the risks and benefits of the investigational product, as well as with 
the moral, ethical and scientific principles governing clinical research as set out in the 
Declaration of Helsinki, as amended in 2013 and the guidelines on Good Clinical Practice.
_____
As time stamp____
Date
Institution: Reneo Pharma Ltd.
CC

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PROTOCOL SYNOPSIS 
Title: 
A DOUBLE-BLIND, PLACEBO-CONTROLLED, 
STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF 24 WEEKS TREATMENT WITH REN001 
IN PATIENTS WITH PRIMARY MITOCHONDRIAL 
MYOPATHY (PMM) 
Sponsor Study No: 
REN001-201 
Compound: 
REN001 
Phase: 
Phase 2b 
Sponsor: 
Reneo Pharma Ltd. 
Chief Investigator: 
 
Design: 
This is a randomized, double-blind, placebo-controlled, 
parallel group, multi-center, study designed to investigate the 
efficacy and safety of REN001 administered once daily over 
a 24-week period to patients with PMM.  
Subjects will be randomized (allocation 1:1) to the following 
two treatment groups: 
x REN001 100 mg/day 
x Placebo 
An independent Patient Screening Oversight Committee 
(PSOC) will review screening criteria to ensure subjects 
enrolled into the study have the correct PMM diagnosis prior 
to randomization. The structure, function and operation of the 
PSOC will be detailed in the REN001-201 PSOC Charter. 
An independently chaired Safety Review Committee (SRC) 
will review safety data at specified intervals for the duration 
of the study. The structure, function and operation of the SRC 
will be detailed in the REN001-201 SRC Charter. 
An exploratory sub-study (REN001-201-DXA) to assess 
change in the bone mineral density using Dual Energy X-ray 
Absorptiometry (DXA) scans after 24 weeks of treatment 
with REN001 is open to subjects at sites where regulatory and 
ethical approval is in place.  
Objectives: 
Primary: 
To evaluate the efficacy of REN001 in subjects with PMM 
treated for 24 weeks, assessed by the effect on exercise 
endurance. 
Secondary: 
To evaluate the efficacy of REN001 in subjects with PMM 
treated for 24 weeks, assessed by the effect on fatigue. 
Safety: 

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To evaluate the safety and tolerability of REN001 in subjects 
with PMM during 24 weeks of treatment. 
Pharmacokinetic (PK): 
To investigate the pharmacokinetics of REN001 in subjects 
with PMM. 
Exploratory: 
To evaluate the efficacy of REN001 in subjects with PMM 
treated for 24 weeks, assessed by the effect on functional 
capacity. 
To evaluate the effect of REN001 on quality of life (QoL) of 
subjects with PMM after treatment for 24 weeks. 
Endpoints 
Primary: 
Change from Baseline at Week 24 in distance walked during 
the 12-Minute Walk Test (12MWT). 
Secondary: 
Change from Baseline at Week 24 in the Modified Fatigue 
Impact Scale (MFIS) Physical sub-scale score. 
Patient Global Impression of Change (PGIC) score (muscle 
symptoms) at the end of treatment. 
Safety: 
Number and severity of adverse events (AE). 
Absolute values, changes from Baseline, and incidence of 
potentially clinically significant changes in: 
x Laboratory safety tests 
x Electrocardiograms (ECG) 
x Supine vital signs 
x Eye assessments 
Pharmacokinetic (PK): 
REN001 plasma concentrations. 
Exploratory: 
Change from Baseline at Week 12 and Week 24 in: 
x Number of sit to stands in the 30 second sit to stand 
(30STS) test 
x Step count from pedometer 
x Patient Global Impression of Severity (PGIS) score – 
muscle symptoms 
x Patient Global Impression of Severity (PGIS) score – 
fatigue symptoms 
x Patient Reported Outcomes Measurement Informal 
System (PROMIS) Short Form – Functional 
Assessment of Chronic Illness Therapy (FACIT) 
Fatigue 13a  

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x 36-Item Short Form Health Survey (SF-36) domain
scores 
x Modified Fatigue Impact Scale (MFIS) Total, 
Cognitive and Psychosocial sub-scale scores 
x Brief Pain Inventory (BPI) pain severity and pain 
interference scores 
x Work Productivity and Activity Impairment 
Questionnaire: Specific Health Problem (WPAI:SHP) 
scores 
PGIC score (fatigue symptoms) at the end of treatment. 
Number of Subjects: 
Approximately 200 subjects will be randomized into the 
study. 
Treatment: 
Investigational Medicinal Product (IMP) and Mode of 
Administration: 
IMP and matched placebo will be presented as Swedish 
orange, hard gelatin, size 0 capsules. Subjects will be required 
to take 2 capsules once each day with food. The dosage 
strength of REN001 capsules is 50 mg. 
Doses and Randomization: 
x REN001 100 mg orally once daily 
x Placebo orally once daily 
The randomization will be stratified by both mutational 
genotype (m.3243A>G or other mitochondrial DNA defects) 
and the screening 12-minute walk distance (12MWD) (≤ 500 
meters or > 500 meters).  
Duration of Treatment: 
24 weeks 
Eligibility Criteria: 
Inclusion: 
Subjects must meet all of the following inclusion criteria to 
be eligible for inclusion in the study: 
1. Subjects aged 18 years or older with PMM as defined by
the International Workshop: Outcome measures and
clinical trial readiness in primary mitochondrial
myopathies in children and adults (Mancuso et al 2017)
(see Appendix 1).
2. A confirmed PMM diagnosis due to a known pathogenic
gene mutation or deletion of the mitochondrial genome.
The Sponsor may authorize local genetic testing at
Screening, if required, but results must be available prior
to randomization of the subject (see Sections 6.1 and
7.1.24 for details).
3. Documented PMM primarily characterized by exercise
intolerance or active muscle pain.

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4. Subjects must be ambulatory and able to perform the 
12MWT independently (walking aids are allowed). 
5. Distance walked of ≤1000 meters at Screening in the 
12MWT (must be obtained at least 4 weeks before 
randomization). 
6. Have no changes to any therapeutic exercise regimen 
within 30 days prior to Day 1 and be willing to remain on 
the same therapeutic exercise regimen for the duration of 
the study. 
7. Be willing and able to swallow gelatin capsules. 
8. Females should be either of non-child-bearing potential or 
must agree to use highly effective methods of 
contraception from Screening through to 30 days after last 
dose in the study. Where females are using hormonal 
contraception therapy, an additional effective non-
hormonal method of contraception is advised. Males with 
partners who are women of child-bearing potential 
(WOCBP) must also use contraception (See Section 5.10 
for details). 
9. Concomitant medications (including supplements) 
intended for the treatment of PMM or other co-
morbidities must be stable for at least 1 month prior to 
randomization and throughout participation in the study.  
10. For subjects under 25 years old only: confirmation of 
bone growth plate closure by wrist radiograph. 
11. Evidence of a personally signed and dated informed 
consent document indicating that the subject has been 
informed of all pertinent aspects of the study.  
Exclusion: 
Subjects presenting with any of the following will not be 
included in the study: 
1. Participation in a prior REN001 (previously known as 
HPP-593) study. 
2. Currently taking or anticipated to need a peroxisome 
proliferator-activated receptor (PPAR) agonist during the 
study. 
3. Bone deformities or motor abnormalities other than those 
related to mitochondrial myopathy that may interfere with 
the outcome measures. 
4. Treatment with an investigational drug within 3 months or 
5 drug half-lives, whichever is longer, prior to Day 1. 
5. Anticipated to need a prescription and/or non-prescription 
drug that might interfere with the study endpoints (See 
Table 1). 

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6. Currently taking drugs with a narrow therapeutic index
and Breast Cancer Resistance Protein (BCRP) mediated
absorption, distribution, metabolism and excretion
(ADME) e.g., aliskiren, ambrisentan, colchicine, digoxin,
everolimus, imatinib, lapatinib, maraviroc, nilotinib,
posaconazole, ranolazine, saxagliptin, sirolimus,
sitagliptin, talinolol, tolvaptan, topotecan, methotrexate,
mitoxantrone, irinotecan, rosuvastatin, and sulfasalazine
(See Table 1).
7. Clinically significant kidney disease or impairment, with
an estimated Glomerular Filtration Rate (eGFR) less than
60 ml/min/1.73m2 using the Chronic Kidney Disease
Epidemiology Collaboration (CKD-EPI) creatinine
equation at Screening.
8. Clinically significant liver disease or impairment, with
aspartate aminotransferase (AST) or alanine
aminotransferase (ALT) >2.5 x Upper limit of normal
(ULN), or Total bilirubin >1.6 x ULN or >ULN with
other signs and symptoms of hepatotoxicity at Screening.
(Subjects with an isolated elevated bilirubin (e.g. < 2 x
ULN) may be included after discussion with the Medical
Monitor if the cause is due to a benign hereditary
disorder of metabolism such as Gilbert’s syndrome.)
9. Uncontrolled diabetes and/or a Screening glycosylated
hemoglobin (HbA1c) of ≥11%.
10. Uncontrolled epilepsy.
11. Evidence of significant concomitant clinical disease that
may need a change in management during the study or
could interfere with the conduct or safety of this study.
(Stable well-controlled chronic conditions such
hypercholesterolemia, gastroesophageal reflux, or
depression under control with medication (other than
tricyclic antidepressants), are acceptable provided the
symptoms and medications would not be predicted to
compromise safety or interfere with the tests and
interpretations of this study.)
12. A history of cancer. A history of in situ basal cell
carcinoma in the skin is allowed.
13. Have been hospitalized within the 3 months prior to
Screening for any major medical condition (as deemed by
the Investigator).
14. Clinically significant cardiac disease and/or clinically
significant ECG abnormalities including a screening
QTcF of ≥ 450 msec, 2nd degree heart block, symptomatic
tachyarrhythmia or unstable arrythmia that in the opinion
of the Investigator should exclude the subject from

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completing the study exercise tests (i.e. 12MWT and 
30STS tests). (Subjects with right bundle branch block, 
left fascicular block and long PR interval which are 
common in PMM may be enrolled if the Investigator 
considers that the condition would not compromise safety 
or interfere with the tests and interpretations of this 
study.) 
15. Any condition possibly reducing drug absorption (e.g.,
gastrectomy or increased motility).
16. Evidence of hospitalization for rhabdomyolysis within the
year prior to enrolment.
17. Positive hepatitis B surface antigen (HBsAg) and hepatitis
B core antibody (HBcAb) at Screening, or positive for
hepatitis C or human immunodeficiency virus (HIV) at
Screening.
18. Pregnant or nursing females.
19. History of sensitivity to PPAR agonists.
20. Donation or intent to donate blood, or blood components
during the study or within one month after completion of
the study.
21. A history of drug dependency. Use of opiates/cannabis for
medical reasons is acceptable with prescription evidence
or at the Investigators discretion.
22. A history of alcohol dependency.
23. Significant impairment due to central or peripheral
nervous system involvement that would interfere with the
exercise tests.
24. Significant weakness not caused by the underlying
primary muscle disease such as post stroke or neurogenic
weakness.
25. Have had an organ transplant.
26. Are not eligible or have a contraindication for cataract
surgery.
27. A history of osteoporosis as evidenced by non-traumatic
(stress) fractures or a prior T-score of -2.5 or worse which
has not been adequately addressed.
28. Inability to comprehend or unwilling to follow the study
requirements including restrictions on treatments,
attendance at the study center, completion of
questionnaires and participation in laboratory testing as
called for by the protocol.
29. Any other severe acute or chronic medical or psychiatric
condition or laboratory abnormality that may increase the
risk associated with study participation or investigational

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product administration or may interfere with the 
interpretation of study results and, in the judgment of the 
Investigator, and in discussion with the Medical Monitor, 
would make the subject inappropriate for entry into this 
study. 
Study Visits: 
There will be a total of 8 visits for each subject. 
Each subject who provides informed consent will complete 
screening activities to confirm eligibility to enter the study. 
The Screening Visit (Visit 1) must be completed no more 
than 8 weeks prior to the start of dosing and will take place at 
the Study Center. There must be a minimum of 4 weeks 
between the Screening 12MWT and the Baseline 12MWT. If 
laboratory tests are outside of the normal range at initial 
screening, tests may be repeated once (this can be done as a 
home nurse visit). Where possible subjects should be pre-
screened to assess the requirement for genotyping. The 
Screening Visit may be accomplished over more than 1 day. 
Subjects who are receiving prohibited medications must 
suspend the medications if this can safely and appropriately 
be done and have sufficient washout during the screening 
period (See Table 1) prior to randomization. Re-screening of 
subjects is allowed only once and requires prior approval by 
the Sponsor, for instance, if the wash-out of prior medications 
or genotyping is longer than 6-8 weeks. Re-screened subjects 
will not be required to have either the eye exam or DXA scan 
(REN001-201 DXA sub-study subjects) repeated within 6 
months of the original assessments. Where a Study Center 
requires it, subjects may be asked to have a negative COVID-
19 test prior to undertaking scheduled visits at the Study 
Center. 
The PSOC will assess if subjects have the correct diagnosis of 
PMM for the study prior to randomization. 
Subjects who successfully complete screening, and are 
approved by the PSOC, will undergo a Baseline Visit (Visit 
2) which may be completed over two days if required. Once 
the Baseline assessments have been completed subjects will 
be randomized 1:1 to receive oral REN001, 100 mg or 
placebo once daily with food for 24 weeks.  
In centers where the Regulatory Authority and the Ethics 
Committee/Institutional Review Board and Institution allows 
Visit 3 (Week 2), Visit 4 (Week 4), Visit 6 (Week 18) and 
Visit 8 (Follow Up) may be conducted either in the Study 
Center or at the subject’s home using a home nursing service.  
Visit 5 (Week 12) and Visit 7 (Week 24) will be completed in 
the Study Center and which may be completed over two days 
if required. A Follow Up Visit (Visit 8) will be performed, 
which can be carried out either in the Study Center or at the 

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subject’s home. Visit 8 will be completed 21-28 days after the 
last dose of study medication. This visit will not be required if 
a subject chooses to enter the REN001 open label extension 
study (REN001-202) at their Week 24 visit; applicable only 
for countries where the open label extension study is being 
conducted. 
A qualified nurse will carry out all the required study 
assessments for Home Visits. Additional Home Visits instead 
of Study Center visits, or delays to Visits beyond the stated 
visit windows, may be allowed in some circumstances e.g. 
global pandemic, with the Sponsor’s prior approval. 
A specialist concierge service will be available to subjects to 
arrange hotel accommodation and transport to and from Study 
Center visits and reimburse any subject study expenses. 
The planned maximum study duration for each subject in the 
study will be 36 weeks (assuming 8 weeks screening, 24 
weeks treatment and 4 weeks follow up). 
Efficacy, safety, pharmacokinetic and exploratory 
assessments are detailed in the study Schedule of Activities 
(Table 2).  
Statistical Methods: 
On the basis of preliminary results of an open-label pilot 
study (REN001-101) involving 17 subjects with PMM who 
received REN001 100 mg/day for 12 weeks, a mean 
improvement of 94 meters was observed in the 12MWT. 
A sample size of 186 subjects (93 per treatment group) 
provides 90% power, with a two-sided significance level of 
5%, of obtaining a statistically significant difference between 
two treatment groups in distance walked during the 12MWT. 
This assumes a treatment effect (difference to placebo in 
mean change from baseline) size of 60 meters. The standard 
deviation for the changes from baseline observed in Study 
REN001-101 was approximately 100 meters. A higher 
standard deviation, 125 meters, has been assumed for this 
study due to the longer assessment period (24 weeks instead 
of 12 weeks) and the increased number of centers 
participating in the study. Allowing for a reduction in power 
due to subject withdrawals a total of approximately 200 
subjects will be randomized. 
To control the Type 1 error rate a fixed sequence testing 
procedure will be adopted. The order of testing will be: 
1. Change from Baseline at Week 24 in distance walked 
during the 12MWT  
2. Change from Baseline at Week 24 in the MFIS 
Physical subscale score   

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3. PGIC score (muscle symptoms) at the end of 
treatment 
The primary population for efficacy will be the full analysis 
set (FAS), defined as all subjects randomized, who receive at 
least one dose of study treatment. Subjects in this population 
will be analyzed by assigned treatment. 
The change from baseline in distance walked during the 
12MWT will be analyzed using a mixed effects model for 
repeated measures (MMRM). The model will include fixed 
terms for treatment, visit and the treatment by visit 
interaction. The model will also include the stratification 
mutation factor and continuous baseline distance walked 
during the 12MWT as covariates. An unstructured covariance 
structure will be used for the repeated visits within a subject. 
The treatment comparison (REN001 100 mg vs placebo) for 
the change from baseline at Week 24 will be estimated. The 
estimate, standard error, 95% confidence intervals and 
associated p-values will be presented.   
Treatment comparisons will also be made at Week 12. 
The primary endpoint will also be analyzed for a per protocol 
population; defined as those subjects in the FAS population 
who have not violated inclusion or exclusion criteria and/or 
deviated from the protocol, in a way that could influence their 
efficacy assessment. 
The MFIS Physical subscale score changes from baseline will 
be analyzed using a MMRM. The model will include fixed 
terms for treatment, visit and the treatment by visit 
interaction. The model will also include the stratification 
mutation factor, continuous baseline MFIS Physical subscale 
score and continuous baseline distance walked during the 
12MWT as covariates. An unstructured covariance structure 
will be used. The treatment comparison for the change from 
baseline at each visit will be estimated. The estimates, 
standard errors, 95% confidence intervals and associated p-
values will be presented for each visit. The primary 
comparison is at Week 24. 
The PGIC (muscle symptom) data will be converted to a 
numerical scale from 3 (very much improved) to -3 (very 
much worse); hence a value of 0 would signify no change. 
This score will then be analyzed using analysis of covariance 
(ANCOVA), using a fixed term for treatment and the 
mutation stratification factor and continuous baseline distance 
walked during the 12MWT as covariates. The treatment 
comparison (REN001 vs placebo) will be estimated, along 
with its standard error, 95% confidence interval and 
associated p-value. 

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Safety analyses will be performed on the Safety Population, 
defined as all subjects who are randomized and receive at 
least one dose of study drug. Subjects will be analyzed by the 
treatment received. 
Treatment-emergent adverse events (TEAEs) will be 
summarized by treatment group and by System Organ Class 
(SOC) and Preferred Term, in accordance with the MedDRA 
coding dictionary. The number of subjects reporting each AE 
preferred term will be tabulated for all TEAEs and separately 
for those considered as at least possibly related to study 
treatment by the Investigator. Number of subjects reporting 
serious adverse events (SAEs) and adverse events of special 
interest (AESI) will also be tabulated. 
Observed values and changes from baseline in clinical 
laboratory tests, vital signs, ECG data and eye examination 
data will be summarized using descriptive statistics by 
treatment group and visit. 
Plasma concentrations of REN001 will be summarized over 
time using descriptive statistics for Day 1, Week 12 and 
Week 24. These data will also be included in a population PK 
analysis. 

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LIST OF STUDY PERSONNEL 
Sponsor 
  
Reneo Pharma Ltd. 
Innovation House, Discovery Park, 
Ramsgate Road, Sandwich, 
Kent CT13 9FF 
United Kingdom 
 
 
 
 
 
Reneo Pharma Ltd. 
Innovation House, Discovery Park, 
Ramsgate Road, Sandwich, 
Kent CT13 9FF 
United Kingdom 
 
 
 
 
Chief Investigator 
 
  
Massachusetts General Hospital 
175 Cambridge St. 
Boston MA 02114 
 
 
 
Contract Research 
Organization 
 
Orphan Reach Ltd. 
The Old School, 
Newport Road, 
Woughton Park, 
Milton Keynes MK6 3AP 
United Kingdom 
 
Telephone: +44 (0)1908 251 480 
 
Medical Monitor 
 
Email: medicalmonitor201@orphan-reach.com 
 
Serious Adverse Event 
Reporting 
Bionical Emas 
Suite 209, Spirella Building 
Bridge Road, 
Letchworth Garden City, 
Hertfordshire 
SG6 4ET 
United Kingdom 
C

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Email: Drug.safety@bionical-emas.com 
Fax: +44 (0) 1462 600 456 
US Fax: +1 206 260 7410  
 
Statistician  
 
  
ParamStat Limited 
 
 
 

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TABLE OF CONTENTS 
LIST OF STUDY PERSONNEL .......................................................................................... 13 
1 
INTRODUCTION.......................................................................................................... 22 
1.1 Indication ............................................................................................................... 22 
1.2 Background ............................................................................................................ 22 
1.3 Study Rationale ...................................................................................................... 22 
1.4 Risk-Benefit Assessment ....................................................................................... 23 
1.5 Dose Selection Rationale ....................................................................................... 25 
2 
STUDY OBJECTIVES .................................................................................................. 26 
2.1 Primary Objective ................................................................................................. 26 
2.2 Secondary Objectives ............................................................................................ 26 
2.3 Safety Objectives ................................................................................................... 26 
2.4 Pharmacokinetic Objectives ................................................................................. 26 
2.5 Exploratory Objectives ......................................................................................... 26 
3 
OVERALL DESIGN AND PLAN OF THE STUDY ................................................. 27 
3.1 Overview ................................................................................................................. 27 
3.2 Endpoints ............................................................................................................... 29 
3.2.1 Primary Endpoint ....................................................................................... 29 
3.2.2 Secondary Endpoints ................................................................................. 29 
3.2.3 Safety Endpoints ........................................................................................ 29 
3.2.4 Pharmacokinetic Endpoints ....................................................................... 29 
3.2.5 Exploratory Endpoints ............................................................................... 29 
3.3 Justification of the Study Design .......................................................................... 29 
3.4 Termination or Suspension of Study ................................................................... 31 
3.5 Termination or Suspension of Investigational Sites ........................................... 31 
3.6 Conditions for Individual Subject Discontinuation of Study Drug or 
Withdrawal from the Study.................................................................................. 31 
3.7 Strategy for Potential Withdrawal due to Laboratory Test Abnormalities .... 33 
3.7.1 Safety Monitoring for Serum Creatine Phosphokinase ............................. 33 
3.7.2 Safety Monitoring For Liver toxicity: Management and Stopping Rules . 34 
3.7.3 Safety Monitoring For Kidney toxicity: Management and Stopping 
Rules .......................................................................................................... 36 
3.8 Replacement of Subjects ....................................................................................... 36 
3.9 Temporary Discontinuations ................................................................................ 36 
3.10 Review of Screening Eligibility Data ................................................................... 36 
3.11 Review of Safety Data ........................................................................................... 36 
4 
STUDY POPULATION ................................................................................................ 38 
4.1 Inclusion Criteria .................................................................................................. 38 
4.2 Exclusion Criteria .................................................................................................. 38 
4.3 Planned Sample Size and Number of Study Centers ......................................... 40 
5 
STUDY DRUG ............................................................................................................... 41 
5.1 Study Drug Identity ............................................................................................... 41 

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5.2 Allocation to Treatment ........................................................................................ 41 
5.3 Maintaining the Blind ........................................................................................... 41 
5.4 Breaking the Blind ................................................................................................. 41 
5.5 Administration ....................................................................................................... 42 
5.6 Release, Labelling and Storage ............................................................................ 42 
5.7 Excessive Pharmacological Effects ...................................................................... 42 
5.8 Drug Accountability .............................................................................................. 42 
5.9 Compliance ............................................................................................................. 43 
5.10 Contraceptive Requirements ................................................................................ 43 
5.11 Concomitant Medications ..................................................................................... 44 
6 
STUDY CONDUCT ....................................................................................................... 45 
6.1 Screening: Visit 1 ................................................................................................... 45 
6.2 Baseline (Day 1): Visit 2 ........................................................................................ 46 
6.3 Weeks 2 (Day 14): Visit 3 ...................................................................................... 48 
6.4 Weeks 4 and 18 (Days 28 and 126): Visits 4 and 6 ............................................. 48 
6.5 Weeks 8, 16 and 20 (Days 56, 112 and 140) ......................................................... 49 
6.6 Weeks 12 and 24 (Days 84 and 168): Visits 5 and 7 ........................................... 49 
6.7 Follow Up Visit ...................................................................................................... 50 
6.8 Early Termination Visit ........................................................................................ 50 
6.9 Subject Continuation In Study Off IMP ............................................................. 51 
7 
PARAMETERS AND METHODS OF ASSESSMENT ............................................ 56 
7.1 Safety Parameters .................................................................................................. 56 
7.1.1 Adverse Events .......................................................................................... 56 
7.1.1.1 Definitions ............................................................................................. 56 
7.1.1.2 Laboratory values and ECG findings .................................................. 56 
7.1.1.3 Pre-existing conditions ......................................................................... 56 
7.1.1.4 Worsening of PTEs or AEs .................................................................. 57 
7.1.1.5 Adverse Events of Special Interest ....................................................... 57 
7.1.1.6 Assessment of Adverse Event ............................................................... 57 
7.1.1.7 Relationship to Study Procedures ........................................................ 58 
7.1.1.8 Collection and Reporting of AEs ......................................................... 59 
7.1.1.9 Reporting Serious Adverse Events ....................................................... 59 
7.1.1.10 Reporting Pregnancies ......................................................................... 60 
7.1.1.11 Follow-up of Adverse Events ............................................................... 61 
7.1.1.12 Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities ............................................................................................. 61 
7.1.2 Clinical Laboratory Safety Tests ............................................................... 61 
7.1.3 Blood Volume ............................................................................................ 63 
7.1.4 Physical Examination................................................................................. 63 
7.1.5 Height and Weight and Body Mass Index ................................................. 63 
7.1.6 Vital Signs Measurements ......................................................................... 64 
7.1.7 Body Temperature ..................................................................................... 64 
7.1.8 Electrocardiogram Recording .................................................................... 64 
7.1.9 Eye Examination ........................................................................................ 64 
7.1.10 12-Minute Walk Test ................................................................................. 65 
7.1.11 36 Item Health Survey V2.0® (SF-36) ....................................................... 65 

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7.1.12 Modified Fatigue Impact Scale (MFIS) ..................................................... 65 
7.1.13 Brief Pain Inventory (BPI) ......................................................................... 66 
7.1.14 Patient Global Impression of Severity (PGIS) – Muscle Symptoms ......... 66 
7.1.15 Patient Global Impression of Severity (PGIS) – Fatigue Symptoms ......... 66 
7.1.16 Patient Global Impression of Change (PGIC) – Muscle Symptoms .......... 66 
7.1.17 Patient Global Impression of Change (PGIC) – Fatigue Symptoms ......... 67 
7.1.18 Work Productivity and Activity Impairment Questionnaire: Specific 
Health Problem (WPAI:SHP) .................................................................... 67 
7.1.19 PROMIS Short Form v1.0 – Fatigue 13a (FACIT-Fatigue) ...................... 67 
7.1.20 30 Second Sit-To-Stand Test ..................................................................... 68 
7.1.21 Pedometer Step Counts and eDiary ........................................................... 68 
7.1.22 PMM Phenotypic Description.................................................................... 68 
7.1.23 Pharmacokinetic Blood Samples ............................................................... 69 
7.1.24 Genotyping Blood Samples ....................................................................... 70 
8 
STATISTICAL METHODS ......................................................................................... 71 
8.1 Study Subjects ........................................................................................................ 71 
8.1.1 Disposition of Subjects .............................................................................. 71 
8.1.2 Protocol Deviations .................................................................................... 71 
8.1.3 Analysis Populations .................................................................................. 71 
8.2 General Considerations ........................................................................................ 72 
8.2.1 Statistical Hypotheses ................................................................................ 72 
8.2.2 Determination of Sample Size ................................................................... 72 
8.2.3 Control of the Type 1 Error Rate ............................................................... 72 
8.2.4 Data Summaries ......................................................................................... 72 
8.3 Demographics, Baseline Characteristics and Concomitant Medications ......... 72 
8.4 Treatment Compliance ......................................................................................... 73 
8.5 Efficacy Analyses ................................................................................................... 73 
8.5.1 Primary Endpoint ....................................................................................... 73 
8.5.2 Secondary Endpoints ................................................................................. 74 
8.5.3 Exploratory Endpoints ............................................................................... 75 
8.6 Safety Analyses ...................................................................................................... 75 
8.7 Pharmacokinetic Endpoints ................................................................................. 75 
8.8 Interim Analyses .................................................................................................... 75 
9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS .................................... 76 
9.1 Data Quality Assurance ........................................................................................ 76 
9.2 Electronic Case Report Forms (eCRF) and Source Documentation ................ 76 
9.3 Access to Source Data ........................................................................................... 76 
9.4 Data Processing ...................................................................................................... 76 
9.5 Archiving Study Records ...................................................................................... 77 
9.6 Good Clinical Practice .......................................................................................... 77 
9.7 Confidentiality ....................................................................................................... 77 
9.8 Informed Consent .................................................................................................. 77 
9.9 Protocol Approval and Amendment .................................................................... 78 
9.10 Duration of the Study ............................................................................................ 78 
9.11 Liability and Insurance ......................................................................................... 78 
9.12 Publication Policy .................................................................................................. 78 

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10 REFERENCES ............................................................................................................... 80 
11 APPENDICES ................................................................................................................ 82 
Appendix 1: 
International Workshop ..................................................................... 82 
Appendix 2: 
Example Modified Fatigue Impact Score (MFIS) ............................ 84 
Appendix 3: 
Example Brief Pain Inventory (Short Form) .................................... 86 
Appendix 4: 
Example Work Productivity and Activity Impairment ................... 88 
Appendix 5: 
Example PROMIS Short Form - Fatigue 13a (FACIT-Fatigue) .... 90 
Appendix 6: 
Amendment 3 ....................................................................................... 91 
 
 
LIST OF TABLES 
Table 1: 
Prohibited Medications .............................................................................44 
Table 2: 
Schedule of Activities ................................................................................53 
Table 3: 
Safety Laboratory Parameters ................................................................62 
Table 4: 
Approximate Blood Volume Required for Study ...................................63 
 
 
 
LIST OF FIGURES 
Figure 1: 
Study Design ..............................................................................................28 
Figure 2: 
Sources of Energy During Exercise .........................................................30 
Figure 3: 
Process For Subject Discontinuation Of IMP Or Withdrawal From 
The Study ...................................................................................................33 
Figure 4: 
CK Algorithm ............................................................................................34 
 
 
 

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List of Abbreviations and Definitions of Terms 
ADME 
Absorption, distribution, metabolism and excretion 
ADR 
Adverse Drug Reaction 
AE 
Adverse event 
AESI 
Adverse event of Special Interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase  
ATP 
Adenosine triphosphate 
BCRP 
Breast Cancer Resistance Protein 
BID 
Bis in die – twice daily 
BMI 
Body mass index 
BP 
Blood Pressure 
BPI 
Brief Pain Inventory 
BSAP 
Bone specific alkaline phosphatase 
CA 
Competent Authorities 
CFR 
Code of Federal Regulations 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CHMP 
Committee for Human Medicinal Products 
CoQ10 
Coenzyme Q10 
CK 
Creatine phosphokinase 
CTX 
Carboxy-terminal collagen crosslinks 
DNA 
Deoxyribonucleic acid 
DSUR 
Drug Safety Update Report 
DXA 
Dual-energy X-ray absorptiometery 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
eGFR 
Estimated Glomerular Filtration Rate 
EIA 
Enzyme immunoassay 
EMA 
European Medicines Agency 
ET 
Early Termination 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FAO 
Fatty Acid Oxidation 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
FU 
Follow Up 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GMP 
Good Manufacturing Practice 
HbA1c 
Glycosylated hemoglobin 
HBcAb 
Hepatitis B core Antibody 
HBsAg 
Hepatitis B surface Antigen 
hCG 
Human Chorionic Gonadotropin 
HDL 
High Density Lipoprotein 
HDPE 
High Density Polyethylene 
HIV 
Human Immunodeficiency Virus 
Hr 
Hour 

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ICH 
International Council on Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IU/L 
International Units per Liter 
IWRS 
Integrated Web-based Response System 
kg 
Kilogram 
LDL 
Low Density Lipoprotein 
LFT 
Liver Function Tests 
LoQ 
Level of Quantification 
MAR 
Missing at random 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFIS 
Modified Fatigue Impact Scale 
mg 
milligrams 
mL 
milliliter 
mmHg 
millimeters of mercury 
MMRM 
mixed effect model for repeated measures 
msec 
millisecond 
mtDNA 
mitochondrial Deoxyribonucleic Acid 
nDNA 
nuclear Deoxyribonucleic Acid 
NASH 
Non-alcoholic steatohepatitis 
NMDAS 
Newcastle Mitochondrial Disease Adult Scale 
NTX 
N-terminal telopeptide 
OXPHOS 
Oxidative phosphorylation 
P-Cr 
Phospho-creatine 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic 
PMM 
Primary mitochondrial myopathy 
PP 
Per protocol 
PRO 
Patient Reported Outcome 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PPAR 
peroxisome proliferator-activated receptor 
PSOC 
Patient Screening Oversight Committee 
PT 
Prothrombin time 
PTE 
Pre-treatment events 
PTH 
Parathyroid hormone 
PV 
Pharmacovigilance 
QD 
Quaque die - once daily 
QoL 
Quality of Life 
QT 
The interval between the start of the Q wave and the end of the 
T wave 
QTcF 
Heart rate corrected QT interval using Fridericia’s formula 
RR 
The interval between the successive R waves 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 

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SF-36 
36 Item Health Survey 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
ULN 
Upper Limit of Normal 
WPAI:SHP 
Work Productivity and Activity Impairment Questionnaire: 
Specific Health Problem 
WOCBP 
Women of childbearing potential 
6MWT 
6-minute walk test 
12MWD 
12-minute walk distance 
12MWT 
12-minute walk test 
30STS 
30 Second Sit to Stand 
 

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1 
INTRODUCTION 
1.1 
Indication 
Primary mitochondrial myopathies are genetic disorders associated with pathogenic variants 
in the mitochondrial or nuclear deoxyribonucleic acid (DNA) that primarily lead to a) 
oxidative phosphorylation (OXPHOS) dysfunction or other disturbances of mitochondrial 
structure and function and b) predominantly, but not exclusively, affect skeletal muscle, with 
motor function deficits affecting endurance not better explained by other systemic or 
neurological conditions (Parikh et al 2014; Mancuso et al 2017). In patients with 
mitochondrial DNA (mtDNA) mutations, inheritance and clinical presentation are further 
complicated by the presence of multiple mtDNA genomes in an individual cell leading to a 
mixture of mutated and wild-type genomes (heteroplasmy) in the same cell or tissue.  
Onset of PMM can occur at any age, although typically the more severe phenotypes present 
earlier in life, and milder phenotypes present later in life. One of the challenges of 
mitochondrial diseases is the marked clinical variation seen in patients, which can delay 
diagnosis. Because mitochondria are the main source of energy production in mammalian 
cells, clinical features typically involve the tissues with the highest energy requirements. 
Furthermore, the presence of mtDNA in all human tissues means that dysfunction occurs in 
multiple organ systems. The most commonly affected organ systems are the nervous, 
muscular, cardiac and endocrine systems. Individuals with PMM often present with a 
constellation of clinical features that may be compatible with a discrete clinical syndrome. 
However, categorizing patients into syndromes is of limited value, as the majority of patients 
do not fit into discrete categories (Gorman et al, 2016). PMMs are usually progressive 
conditions which produce significant disability and, in some instances, premature death. 
The molecular genetic investigation of suspected mitochondrial disease can be complex, and 
has to be guided by previous clinical, histochemical and biochemical findings. Definitive 
diagnostic confirmation now relies on genetic testing and the identification of a pathogenic 
mutation in a recognized mitochondrial gene.  
The management of patients with mitochondrial diseases is focused on strategies to reduce 
morbidity and mortality and early treatment of organ-specific complications. Several agents 
(mostly nutritional supplements) have been investigated in double-blind, placebo-controlled 
studies. These include carnitine, creatine, Coenzyme Q10 (CoQ10), cysteine, dichloroacetate, 
dimethylglycine, and the combination of creatine and lipoic acid. No agent or combination 
regimen has demonstrated efficacy in clinical disease endpoints (Pfeffer & Chinnery, 2013). 
PMMs represent an area of significant unmet medical need; there is currently no available 
disease -modifying therapy for patients with PMM.  
1.2 
Background  
Full details of the REN001 chemistry, non-clinical and clinical data can be found in the 
current Investigator’s Brochure.  
1.3 
Study Rationale 
There is a strong rationale for the use of REN001, a selective PPARδ agonist, in patients with 
PMM. The PPARδ receptor is a nuclear receptor primarily found in skeletal muscle. Patients 
with PMM caused by genetic mutations in the mitochondrial genome have impaired oxidative 
phosphorylation. Selective PPAR agonists may ameliorate the cellular energy deficit in 
patients with these mutations by: 
x Increasing fatty acid oxidation (FAO) and OXPHOS activity resulting in enhanced 
mitochondrial adenosine triphosphate (ATP) generating capacity;  

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x Increasing the proportion of wild-type mitochondria. Although mitochondrial disease 
induced mitochondrial proliferation may favor mutated mitochondria, 
pharmacological upregulation of mitochondrial biosynthesis increases the number of 
both mutated and wild-type mitochondria, which allows wild-type mitochondria to 
compensate for mutant mitochondria; and, 
x Increasing mitochondrial biogenesis and thereby increasing residual OXPHOS 
activity, which would enhance the cellular ATP synthesis capacity. 
1.4 
Risk-Benefit Assessment 
Benefits 
In the open-label Phase 1b study (REN001-101) in subjects with PMM, oral REN001 dosed 
at 100 mg per day was safe and well tolerated for 12 weeks (Part A) and up to an additional 
24 weeks in the subjects who continued into an extension part of the study (Part B). 
Following 12 weeks of dosing, the majority of patients with PMM experienced improvement 
in the outcome measures of distance walked in the 12MWT and symptoms of fatigue and 
pain evaluated with questionnaires. 
Risks 
Elevated creatine phosphokinase  
Subjects with PMM may be found to have asymptomatic benign raised baseline creatine 
phosphokinase (CK) levels as part of the PMM disease, and even among healthy individuals 
CK levels transiently rise after exercise or heavy manual labor. In patients with PMM serum 
CK levels may increase to as much as 30 times the ULN within 24 hours of strenuous 
physical activity, then slowly decline over the next 7 days. The degree of CK elevation 
depends on the type and duration of exercise, with greater elevation in those who are 
untrained (Moghadam-Kia, Oddis, & Aggarwal, 2016). It is possible that improvements in 
the cellular energy deficit with REN001 treatment may result in increased muscle use and 
transient benign muscle enzyme elevations. 
Serum CK data from subjects with PMM in the Phase 1b study (REN001-101) demonstrated 
a pattern of transient, elevated CKs following exercise and the collection of muscle biopsies; 
none of these elevations were associated with myoglobinuria. The elevations seen were self-
limiting and resolved with no intervention despite continued treatment with REN001 and 
continuation of the subject’s normal activities of daily living including exercise. In all the 
clinical trials that have included REN001 to date, elevations in CK tended to be modest and 
reversible and were usually determined by investigators as unlikely to be associated with 
REN001 treatment. In the current study CK levels will be assessed throughout the study with 
particular emphasis at Baseline and Week 2, based on the expected (asymptomatic) increases 
in CK previously observed in subjects with PMM following exercise testing. 
Cataract formation 
A single-species finding of cataract was observed in a high dose 6-month rat chronic 
toxicology study. Importantly, no cataracts were observed in any other toxicology studies, 
including in a 3-month rat study and a 12-month primate study. It is anticipated that the 
changes observed in the 6-month rat study are rat strain specific. Nevertheless, following this 
observation, taking a conservative approach, ophthalmology examinations were included in 
all REN001 trials. Slit lamp eye examinations will be conducted together with assessments of 
best corrected visual acuity at Screening and Weeks 12 and 24 in this study. 
Potential Drug-Drug Interactions 

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REN001 is not a direct or time-dependent inhibitor of CYP3A4. However, REN001 has been 
shown to be a weak inducer of CYP3A4 in vitro. A potential for drug interactions between 
REN001 and drugs that are metabolized through the CYP3A4 is considered low but cannot 
be ruled out. Therefore, drugs that are metabolized primarily by CYP3A4 and have a narrow 
therapeutic index should be administered with caution in subjects participating in REN001 
studies. 
REN001 was identified as a P-glycoprotein (P-gp) substrate in vitro. Strong P-gp inhibitors 
may have an impact on the absorption and metabolism of a P-gp substrate, however 
preliminary human metabolism for REN001 indicates numerous metabolic pathways are 
involved in the clearance of REN001. Therefore, it is unlikely that co-administration of a 
strong P-gp inhibitor with REN001 will result in higher systemic exposures of REN001. Co-
administration of REN001 with a strong P-gp inducer may reduce REN001 plasma 
concentrations. 
Fertility and Contraception 
In accordance with the latest European regulatory discussions and guidelines (Clinical Trials 
Facilitation Group, 2014 and 2020), WOCBP are eligible for the study provided they are 
using a highly effective form of contraception from Screening, while taking the study drug 
and for 30 days after stopping study drug (at least one menstrual cycle after drug exposure). 
Serum pregnancy testing will be completed at Screening and urine pregnancy tests will be 
carried out monthly thereafter and at Follow Up. 
Fertile men (i.e., unless permanently sterile by bilateral orchidectomy) must use a condom 
during intercourse with a WOCBP from Baseline through to at least 14 weeks after stopping 
study drug (at least one sperm cycle after drug exposure) and should not father a child in this 
period. A condom is also required to be used by vasectomized men to prevent delivery of the 
drug via seminal fluid.  
As REN001 is a weak inducer of CYP3A4 in vitro, caution is advised when co-administering 
REN001 and oral contraceptive agents. Therefore, as a precautionary measure, women 
receiving highly effective hormonal contraception therapy will be advised to use an 
additional effective non-hormonal method of contraception during treatment with REN001 
and for 30 days after the final dose. Women using a highly effective non-hormonal 
contraception method (i.e., intrauterine device) will not be required to use additional methods 
of contraception. 
Carcinogenicity 
Long-term carcinogenicity studies have been initiated with REN001 in rats and mice. Animal 
carcinogenicity data in rodents suggest that some, but not all, PPAR agonists have 
carcinogenicity potential. The mechanism by which these compounds produce tumors in 
rodents is not well understood and the possibility that the rodent carcinogenicity findings may 
be relevant to humans cannot be ruled out at this time. Subjects with a history of cancer, 
except in situ basal cell carcinoma in the skin, will not be allowed to participate in the study.  
Bone  
a) Nonclinical finding of premature bone plate closure in rats.  
This finding has not been replicated in non-human primates. As a precaution, subjects under 
25 years of age in studies with REN001 over 12 weeks duration will have a wrist x-ray prior 
to enrolment to confirm skeletal maturity. 
b) Bone turnover 

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Currently, it is not known if REN001 (a selective PPARδ agonist) will have any impact on 
bone mineral density. Nonetheless, given the study requirements for walk tests and taking a 
highly conservative approach, the Sponsor has excluded subjects with a history of 
fragility/stress fractures or an osteoporosis concomitant condition which has not been 
addressed, and will monitor markers of bone turnover during the study. Any reports of bone 
fracture will be captured as adverse events of special interest. 
Safety Review Committee 
The ongoing safety of study subjects will be reviewed by the Medical Monitor and study site 
physicians as data are received. In addition, safety data will be reviewed by an independently 
chaired Safety Review Committee (SRC). See Section 3.11. 
Conclusion 
In conclusion, the safety profile of REN001 supports further development in clinical studies 
subject to appropriate subject selection and safety monitoring.  
1.5 
Dose Selection Rationale 
To date, a total of 162 subjects have been enrolled and 106 subjects received REN001 in four 
clinical trials (HPP593-101 (single dose, healthy volunteers); HPP593-102 (14 day, repeat 
dose study in obese moderately dyslipidemic subjects; HPP593-103, (28 day, healthy 
volunteer pharmacodynamic study in induced muscle atrophy); REN001-101, (up to 40 
weeks, repeat dose in PMM subjects)). In the single dose study, doses ranged from 25 mg to 
250 mg, doses in the 14-day study ranged from 50 mg to 200 mg QD or 100 mg BID, in the 
28-day study the dose was 100 mg BID and in the 48-week study the dose was 100 mg QD. 
Overall, REN001 was considered safe and well tolerated in all four clinical studies. No 
treatment related SAEs were reported. No clinically significant abnormalities were observed 
in any safety parameters including vital signs, ECGs, and physical exams. 
In study REN001-101, in subjects with PMM, the majority of subjects dosed for at least 12 
weeks showed improvements in distance walked at Week 12 compared to Baseline, and also 
reported a reduction in muscle related symptoms and fatigue. Pharmacological activity of 
REN001 at 100 mg per day was also shown in Phase 1 studies in other indications (see 
current Investigator’s Brochure for details).  
The safety and the pharmacodynamic effects observed in these studies support the 100 mg 
QD dose level in this Phase 2b study. 

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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To evaluate the efficacy of REN001 in subjects with PMM treated for 24 weeks, assessed by 
the effect on exercise endurance. 
2.2 
Secondary Objectives 
To evaluate the efficacy of REN001 in subjects with PMM treated for 24 weeks, assessed by 
the effect on fatigue. 
2.3 
Safety Objectives 
To evaluate the safety and tolerability of REN001 in subjects with PMM during 24 weeks of 
treatment. 
2.4 
Pharmacokinetic Objectives 
To investigate the pharmacokinetics of REN001 in subjects with PMM. 
2.5 
Exploratory Objectives 
To evaluate the efficacy of REN001 in subjects with PMM treated for 24 weeks, assessed by 
the effect on functional capacity. 
To evaluate the effect of REN001 on QoL of subjects with PMM after treatment for 24 
weeks. 

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3 
OVERALL DESIGN AND PLAN OF THE STUDY 
3.1 
Overview 
There will be a total of 8 visits for each subject. 
Each subject who provides informed consent will complete screening activities to confirm 
eligibility to enter the study. The Screening Visit (Visit 1) must be completed no more than 8 
weeks prior to the start of dosing and will take place at the Study Center. There must be a 
minimum of 4 weeks between the Screening 12MWT and the Baseline 12MWT. If laboratory 
tests are outside of the normal range at initial screening, tests may be repeated once (this can 
be done as a home nurse visit). Where possible subjects should be pre-screened to assess the 
requirement for genotyping. The Screening Visit may be accomplished over more than 1 day. 
Subjects who are receiving prohibited medications must suspend the medications, if this can 
safely and appropriately be done and have sufficient washout during the screening period 
(See Table 1) prior to randomization. Re-screening of subjects is allowed only once and 
requires prior approval by the Sponsor, for instance, if the wash-out of prior medications or 
genotyping is longer than 6-8 weeks. Re-screened subjects will not be required to have either 
the eye exam or DXA scan (REN001-201 DXA sub-study subjects) repeated within 6 months 
of the original assessments. Where a Study Center requires it, subjects may be asked to have 
a negative COVID-19 test prior to undertaking scheduled visits at the Study Center. 
The PSOC will assess if subjects have the correct diagnosis of PMM for the study prior to 
randomization. 
Subjects who successfully complete screening and are approved by the PSOC will undergo a 
Baseline Visit (Visit 2) which may be completed over two days if required. Once the Baseline 
assessments have been completed subjects will be randomized 1:1 to receive oral REN001, 
100 mg or placebo once daily for 24 weeks.  
In centers where the Regulatory Authority and the Ethics Committee/IRB and Institution 
allows Visit 3 (Week 2), Visit 4 (Week 4), Visit 6 (Week 18) and Visit 8 (Follow Up) may be 
conducted either in the Study Center or at the subject’s home using a home nursing service.  
Visit 5 (Week 12) and Visit 7 (Week 24) will be completed in the Study Center and which 
may be completed over two days if required. 
A Follow Up Visit (Visit 8) will be performed, which can be carried out either in the Study 
Center or at the subject’s home. Visit 8 will be completed 21-28 days after the last dose of 
study medication. This visit will not be required if a subject chooses to enter the REN001 
open label extension study (REN001-202) at their Week 24 visit; applicable only in countries 
where the open label extension study is being conducted. 
A qualified nurse will carry out all the required study assessments for home visits. Additional 
home visits instead of Study Center visits, or delays to visits beyond the stated visit windows, 
may be allowed in some circumstances e.g. global pandemic with the Sponsor’s prior 
approval. 
A specialist concierge service will be available to subjects to arrange hotel accommodation 
and transport to and from Study Center visits and reimburse any subject study expenses. 
The planned maximum study duration for each subject in the study will be 36 weeks 
(assuming 8 weeks screening, 24 weeks treatment and 4 weeks follow up). See Figure 1. 
Efficacy, safety, pharmacokinetic, pharmacodynamic and exploratory assessments are 
detailed in the study Schedule of Activities (Table 2).  

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Figure 1:
Study Design
Baseline (Day 1)
Follow Up (21-28 days post last dose)
Screening (up to 56 days before Day 1)
REN001 100 mg or Placebo once daily for 24 
weeks

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3.2 
Endpoints 
3.2.1 Primary Endpoint 
Change from Baseline at Week 24 in distance walked during the 12MWT. 
3.2.2 Secondary Endpoints 
Change from Baseline at Week 24 in MFIS Physical sub-scale score. 
PGIC score (muscle symptoms) at the end of treatment. 
3.2.3 Safety Endpoints 
Number and severity of adverse events. 
Absolute values, changes from Baseline and incidence of potentially clinically significant 
changes in: 
x Laboratory safety tests 
x ECGs 
x Supine vital signs 
x Eye assessments 
3.2.4 Pharmacokinetic Endpoints 
REN001 plasma concentrations. 
3.2.5 Exploratory Endpoints 
Change from Baseline at Week 12 and 24 in: 
x Number of sit to stands in 30STS test 
x Step count from pedometer 
x PGIS score - muscle symptoms 
x PGIS score - fatigue symptoms  
x PROMIS Short Form – FACIT Fatigue 13a 
x SF-36 domain scores 
x MFIS Total, Cognitive and Psychosocial sub-scale scores  
x BPI pain severity and pain interference scores 
x WPAI:SHP scores 
PGIC (fatigue symptoms) score at the end of treatment. 
3.3 
Justification of the Study Design 
There are no specific regulatory guidelines for the design of studies in patients with PMM 
and no approved safe and effective treatments for the disease. This study is primarily 
designed to assess the safety and efficacy of REN001 in patients with PMM caused by 
mtDNA gene mutations. PMM presents with a wide range of phenotypic heterogeneity. To 
address heterogeneity the study will aim to recruit 1) subjects with  mt DNA defects 
(including the most common point mutation m.3243A>G) and 2) subjects with a primary 
phenotypic presentation of myopathy. In addition, the PSOC will review the screening 
criteria as described above. 
Subjects will be randomized 1:1 to receive REN001 or a matching placebo for 24 weeks.  
Placebo-controlled studies have been used in this indication previously. A placebo arm as 

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comparator has been included to establish the magnitude of change in endpoints that may 
occur spontaneously during the treatment period. The use of a placebo is justified as no 
approved therapy is available and international ethical guidelines permit the use of placebo 
controls in randomized trials when there are compelling methodological reasons and 
withholding treatment does not pose a risk of serious harm to participants (Millum & Grady, 
2013).  
The 24 week duration of the study offers the opportunity to evaluate the long-term effects of 
REN001 on physical endurance and symptoms associated with PMM. It also provides a 
longer exposure duration to evaluate the safety and tolerability of the drug in the intended 
treatment population.  
The primary outcome measure of this study is the distance walked in the 12MWT. Both the 
6-minute walk test (6MWT) and 12MWT have been used in clinical trials and in clinical 
practice. In order to demonstrate the effect of REN001 on increasing FAO and OXPHOS, a 
walk test of greater than 6 minutes is required. At the onset of exercise, the body relies on 
readily available phospho-creatine (P-Cr) stored in the cytosol (see Figure 2). P-Cr is quickly 
depleted. For the next 2-4 minutes of exercise, the body primarily uses glycolytic metabolism 
of glucose derived from skeletal glycogen. The third source of energy is the oxidative 
phosphorylation of fatty acids and carbohydrates that occurs in the mitochondria and is 
impaired in patients with PMM.  This process occurs after approximately 4 minutes of 
exercise onset and constitutes the primary source of energy for sustained exercise.
Figure 2: 
Sources of Energy During Exercise 
Adapted from Human Physiology: An Integrated 
Approach, Sixth Edition (2013) Dee Unglaub 
Silverthorn 
Although, the 6MWT is a good measure to assess the submaximal level of functional 
capacity, the 6MWT duration is not sufficient to fully capture the potential benefits on 
physical endurance caused by improvements in mitochondrial function. In contrast, the self-
paced 12MWT assesses the submaximal level of functional capacity during the period of 
exercise supported by mitochondrial function. A prior clinical trial conducted by the Sponsor 
(REN001-101), showed that subjects with PMM progressively slowed their walking speed 
over the course of the 12MWT, with the greatest decline occurring from minute 6 to minute 
9, coinciding with the increased requirement for mitochondrial oxidative phosphorylation 
[data on file]. Most patients do not achieve maximal exercise capacity during the test; rather, 
they choose their own intensity of exercise and, if needed, are allowed to stop and rest during 
the test. This approximates to the activities of daily living, which are typically performed at 
submaximal levels of exertion for periods of more than 6 minutes.  

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One limitation of all walk tests is an associated ‘training’ effect whereby subjects may 
improve the distance walked on subsequent tests due to familiarity with the test (Kierkegaard 
& Tollback, 2007). This effect can be seen regardless of the interval duration (weeks to 
months) between tests (Wu et al, 2003; Prahm et al, 2014; Knak et al, 2017; Karaa et al, 
2018). Various methods have been used to overcome this effect, such as 1) conducting two 
walk tests on the same day and using the longest distance (Kierkegaard & Tollback, 2007); 2) 
correcting the distance walked using average heart rate during the test (Knak et al, 2017);  or 
3) conducting a walk test at screening to act as a familiarization walk test (Karaa et al, 2018). 
In this study the training effect will be minimized using a screening, familiarization 12MWT. 
To minimize variability attributed to the training effect the Screening and Baseline 12MWTs 
in this study have been set at a minimum of at least 4 weeks apart, subsequent 12MWTs in 
the study will be 12 weeks apart at Weeks 12 and 24. 
3.4 
Termination or Suspension of Study 
The study will be completed as planned unless one or more of the following criteria occur 
that require temporary suspension or early termination of the study: 
x New information or other evaluation regarding the safety of REN001 that indicates a 
change in the known risk/benefit profile for the compound, such that the risk/benefit 
is no longer acceptable for subjects participating in the study. 
x Significant violation of Good Clinical Practice (GCP) that compromises the ability to 
achieve the primary study objectives or compromises subject safety. 
x Occurrence of local or global events (e.g., COVID-19 Pandemic) that would impact 
the safety monitoring of subjects in the study. 
A Safety Review Committee will conduct periodic reviews of all safety data as described in 
Section 3.11. 
3.5 
Termination or Suspension of Investigational Sites 
A study site may be terminated prematurely or suspended if the site (including the 
Investigator) is found to be in significant violation of GCP, the protocol, or the contractual 
agreement, or is unable to ensure adequate performance of the study, or for reasons as 
otherwise permitted by the contractual agreement.  
3.6 
Conditions for Individual Subject Discontinuation of Study Drug or Withdrawal 
from the Study 
The primary reason for permanent discontinuation of a subject from the study drug should be 
recorded in the electronic Case Report Form (eCRF). Individual subjects may be 
discontinued from the study drug in the following circumstances: 
1. Concurrent enrolment in other clinical studies involving investigational products or 
enrolment in other types of clinical research judged not to be scientifically or 
medically compatible with this study. 
2. Use of a prohibited concomitant medication. 
3. Major protocol deviation e.g., the discovery after administration of the first dose of 
study medication that the subject failed to meet protocol entry criteria or did not 
adhere to protocol requirements, and continued participation poses an unacceptable 
risk to the subject’s health or undermines the ability to achieve the objectives of the 
study. 

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4. Lost to follow-up. The subject did not return to the study center and attempts to
contact the subject were unsuccessful. Attempts to contact the subject must be
documented.
5. Evidence of pregnancy during the treatment period of the study.
6. Clinically significant changes from baseline in ECG recordings considered treatment-
related including an increase from baseline in heart rate corrected QT interval using
Fridericia’s formula (QTcF) to a value of t500 millisecond (msec). Single ECGs
should be repeated at 5-minute intervals, 3 times, to confirm any increased QTcF
interval values. In the event of an increased QTcF interval of t500 msec, the subject
must be monitored until the value returns to below 500 msec.
7. Clinically significant muscle injury including test abnormalities (e.g., CK) as defined
in Section 3.7.1.
8. Clinically significant liver toxicity including test abnormalities (e.g., ALT/AST) as
defined in Section 3.7.2.
9. Clinically significant kidney toxicity including test abnormalities (e.g., creatinine
levels) as defined in Section 3.7.3.
10. A TEAE that could result in a transient or permanent significant impairment. Subjects
should be followed with appropriate medical management until there is a return to
normal or baseline values or a clinical diagnosis of an emergent illness is confirmed.
11. Voluntary withdrawal. The subject wishes to withdraw from the study. Subjects may
withdraw from the study at any time without penalty and for any reason without
prejudice to their future medical care. In all cases, the reason(s) for withdrawal,
including the primary reason, must be recorded in the eCRF. Note: All attempts
should be made to determine the underlying reason for the withdrawal and, where
possible, the primary underlying reason should be recorded (i.e., withdrawal due to an
AE should not be recorded in the “voluntary withdrawal” category).
If a subject discontinues study drug the following process (see Figure 3) should be followed 
by the Investigator in order to satisfy the regulatory desire to continue to follow subjects 
where possible (ICH E9-R1) after discontinuation of a study intervention. Hence, if the 
subject discontinues taking study drug they will be encouraged, where appropriate, to 
continue with reduced assessments at the Week 12 and Week 24 visits. 

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Figure 3: 
Process For Subject Discontinuation Of IMP Or Withdrawal From The 
Study 
3.7 
Strategy for Potential Withdrawal due to Laboratory Test Abnormalities 
3.7.1 Safety Monitoring for Serum Creatine Phosphokinase 
Patients with PMM often present with mild to moderate baseline elevations in CK and can 
experience transient episodes of significantly elevated CK induced by vigorous exercise, and 
other environmental conditions. These elevations are not associated with symptoms or signs 
and the patients are typically well. CK elevations are generally of the skeletal muscle 
fraction. However, a small proportion of the total CK may be from the myocardial fraction 
reflecting a small amount of this fraction found in skeletal muscle rather than the presence of 
myocardial injury. Importantly, these elevations are entirely to be expected in this patient 
population with underlying muscle disease and are not synonymous with rhabdomyolysis. 
Similarly, elevations in serum aminotransferases and uric acid can accompany CK elevations 
and may not be indicative of liver disease.  
True rhabdomyolysis may also occur in these patients and must be managed appropriately. 
Rhabdomyolysis is characterized by severe acute muscle injury resulting in muscle pain, 
weakness, and/or swelling with release of myofiber contents into the bloodstream. Symptoms 
develop over hours to days following an inciting factor and may be associated with dark 
pigmentation of the urine (Nance & Mammen, 2015). Acute kidney injury is a potential 
Subject discontinues IMP 
(reason documented in eCRF) 
Subject Does Not Agree to 
Continue in Study Off IMP: 
Subject withdrawn from the study 
Subject Agrees to Continue in Study Off IMP 
(Section 6.9): Subject completes Week 12 and 
Week 24 reduced visit assessments of: 
x 
Review of concomitant medications and 
non-drug treatments 
x 
Review of AEs 
x 
Vital signs (including temperature) 
x 
MFIS 
x 
12MWT 
(unless ET is within 2 weeks of either of the 
Week 12 or Week 24 visits) 
Subject encouraged to remain in study, but off-IMP 
by the Investigator 
Early Termination (ET) Visit (Section 6.8) 
scheduled at study center as soon as possible 
Follow Up (FU) Visit completed 
21-28 days after last dose of IMP
(unless ET visit is over 21 days after 
last dose of IMP) 

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complication of rhabdomyolysis. The risk of acute kidney injury is low in patients with CK 
levels less than 15,000 international units per liter (IU/L). The CK algorithm below (Figure 4) 
has been designed to identify those subjects potentially at risk of true rhabdomyolysis and 
ensure appropriate early action is taken to monitor and treat the subjects accordingly. 
Figure 4: 
CK Algorithm 
3.7.2 Safety Monitoring For Liver toxicity: Management and Stopping Rules 
In this study, subjects with significant liver disease or impairment of AST or ALT >2.5 x 
ULN, or total bilirubin >1.6 x ULN or >ULN with other signs and symptoms of 
hepatotoxicity at Screening will be excluded. It would be inappropriate to exclude all subjects 
with milder elevations in LFTs out of the normal range because patients with PMM can 
present with elevations in CK levels that are often accompanied by elevated LFTs (ALT and 
AST), which are not indicative of liver disease. Accordingly, these elevations appear to be 
transient and resolve spontaneously (Tarnopolsky 2016). Although serum ALT and AST 
In the event that: 
x 
a subject with a normal CK at Baseline has a blood CK level >10 x ULN, or 
x 
a subject with a CK above ULN at Baseline has blood CK level ≥10 x their Baseline 
level, or 
x 
a subject has a CK level of >10,000 IU/L 
The subject should be contacted promptly and evaluated for the 
presence of muscle pain, stiffness, cramping and myoglobinuria i.e., 
reddish-brown urine. 
If no clinical symptoms 
and no urine color 
change is present 
Advise subject to rest, 
drink plenty of water 
and monitor condition 
If any clinical symptoms are present: Alert 
Medical Monitor and advise subject to 
rest, drink plenty of water and monitor 
condition. In addition, repeated daily CK 
levels should be measured (e.g. via local 
physician) until signs of CK levels are 
trending downwards 
If symptoms worsen, or myoglobinuria 
develops or CK levels do not recover after 
7-10 days. The Investigator, Sponsor and 
Medical Monitor should discuss whether 
the subject remains on IMP or a temporary 
or permanent discontinuation of IMP and 
further monitoring is needed 

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values have shown good diagnostic accuracy in patients with chronic liver disease, AST and 
ALT levels can be increased immediately after muscular exertion as well (Lippi 2008). 
In the event that a subject presents with raised LFTs during the study the following 
management guidelines and stopping rules should be followed: 
x For subjects who enroll with a baseline below the ULN and present with an 
increase in serum ALT or AST > 3xULN, repeat testing of ALT, AST, ALP and 
total bilirubin will be obtained as soon as possible, ideally within 48-72 hours, to 
confirm the abnormality and whether the abnormality is increasing or decreasing. 
x For subjects who enroll with a baseline above the ULN and present with an 
increase in serum ALT or AST > 3xULN and at least 2x their Baseline value, 
repeat testing of ALT, AST, ALP and total bilirubin will be obtained as soon as 
possible, ideally within 48-72 hours, to confirm the abnormality and whether the 
abnormality is increasing or decreasing. 
x If symptoms persist or repeat testing shows ALT > 3xULN for subjects with 
normal baseline measures or 2x their Baseline value for subjects with elevated 
values at Baseline, initiate close observation with repeat testing 2-3 times weekly, 
or as clinically mandated, to determine whether the abnormalities are improving 
or worsening (see below for further details).  
x If close monitoring is not possible, as a precautionary measure study drug should 
be withheld and continued participation in the study should be discussed with the 
Medical Monitor (See also Section 6.9). 
Guidelines for Close Observation: 
x Repeated ALT, AST, ALP, and total bilirubin tests two or three times weekly. 
x Frequency of re-testing can decrease to once a week or less if abnormalities 
stabilize or the study drug has been discontinued and the subject is 
asymptomatic. 
x Obtain a more detailed history of symptoms and prior or concurrent diseases. 
x Recheck history of concomitant drug use (including non-prescription 
medications and herbal and dietary supplement preparations), alcohol use, 
recreational drug use, and any special diets. 
x Rule out acute viral hepatitis types A, B, C, D, and E; autoimmune or 
alcoholic hepatitis; Non-alcoholic steatohepatitis (NASH); hypoxic/ischemic 
hepatopathy; and biliary tract disease. 
x Obtain a history of exposure to environmental chemical agents. 
x Obtain additional tests to evaluate liver function, as appropriate (e.g., 
International normalized ratio (INR) or Prothrombin time (PT), direct 
bilirubin). 
x Consider gastroenterology or hepatology consultations. 

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Discontinuation: 
Discontinuation or interruption of study drug should be considered, in consultation with the 
Medical Monitor and Reneo CMO or designee where possible, if: 
x ALT or AST > 8xULN. 
x ALT or AST > 5xULN for more than 2 weeks. 
x ALT or AST > 3xULN and total bilirubin > 2xULN or INR >1.5. 
x ALT or AST > 3xULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
3.7.3 Safety Monitoring For Kidney toxicity: Management and Stopping Rules 
If subjects develop a creatinine elevation > 2xULN and more than 2x Baseline value: 
x Monitor creatinine 2 times per week, or as clinically indicated, until recovery. 
x For subjects with > 3xULN creatinine elevation the study drug should be 
withheld and the subject should continue to be followed closely. 
x In the event of either of the above continued participation in the study should 
be discussed with the Medical Monitor. 
Discontinuation: 
Discontinuation of study drug should be considered, in consultation with the Medical 
Monitor and Reneo CMO or designee where possible, if: 
x A > 3xULN creatinine elevation is sustained or deteriorating. 
x The subject is unwell and has hyperkalemia. 
3.8 
Replacement of Subjects 
Subjects who withdraw due to reasons other than AEs or SAEs may be replaced to ensure 
that sufficient subjects are available to satisfy the statistical assumptions of the study.  
3.9 
Temporary Discontinuations 
Subjects may be temporarily discontinued from study drug while AEs and/or laboratory test 
abnormalities are being investigated and/or at the request of the Medical Monitor. The 
Investigator should discuss with the Medical Monitor and Sponsor any subject for whom 
temporary or permanent discontinuation of study drug is being considered. 
If a subject misses several consecutive doses due to personal circumstances or due to an AE 
not related to study drug, they may be allowed to restart dosing after discussion between the 
Investigator, Medical Monitor and Sponsor (See Section 5.9). 
3.10 
Review of Screening Eligibility Data 
An independent Patient Screening Oversight Committee with experts in the diagnosis of 
PMM will be set up to review screening data to ensure subjects enrolled into the study have 
the correct diagnosis of PMM. Details regarding the structure, function and operation of the 
PSOC will be detailed in the REN001-201 PSOC Charter. 
3.11 
Review of Safety Data 
Review of subject safety data (including, but not limited to, AEs, ECGs, laboratory safety 
tests and vital signs) will be performed by the independently chaired Safety Review 

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Committee (SRC) in accordance with the REN001-201 SRC Charter. Safety reviews will be 
conducted throughout the study in order to identify any potential safety signals during the 
trial that may have an impact on the safety of the participants. The SRC may make 
recommendations concerning continuation, termination or study modifications based on these 
reviews. 

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4 
STUDY POPULATION 
To fulfil the study objectives, it is essential that appropriate subjects are enrolled. The 
following eligibility criteria are designed to select subjects considered appropriate for 
participation in the study. Subject eligibility should be reviewed and documented by the 
Investigator or an appropriate designee member of the site study team. In addition, subjects 
screening data will be reviewed independently by the PSOC for confirmation of eligibility 
prior to randomization.  
4.1 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for inclusion in the 
study: 
1. Subjects aged 18 years or older with PMM as defined by the International Workshop:
Outcome measures and clinical trial readiness in primary mitochondrial myopathies in
children and adults (Mancuso et al 2017) (see Appendix 1).
2. A confirmed PMM diagnosis due to a known pathogenic gene mutation or deletion of the
mitochondrial genome. The Sponsor may authorize local genetic testing at Screening, if
required, but results must be available prior to randomization of the subject (see Sections
6.1 and 7.1.24 for details).
3. Documented PMM primarily characterized by exercise intolerance or active muscle pain.
4. Subjects must be ambulatory and able to perform the 12MWT independently (walking
aids are allowed).
5. Distance walked of ≤1000 meters at Screening in the 12MWT (must be obtained at least 4
weeks before randomization).
6. Have no changes to any therapeutic exercise regimen within 30 days prior to Day 1 and
be willing to remain on the same therapeutic exercise regimen for the duration of the
study.
7. Be willing and able to swallow gelatin capsules.
8. Females should be either of non-child-bearing potential or must agree to use highly
effective methods of contraception from Screening through to 30 days after last dose in
the study. Where females are using hormonal contraception therapy, an additional
effective non-hormonal method of contraception is advised. Males with partners who are
WOCBP must also use contraception (See Section 5.10 for details).
9. Concomitant medications (including supplements) intended for treatment of PMM or
other co-morbidities must be stable for at least 1 month prior to randomization and
throughout participation in the study.
10. For subjects under 25 years old only: confirmation of bone growth plate closure by wrist
radiograph.
11. Evidence of a personally signed and dated informed consent document indicating that the
subject has been informed of all pertinent aspects of the study.
4.2 
Exclusion Criteria 
Subjects presenting with any of the following will not be included in the study: 
1. Participation in a prior REN001 (previously known as HPP-593) study.
2. Currently taking or anticipated to need a PPAR agonist during the study.

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3. Bone deformities or motor abnormalities other than related to the mitochondrial
myopathy that may interfere with the outcome measures.
4. Treatment with an investigational drug within 3 months or 5 drug half-lives, whichever is
longer, prior to Day 1.
5. Anticipated to need a prescription and/or non-prescription drug that might interfere with
the study endpoints (See Table 1).
6. Currently taking drugs with a narrow therapeutic index and BCRP mediated ADME e.g.,
aliskiren, ambrisentan, colchicine, digoxin, everolimus, imatinib, lapatinib, maraviroc,
nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan,
topotecan, methotrexate, mitoxantrone, irinotecan, rosuvastatin, and sulfasalazine (See
Table 1).
7. Clinically significant kidney disease or impairment, with an eGFR less than
60ml/min/1.73m2 using the CKD-EPI creatinine equation at Screening.
8. Clinically significant liver disease or impairment, with AST or ALT >2.5 x ULN, or Total
bilirubin > 1.6 x ULN or >ULN with other signs and symptoms of hepatotoxicity at
Screening. (Subjects with an isolated elevated bilirubin (e.g., < 2 x ULN) may be
included after discussion with the Medical Monitor if the cause is due to a benign
hereditary disorder of metabolism such as Gilbert’s syndrome.)
9. Uncontrolled diabetes and/or a Screening HbA1c of ≥11%.
10. Uncontrolled epilepsy.
11. Evidence of significant concomitant clinical disease that may need a change in
management during the study or could interfere with the conduct or safety of this study.
(Stable well-controlled chronic conditions such hypercholesterolemia, gastroesophageal
reflux, or depression under control with medication (other than tricyclic antidepressants),
are acceptable provided the symptoms and medications would not be predicted to
compromise safety or interfere with the tests and interpretations of this study.)
12. A history of cancer. A history of in situ basal cell carcinoma in the skin is allowed.
13. Have been hospitalized within the 3 months prior to Screening for any major medical
condition (as deemed by the Investigator).
14. Clinically significant cardiac disease and/or clinically significant ECG abnormalities
including a screening QTcF of ≥ 450 msec, 2nd degree heart block, symptomatic
tachyarrhythmia or unstable arrythmia that in the opinion of the Investigator should
exclude the subject from completing the study exercise tests (i.e., 12MWT and 30STS
tests). (Subjects with right bundle branch block, left fascicular block and long PR interval
which are common in PMM may be enrolled if the Investigator considers that the
condition would not compromise safety or interfere with the tests and interpretations of
this study.)
15. Any condition possibly reducing drug absorption (e.g., gastrectomy or increased
motility).
16. Evidence of hospitalization for rhabdomyolysis within the year prior to enrolment.
17. Positive HBsAg and HBcAb at Screening, or positive for hepatitis C or HIV at Screening.
18. Pregnant or nursing females.
19. History of sensitivity to PPAR agonists.

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20. Donation or intent to donate blood, or blood components during the study or within one
month after completion of the study.
21. A history of drug dependency. Use of opiates/cannabis for medical reasons is acceptable
with prescription evidence or at the Investigators discretion.
22. A history of alcohol dependency.
23. Significant impairment due to central or peripheral nervous system involvement that
would interfere with the exercise tests.
24. Significant weakness not caused by the underlying primary muscle disease such as post
stroke or neurogenic weakness.
25. Have had an organ transplant.
26. Are not eligible or have a contraindication for cataract surgery.
27. A history of osteoporosis as evidenced by non-traumatic (stress) fractures or a prior T-
score of -2.5 or worse which has not been adequately addressed.
28. Inability to comprehend or unwilling to follow the study requirements including
restrictions on treatments, attendance at the study center, completion of questionnaires
and participation in laboratory testing as called for by the protocol.
29. Any other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation of study
results and, in the judgment of the Investigator, and in discussion with the Medical
Monitor, would make the subject inappropriate for entry into this study.
4.3 
Planned Sample Size and Number of Study Centers 
It is envisaged that approximately 265 subjects will be screened to achieve 200 randomized 
subjects. Recruitment will be from across a minimum of 35 centers worldwide. 

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5 
STUDY DRUG 
5.1 
Study Drug Identity 
Study drug and placebo are presented as Swedish orange, hard gelatin, size 0 capsules, 
manufactured by Xcelience LLC, a Lonza company.  
The dosage strength of REN001 capsules is 50 mg. Matched placebo capsules will also be 
supplied, containing approximately 30 mg microcrystalline cellulose.  
Capsules are packaged in 200 mL high-density polyethylene (HDPE) bottles, with a 
heat induction seal and child-resistant lids, containing 100 capsules of either 50mg REN001, 
or placebo. Supplies will be identified by the blinded batch number and expiry date.  
As each subject will take 2 capsules per day the bottle will contain sufficient capsules for 50 
days of dosing.  
Sufficient bottles will be supplied to ensure subjects have at least enough capsules to 
maintain dosing between Study Center visits. 
5.2 
Allocation to Treatment 
Upon Screening, each subject will receive a 6 digit study number allocated by the Integrated 
Web-based Response System (IWRS), which will be used throughout the study. The IWRS 
will use a computer-generated randomization schedule to assign subjects to a treatment 
sequence on a 1:1 basis. The randomization will be stratified by both mutational genotype 
(m.3243A>G or other mitochondrial DNA defects) and the screening 12-minute walk 
distance (12MWD) (≤ 500 meters or > 500 meters). 
Screened subjects who drop out of the study before receiving study drug or require repeat 
safety lab tests will retain their study number. A subject may be rescreened once only (with 
prior approval by the Sponsor); for instance, if a washout of prior medications of longer than 
6-8 weeks is required. Rescreened subjects will be given a new study number and their
previous study number will also be recorded.
5.3 
Maintaining the Blind 
This study is a double-blind study i.e., the study will be Sponsor, subject- and investigator-
blinded. All personnel involved in the conduct of the study will remain blinded to treatment 
until the conclusion of the study. To minimize the potential for bias, treatment randomization 
information will be kept confidential by the IWRS vendor and will not be released to the 
Sponsor, Investigator, site personnel, or the study monitors until the conclusion of the study. 
REN001 and placebo will be provided as visually matched capsules. All study drug will be 
supplied in identical bottles thereby maintaining the double blind conditions for the subject 
and Investigator. 
5.4 
Breaking the Blind 
Details of personnel who will be unblinded to subject data during the study will be recorded 
in a document maintained by the Sponsor. 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind. The study blind should not be broken except in a medical emergency, where 
knowledge of the study drug received would affect the treatment of the emergency or 
obtaining this information is a regulatory requirement. As a courtesy, and only if time 
permits, the Investigator may notify the Sponsor prior to unblinding. All Investigator 
unblinding events will be automatically reported by the IWRS to the Sponsor. 

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If the blind is broken, the date, time and reason must be recorded in the subject’s eCRF. 
Information concerning the treatment allocated should only be available to those who need to 
know for the appropriate action to be taken with the subject. 
5.5 
Administration 
Subjects will receive either 100 mg REN001 as 2 x 50 mg or placebo as 2 x placebo capsules 
for oral administration once daily for 24 weeks. 
Medication should be taken with food, for consistency of exposure, at a convenient time to 
the subject (ideally in the morning). The exception to this will be when the subject is required 
to attend the Study Center for their Baseline, Week 12 and Week 24 Visits, when they should 
take the study medication at the Study Center, when instructed to do so, by the site staff. On 
these visits, sites will ensure the subjects take the study medication with food. 
Subjects will be supplied with a dose recording card and will be requested to record the date 
and time of dosing for study visit days (other than Baseline, Week 12 and Week 24).  
5.6 
Release, Labelling and Storage 
Bottles will be labelled and released in accordance with the Clinical Trials Directive 
2001/20/EC (European Commission, 2001), GMP Directive 2003/94/EC for Investigational 
Medicinal Products (European Union, 2003) and US Code of Federal Regulations 
21CFR312.6 and 21CFR211.165. 
All study drug supplies must be stored in accordance with the manufacturer’s instructions. 
Until dispensed to the subjects, the study medication (REN001 and placebo capsules) should 
be stored at refrigerated temperature (2-8oC), in a securely locked area, accessible to 
authorized personnel only. A daily temperature log of the study drug storage area must be 
recorded and checked every day. Temperature excursions must be reported to the Sponsor or 
delegate as soon as possible. 
Once the study medication has been dispensed to subjects, it should be stored refrigerated (2-
8oC) at the subject’s home. Study medication does not need to be kept refrigerated during 
transport to and from the subject’s home and the Study Center. Subjects should only open and 
use one bottle of study medication at a time. Study medication should be kept away from 
children. 
5.7 
Excessive Pharmacological Effects 
No specific antidotes for REN001 are available and standard supportive measures should be 
used in the case of excessive pharmacological effects. 
5.8 
Drug Accountability 
The Investigator is responsible for maintaining accurate accountability records for study drug 
throughout the study. 
Each dispensing of study drug will be documented in the IWRS and the study supplies 
management system. 
The subject must bring all study medication (including empty bottles) to the Study Center at 
each visit, for compliance, reconciliation and quarantine of any expired study medication 
ahead of destruction. 
Any study medication remaining at the end of study will be returned to the Sponsor or their 
representative or destroyed locally on behalf of the Sponsor (with written permission of the 
Sponsor) and the destruction fully documented. 

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5.9 
Compliance 
At all study visits subject compliance with the study drug regimen will be monitored by 
capsule counts. Subjects failing to take 2 or more doses in a 1- or 2-week visit period or 4 or 
more doses in a 4-week visit period will be reminded of the importance of complying with 
the dosing requirements. If a subject consistently fails to take their study medication, the 
Investigator should alert the Sponsor, Medical Monitor and site monitor and a decision will 
be made as to whether the subject should be withdrawn for non-compliance. 
5.10 
Contraceptive Requirements 
In countries where the regulatory authority allows this, WOCBP at risk for pregnancy and 
fertile men will be allowed to enter the study provided adequate contraceptive requirements 
are followed as outlined below. Contraceptive requirements for the study have been defined 
using the recommendations of the Clinical Trials Facilitation Group, Rome September 2014 
meeting and subsequent update in September 2020 (Clinical Trials Facilitation Group, 2014 
and 2020) and also the International Council on Harmonization (ICH) M3(R2) guidance 
(European Medicines Agency, 2009).  
Females 
Females of child-bearing potential must agree to use highly effective methods of 
contraception from Screening to 30 days after the last study dose. Highly effective methods 
are: 
x combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation administered by oral or intravaginal route. 
x oral, injectable or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation. 
x intrauterine device. 
x intrauterine hormone-releasing system. 
x bilateral tubal occlusion. 
x bilaterally orchiectomized or vasectomized partner, provided that partner is the sole 
sexual partner of the subject, and in the case of a vasectomized partner has received 
medical assessment of the surgical success. 
x true sexual abstinence, where this is in line with the usual lifestyle of the subject. 
Periodic (calendar, ovulation, symptothermal or post-ovulation) abstinence and withdrawal 
are not acceptable methods of contraception. 
However, caution with co-administration of REN001 and hormonal contraceptives is advised 
due to the potential for drug-drug interaction, see Section 1.4. In addition to highly effective 
hormonal contraception therapy, WOCBP at risk of pregnancy are advised to also use an 
additional effective non-hormonal method of contraception. 
Females are considered to be of non-child-bearing potential if they fulfill at least one of the 
following criteria: 
x Postmenopausal, defined as 45 years of age or older and amenorrhoeic for at least 1 
year PLUS have a serum follicle stimulating hormone (FSH) level within the 
laboratory’s reference range for postmenopausal women, at Screening Visit. 
x Have undergone a documented hysterectomy and/or bilateral oophorectomy. 
Males who are considered fertile and with partners who are WOCBP 

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Males are considered fertile after puberty unless permanently sterile by bilateral 
orchidectomy or vasectomy (following medical assessment of surgical success). Fertile males 
with partners who are WOCBP must agree to use contraception (condom) from Baseline until 
14 weeks after the last dose of study medication. A condom is also required to be used by 
vasectomized men to prevent delivery of the drug via seminal fluid. In addition, they must be 
advised not to donate sperm during this period. 
5.11 
Concomitant Medications 
Any medication the subject takes during the study, prescription and non-prescription, other 
than the study drug is considered a concomitant medication. All concomitant medications 
must be recorded in the eCRF. The following information must be recorded in the eCRF for 
each concomitant medication: generic name, route of administration, dose, start date, stop 
date (and whether it is a prior medication) and indication.  
At Screening, subjects will be asked what medications they are currently taking. At each 
subsequent study visit, subjects will be asked what medications they have taken since the last 
study visit. 
Any medications taken prior to the start of dosing will be documented as prior medications. 
Medications taken after the first dose of study medication will be documented as concomitant 
medications. Medications that start before the first dose of study medication and continue into 
the study are considered both prior and concomitant medications. 
Subjects may not use the medications and treatments listed in Table 1 within the indicated 
time interval prior to Day 1 and these medications must be withheld for the duration of the 
study and where possible until completion of the Follow Up visit. 
Table 1: 
Prohibited Medications 
Medication 
Time interval prior to Day 1 
Statins (including atorvastatin, lovastatin and 
rosuvastatin) * 
1 week 
Anticoagulants * 
1 week or 5 half-lives 
(whichever is longer) 
Bezafibrate and other PPAR agonists 
4 weeks 
Cyclosporine and other immunosuppressive drugs 
4 weeks 
Oral or systemic steroids * 
4 weeks 
Investigational drugs 
3 months or 5 half-lives 
(whichever is longer) 
Drugs with a narrow therapeutic index and BCRP 
mediated ADME e.g., aliskiren, ambrisentan, 
colchicine, digoxin, everolimus, imatinib, 
lapatinib, maraviroc, nilotinib, posaconazole, 
ranolazine, saxagliptin, sirolimus, sitagliptin, 
talinolol, tolvaptan, topotecan, methotrexate, 
mitoxantrone, irinotecan, and sulfasalazine. 
No washout period 
applicable, subjects should be 
excluded from the study (see 
Section 4.2) 
* Other statins,anticoagulants and steroids may be allowed, if it is considered medically
appropriate, following discussion with the Medical Monitor who will discuss with
Sponsor.

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6 
STUDY CONDUCT 
This is a multi-center study which will be conducted at a minimum of 35 study sites. 
A schedule of Activities is presented in Table 2. Details of study assessments are provided in 
Section 7. 
Visits should occur within the scheduled timeslot for the visit: see Table 2, Schedule of 
Activities. Where possible, visits should occur on the target visit day in relation to the 
Baseline visit. All dates should be recorded as DD-MMM-YYYY (e.g., 01 JAN 2018), and 
times should be recorded using the 24-hour clock (e.g., 23:20 not 11:20 pm). 
Assessments should be completed in the order below: 
x PROs must be completed prior to exercise testing 
x The 12MWT must be done before the 30STS  
x 30STS must be done last (at least 1 hour after 12MWT) 
6.1 
Screening: Visit 1 
All subjects will be given both a written and verbal description of the study. Subjects should 
be given adequate time to think about whether they want to participate and to ask questions. 
The Investigator (or an appropriate delegate at the site) will obtain written consent from each 
subject prior to commencing any study related activities or assessments. Following consent, 
the Screening Visit (Visit 1) must be completed no more than 8 weeks prior to the start of 
dosing and will take place at the Study Center. There must be a minimum of 4 weeks between 
the Screening 12MWT and the Baseline 12MWT. If laboratory tests are outside of the normal 
range at initial screening, tests may be repeated once (this can be done by a home nursing 
visit). Where possible subjects should be pre-screened to assess the requirement for 
genotyping. The Screening Visit may be accomplished over more than 1 day. Subjects who 
are receiving prohibited medications must suspend the medications, if this can safely and 
appropriately be done and have sufficient washout during the screening period (see Table 1). 
Re-screening of subjects (once only and with prior Sponsor approval) is allowed, for instance 
if wash-out of prior medications or genotyping is longer than 6-8 weeks. Re-screened 
subjects will not be required to have either the eye exam or DXA scan (REN001-201 DXA 
sub-study subjects) repeated within 6 months of the original assessments.  Where a Study 
Center requires it, subjects may be asked to have a negative COVID-19 test prior to 
undertaking scheduled visits at the Study Center. 
At Screening, all subjects will be allocated a unique 6-digit study number, which will be used 
for the duration of the study. 
Site staff will need to provide subjects with meals and snacks at appropriate times during the 
visit to ensure subjects have enough energy prior to completing the exercise tests. 
The following procedures will be performed: 
x Subject demography (including ethnicity for calculation of eGFR) 
x Complete medical history (including prescription and non-prescription 
drugs/treatments, non-drug treatments, topical products, vitamins and dietary 
supplements taken in the last 4 weeks, alcohol, drugs of abuse and tobacco use) 
x Full physical examination (including height and weight) 
x 12-lead ECG
x Vital signs (including temperature) 

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x Obtain blood samples for: 
o
Hematology and HbA1c
o
Biochemistry, HIV/Hepatitis B/C serology, serum FSH test (postmenopausal
females only) and serum pregnancy test (WOCBP only)
o
Genotyping (only with prior approval of Sponsor)
x Obtain urine samples for: 
o
Urinalysis
o
Drugs of abuse
x MFIS 
x PGIS – muscle symptoms 
x PGIS – fatigue symptoms 
x PROMIS Short Form – FACIT Fatigue 13a 
x 12MWT 
x Eye examination (may be completed at any time between the initial Screening and 
Baseline visits) 
x For subjects <25 years old (only) a wrist radiograph will be required to confirm bone 
growth plate closure. 
x Input of the Pro-forma Screening data into eCRF for PSOC approval 
x Subjects will be provided with a pedometer and instructions on how to use the device 
and complete the eDiary prior to leaving the Study Center (including the requirement 
for collecting the Screening, pre-treatment, pedometer data for 14 days from the 
Screening visit) 
x Subjects will be provided with a urine collection cup and instructions for collecting a 
second morning void at the Baseline visit if they are unable to do this at the Study 
Center for any reason. 
Provided the subject fulfils all the inclusion and exclusion criteria, and the PSOC has 
confirmed their agreement, the subject may enter the study and proceed with the Baseline 
Visit. 
6.2 
Baseline (Day 1): Visit 2 
Site staff will need to provide subjects with meals and snacks at appropriate times during the 
visit to ensure subjects have enough energy prior to completing the exercise tests. 
Subjects will attend the Study Center for the Baseline Visit when the following assessments 
will be carried out prior to dosing: 
Prior to dosing: 
x Obtain second morning void urine sample for: 
o
Bone marker - N-terminal telopeptide (NTX)
o
Urinalysis
o
Drugs of abuse
o
Urine for pregnancy testing (WOCBP only)
x Obtain blood samples for: 
o
Hematology
o
Biochemistry

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o
Additional bone and calcium metabolism markers
o
Additional serum for possible use as baseline reference, to be stored frozen at the
central laboratory through to completion of the study
o
Pre-dose plasma sample for pharmacokinetic analysis of REN001
x Review of concomitant medications including contraception and non-drug treatments 
x Review of pre-treatment events (see Section 7.1.1.1) 
x Physician completion of subjects PMM phenotypic description 
x Review of Screening pedometer eDiary data 
x Full physical examination (including weight) 
x 12-lead ECG
x Vital signs (including temperature) 
x MFIS 
x BPI 
x SF-36 
x PGIS – muscle symptoms 
x PGIS – fatigue symptoms 
x PROMIS Short Form – FACIT Fatigue 13a 
x WPAI:SHP 
x 12MWT 
x 30STS 
Assessments should be conducted to ensure that the PRO questionnaires are completed prior 
to exercise testing and the 12MWT must be done at least 1 hour before the 30STS. 
Provided the subject meets all the study entry criteria they will be randomized to study 
treatment. The IWRS will allocate study drug to be dispensed to the subject. The first dose 
should be taken with food under the supervision of site staff and the time of dosing recorded. 
Subjects will remain in the Study Center after study drug administration for the 
following assessments to be carried out: 
x Obtain plasma samples for pharmacokinetic analysis of REN001 (1, 2, 3 and 4* hours 
postdose) 
x Review of adverse events 
x Subjects will be provided with a urine collection cup and instructions for collecting a 
second morning void at the Week 12 visit if they are unable to do this at the Study 
Center for any reason 
* To ease subject burden, the 4-hour post dose blood may be omitted if the visit is extending
beyond what is reasonable, at the Investigator’s discretion.
Subjects may then leave the Study Center at the discretion of the supervising clinical staff 
after being provided with sufficient study medication to last until their next scheduled Study 
Center visit. Subjects will be reminded of the study restrictions and instructed on study 
medication dosing requirements. 
If feasible, and at the Investigator’s discretion, the Baseline Visit may be conducted over two 
days. 

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6.3 
Weeks 2 (Day 14): Visit 3 
Subjects will either attend the Study Center or receive a home nursing visit (in countries 
where the regulatory authority allows) on Day 14. On this day, the subject will take their 
daily dose at home as usual and record the time of dose on the subject dosing card. The 
following assessments will be carried out:  
x Review concomitant medications, non-drug treatments and study medication 
compliance 
x Review of adverse events 
x Vital signs (including temperature) 
x Obtain blood samples for: 
o
Hematology
o
Biochemistry
o
Plasma sample for pharmacokinetic analysis of REN001
x Obtain urine samples for: 
o
Urinalysis
x Capsule counts of remaining capsules including any opened IMP bottles 
Subjects will be reminded of the study restrictions and instructed on study medication dosing 
requirements. 
6.4 
Weeks 4 and 18 (Days 28 and 126): Visits 4 and 6 
Subjects will either attend the Study Center or receive a home nursing visit (in countries 
where the regulatory authority allows) on Days 28 and 126. On these days, the subject will 
take their daily dose at home as usual and record the time of dose in the subject dosing card. 
The following assessments will be carried out:  
x Review concomitant medications, non-drug treatments and study medication 
compliance 
x Review of adverse events 
x Vital signs (including temperature) 
x Obtain blood samples for: 
o
Hematology
o
Biochemistry
o
Plasma sample for pharmacokinetic analysis of REN001
x Obtain urine samples for: 
o
Urinalysis
o
Urine for pregnancy testing (WOCBP Week 4 only)
x Review of last 7 days pedometer data 
x MFIS 
x BPI 
x SF-36 
x PGIS – muscle symptoms 
x PGIS – fatigue symptoms 
x PROMIS Short Form – FACIT Fatigue 13a 

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x WPAI:SHP 
x Capsule counts of remaining capsules including any opened IMP bottles 
Subjects will be reminded of the study restrictions and instructed on study medication dosing 
requirements. 
6.5 
Weeks 8, 16 and 20 (Days 56, 112 and 140) 
Subjects who are WOCBP at risk of pregnancy will be supplied with urine pregnancy tests to 
use at home at Weeks 8, 16 and 20. Study Center staff will need to contact the subjects by 
telephone to obtain the result of the pregnancy test and enter the result into the eCRF. 
Subjects may be given a reminder telephone call to conduct the test if necessary. 
6.6 
Weeks 12 and 24 (Days 84 and 168): Visits 5 and 7 
Site staff will need to provide subjects with meals and snacks at appropriate times during the 
visit to ensure subjects have enough energy prior to completing the exercise tests. 
Subjects will attend the Study Center on Days 84 and 168. On these days, the subject will 
take their daily dose in the Study Center. The following assessments will be carried out:  
x Obtain second morning void urine sample for: 
o
Bone marker - NTX
o
Urinalysis
o
Drugs of abuse
o
Urine for pregnancy testing (WOCBP only)
x Obtain blood samples for: 
o
Hematology (including HbA1c at Week 24 only)
o
Biochemistry
o
Additional bone and calcium metabolism markers
o
Pre-dose plasma sample for pharmacokinetic analysis of REN001
x Administer the study drug with food under supervision of clinical staff and the time of 
dosing recorded. 
x Review concomitant medications, non-drug treatments and study medication 
compliance 
x Review of adverse events 
x Physician completion of subjects PMM phenotypic description (Week 24 only) 
x Review of pedometer eDiary data 
x Brief physical examination (including weight) 
x 12-lead ECG
x Vital signs (including temperature) 
x Obtain plasma samples for pharmacokinetic analysis of REN001 (1, 2, 3 and 4* hours 
postdose) 
x Review of last 7 days pedometer data 
x MFIS 
x BPI 
x SF-36 
x PGIS – muscle symptoms 

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x PGIS – fatigue symptoms 
x PGIC – muscle symptoms (Week 24 only) 
x PGIC – fatigue symptoms (Week 24 only) 
x PROMIS Short Form – FACIT Fatigue 13a 
x WPAI:SHP 
x 12MWT 
x 30STS 
x Capsule counts of remaining capsules including any opened IMP bottles 
x Subjects will be provided with a urine collection cup and instructions for collecting a 
second morning void at the Week 24 visit if they are unable to do this at the Study 
Center for any reason (Week 12 only) 
x Eye examinations (may be completed ± 14 days of the visit if required) 
Assessments should be conducted to ensure that the PRO questionnaires are completed prior 
to exercise testing and the 12MWT must be done at least 1 hour before the 30STS. 
*To ease subject burden, the 4-hour post dose blood may be omitted if the visit is extending
beyond what is reasonable, at the Investigator’s discretion.
If feasible, and at the Investigator’s discretion, these Visits may be conducted over two days. 
At the end of Visit 7 (Week 24) subjects must return all their unused study medication and 
may then leave the Study Center at the discretion of the supervising clinical staff after being 
provided with details of their Follow Up visit. 
6.7 
Follow Up Visit 
Subjects will either attend the Study Center or receive a home nursing visit (in countries 
where the regulatory authority allows), 21-28 days following the last dose of study 
medication for a Follow Up Visit. This visit will not be required if a subject chooses to enter 
the REN001 open label extension study at their Week 24 visit.  
At this visit, the following activities will be completed: 
x Review concomitant medications and non-drug treatments 
x Review of adverse events 
x Vital signs (including temperature) 
x Obtain a urine sample for pregnancy testing (WOCBP only) 
If clinically significant safety laboratory findings were apparent at the subjects last visit these 
should be followed up until resolved with blood samples for hematology and biochemistry 
and a urine sample for urinalysis as appropriate. 
6.8 
Early Termination Visit 
Subjects who discontinue taking study drug early should, if possible, have an Early 
Termination visit as soon as possible after the subject stops taking study drug. Where 
possible the Early Termination visit assessments should be completed in the study center as 
listed below. Site staff will need to provide subjects with meals and snacks at appropriate 
times during the visit to ensure subjects have enough energy prior to completing the exercise 
tests. 
x Review concomitant medications and non-drug treatments* 
x Review of adverse events* 

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x Brief physical examination (including weight) 
x Physician completion of subjects PMM phenotypic description 
x 12-lead ECG
x Vital signs (including temperature) * 
x Obtain blood samples for: 
o
Hematology (incl HbA1c)*
o
Biochemistry*
o
Additional bone and calcium metabolism markers
o
Plasma sample for pharmacokinetic analysis of REN001*
x Obtain second morning void urine sample for: 
o
Bone marker – NTX*
o
Urinalysis*
o
Drugs of abuse*
o
Urine for pregnancy testing (WOCBP only) *
x MFIS* 
x BPI* 
x SF-36* 
x PGIS – muscle symptoms* 
x PGIS – fatigue symptoms* 
x PROMIS Short Form – FACIT Fatigue 13a* 
x PGIC muscle symptoms (with respect to how they were on their last dosing day) * 
x PGIC fatigue symptoms (with respect to how they were on their last dosing day) * 
x WPAI:SHP* 
x 12MWT  
x 30STS 
x Capsule counts of remaining capsules including any opened IMP bottles* 
x Eye examination (may be completed ± 14 days of the visit if required) 
If the subject is unable to attend the Study Center for the full visit, then every effort should be 
made to complete the assessments marked with an asterisk (*) at the discretion of the 
Investigator this may be completed over 2 days if feasible. 
If the subject is withdrawing from the study: after their Early Termination Visit they should 
be instructed to return for the Follow Up Visit 21-28 days after their last dose of study 
medication. If the Early Termination Visit is 21 or more days after the last dose, then the 
Follow Up Visit is not needed. 
6.9 
Subject Continuation In Study Off IMP 
If a subject discontinues taking study drug, they will be strongly encouraged to continue in 
the study for their Week 12 and Week 24 visits (see Figure 3). If they agree to remain in the 
study off-IMP as a minimum they will be requested to complete the following assessments:  
x Review concomitant medications and non-drug treatments 
x Review of adverse events 

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x Vital signs (including temperature) 
x MFIS 
x 12MWT 

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Table 2: 
Schedule of Activities 
Time and Events Table 
Screening 
Baseline1,
2
(Day 1) 
Week 23 
(Day 14) 
Week 43 
(Day 28) 
Week 8
(Day 56) 
Week 122,
4
(Day 84) 
Week 
16 (Day 
112) 
Week 183 
(Day 126) 
Week 
20 (Day 
140) 
Week 242,
4
(Day 
168). 
Early 
Termn,2, 5
Follow 
Up3 (21-
28 days 
post last 
dose) 
Visit number
1 
2 
3 
4
5
6 
7
8
Window (days) 
±3 
±3 
±7 
±7 
±7 
Informed Consent 
X
Completion of Proforma and 
data entered into eCRF6 
X
Demographics 
X 
Medical/medication/drug/ 
alcohol/tobacco history7 
X
Physician completion of PMM 
phenotypic description 
X
X 
X 
Physical exam8 
X 
X 
X 
X 
X 
12-lead ECG
X
X
X 
X 
X 
Supine Vital signs (BP, PR 
and temperature) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum FSH9 
X 
HbA1c  
X 
X 
X 
Hepatitis B/C/HIV 
X 
Safety labs (inc. urinalysis) 
X 
X10 
X 
X 
X 
X 
X11 
X 
X11 
Blood sample for bone and 
calcium markers 
X
X 
X 
X 
Pregnancy Test (WOCBP 
only)12 
X
X
X 
X 
X 
X 
X 
X 
X 
X
Blood sample for genotyping13 
X 
Population PK blood sample14 
X 
X 
X 
X 
X 
X 
X 
Urine drugs of abuse 
X 
X 
X 
X 
X 
Urine NTX 
X 
X 
X 
X 

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Time and Events Table 
Screening 
Baseline1,
2
(Day 1) 
Week 23 
(Day 14) 
Week 43 
(Day 28) 
Week 8
(Day 56) 
Week 122,
4
(Day 84) 
Week 
16 (Day 
112) 
Week 183 
(Day 126) 
Week 
20 (Day 
140) 
Week 242,
4
(Day 
168). 
Early 
Termn,2, 5
Follow 
Up3 (21-
28 days 
post last 
dose) 
Sites to provide appropriate 
snacks and lunch 
X
X
X 
X 
X 
Pedometer eDiary data 
collection (inc. review) 
X
X15 
X 
X 
X 
X 
MFIS / PGIS (muscle 
symptoms), PGIS (fatigue 
symptoms) and PROMIS – 
Short form FACIT fatigue 
13a 
X
X
X 
X 
X 
X 
X 
SF-36 / BPI and WPAI:SHP 
X 
X 
X 
X 
X 
X 
PGIC (muscle symptoms) and 
PGIC (fatigue symptoms) 
X 
X 
12 Minute Walk Test 
X16 
X 
X 
X 
X 
30STS 
X 
X 
X 
X 
IMP Capsule Counts 
X 
X 
X 
X 
X 
X 
Eye examination 
X17 
X 
X 
X 
Wrist radiograph 
X18 
Concomitant medication 
review 
X-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
Dosing 
X19--------------------------------------------------------------------------------------------------------------------------------------------X 
AE collection and reporting 
X-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
1.
Screening visit must take place a maximum of 8 weeks before the Baseline visit. 
2.
If appropriate and feasible Baseline, Week 12, Week 24/Early Termination visits may be conducted over 2 days at the Investigators discretion. 
3.
In countries where the regulatory body allows, visit may be in the Study Center or a home nursing visit. 
4.
Only review of concomitant medications, AE’s MFIS and 12MWT will be conducted if the subject has discontinued from study drug treatment but has not withdrawn from the study. If the subjects 
had an ET visit within 2 weeks of either of these a visit is not required.
5.
As a minimum, subjects should have review of concomitant medication and AE’s, vital signs (including temperature), complete questionnaires, safety laboratory blood (including HbA1c, bone and
calcium markers and PK analysis) and urinalysis (including pregnancy tests for WOCBP, drugs of abuse and NTX) and IMP capsule counts. 
6.
Patient Screen Oversight Committee will review Proforma data and give a decision or request more information within 7 working days.
7.
Subjects will be excluded from the study at the Investigators discretion for alcohol and/or drug dependency. Use of opiates/cannabis for medical reasons is acceptable with prescription evidence or at 
the Investigators discretion. 
8.
Full physical exam, height and weight at Screening; full physical exam and weight at Baseline; brief, symptom-directed physical exam and weight only at Weeks 12 and 24.

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9.
Serum FSH testing for postmenopausal females 45years and older. 
10.
An additional 10 mL blood sample will be taken pre-dose at baseline and the serum will be stored frozen at the central laboratory as a reference sample in the event that re-analysis of protocol stated
tests are required.
11.
If any clinically significant abnormalities are noted at the Week 24 visit, these should be followed up until resolved.
12.
WOCBP will be supplied with urine home pregnancy test kits at Study Center visits to test at Weeks 8, 16 and 20. The Study Center must contact the subject to confirm the pregnancy test result in a
timely manner.
13.
Blood sample for local genotype testing will only be conducted with prior Sponsor approval and definitive results must be available prior to the Baseline visit.
14.
At the Baseline, Week 12 and Week 24 visits, blood samples will be taken pre-dose and then at 1, 2, 3, and 4 hours post-dose. On the other visits, a single sample can be taken at any time post-dose 
provided the dosing date and time are recorded. 
15.
Review of Screening (pre-treatment) pedometer data at Baseline.
16.
Screening 12MWT must be at least 4 weeks before the Baseline 12MWT.
17.
The Screening eye examination can be performed at any time between the initial Screening and Baseline Visit for scheduling reasons. 
18.
Subjects <25 years old only.
19.
Dosing on Baseline, Week 12 and Week 24 visits should be under the supervision of the site staff.

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7 
PARAMETERS AND METHODS OF ASSESSMENT 
7.1 
Safety Parameters 
7.1.1 Adverse Events 
7.1.1.1 Definitions 
Pre-treatment Event (PTE) 
A PTE is defined as any untoward medical occurrence in a clinical investigation 
subject who has signed informed consent to participate in a study but prior to 
administration of any study medication; it does not necessarily have to have a causal 
relationship with study participation. 
Adverse Event (AE) 
An AE is any untoward medical event that occurs in a subject who has received study 
medication and does not necessarily have a causal relationship with study treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an 
investigational product, whether or not related to the product. 
A treatment-emergent AE will be defined as an AE that begins or that worsens in 
severity after the first dose of study drug has been administered. 
An adverse drug reaction (ADR) is any untoward and unintended response in a 
subject to an IMP which is related to any dose administered to that subject. 
An unexpected adverse reaction is an adverse reaction the nature and severity of 
which is not consistent with the information about the medicinal product in the 
Investigator's Brochure. 
All PTEs/AEs, including intercurrent illnesses, occurring during the study will be 
documented in the eCRF. 
Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should 
be recorded appropriately as a PTE(s) or as an AE(s). 
7.1.1.2 Laboratory values and ECG findings 
Changes in laboratory values or ECG parameters are only considered to be PTEs or 
AEs if they are judged to be clinically significant (i.e., if some action or intervention 
is required or if the Investigator judges the change to be beyond the range of normal 
physiologic fluctuation). A laboratory re-test and/or continued monitoring of an 
abnormal value are not considered an intervention. In addition, repeated or additional 
noninvasive testing for verification, evaluation or monitoring of an abnormality is not 
considered an intervention. 
If abnormal laboratory values or ECG findings are the result of pathology for which 
there is an overall diagnosis (e.g., increased creatinine in renal failure), the diagnosis 
only should be reported appropriately as a PTE or as an AE. 
7.1.1.3 Pre-existing conditions 
Pre-existing conditions (present at the time of signing of informed consent) are 
considered concurrent medical conditions and should NOT be recorded as PTEs. 
Baseline evaluations (e.g., laboratory tests, ECG, X-rays etc.) should NOT be 

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recorded as PTEs. However, if the subject experiences a worsening or complication of 
such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE/AE. Investigators should ensure that the event term recorded 
captures the change in the condition (e.g., “worsening of…”).  
If a subject has a pre-existing episodic condition (e.g., asthma, epilepsy) any 
occurrence of an episode should only be captured as a PTE/AE if the episodes become 
more frequent, serious or severe in nature, that is, Investigators should ensure that the 
AE term recorded captures the change in the condition from Baseline (e.g., 
“worsening of…”). 
If a subject has a degenerative concurrent condition (e.g., cataracts, arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a 
greater extent to that which would be expected. Again, Investigators should ensure 
that the AE term recorded captures the change in the condition from Baseline (e.g., 
“worsening of…”). 
7.1.1.4 Worsening of PTEs or AEs 
If the subject experiences a worsening or complication of a PTE after starting 
administration of the study medication, the worsening or complication should be 
recorded appropriately as an AE. Investigators should ensure that the AE term 
recorded captures the change in the condition (e.g., “worsening of…”). 
If the subject experiences a worsening or complication of an AE after any change in 
study medication, the worsening or complication should be recorded as a new AE. 
Investigators should ensure that the AE term recorded captures the change in the 
condition (e.g., “worsening of…”). 
7.1.1.5 Adverse Events of Special Interest 
Adverse events of special interest are those of scientific and medical concern specific 
to the Sponsor’s product for which ongoing monitoring and rapid communication by 
the Investigator to the Sponsor may be warranted. These events require further 
investigation in order to characterize and understand them. Based on this assessment, 
the Sponsor plans to include events of special interest as follows: 
x Changes in laboratory parameters of muscle injury associated with clinically 
significant adverse events  
x Changes observed after Baseline in formation or exacerbation of cataracts or, 
visual acuity. A spherical equivalent change of >0.75 diopters will be 
considered to be a clinically significant change regardless of changes in lens 
clarity. 
x Occurrence of fractures after Baseline. 
While AESIs may not meet the definition of an SAE, they should be reported in the 
same manner as SAEs (See Section 7.1.1.9). This allows them to be tracked in more 
detail and followed up for additional information if required. When completing the 
SAE form there is an extra box to check to confirm that the event is an AESI. AESIs 
will not be reported to the Regulatory Authorities unless they are also SUSARs.  
7.1.1.6 Assessment of Adverse Event 
Each AE will be assessed by the Investigator with regard to the following categories. 

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7.1.1.6.1 Seriousness 
A serious AE (SAE) (or serious ADR or unexpected serious adverse reaction) is 
defined as any untoward medical occurrence that at any dose: 
x Results in death 
x Is life-threatening. (This means that the subject is at risk of death at the time of 
the event; it does not mean that the event hypothetically might have caused 
death if it were more severe.) 
x Requires inpatient hospitalization or prolongs existing hospitalization 
x Results in persistent or significant disability or incapacity 
x Is a congenital anomaly or birth defect 
x Is an important medical event(s) that may not be immediately life-threatening 
or result in death or hospitalization but that may jeopardize the subject or 
require intervention to prevent one of the above outcomes. 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 subject hospitalization, or the development of drug dependency or 
drug abuse. 
Note: Cases of potential drug-induced liver injury as assessed by laboratory test 
values (“Hy’s Law Cases”) are also reportable. If a subject develops abnormal values 
in AST or ALT or both, concurrent with abnormal elevations in total bilirubin and no 
other known cause of liver injury, that event would be classified as a Hy’s Law Case. 
In this clinical study, the term SAE will be understood to also include Hy’s Law 
Cases. 
Medical and scientific judgment should be exercised in deciding whether a case is 
serious and whether expedited reporting is appropriate. 
7.1.1.6.2 Severity 
The intensity of each PTE/AE must be assessed by the Investigator using one of the 
following categories, and recorded in the eCRF: 
x Mild: An AE that does not interfere with usual activities 
x Moderate: An AE that interferes with usual activities 
x Severe: An AE that prevents usual activities 
7.1.1.6.3 Causality 
The Investigator will assess the causality / relationship between the study drug and the 
AE and record that assessment in the eCRF. Causality will be shown as Related, 
Possibly Related, or Not related. 
7.1.1.7 Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs and 
AEs. 
The relationship should be assessed as Yes if the Investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the 
relationship should be assessed as No. 

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7.1.1.8 Collection and Reporting of AEs 
7.1.1.8.1 PTE and AE Collection Period 
Collection of PTEs will commence from the time the subject signs the informed 
consent to participate in the study and continue until the subject is first administered 
study medication (Day 1) or until screen failure.  
Collection of AEs will commence from the time that the subject is first administered 
study medication (Day 1). Routine collection of AEs will continue until the Follow 
Up visit 21 to 28 days after the last study dose. 
7.1.1.8.2 PTE and AE Reporting 
At each study visit, the Investigator will assess whether any subjective AEs have 
occurred. A neutral question, such as “How have you been feeling since your last 
visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects 
experiencing a serious PTE must be monitored until the symptoms subside and any 
clinically relevant changes in laboratory values have returned to baseline or there is a 
satisfactory explanation for the change. 
Non-serious PTEs, related or unrelated to the study procedure, do not need to be 
followed-up for the purposes of the protocol. 
All subjects experiencing AEs, whether considered associated with the use of the 
study medication or not, must be monitored until the symptoms subside and any 
clinically relevant changes in laboratory values have returned to baseline or until there 
is a satisfactory explanation for the changes observed. All PTEs and AEs will be 
documented in the PTE/AE page of the eCRF, whether or not the Investigator 
concludes that the event is related to the study medication. The following information 
will be documented for each event: 
x Event term. 
x Start and stop date {and time}. 
x Severity. 
x Investigator’s opinion of the causal relationship between the event and 
administration of study medication (not completed for PTEs). 
x If no, provide alternative etiology or explanation. 
x Investigator’s opinion of the causal relationship to study procedure(s), 
including the details of the suspected procedure. 
x Action concerning study medication (not applicable for PTEs). 
x Outcome of event. 
x Seriousness. 
7.1.1.9 Reporting Serious Adverse Events 
All SAEs that occur during the study from the signing of the informed consent and up 
to 30 days after receiving the last dose of study drug, whether considered to be 
associated with the study drug or not, must be reported within 24 hours by email or 
fax to the study pharmacovigilance (PV) team. The minimum information required for 
an initial report is: 
x Sender of report (name, address of Investigator) 

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x Subject identification (subject study number, initials, NOT subject name) 
x Protocol number 
x Description of SAE and reason why the event is categorized as serious 
x Causality assessment, if possible 
However, as far as possible all points on the SAE form should be covered in the initial 
report and the completed SAE form faxed or emailed to the pharmacovigilance team 
(details below). The original SAE form should be sent to the address below and the 
Medical Monitor and the Sponsor Chief Medical Officer informed by email. In 
addition, the event must be documented in the eCRF. 
SAE info 
Bionical Emas 
Suite 209, Spirella Building 
Bridge Road 
Letchworth Garden City 
Hertfordshire 
SG6 4ET 
United Kingdom 
Email: Drug.safety@bionical-
emas.com Fax: +44 (0) 1462 600 456 
US Fax: +1 206 260 7410 
After receipt of the initial report, the PV team will review the information and, if 
necessary, contact the Investigator, to obtain further information for assessment of the 
event. Bionical Emas the PV vendor will be responsible for all information processing 
and reporting according to local legal requirements. Where necessary, Investigators 
will inform the authorities in their own countries. 
7.1.1.10 Reporting Pregnancies 
Although pregnancy should not be considered as an SAE per se, any pregnancies 
occurring in a study subject between Screening and the end of the contraception 
requirements (14 weeks after last dose for males, 30 days after last dose for WOCBP) 
must be reported and captured as if they were SAEs. 
If any subject is found to be pregnant during the study, she should be withdrawn and 
study drug should be immediately discontinued. In addition, any pregnancies in the 
partner of a male subject during the study or for 14 weeks after the last dose should 
also be recorded following authorization from the subject’s partner. 
All reported pregnancies will be followed up to final outcome, using the paper 
Pregnancy Monitoring Report Form. The outcome, including any premature 
termination, must be reported to the Sponsor. An evaluation after the birth of the child 
will also be conducted. 
Reports should be sent within 24 hours to the contacts detailed above, using the 
Pregnancy Monitoring Report Form. If the female subject and/or female partner of a 
male subject agrees to the primary care physician being informed, the Investigator 
should notify the primary care physician that the subject/female partner of the subject 

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was participating in a clinical study at the time she became pregnant and provide 
details of treatments the subject received. 
7.1.1.11 Follow-up of Adverse Events 
All AEs experienced by a subject, irrespective of the suspected causality, will be 
monitored until the event has resolved, any abnormal laboratory values have returned 
to baseline or stabilized at a level acceptable to the Investigator, Medical Monitor 
and/or Sponsor Chief Medical Officer or designee, or until there is a satisfactory 
explanation for the changes observed, or until the subject is lost to follow-up. 
7.1.1.12 Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities 
The Sponsor will be responsible for reporting all suspected unexpected serious 
adverse reactions (SUSARs) and any other applicable SAEs to regulatory authorities, 
Investigators and IRBs or IECs, as applicable, in accordance with national or regional 
regulations in the countries where the study is conducted. Relative to the first 
awareness (Day Zero) of the event by/or further provision to the Sponsor or Sponsor’s 
designee, SUSARs will be submitted within 7 days for fatal and life-threatening 
events and 15 days for other serious events, unless otherwise required by national 
regulations. The Sponsor will also prepare an expedited report for Events Requiring 
Other Actions, where these might materially alter the current risk-benefit assessment 
of an IMP or that would be sufficient to consider changes in the investigational 
medicinal products administration or in the overall conduct of the trial. The 
investigational site also will forward a copy of all expedited reports to his or her IRB 
or IEC in accordance with national regulations. In addition, once a year throughout 
the clinical trial or upon request, a Development Safety Update Report (DSUR) will 
be submitted to the concerned Competent Authorities (CAs) and IEC/IRBs taking into 
account all new available safety information received during the reporting period. 
7.1.2 Clinical Laboratory Safety Tests 
Laboratory assessments will be performed by a central laboratory. Details of the urine 
and blood sampling procedures and any subject restrictions (e.g. withholding 
supplements) and subsequent storage and shipment of samples can be found in the 
REN001-201 Laboratory Manual. Sites will be provided with lab kits from the central 
laboratory. Details of parameters to be tested are listed in Table 3. 

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Table 3: 
Safety Laboratory Parameters 
Biochemistry 
Albumin 
Alanine aminotransferase (ALT) 
Aldolase 
Alkaline phosphatase  
Aspartate aminotransferase (AST) 
Bilirubin (Total, direct and indirect) 
Bone specific alkaline phosphatase (BSAP)* 
Calcium 
Cholesterol (Total, Low Density Lipoprotein (LDL) and 
High Density Lipoprotein (HDL)) 
C-reactive protein
Creatinine
Creatine phosphokinase (CK)
eGFR using CKD-EPI (at Screening only)**
FSH (screening, postmenopausal females only)
Gamma glutamyl transferase (GGT)
Glucose (non-fasted)
Human chorionic gonadotropin (hCG) (at screening,
WOCBP only)
Lipase
Magnesium
Parathyroid hormone (PTH)*
Phosphate
Potassium
Protein (Total)
Sodium
Triglycerides
Troponin I
Urea
Uric acid
Vitamin D*
* Collected at Baseline, Week 12, Week 24 or ET visit only
** subjects ethnicity data will be required to calculate 
eGRF accurately 
Hematology 
Basophils 
Eosinophils 
Hemoglobin 
HbA1c (Screening and Week 24/ET 
only) 
Hematocrit (Packed cell volume) 
Large unstained cells 
Lymphocytes  
Mean corpuscular volume (MCV) 
Monocytes 
Neutrophils 
Platelet count 
Red cell count 
Reticulocytes 
White cell count 
Serological Markers (Screening only) 
HIV 
HBsAg 
HBcAb 
Anti-hepatitis C virus serology (by multi-antigen enzyme immunoassay (EIA)) 
Urinalysis 
Blood, Glucose, Ketone, Protein, pH, Specific Gravity, Nitrite, Leukocytes, Bilirubin and 
Urobilinogen. 
Any significant abnormalities in the urinalysis should be investigated via microscopy and the 
findings reported in the eCRF.  
hCG: To be measured at the Study Center at Weeks 4, 12, 24 and Follow Up. To be measured by 
subject at home (using tests supplied) at Weeks 8, 16 and 20. 
Drugs of abuse: cocaine, cannabinoids, opiates, barbiturates, benzodiazepines, methadone, and 
amphetamines (at Screening, Baseline, Week 12, Week 24 or ET visit only) 
Urine N-terminal telopeptide (NTX) will collected at second morning void (at Baseline, Week 12, 
Week 24 or ET visit only) 
An extra blood sample (10 mL) will be taken pre-dose at the Baseline visit and the 
serum will be stored frozen at the central laboratory through to completion of the 
study for possible use as a baseline reference should additional safety laboratory tests 

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or markers of disease activity be indicated. Samples will be stored frozen until the end 
of the study, when they will be destroyed, on approval from the Sponsor. 
Laboratory test results can be repeated if necessary. Any clinically significant 
abnormal laboratory test result (e.g., findings that lead to more extensive investigation 
and/or indicate a risk to the health of the subject) should be reported as an adverse 
event. (The Investigator should assess the possible relationship to study drug as is the 
case for all other adverse events.) 
7.1.3 Blood Volume 
The approximate volume of blood to be taken from each subject during the study is 
detailed in Table 4. Additional blood may be required for repeats of safety laboratory 
tests. 
Table 4: 
Approximate Blood Volume Required for Study 
Test 
Number of 
Samples 
Volume 
(mL) 
Total 
(mL) 
Hematology (including HbA1c) 
7 
2 
14 
Biochemistry (including aldolase, 
troponin I, FSH and hCG as applicable) 
7
5
35 
Serology (including Hep B/C/HIV) 
1 
8.5 
8.5 
PK samples 
18 
4 
72 
Baseline serum sample 
1 
10 
10 
Bone and calcium markers (including 
BSAP, PTH, and vitamin D) 
3
4
12 
Genotyping (if required) 
1 
5 
5 
Total volume (mL) 
156.5 
7.1.4 Physical Examination 
All physical examinations will be carried out by a suitably qualified doctor or 
equivalent. At Screening and Baseline the subject will have a full physical 
examination, to include an assessment of head, neck, heart, lungs, abdomen, skin 
(including hair and nails), peripheral circulation, joints, general appearance, and a 
neurological examination. Any abnormalities should be recorded in the study eCRF. 
At Weeks 12 and Weeks 24 subjects will have a brief symptom-directed physical 
examination, which should include general appearance, heart, lungs, skin, and a 
neurological examination. Clinically significant changes from the baseline 
examination should be assessed. Other systems examined should be determined by 
clinical findings and any adverse events reported. 
7.1.5 Height and Weight and Body Mass Index 
Subjects should have weight and height measured while wearing indoor clothing and 
with shoes off. The Body Mass Index (BMI) will be calculated in the eCRF 
(expressed to 1 decimal place) using metric units with the formula provided below: 
x 
BMI = weight (kg)/height (cm) 2 

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x Height will be collected in centimeters (without decimal places) at Screening 
only, and weight will be collected in kilograms (to 1 decimal place). 
7.1.6 Vital Signs Measurements 
Blood pressure (systolic and diastolic mmHg) and pulse (beats per minute) will be 
measured. Subjects should be supine for at least 5 minutes before taking the 
measurement. All measurements will be taken with the subject in a supine position. 
Blood pressure will be measured using the subject’s dominant arm, where possible 
this should be done throughout the study, and recorded to the nearest mmHg.  
Pulse should be measured in the brachial/radial artery for at least 30 seconds. 
7.1.7 Body Temperature 
Body temperature will be recorded using a digital thermometer. Any results <35oC 
should be repeated to ensure correct placement of the thermometer. 
7.1.8 Electrocardiogram Recording 
Single ECG measurements using a 12-lead ECG machine will be taken after the 
subject has rested for at least 10 minutes in a supine position. To ensure safety of the 
subjects, a qualified individual at the site will evaluate all ECGs. 
If the QTcF is t450 msec at Screening or QTcF is t500 msec for any post-baseline 
ECG, the ECG intervals should be inspected carefully to ensure that the RR interval 
has been recorded correctly, and a single ECG will be repeated at 5-minute intervals 3 
times. If these values are consistently high (t450 or 500 msec, respectively), or if the 
Investigator or Medical Monitor has any concern, as a precautionary measure, the 
subject will be screen failed or discontinue study treatment as appropriate (see Section 
3.6). 
If a machine read QTcF value is prolonged, as defined above, repeat measurements 
may not be necessary, provided a qualified physician’s interpretation determines that 
the QTcF values are acceptable for the individual. In some cases, it may be necessary 
to repeat abnormal ECGs to rule out improper lead placement as contributing to the 
ECG abnormality. It is important that leads are placed in the same positions each time 
in order to achieve precise ECG recordings.  
ECGs may be sent to an ECG vendor for centralized reading at a later date if deemed 
necessary. 
7.1.9 Eye Examination 
All eye examinations should be carried out by an appropriately qualified professional. 
Best efforts should be made to ensure the same professional undertakes the slit lamp 
examinations for a particular subject. Each lens should be classified and graded 
against the Lens Opacity Classification System III, (Chylack et al, 1993).  
In addition, best corrected distance visual acuity (including refraction) should also be 
assessed. A spherical equivalent change of >0.75 diopters will be considered to be a 
clinically significant change regardless of changes in lens clarity. 
It is important that qualified professionals administering the examination are fully 
trained to reduce variability across Study Centers. The data should be collected in the 
separate eye examination workbook. 

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For scheduling reasons, the above assessments may be conducted any time between 
the initial Screening visit and Baseline for the pre-treatment assessment and ± 14 days 
of the visit window given for the eye assessments performed at the Week 12 and 
Week 24 visits. Note for re-screened subjects their original eye examination can be 
used and the examination does not need to be repeated if its within 6 months of the 
original eye examination date. 
In addition, any subject who experiences any visual symptoms during the study 
should have an additional ophthalmic examination as appropriate. 
7.1.10 12-Minute Walk Test 
The 12MWT is a practical test that requires simple equipment to execute. This test 
measures the distance a subject can walk on a flat, hard surface in a period of 12 
minutes. It is important that operators administering the test are fully trained to reduce 
variability across Study Centers. There must be a minimum of 4 weeks between the 
Screening and Baseline 12MWT to minimize any training effect. Subjects who walk 
further than 1000 m at Screening will be excluded from the study. Subjects who walk 
≤ 1000 m at Screening but subsequently walk greater than 1000 m at Baseline will be 
allowed to continue into the study but will be excluded from the per protocol analysis. 
Further details are given in the REN001-201 Exercise Manual. 
7.1.11 36 Item Health Survey V2.0® (SF-36) 
The 36-Item Health Survey Version 2.0® asks questions which cover eight health 
concepts: physical functioning, bodily pain, role limitations due to physical health 
problems, role limitations due to personal or emotional problems, emotional well-
being, social functioning, energy/fatigue, and general health perceptions. It also 
includes a single item that provides an indication of perceived change in health. A 
one-week recall period will be used. 
7.1.12 Modified Fatigue Impact Scale (MFIS) 
The MFIS is a detailed tool, that is completed by the subject personally, rather than 
having an interview and thus, no training is required to deliver it. Scoring is simple, 
the score reflects functional limitation due to fatigue experienced within the previous 
7 days rather than a measure of the current level of fatigue. It may be used in both the 
clinical and the research setting in people for whom fatigue is a predominant 
symptom.  
There are 21 items, each of which is scored 0 (Never) to 4 (Almost always), providing 
a continuous scale of 0–84. It is composed of three subscales that describe the impact 
of fatigue on physical, cognitive and psychosocial functioning: 
Physical functioning (9 items) reflects motivation, effort, stamina, and coordination. 
The physical subscale can range from 0 to 36. It is calculated by adding items 
4+6+7+10+13+14+17+20+21. 
Cognitive functioning (10 items) concerns concentration, memory, thinking and 
organization of thoughts. The cognitive subscale can range from 0 to 40. It is 
calculated by adding items 1+2+3+5+11+12+15+16+18+19. 
Psychosocial functioning (2 items) describes the impact of fatigue upon isolation, 
emotions, workload, and coping. The psychosocial subscale can range from 0 to 8. It 
is calculated by adding items 8+9. 
All items are scaled so that a higher score indicates a greater level of fatigue.  

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See Appendix 2. 
7.1.13 Brief Pain Inventory (BPI) 
The Brief Pain Inventory (Short Form) rapidly assesses the severity of pain and its 
impact on functioning. It is widely used in research and clinical settings. 
Four severity items will be investigated by the responses to the worst, least and 
average pain in last 24 hours and the pain right now (Questions 3, 4, 5 and 6). The 
higher score indicates worse pain. A pain severity score will be calculated as the mean 
of the non-missing 4 severity items. A higher score indicates greater pain severity. 
In addition, the average pain interference score will be derived as the average of the 
responses to the 7 components to Question 9. A higher score indicates the more pain 
interferes with daily functioning. 
See Appendix 3. 
7.1.14 Patient Global Impression of Severity (PGIS) – Muscle Symptoms 
The patient will be asked to rate the severity of their PMM muscle symptoms over the 
past 7 days. 
Overall, how would you rate the severity of your muscle symptoms related to your 
Primary Mitochondrial Myopathy over the past 7 days? 
a.
 Absent
b.  Mild
c.
 Moderate
d.  Severe
e.
 Very Severe
7.1.15 Patient Global Impression of Severity (PGIS) – Fatigue Symptoms 
The patient will be asked to rate the severity of their PMM fatigue symptoms over the 
past 7 days. 
Overall, how would you rate the severity of your fatigue symptoms related to your 
Primary Mitochondrial Myopathy over the past 7 days? 
a.
 Absent
b.  Mild
c.
 Moderate
d.  Severe
e.
 Very Severe
7.1.16 Patient Global Impression of Change (PGIC) – Muscle Symptoms 
At the end of study treatment (Day 168) or Early Termination visit with respect to the 
last day of study treatment, the subject will be asked to rate their degree of 
improvement or worsening of PMM muscle symptoms compared to before the start of 
study drug, using a 7-point scale, standardized PGIC scale. 
Overall, how would you rate the change in the severity of your muscle symptoms 
related to your Primary Mitochondrial Myopathy since starting the study? 

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a.
Very much improved
b.
Moderately improved
c.
Minimally improved
d.
No change
e.
Minimally worse
f.
Moderately worse
g.
Very much worse
7.1.17 Patient Global Impression of Change (PGIC) – Fatigue Symptoms
At the end of study treatment (Day 168) or Early Termination visit with respect to the 
last day of study treatment, the subject will be asked to rate their degree of 
improvement or worsening of PMM fatigue symptoms compared to before the start of 
study drug, using a 7-point scale, standardized PGIC scale.
Overall, how would you rate the change in the severity of your fatigue symptoms 
related to your Primary Mitochondrial Myopathy since starting the study?
a.
Very much improved
b.
Moderately improved
c.
Minimally improved
d.
No change
e.
Minimally worse
f.
Moderately worse
g.
Very much worse
7.1.18 Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem (WPAI:SHP)
The Work Productivity and Activity Impairment (WPAI) questionnaire is a well 
validated instrument to measure impairments in work and activities due to a specific 
disease. Outcomes are expressed as impairment percentages, with higher numbers 
indicating greater impairment and less productivity, i.e., worse outcomes. See 
calculation below:
Scores:
Percent work time missed due to PMM: 100 x Q2 / (Q2 + Q4)
Percent impairment while working due to PMM: 100 x Q5 / 10
Percent overall work impairment due to PMM: 100 x Q2 / (Q2 + Q4) + [ (1-
(Q2 / (Q2 + Q4))) x (Q5 / 10)]
Percent activity impairment due to PMM: 100 x Q6 / 10
See Appendix 4.
7.1.19 PROMIS Short Form v1.0 – Fatigue 13a (FACIT-Fatigue)
The PROMIS® (Patient-Reported Outcomes Measurement Information System) 
Fatigue items assess a range of self-reported symptoms, from mild subjective feelings 
of tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that 
likely decreases one’s ability to execute daily activities and function normally in 

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family or social roles. The fatigue short forms are universal rather than disease-
specific. All assess fatigue over the past seven days. The score is calculated by adding 
all the individual question scores (scores of 1 to 5) together to give a total score. 
Hence a range of scores between 13 and 65 are possible with a higher score indicating 
a greater level of fatigue. 
See Appendix 5. 
7.1.20 30 Second Sit-To-Stand Test 
The purpose of the 30 second sit-to-stand test is to assess leg strength and endurance. 
Subjects are required to sit and rise to full standing position as many times as they can 
in 30 seconds. A subject can only conduct the test if they are able to stand without 
using their arms to assist them out of the chair. A score of 0 and a reason for not 
completing the test must be noted in the eCRF in these circumstances. Details of any 
orthotics used should also be recorded in the eCRF. This test must be completed at 
least an hour after the 12MWT. 
Further details are given in the REN001-201 Exercise Manual. 
7.1.21 Pedometer Step Counts and eDiary  
At the completion of the Screening visit each subject will be given a pedometer 
(3DFitBud model A420S or equivalent). The site staff will set-up the pedometer with 
the eDiary (Medrio formerly HMD Clinical Ltd) and train the subject on how and 
when to use it. Subjects will collect their daily step counts (from waking until 
bedtime) and should enter the total step count each day in the eDiary. Subjects will be 
asked to start using the pedometer for 14 days once they have returned home after 
their Screening visit. For the remainder of the study subjects will use the pedometer 
and collect the daily step counts for 7 consecutive days within a 2-week window 
before each study visit. Reminders will be sent to subjects who forget to record the 
step count data. In addition, the eDiary will allow subjects to enter missed data up 
until midday the next day. If subjects are unable or non-compliant in using either the 
pedometer or eDiary for any reason, data will not be analyzed for that subject. 
7.1.22 PMM Phenotypic Description 
To enable comparative descriptions of the phenotypic state of each subjects’ disease, 
3 questions, taken from the Newcastle Mitochondrial Disease Adult Scale (NMDAS) 
will be completed by the physician. A physician will complete the questions at 
Baseline and Week 24 (or at the Early Termination Visit).  
The questions do not need to be read verbatim, but the subject should be questioned to 
determine the response which best describes the subject’s function. To ensure 
consistency in interpretation the same physician (where possible) should assess 
subjects on both occasions. 
Rate function over the preceding 4-week period, according to patient and/or 
caregiver interview only. The clinician’s subjective judgement of functional ability 
should not be taken into account. 
Question 1 – Exercise Tolerance 
0. Normal
1. Unlimited on flat – symptomatic on inclines or stairs.

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2. Able to walk <1000m on the flat. Restricted on inclines or stairs - rest needed
after 1 flight (12 steps).
3. Able to walk <500m on the flat. Rest needed after 8 steps on stairs.
4. Able to walk <100m on the flat. Rest needed after 4 steps on stairs.
5. Able to walk <25m on the flat. Unable to do stairs alone.
Question 2 – Gait Stability 
0. Normal
1. Normal gait – occasional difficulties on turns, uneven ground, or if required to
balance on narrow base.
2. Gait reasonably steady. Aware of impaired balance. Occasionally off balance
when walking.
3. Unsteady gait. Always off balance when walking. Occasional falls. Gait
steady with support of stick or person.
4. Gait grossly unsteady without support. High likelihood of falls. Can only
walk short distances (< 10m) without support.
5. Unable to walk without support. Falls on standing.
Rate current status according to examination performed at the time of assessment 
Question 3 – Myopathy 
0. Normal
1. Minimal reduction in hip flexion and/or shoulder abduction only (e.g., MRC
4+/5).
2. Mild but clear proximal weakness in hip flexion and shoulder abduction
(MRC 4/5). Minimal weakness in elbow flexion and knee extension (MRC
4+/5 – both examined with joint at 90 degrees).
3. Moderate proximal weakness including elbow flexion and knee extension
(MRC 4/5 or 4 -/5) or difficulty rising from a 90-degree squat.
4. Waddling gait. Unable to rise from a 90-degree squat (=a chair) unaided.
5. Wheelchair dependent primarily due to proximal weakness.
7.1.23 Pharmacokinetic Blood Samples 
Blood samples for determination of REN001 concentrations will be collected via a 
direct venipuncture or indwelling cannula.  
A 4.0 mL blood sample, to provide approximately 2 mL of plasma for 
pharmacokinetic analysis, will be collected into an appropriately labelled tube. 
Sample handling instructions will be provided in the REN001-201 Laboratory 
Manual. The plasma samples will be stored at the central lab prior to analysis. Plasma 
samples will be transferred from the central lab to the bioanalytical laboratory on dry 
ice to maintain frozen conditions. 
Analysis of REN001 concentrations in plasma will be performed using a validated 
analytical method.  

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After completion of the study any remaining PK samples may also be analyzed for 
metabolites. 
7.1.24 Genotyping Blood Samples 
If a subject meets all criteria for enrollment into the study but a definitive 
mitochondrial DNA genotype has not been established, the Study Center should seek 
Sponsor approval to conduct local genotype testing for the subject. The Sponsor will 
evaluate and approve this testing for the study on a case by case basis. 
A 5.0 mL blood sample for the determination of mitochondrial DNA genotyping will 
be collected via a direct venipuncture or indwelling cannula. Samples should be 
handled and processed according to local recommendations. 
Definitive results of mitochondrial DNA mutation must be available before 
commencement of the subjects Baseline visit. The Screening period may be extended 
to accommodate collection of genotyping results. 

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8 
STATISTICAL METHODS 
A formal Statistical Analysis Plan (SAP) will be developed and finalized prior to 
locking the study database. The full details of data presentations and analyses will be 
provided in the SAP. Additional statistical analyses other than those described in this 
section may be performed if deemed appropriate and included in the SAP. Any 
deviations from the final SAP will be discussed in the final study report.  
8.1 
Study Subjects  
8.1.1 Disposition of Subjects 
The number and percentage of subjects entering and completing the study will be 
presented overall and by treatment group. Reasons for withdrawal will also be 
summarized. 
8.1.2 Protocol Deviations 
Deviations from the protocol will be categorized as “minor” or “major” in cooperation 
with the Sponsor. Deviations will be assessed regularly and finalized prior to database 
lock.  
8.1.3 Analysis Populations  
Screened Set 
All subjects who sign the informed consent form. 
Randomized Set 
All subjects who are randomized. 
Full Analysis Set (FAS) 
All randomized subjects who receive at least one dose 
of study treatment. 
Modified Analysis Set 
All randomized subjects who receive at least one dose 
of study treatment and at least one on-treatment 
measurement*. 
Safety Set 
All subjects who receive at least one dose of study 
treatment. 
Per protocol (PP) Set 
All subjects in the FAS who do not violate inclusion or 
exclusion criteria and/or deviate from the protocol, in a 
way that could influence their efficacy assessment. 
Subjects who walk more than 1000m in the Baseline 
12MWT will also be excluded from the set. 
PK Set 
All subjects in the FAS who receive REN001 and have 
at least 1 evaluable post-dose PK measurement (even if 
this is ˂Level of Quantification (LOQ)). 
* For the primary endpoint this will be 12MWD
The FAS will be used for reporting demographic and baseline characteristic data, and 
as the primary analysis population for efficacy. Subjects will be analyzed by planned 
treatment. The PP set will be used for sensitivity analyses of the primary and 
secondary endpoints.  
All safety analyses will be based upon the Safety Set. Subjects will be analyzed by the 
treatment received. 
After all the data have been verified/coded/entered into the database, a review will be 
performed. The purpose of this review will be to define the analysis populations. The 
review will also check the quality of the data, identify outliers, and make decisions on 
how to deal with any data issues (e.g., missing values, withdrawals, protocol 

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deviations). After the pre-analysis review, resolution of all issues and documentation 
of all decisions, the database will be locked.  
8.2 
General Considerations 
8.2.1 Statistical Hypotheses 
The null (H0) and alternative (H1) hypotheses for the primary endpoint, can be 
expressed as: 
H0: PREN = PPLA
H1: PREN ≠ PPLA
where PREN and PPLA are the Week 24 mean changes from baseline in 12MWD for 
REN001 and Placebo respectively. 
All statistical testing will be at the 5% level of significance (2-sided) and all point 
estimates for the comparison between treatment groups will be accompanied by 2-
sided 95% confidence intervals. 
8.2.2 Determination of Sample Size 
A sample size of 186 subjects (93 per treatment group) provides 90% power, with a 
two-sided significance level of 5%, of obtaining a statistically significant difference 
between two treatment groups for the distance walked during the 12MWT. This 
assumes a treatment effect (difference to placebo in mean change from baseline) size 
of 60 meters. The standard deviation for the changes from baseline observed in Study 
REN001-101 was approximately 100 meters. A higher standard deviation, 125 
meters, has been assumed for this study due to the longer assessment period (24 
weeks instead of 12 weeks) and the larger number of sites included in this study. 
Allowing for a reduction in power due to subject withdrawals a total of approximately 
200 subjects will be randomized. 
8.2.3 Control of the Type 1 Error Rate 
To preserve the Type 1 error a fixed sequence testing procedure will be adopted. The 
order of testing will be: 
1. Change from Baseline at Week 24 in distance walked during the 12MWT
2. Change from Baseline at Week 24 in the MFIS Physical subscale score
3. PGIC score (muscle symptoms) at the end of treatment
8.2.4 Data Summaries 
All endpoints will be summarized by treatment group and visit. Continuous data will 
be summarized using descriptive statistics (e.g., mean and standard deviation) and 
categorical data will be summarized using frequency tables (counts and percentages). 
8.3 
Demographics, Baseline Characteristics and Concomitant Medications 
Demographics, baseline characteristics, medical history and concomitant medication 
data will be summarized by treatment group and over all subjects.  
WHODrug and MedDRA coding dictionaries will be used for the concomitant 
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8.4 
Treatment Compliance 
Treatment compliance will be assessed through capsule counts and will be 
summarized by treatment group.  
8.5 
Efficacy Analyses 
8.5.1 Primary Endpoint 
The changes from baseline in distance walked during the 12MWT for the FAS will be 
analyzed using a MMRM. The model will include fixed terms for treatment, visit and 
the treatment-by-visit interaction. The model will also include the stratification 
mutation factor and continuous baseline distance walked during the 12MWT as 
covariates. An unstructured covariance structure will be used for the repeated visits 
within a subject. The Kenward-Rogers approximation (Kenward & Roger 1997) will 
be used to estimate the denominator degrees of freedom. The treatment comparison 
(REN001 100mg - placebo) for the change from baseline at both Weeks 12 and 24 
will be estimated. The estimates, standard errors, 95% confidence intervals and 
associated p-values will be presented. The primary comparison is Week 24. 
Intercurrent Events 
The following potential intercurrent events are currently identified: 
x 
Discontinuation of study drug  
x Inability to perform the test or stopping the test prematurely due to reasons at least 
possibly related to PMM 
A treatment policy strategy will be used; hence the distance walked at the relevant 
visit will be included in the analysis, regardless of intercurrent events. If the subject is 
unable to perform the test a distance of 0 meters will be imputed for the visit. 
Using this treatment policy strategy, the estimand is defined as the difference in 
means between the treatments in the target patient population for the change from 
baseline at Week 24 in 12MWD, regardless of whether or not the subject continues 
with treatment or is unable to walk for 12 minutes. 
Missing data 
All possible efforts will be made to ensure that subjects complete all the required 
assessments. Subjects who discontinue study drug will be encouraged, where 
appropriate, to continue with reduced assessments at the Week 12 and Week 24 visits 
(see Section 3.6). However missing data may arise for the following reasons: 
x Withdrawal from the study 
x Unable to perform the test for reasons unrelated to their PMM (e.g., site unable to 
perform the test at the visit, or the subject suffers an accidental injury prior to the 
visit) 
x Unable to walk for 12 minutes for reasons unrelated to their PMM (e.g., 
unexpected fire alarm at the study center means the test has to be aborted) 
For the primary analysis the data will be considered as MAR. Missing scores (as 
opposed to intercurrent events) will be imputed using the technique of multiple 
imputations. The multiple imputation step will be performed prior to any fixed 
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Each dataset with complete data for each subject will be analyzed using the MMRM 
model described above and the results obtained will be combined using Rubin’s 
imputation rules (Rubin, 1987) to produce pooled estimates of the treatment 
difference, along with their standard errors, 95% confidence intervals, and associated 
p-values.
As rules for handling intercurrent events and missing data may potentially bias the 
outcome of the statistical analyses and the subsequent estimation of the magnitude of 
the treatment effect, sensitivity analyses will be conducted to provide a balanced 
assessment of treatment efficacy. 
The following sensitivity analyses will be conducted: 
x a pattern-mixture multiple imputation approach where missing data from subjects 
who receive either treatment will be assumed to follow a similar trajectory to those 
in the placebo group. 
x a tipping point analysis (O’Kelly & Ratitch, 2014) will be used, imputing different 
changes from baseline for the missing data. 
In addition, the primary analysis will be replicated using the PP set. 
A while on-treatment policy strategy will also be employed in a supplementary 
analysis utilizing only the on-treatment measurements for each subject. All missing 
data will be taken as MAR and so a MMRM will be used, without multiple 
imputation.  As all subjects would be required to have at least one post-baseline on-
treatment measurement this analysis will use the modified analysis set. 
All model assumptions will be checked by evaluating model residuals. If the 
evaluation of residuals indicates a problem with the model assumptions, a 
transformation of the data or non-parametric analyses may be considered. 
8.5.2 Secondary Endpoints  
The MFIS Physical subscale score changes from baseline will be analyzed using a 
MMRM. The model will include fixed terms for treatment, visit and the treatment-by-
visit interaction. The model will also include the stratification mutation factor, 
continuous baseline MFIS physical subscale score and continuous baseline distance 
walked during the 12MWT as covariates. An unstructured covariance structure will be 
used. The treatment comparison for the change from baseline at each visit will be 
estimated. The estimates, standard errors, 95% confidence intervals and associated p-
values will be presented for each visit. The primary comparison is Week 24. 
The MFIS assessment may also be impacted by intercurrent events.  Similar to the 
primary endpoint a treatment policy strategy will be adopted. Pattern mixture and 
tipping point analyses will be included as sensitivity analyses and a while on 
treatment policy strategy will also be employed as a supplementary analysis. 
The PGIC (muscle symptoms) data will be converted to a numerical scale from 3 
(very much improved) to -3 (very much worse); hence a value of 0 would signify no 
change. This score will then be analyzed using ANCOVA, using a fixed term for 
treatment and the mutation stratification factor and continuous baseline distance 
walked during the 12MWT as covariates. The treatment comparison will be 
estimated, along with its standard error, 95% confidence interval and associated p-
value.  

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As the PGIC is assessed at the end of study treatment (Week 24 or Early Termination) 
a while on treatment strategy will be employed. 
The primary analyses for these endpoints will also be replicated using the PP set. 
8.5.3 Exploratory Endpoints 
Exploratory endpoints will be summarized and analyzed, using the FAS, to estimate 
the treatment effect and corresponding 95% confidence interval. Full details of 
analyses will be provided in the SAP. 
8.6 
Safety Analyses  
No imputation will be used for handling missing data, with the exception of 
conservative approaches taken for missing adverse event information (e.g., intensity). 
Details of such conventions will be documented in the Statistical Analysis Plan 
(SAP).  
Treatment-emergent adverse events will be summarized by treatment group and by 
SOC and Preferred Term, in accordance with the MedDRA coding dictionary. The 
number of subjects reporting each AE preferred term will be tabulated for all TEAEs 
and separately for those considered as at least possibly related to study treatment by 
the Investigator. Number of subjects reporting SAEs and AESI will also be tabulated. 
Changes from baseline in laboratory parameters, vital signs and ECG data will be 
summarized by treatment group and by visit. Baseline will be taken as the last 
measurement prior to dosing. 
A categorical shift table of change from baseline will be summarized by treatment 
group and by visit for the eye examination parameters.  
The incidence of potentially clinically significant laboratory and ECG values (e.g., 
increase in QTcF ≥30 msec from baseline or an absolute QTcF value of ≥500 msec) 
will be flagged in listings and summarized by treatment group. 
8.7 
Pharmacokinetic Endpoints 
Plasma concentrations of REN001 will be summarized over time using descriptive 
statistics for Day 1, Week 12 and Week 24.  
Individual subject concentration-time data on Day 1, Week 12 and Week 24 will be 
plotted over actual PK sampling times. Median profiles of the concentration-time 
data, using nominal PK sampling times, will also be presented for Day 1, Week 12 
and Week 24. Both linear-linear and linear-log plots will be presented. 
The data will be used for a population PK analysis which will be reported as a 
standalone report to the Clinical Study Report.  
8.8 
Interim Analyses 
No formal interim analyses are planned for the primary endpoint; however, an 
independently chaired Safety Review Committee (SRC) will review safety data at 
specified intervals for the duration of the study. The structure, function and operation 
of the SRC will be detailed in the REN001-201 SRC charter. 

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9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
9.1 
Data Quality Assurance 
The Sponsor (or its delegate) will conduct a site visit/telephone call to verify the 
qualifications of each Investigator, inspect the site facilities, and inform the 
Investigator of responsibilities and the procedures for ensuring adequate and correct 
documentation. 
The Investigator is required to prepare and maintain adequate and accurate case 
histories designed to record all observations and other data pertinent to the study for 
each study participant. All information recorded in the eCRFs for this study must be 
consistent with the subjects’ source documentation (e.g., medical records). 
9.2 
Electronic Case Report Forms (eCRF) and Source Documentation 
All data obtained during this study should be entered in the eCRFs promptly. All 
source documents from which eCRF entries are derived should be placed in the 
subject’s medical records. Measurements for which source documents are usually 
available include laboratory assessments, and ECG recordings.  
The original eCRFs for each subject will be checked against source documents at the 
study site by the site monitor. 
After review by the site monitor, completed eCRFs will be marked as complete and 
verified. Data Management will review the eCRFs within the electronic data capture 
(EDC) system. Where data is discrepant, Data Management will raise queries for the 
site to resolve within the EDC. 
9.3 
Access to Source Data 
During the course of the study, a monitor will make site visits to review protocol 
compliance, compare eCRFs and individual subject’s medical records, assess drug 
accountability, and ensure that the study is being conducted according to pertinent 
regulatory requirements. eCRF entries will be verified with source documentation. 
The review of medical records will be performed in a manner to ensure that subject 
confidentiality is maintained. 
Checking of the eCRFs for completeness and clarity, and cross-checking with source 
documents in the presence of the Investigator, will be required to monitor the progress 
of the study. Moreover, regulatory authorities of certain countries, IECs, and/or the 
Sponsor’s Clinical Quality Assurance consultant may wish to carry out such source 
data checks and/or on-site audit inspections. Direct access to source data will be 
required for these inspections and audits; they will be carried out giving due 
consideration to data protection and medical confidentiality. The Investigator assures 
Orphan-Reach Ltd and the Sponsor of the necessary support at all times. 
9.4 
Data Processing 
The site will be supplied with the following data collection tool: a web browser 
address for EDC that has been fully validated and conforms to 21CFR11 
requirements. The trained Investigator site staff will enter the data required by the 
protocol into the eCRFs from source documents (e.g., medical records and study-
specific data capture tools as needed) using the supplied data collection tool. All 
information in the eCRFs must be traceable to these source documents. Data recorded 
directly into the eCRFs will be defined before study start and the eCRFs will be 
considered the source data. Site monitors and data managers will review eCRFs 

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entered by investigational staff for completeness and accuracy. Automatic quality 
programs check for data discrepancies in the eCRFs and the resulting queries will be 
notified to the investigational site using an electronic data query process within the 
EDC. Designated Investigator site staff are required to respond to queries and make 
any necessary changes to the data promptly. Details of the data correction process will 
be specified in the Data Management Plan. After database lock, the Investigator will 
receive a compact disc (or equivalent) of the subjects’ eCRFs (portable document 
format) for archiving at the investigational site. 
A validated, electronic database will be employed from the EDC system. An audit 
trail of all changes to this database, including the date, reason for the data change and 
who made the change, will be maintained within the same database. The audit trail 
will be part of the archived data at the end of the study. 
9.5 
Archiving Study Records 
Adequate records as required by ICH GCP and Food and Drug Administration (FDA) 
Code of Federal Regulations (CFR), will be maintained for the study. This will 
include subject medical records, Investigator logs, eCRFs, laboratory reports, work 
sheets, signed Informed Consent Forms, drug dispensing records, adverse experience 
reports, information regarding subjects’ discontinuation and electronic data. Essential 
documents should be retained 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 have elapsed 
since the final discontinuation of clinical development of the investigational product. 
However, if required by the applicable regulatory requirements or by an agreement 
with the Sponsor these documents should be retained for a longer period. It is the 
responsibility of the Sponsor to inform the Investigator/institution as to when these 
documents no longer need to be retained. 
9.6 
Good Clinical Practice 
The procedures set out in this study protocol are designed to ensure that the Sponsor 
and Investigator abide by the principles of GCP guidelines of the ICH, and of the 
Declaration of Helsinki (2013). The study also will be carried out in keeping with 
local legal requirements. 
9.7 
Confidentiality 
All study findings and documents will be regarded as confidential. The Investigator 
and members of his/her research team must not disclose such information without 
prior written approval from the Sponsor. 
The anonymity of participating subjects must be maintained. Subjects will be 
identified in eCRFs and other documents submitted to Orphan-Reach Ltd by their 
subject number and/or birth year, not by name. Documents not to be submitted to 
Orphan-Reach Ltd that identify the subject (e.g., the signed informed consent) must 
be maintained in confidence by the Investigator. 
9.8 
Informed Consent 
Before each subject is admitted to the study, a personally signed and dated informed 
consent will be obtained from the subject according to the regulatory and legal 
requirements of the participating country (i.e., the Declaration of Helsinki, ICH GCP, 
and other applicable local regulations). This consent form must also be signed by the 
person collecting the informed consent and the original will be retained in the site file 

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and a copy retained in the subject medical records. The subject will also receive a 
copy of the signed consent. The Investigator will not undertake any investigation 
specifically required only for the clinical study until valid consent has been obtained. 
The terms of the consent and when it was obtained must also be documented in the 
eCRF. 
If a protocol amendment is required, the informed consent form may need to be 
revised to reflect the changes to the protocol. If the consent form is revised, it must be 
reviewed and approved by the appropriate IEC/IRB and signed by all subjects 
subsequently enrolled in the study as well as those currently enrolled in the study. 
9.9 
Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will 
be approved by the IEC/IRB/CA’s, in accordance with local legal requirements. The 
Sponsor must ensure that all ethical and legal requirements have been met before the 
first subject is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be 
written, receive approval from the appropriate personnel, and receive IRB/IEC/CA 
approval prior to implementation (if appropriate). All amendments will be distributed 
to all protocol recipients, with appropriate instructions. 
9.10 
Duration of the Study 
The planned duration of the study for each subject will be approximately 36 weeks 
(assuming up to 8 weeks screening, 24 weeks treatment and 3-4 weeks follow-up). 
The study will close when all subjects have completed the Week 24 (or Early 
Termination) visit and the subsequent Follow Up Visit (21-28 days after last study 
treatment). 
9.11 
Liability and Insurance 
The conduct of this trial will be under reasonable third-party liability insurance cover 
in accordance with all local legal requirements. The civil liability of the Investigator, 
the persons instructed by him and the hospital, practice or institute in which they are 
employed and the liability of the Sponsor with respect to financial loss due to personal 
injury and other damage that may arise as a result of the carrying out of this study are 
governed by the applicable law. 
Subjects participating in this study will have access to insurance against financial loss 
due to personal injury caused by the study drug being tested or by medical steps taken 
in the course of the study.  
9.12 
Publication Policy 
By signing the study protocol, the Investigator agrees with the use of results of the 
study for the purposes of national and international registration, publication and 
information for medical and pharmaceutical professionals. If necessary, the 
authorities will be notified of the Investigator's name, address, qualifications and 
extent of involvement. 
After study completion, data from the entire study will be considered for reporting at 
a scientific meeting and for publication in a scientific journal. The Sponsor will 
coordinate these activities and will work with the Investigator to determine how the 
manuscript is written and edited, the number and order of authors, the publication to 
which it will be submitted and other related issues. Authorship will be based on 

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criteria stipulated by leading clinical journals (e.g., contribution to one or more areas 
of study design, data analysis and interpretation, manuscript preparation and review, 
etc.). 
An Investigator shall not publish any data (poster, abstract, paper, etc.) without having 
consulted with the Sponsor in advance. 

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Parikh, S., Goldstein, A., Koenig, M.K., Scaglia, F., Enns, G.M., Saneto, R., Anselm, 
I., Cohen, B. H., Falk, M. J., Greene, C., Gropman, A.L., Haas, R., Hirano, M., 
Morgan, P., Sims, K., Tarnopolsky, M., Van Hove, J. L. K., Wolke, L., & 
DiMauro, S. (2014) Diagnosis and management of mitochondrial disease: a 
consensus statement from the Mitochondrial Medicine Society. Genetics in 
Medicine, 1-13. 
Pfeffer, G., & Chinnery, P. (2013, Feb). Diagnosis and treatment of mitochondrial 
myopathies. Ann Med, 45, 4-16. 
Prahm, K. P., Witting, N., & Vising J. (2014) Decreased variability of the 6-minute 
walk test by heart rate correction in patients with neuromuscular disease. PloS 
ONE, 9, (12) 1-8. 
Rubin, D.B multiple Imputation for Nonresponse in Surveys, New York, Wiley, 1987. 
Sources of Energy Adapted from Human Physiology: An Integrated Approach, Sixth 
Edition (2013) Dee Unglaub Silverthorn. 
Tarnopolsky MA. (2016) Metabolic Myopathies. Continuum (Minneap Minn) 22 (6) 
1829–1851. 
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1.165 
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2.6 
Wu, G., Sanderson, B., & Bittner, V. (2003) The 6-minute walk test: How important 
is the learning effect? Am Heart J 146, 129-133. 

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11 APPENDICES 
Appendix 1: International Workshop 
Outcome measures and clinical trial readiness in primary mitochondrial 
myopathies in children and adults. Consensus recommendations. 16–18 
November 2016, Rome, Italy 
(Mancuso, McFarland, Klopstock, & Hirano, 2017) 
Primary mitochondrial myopathies (PMM), as defined by this consortium of 
international experts in mitochondrial disease, are genetically defined disorders 
leading to defects of oxidative phosphorylation affecting predominantly, but not 
exclusively, skeletal muscle (see below for methodology). Thus, secondary 
involvement of mitochondria, frequently observed in multiple neuromuscular diseases 
(e.g., inclusion body myositis, Duchenne muscular dystrophy, Kennedy disease) is not 
considered PMM. 
PMM may present at any age, patients with severe generalized muscle involvement 
typically present early in life, although individuals with milder forms of the disease, 
or symptoms confined to specific muscles tend to have later presentations. The most 
common presentation of PMM is chronic progressive external ophthalmoplegia 
(PEO). Chronic PEO is characterized by a slowly progressive, usually bilateral 
limitation of eye movements (ophthalmoplegia) in all directions of gaze so that 
patients turn their heads to see a target at the periphery of the visual field; patients 
sometimes report diplopia, especially when onset of ophthalmoplegia is asymmetric. 
Intrinsic ocular muscles are not involved. PEO is usually accompanied by bilateral 
eyelid ptosis, which is often the presenting symptom, associated with a compensatory 
frontalis muscle hyperactivity and, in severe cases, tilting of the head backwards. PEO 
is often associated with other signs of skeletal muscle involvement, typically a slowly 
progressive axial and proximal limb weakness affecting predominantly the hip and 
shoulder girdle as well as neck flexor muscles often with variable muscle wasting. 
Muscle weakness may also cause dysphagia and dysarthria due to oropharyngeal 
weakness, as well as respiratory failure. Distal myopathic weakness may be present 
but is rarely seen early in the disease.  
From a genetic point of view, PEO may be autosomal dominant or recessive, sporadic 
(usually due to single largescale deletions of mtDNA), or maternally inherited. 
Autosomal PEO can be associated with multiple deletions and/or depletion of 
mtDNA, caused by nuclear gene defects and subsequent impairment of mtDNA 
maintenance. PEO is also the most frequent phenotype associated with a single 
sporadic largescale deletion of mtDNA. The “common deletion” is 4.9-kb and 
accounts for about one-third of all single large-scale deletions of mtDNA. 
Myopathy can be the only clinical feature of a mitochondrial disease but may also be 
part of a component of other mitochondrial syndromes. For example, Kearns-Sayre 
syndrome is defined by the early onset of PEO before age 20 years in association with 
pigmentary retinopathy, and at least one of the following: cerebellar ataxia, cardiac 
conduction block, or cerebrospinal fluid protein levels >0.1 g/L. 
Other manifestations of PMM are exercise intolerance often with myalgia, fatigue 
(defined as an overwhelming sense of tiredness, lack of energy, and feeling 
exhausted), muscle wasting, muscle cramps, and recurrent rhabdomyolysis with 
myoglobinuria triggered by exercise as seen in cytochrome b deficiency or in the 
myopathic form of CoQ10 deficiency. Exercise-induced symptoms are common in 

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PMM and reflect lack of energy production due to mitochondrial dysfunction in 
skeletal muscle, increased lactate production and phosphocreatine depletion. 

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Appendix 2: Example Modified Fatigue Impact Score (MFIS) 

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Appendix 3: Example Brief Pain Inventory (Short Form) 

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Appendix 4: Example Work Productivity and Activity Impairment 
Questionnaire: Specific Health Problem V2.0 (WPAI:SHP) 
Work Productivity and Activity Impairment Questionnaire: 
Primary Mitochondrial Myopathy Disease V2.0 (WPAI:PMM) 
The following questions ask about the effect of your Primary Mitochondrial 
Myopathy Disease (PMM) on your ability to work and perform regular 
activities.  Please fill in the blanks or circle a number, as indicated. 
1. Are you currently employed (working for pay)?
_____ NO ___ YES 
If NO, check “NO” and skip to question 6. 
The next questions are about the past seven days, not including today. 
2. During the past seven days, how many hours did you miss from work
because of problems associated with your PMM?  Include hours you missed
on sick days, times you went in late, left early, etc., because of your PMM.  Do
not include time you missed to participate in this study.
_____ HOURS 
3. During the past seven days, how many hours did you miss from work
because of any other reason, such as vacation, holidays, time off to
participate in this study?
_____HOURS 
4. During the past seven days, how many hours did you actually work?
_____HOURS (If “0”, skip to question 6.) 
5. During the past seven days, how much did your PMM affect your
productivity while you were working?
Think about days you were limited in the amount or kind of work you could do, 
days you accomplished less than you would like, or days you could not do 
your work as carefully as usual.  If PMM affected your work only a little, 
choose a low number.  Choose a high number if PMM affected your work a 
great deal.   

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Consider only how much PMM affected 
productivity while you were working. 
PMM had no 
effect on my 
work 
PMM 
completely 
prevented me 
from working 
0 1 2 3 4 5 6 7 8 9 10 
CIRCLE A NUMBER 
6. During the past seven days, how much did your PMM affect your ability to
do your regular daily activities, other than work at a job?
By regular activities, we mean the usual activities you do, such as work 
around the house, shopping, childcare, exercising, studying, etc.  Think about 
times you were limited in the amount or kind of activities you could do and 
times you accomplished less than you would like.  If PMM affected your 
activities only a little, choose a low number.  Choose a high number if PMM 
affected your activities a great deal.  
Consider only how much PMM affected your ability to do your regular daily 
activities, other than work at a job. 
PMM had no 
effect on my 
daily activities 
PMM 
completely 
prevented me 
from doing my 
daily activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CIRCLE A NUMBER 
WPAI:SHP  V2.0 (US English)   

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Appendix 5: Example PROMIS Short Form - Fatigue 13a (FACIT-Fatigue) 

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Appendix 6: Amendment 3 
Amendment Rationale 
a) A global update to remove the requirement for at least 40% of subjects in study
REN001-201 to have the m.3243A>G genotype. Reneo’s Phase 1b study
(REN001-101) was used as the indicator of the proportion of subjects with
m.3243A>G point mutations in the general PMM population. However recent
information from external and internal recruitment data, and discussion with
experts indicates that the initial intent of recruiting ‘at least 40% of subjects with
the m.3243A>G’ genotype is neither viable nor desirable. Requiring 40% of
subjects to have m.3243A>G mutation would result in a genotypic mix in the
REN001-201 study that is not representative of the primary mitochondrial
myopathy population. Furthermore, this amendment to remove the requirement
for ‘at least 40% of subjects with the m.3243A>G’ genotype is consistent with
advice received from the European Medicines Agency to include a broader
population than was studied in REN001-101. Review of baseline characteristics of
subjects recruited into REN001-201 to date indicate that when grouped into
m.3243 A>G, other single point mutations and single large deletions, these groups
have comparable baseline characteristics. Thus, the intent of recruiting based on
phenotype is effective. The Sponsor has therefore removed the requirement for at
least 40% of subjects in study REN001-201 to have the m.3243A>G genotype.
b) A global update to Section 7.1.9 eye examination has been made to delete
redundant text and clarify lens grading and visual acuity.
c) A global update to Section 8 Statistical Methods - The primary analysis model has
been updated to a mixed effect model for repeated measures (MMRM) to allow
the estimation of different between subject variances for the two visits. The model
for the analysis of the secondary endpoint, MFIS physical subscale, has been
updated to remove the random subject effect as the different sources of variability
are accounted for within the covariance structure of the MMRM.
d) A global update to clarify that re-screened subjects are not required to repeat their
Screening eye examinations or DXA scans repeated within 6 months of the
original assessments.
e) A global update to reflect that the REN001 open-label extension study is now
available, for subjects who complete REN001-201, in countries where the
extension study is approved.
f)
A global update to clarify that study centers can complete the Baseline, Week 12,
Week 24 and Early Termination visits over two days at the Investigator’s
discretion due to the complexity of scheduling all the assessments on these visits.
g) A global update to clarify the postmenopausal definition for consistency with the
central lab to women of 45 years and older and amenorrhoeic for 1 year in
addition to an FSH level indicating postmenopausal state.
h) Belgium ethics committee requested that the reason for ethnicity being collected
(regarding eGRF calculation) is mentioned in the protocol. This has been added to
Section 6.1 in the Subject Demography bullet point.
i)
Minor typographical errors and corrections have been updated throughout.

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Details of Amended Text 
The following changes to the study protocol have been made: 
1) Synopsis – Design section introduction of DXA sub-study
2) Synopsis – Treatment section removal of ‘At least 40% of subjects will be
recruited with a mutational genotype of m.3243A>G’.
3) Synopsis – Exclusion Criteria 14 states ‘….long pulse rate (PR) interval…’ this 
has been corrected to ‘long PR interval’. 
4) Synopsis – Exclusion Criteria 17 updated for clarity to ‘Positive hepatitis B
surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) at Screening, or
positive for hepatitis C or human immunodeficiency virus (HIV) at Screening’.
5) Synopsis – Study Visits section addition of ‘Re-screened subjects will not be
required have either the eye exam or DXA scan (REN001-201 DXA sub-study
subjects) repeated within 6 months of the original assessments.’ Clarification that
the Follow-Up visit ‘… This visit will not be required if a subject chooses to enter
the REN001 open label extension study (REN001-202) at their Week 24 visit;
applicable only for countries where the open label extension study is being
conducted.’ Clarification that the Baseline, Week 12 and Week 24 visits may be
completed over two days if needed.
6) Synopsis – Statistical Methods section updated to replace the ‘random effect
model’ to a ‘mixed effects model for repeated measures’.
7) Section 1.4 Risk-Benefit Section – update to the indicate the non-clinical
carcinogenicity studies have been initiated.
8) Section 3.1 Addition of ‘Re-screened subjects will not be required have either the
eye exam or DXA scan (REN001-201 DXA sub-study subjects) repeated within 6
months of the original assessments.’ Clarification that the Follow-Up visit ‘…
This visit will not be required if a subject chooses to enter the REN001 open label
extension study (REN001-202) at their Week 24 visit; applicable only for
countries where the open label extension study is being conducted.’ Clarification
that the Baseline, Week 12 and Week 24 visits may be completed over two days if
needed.
9) Section 3.3 Justification of the Study Design text updated to the ‘… study will aim
to recruit 1) subjects with the mt DNA defects (including the most common point
mutation m.3243A>G) and 2) subjects with a primary phenotypic presentation of
myopathy.
10) Section 4.2 Exclusion criteria 17: Updated for clarity to ‘Positive HBsAg and
HBcAb at Screening, or positive hepatitis C or HIV at Screening’.
11) Section 5.2 Allocation to Treatment – removal of sentence stating ‘At least 40%
of subjects will be recruited with a mutational genotype of m.3243A>G.
12) Section 5.4 Breaking the Blind – The break blind process has been clarified to
indicate the Investigator may break the blind in a medical emergency without
notifying the Sponsor prior to breaking the blind.
13) Section 5.10 – Age of collection of FSH sample clarified to 45 years and older and
duration of amenorrhoeic reduced to 1 year from 2 years.
14) Section 5.11 - Table 1 Prohibited Medications – addition of anticoagulants and
steroids to be reviewed on a case by case basis by medical monitor and Sponsor.
15) Section 6.1 Screening - Addition of ‘Re-screened subjects will not be required
have either the eye exam or DXA scan (REN001-201 DXA sub-study subjects)

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repeated within 6 months of the original assessments.’ Clarification that the 
collection of Subject Demography includes ethnicity for accurate calculation of 
eGFR. 
16) Section 6.6 Weeks 12 and 24 Visits - Clarification that the Week 12 and Week 24
visits may be completed over two days if needed.
17) Section 6.7 Follow Up Visit - Clarification that the Follow-Up visit ‘… will not be
required if a subject chooses to enter the REN001 open label extension in
countries where the open label extension study is approved’.
18) Section 6.8 Early Termination Visit - Clarification that the Early Termination visit
may be completed over two days if needed.
19) Table 2 Schedule of Activities footnote 2 – updated to indicate that in addition to
the Baseline visit the Week 12, Week 24/Early Termination visits may also be
conducted over 2 days at the Investigators discretion.
20) Table 2 Schedule of Activities footnote 9 – updated for consistency to ‘Serum
FSH testing for postmenopausal females 45 years and older’.
21) List of Study Personnel and Section 7.1.1.9 – As highlighted at site initiation visits
SAE reporting email address corrected from ‘Drug.safety@bionical-emas’ to
‘Drug.safety@bionical-emas.com’. Physical address also updated as office
location has changed since last protocol release.
22) Section 7.1.2 - Table 3 biochemistry – additional note to indicate subject’s
ethnicity is required for accurate calculation of eGFR.
23) Section 7.1.2 - Table 3 hematology – HbA1c assessment moved from serology to
hematology to correctly reflect collection of samples.
24) Section 7.1.2 - Table 3 Urinalysis – Collection of hCG at week 18 removed as an
error in table and correct elsewhere in the protocol.
25) Section 7.1.8 ECG Recording – updated to fully reflect Exclusion Criteria 14.
26) Section 7.1.9 Eye examination – Redundant text removed for clarity to say ‘Each
lens should be classified and graded against the Lens Opacity Classification
System III, (Chylack et al, 1993)’ and ‘best corrected distance visual acuity
(including refraction) should also be assessed.
27) Section 7.1.12 MFIS – correction of the description of the scoring categories.
28) Section 8.5.1 Primary Endpoint – Random effects model updated to MMRM.
29) Section 8.5.2 Secondary Endpoints – removal of ‘a random subject effect’.
30) Minor typographical errors updated throughout.