Conditions: Primary Mitochondrial Myopathy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 213
Healthy volunteers: no

Brief summary:
This is a randomized, double-blind, placebo-controlled, parallel group, multi-centre, study designed to investigate the efficacy and safety of REN001 administered once daily over a 24-week period to patients with PMM.

Detailed description:

Arms:
arm 1: Once daily arm 2: Once daily

Interventions: intervention 1: Mavodelpar intervention 2: Placebo
Intervention descriptions: intervention 1: Once daily intervention 2: Once daily

Protocol document:
Prot_000.pdf: 
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 
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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 
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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 
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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-
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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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Workshop: Outcome measures and clinical trial readiness in primary 
mitochondrial myopathies in children and adults. Consensus recommendations. 
16–18 November 2016, Rome, Italy. Neuromuscul Disord (12), 1126-1137. 
Millum, J., & Grady, C. (2013) The Ethics of Placebo-controlled trials: 
methodological justifications. Contemp Clin Trials, 36, 510-514. 
Moghadam-Kia, S., Oddis, C. V., & Aggarwal, R. (2016, January). Approach to 
asymptomatic creatine kinase elevation. Cleve Clin J Med, 83, 37-42. 
Nance, J. R., & Mammen, A. L. (2015) Diagnostic evaluation of rhabdomyolysis. 
Muscle Nerve. 51(6):793-810.  
O’Kelly, M., & Ratitch, B. (editors). (2014) Clinical Trials with Missing Data: A 
Guide for Practitioners. Wiley. 
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. 
US Code of Federal Regulations 21CFR211.165 retrieved from 
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=21
1.165 
US Code of Federal Regulations 21CFR312.6 retrieved from 
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=31
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.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
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: 16 November 2023


 
Statistical Analysis Plan 
Confidential  
 
Page 1 of 86 
 
 
Sponsor Name: 
Reneo Pharma Ltd. 
Protocol 
Numbers, Titles, 
Version and 
Dates*:  
 
REN001-201  
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) 
Version/Dates: 
1.0 (3 September 2020) 
Amendment 1, Version 2.0 (3 December 2020) 
Amendment 2, Version 3.0 (26 January 2021) 
Amendment 3, Version 4.0 (21 July 2022) 
REN001-201-DXA  
An exploratory study to assess change in bone mineral density 
(BMD) after 24 weeks treatment of REN001 in subjects taking part 
in the STRIDE study, using dual-energy x-ray absorptiometry 
(DXA) 
Version/Dates: 
1.0 (20 April 2021) 
Amendment 1, Version 2.0 (26 April 2021) 
Author(s): 
 
SAP Version/Date: Final v3.0 / 16 November 2023 
* Country specific protocol amendments are listed in Appendix 2. 
 
 
 
 
Notice of Confidential and Proprietary Information: 
This document is confidential. It contains proprietary information of Reneo Pharma Ltd. Any 
viewing or disclosure of such information that is not authorized in writing by Reneo Pharma Ltd. is 
strictly prohibited. Such information may be used solely for the purpose of reviewing or 
performing this study. 
 


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Signature Page 
 
Protocol 
Number:   
REN001-201 (and sub-study REN001-201-DXA) 
Protocol Titles: 
REN001-201 - 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) 
 
REN001-201-DXA - An exploratory study to assess change in bone 
mineral density (BMD) after 24 weeks treatment of REN001 in 
subjects taking part in the STRIDE study, using dual-energy x-ray 
absorptiometry (DXA) 
 
Version: 
 
Final v3.0 
Version Date: 
16 November 2023 
I confirm that I have reviewed this document and agree with the content. 
Author 
 
 
 
_____________________________________ 
{See Electronic Signature Page} 
 ParamStat Limited 
 
Approvals 
 
 
 
_____________________________________ 
{See Electronic Signature Page} 
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__________________________________________ 
{See Electronic Signature Page} 
, Reneo Pharma Ltd. 
 
 


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Signature Page (continued 1) 
 
Protocol 
Number:   
REN001-201 (and sub-study REN001-201-DXA) 
Protocol Titles: 
REN001-201 - 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) 
 
REN001-201-DXA - An exploratory study to assess change in bone 
mineral density (BMD) after 24 weeks treatment of REN001 in 
subjects taking part in the STRIDE study, using dual-energy x-ray 
absorptiometry (DXA) 
 
Version: 
Final v3.0 
Version Date: 
16 November 2023 
I confirm that I have reviewed this document and agree with the content. 
 
 
 
 
Veristat  
 
 
Date (MM-DD-YYYY) 


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Revision History 
Version 
(Date) 
Summary of Changes 
1.0 
(04Oct2022) 
NA 
2.0 
(12Apr2023) 
Updates following feedback from the United States Food and Drug 
Administration (FDA) (Reference: 5090787) and team review: 
• Sections 3.2.2, 3.2.5, 10.2 and 10.3: Secondary Endpoints and 
Exploratory Endpoints – following FDA advice the Patient-Reported 
Outcomes Measurement Information System (PROMIS) Short-Form 
Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue 
13a T-score has been promoted to a secondary endpoint and Modified 
Fatigue Impact Scale (MFIS; physical sub-scale score) and Patient 
Global Impression of Change (PGIC; muscle symptoms) have been 
moved to exploratory endpoints.  
• Section 3.2.5 Exploratory Endpoints - Added phenotypic description 
questions as exploratory endpoints and included new Sections 4.11 
and 10.3.10 to describe the endpoints and analyses. 
• Section 4.2 PROMIS - Moved from Section 4.7 to Section 4.2. 
Updated text to state PROMIS T-score is a secondary endpoint. 
• Sections 4.7 and 10.3.5: Modified Fatigue Impact Scale – moved 
from Section 4.2 to Section 4.7. Changes made concerning the recall 
period used. Added percent changes from baseline endpoint for each 
sub-scale score and the total score. Updated text to state MFIS 
physical sub-scale is an exploratory endpoint. 
• Section 4.3 Patient Global Impression of Change – updated section to 
include both muscle and fatigue symptoms, as both are now 
exploratory endpoints. Original Section 4.11 for PGIC (fatigue 
symptoms) removed. 
• Section 4.5 and 10.3.2: Pedometer Step Count – clarified that the 
collection of this data is optional and only subjects who have at least 
one average step count for a visit will be analysed. Clarified the 
analysis window for Week 4 data. 
• Section 6.7 and 12.7 Eye Examination – updated the spherical 
equivalent worst change to a decrease from baseline and updated the 
corresponding summary presentation.  Added a listing for subjects 
with a ≥0.75 diopter change during the study. 
• Section 7.4 Full Analysis Set – modified definition to exclude 
subjects who were randomized but subsequently discontinued from 
the study for failing eligibility criteria. 
• Section 7.6 Per Protocol Analysis Set – updated criteria. 
• Section 8.2 General Methods – updated the order of testing to account 
for the change to the secondary endpoints.  Clarified that baseline 


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Version 
(Date) 
Summary of Changes 
measurements for QoL endpoints can be taken from data collected on 
Day 1. 
• Section 8.3.1 Efficacy Data – clarified the worst imputation mean and 
standard deviation is based on all data irrespective of treatment.  
Inclusion of an independent Primary Endpoint Missing Data 
Adjudication Committee, who will review cases of missing 12MWT 
data to determine if the reasons for intercurrent events and missing 
data are or are not related to the subject’s PMM or study treatment. 
Additionally, clarified reasons for not completing or performing the 
assessment that will be considered related to a subject’s PMM. 
Clarified that relatedness of an event includes both related to a 
subject’s PMM or to study treatment. 
Clarified imputation steps when there is a missing baseline record. 
• Section 8.4 Visit Windows – widened analysis visit windows. 
• Section 8.5 Subgroups – updated the definition of post-menopausal 
and region categories. Removed the 75-year age subgroup as no 
subjects over 75 years at screening have been randomized in the 
study. 
• Section 9.2 Demographic and Baseline Characteristics – inclusion of 
age group categories and baseline PROMIS T-score 
• Section 9.3 Medical History and Concomitant Diseases – added 
clarification on how to define past and current medical history when 
incomplete dates are recorded. 
• Section 10.1.2 Primary Analysis – updated approach if primary model 
does not converge to use ANCOVA. Added ANCOVA as sensitivity 
analysis. Added worst case imputation supplementary analysis. 
Renamed supplementary while on-treatment analysis to a treatment 
period restricted analysis and included a while on-treatment analysis.  
• Section 10.2.1 PROMIS T-score – Due to reordering of endpoints this 
section now details the secondary endpoint PROMIS T-score 
analyses. All sensitivity analyses appropriate for the secondary 
endpoint have been added. Original Section 10.3.4 has been removed.  
• Section 10.3.1 30 Second Sit to Stand – updated approach if primary 
model does not converge to use ANCOVA.  
• Section 10.3.5 Modified Fatigue Impact Scale – updated the section 
to include physical subscale and detail the analysis for each endpoint 
that was originally detailed in Section 10.2.1. 
• Section 10.3.8 Patient Global Impression of Change– updated the 
section for muscle symptoms and fatigue symptoms scores to detail 
the analyses originally detailed in Section 10.2.2. Removed Section 
10.2.2.   


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Version 
(Date) 
Summary of Changes 
• Section 10.3.9 6 Minute Walk Distance – clarified analysis model. 
• Section 10.4 Relationship of Endpoints – updated the secondary 
endpoint. 
• Section 12.1 Adverse Events – added a summary of lower-level terms 
for the AESI of refraction disorders. 
• Section 12.5 ECG – Added a shift table from baseline to the 
maximum post baseline QTcF. 
• Section 14 Changes from Planned Analyses Specified in the Protocol 
– documented the change in secondary endpoints, the change to the 
while on treatment analysis for the primary endpoint, and the addition 
of the phenotypic description questions as exploratory endpoints. 
Other minor clarifications and typographical errors have also been 
corrected. 
3.0 
(16Nov2023) 
• Section 4.2 Patient-Reported Outcomes Measurement Information 
System (PROMIS) Short Form – updated method for deriving T-
score. 
• Section 4.5 and 10.3.2 Pedometer Step Count – added median daily 
step count endpoint and removed the exclusion of extreme values 
from the calculation of the endpoints. 
• Section 4.10 Work Productivity and Activity Impairment 
Questionnaire: Specific Health Problems – correction to calculation 
of Percent overall work impairment due to PMM formula. Clarified 
the calculation of percent overall work impairment due to PMM score 
when all the work time missed is due to PMM. 
• Section 6.7 and Section 12.7. Eye Examinations – updated the 
derivation for best corrected visual acuity (BCVA) to LogMAR scale 
and the reference used. Removed summaries of BCVA and spherical 
equivalence as this data is only considered as supportive information 
for the medical assessment of cataracts. 
• Section 7.5 Modified Full Analysis Set – updated definition to 
exclude late baseline visit data from on-treatment measurements. 
• Section 7.6 Per Protocol Analysis Set – added an additional criterion. 
• Section 7.8.2 Scan Analysis Set – clarified that the scan analysis set 
includes subjects that received at least one dose of study drug. 
• Section 8.2 General Methods – clarified precision to use for endpoints 
and any changes to the rule for precision is detailed in the relevant 
analysis sections. 
• Section 8.3.1 Efficacy Data – clarified intercurrent events where 
subjects still have ambulation but may be prevented from performing 
the test. Updated worst case imputation to clarify that the mean and 
standard deviation will be based on assessments where subjects 


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Version 
(Date) 
Summary of Changes 
walked for the full 12 minutes (i.e., assessments where there were no 
intercurrent events). Clarified when the walk distance is used for 
subjects who walk for less than 12 minutes. Added approach for 
handling missing PGIS endpoint data. Added range for PROMIS T-
score and clarified that Reneo will adjudicate the missing PROMIS 
T-score and 30 STS cases. 
• Section 8.5 Subgroups – added an additional 12MWD subgroup and 
updated that the 12MWD subgroups will be based on the Baseline 
value and not the screening visit value. Provided the approach to 
defining the extended genotype categories and clarified in the event 
of a mis-stratification the actual genotype recorded will be used. 
Updated vitamin D deficiency subgroup. Clarified approach to 
summaries and analyses of subgroups based on a blinded review of 
the baseline data. 
• Section 9.2 Demographic and Baseline Characteristics – clarified that 
the screening 12MWD categorical summary will be performed and 
will be based on the actual screening value in the event of a mis-
stratification. 
• Section 9.3 Medical History and Concomitant Diseases – clarified 
associated PMM preferred terms to be excluded from summary 
tables. 
• Section 9.4 Prior and Concomitant Medications – bone medications 
are now split by those having an adverse impact and those having a 
positive impact. 
• Section 9.5 Treatment Exposure – updated the handling of missing 
data for treatment compliance. 
• Section 10 Analysis of Efficacy Data – clarified throughout efficacy 
subsections that 95% confidence intervals will be presented for 
observed values as well as change from baseline values. 
• Section 10.1.3 Summaries and plots – clarified that if a subject does 
not walk for 12 minutes, then this will be counted as an additional 
stop in the summary of number of stops. 
• Section 10.1.5 Supplementary Analyses and Section 10.2.1 Patient-
Reported Outcomes Measurement Information System (PROMIS) 
Short Form –included non-parametric sensitivity supplementary 
analyses for the primary and secondary endpoints. 
• Section 10.2.1 Patient-Reported Outcome Measurement Information 
System (PROMIS) Short Form – updated plausible value for 
PROMIS T-score. Updated tipping point analysis to use increments 
of 5 which is equivalent to half a standard deviation based on a US 
population. 


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Version 
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Summary of Changes 
• Section 10.3.6 Brief Pain Inventory (BPI) Short Form – added an 
additional analysis excluding subjects who have a baseline pain 
severity score <4 points.  
• Section 10.3.8 Patient Global Impression of Change (PGIC) Muscle 
Symptoms and Fatigue Symptoms – removed the per protocol 
analysis as PGIC is now an exploratory endpoint. 
• Section 10.3.9 6-Minute Walk Distances – added example of when 
imputation is used only for the last 6-minute walk distance. 
• Section 12.1 Adverse Events – clarified the summaries for TEAEs 
that are emergent no more than 7 days after the last dose of study 
drug. Added a calculation for duration of event for ongoing adverse 
events and clarified the derivation for events with no start/stop time 
recorded. 
• Section 12.2 Laboratory Evaluations – added that only subjects who 
have a second void collected will be included in summaries of the 
NTx data. 
Other minor clarifications and typographical errors have also been 
corrected. 
 
 
 


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TABLE OF CONTENTS 
1. 
GLOSSARY OF ABBREVIATIONS .............................................................. 14 
2. 
INTRODUCTION ............................................................................................. 17 
2.1. 
Responsibilities ................................................................................................. 17 
3. 
STUDY OVERVIEW ....................................................................................... 18 
3.1. 
Study Objectives ............................................................................................... 18 
3.1.1. 
Primary Objective ............................................................................................. 18 
3.1.2. 
Secondary Objective ......................................................................................... 18 
3.1.3. 
Safety Objective ................................................................................................ 18 
3.1.4. 
Pharmacokinetic Objective ............................................................................... 18 
3.1.5. 
Exploratory Objectives ...................................................................................... 18 
3.1.6. 
REN001-201-DXA Sub-Study Objective ......................................................... 18 
3.2. 
Study Endpoints ................................................................................................ 18 
3.2.1. 
Primary Endpoint .............................................................................................. 19 
3.2.2. 
Secondary Endpoint .......................................................................................... 19 
3.2.3. 
Safety Endpoints ............................................................................................... 19 
3.2.4. 
Pharmacokinetic Endpoints ............................................................................... 19 
3.2.5. 
Exploratory Endpoints....................................................................................... 19 
3.2.6. 
REN001-201-DXA Sub-Study Endpoints ........................................................ 20 
3.3. 
Study Design ..................................................................................................... 20 
3.3.1. 
REN001-201 Study ........................................................................................... 20 
3.3.2. 
REN001-201-DXA Sub-Study .......................................................................... 21 
3.4. 
Schedule of Assessments .................................................................................. 22 
3.5. 
Determination of Sample Size........................................................................... 25 
3.6. 
Treatment Assignment and Blinding................................................................. 25 
3.7. 
Administration of Study Medication ................................................................. 25 
4. 
EFFICACY ASSESSMENTS ........................................................................... 26 
4.1. 
12-Minute Walk Test (12MWT) ....................................................................... 26 


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4.2. 
Patient-Reported Outcomes Measurement Information System (PROMIS) 
Short Form – Functional Assessment of Chronic Illness Therapy (FACIT) 
Fatigue 13a ........................................................................................................ 27 
4.3. 
Patient Global Impression of Change (PGIC) – Muscle Symptoms and Fatigue 
Symptoms ......................................................................................................... 27 
4.4. 
30 Second Sit to Stand Test (30STS) ................................................................ 28 
4.5. 
Pedometer Step count ........................................................................................ 28 
4.6. 
Patient Global Impression of Severity (PGIS) score - muscle symptoms and 
fatigue symptoms .............................................................................................. 29 
4.7. 
Modified Fatigue Impact Scale (MFIS) ............................................................ 29 
4.8. 
36 Item Short Form Survey (SF-36) ................................................................. 30 
4.9. 
Brief Pain Inventory (BPI) Short Form ............................................................. 31 
4.10. 
Work Productivity and Activity Impairment Questionnaire: Specific Health 
problems (WPAI: SHP) .................................................................................... 31 
4.11. 
PMM Phenotypic Description ........................................................................... 32 
5. 
PHARMACOKINETIC ASSESSMENT .......................................................... 34 
6. 
SAFETY ASSESSMENTS ............................................................................... 35 
6.1. 
Adverse Event ................................................................................................... 35 
6.2. 
Laboratory Evaluations ..................................................................................... 35 
6.3. 
Dual-Energy X-Ray Absorptiometry (DXA) Scan ........................................... 35 
6.4. 
Vital Signs ......................................................................................................... 36 
6.5. 
ECGs ................................................................................................................. 36 
6.6. 
Physical Examination ........................................................................................ 36 
6.7. 
Eye Examinations .............................................................................................. 36 
6.8. 
COVID-19 Exposure and Vaccination Data ..................................................... 37 
7. 
ANALYSIS SETS AND PROTOCOL DEVIATIONS .................................... 38 
7.1. 
Screened Analysis Set ....................................................................................... 38 
7.2. 
Randomized Analysis Set.................................................................................. 38 
7.3. 
Safety Analysis Set............................................................................................ 38 
7.4. 
Full Analysis Set ............................................................................................... 38 


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7.5. 
Modified Full Analysis Set ............................................................................... 38 
7.6. 
Per Protocol Analysis Set .................................................................................. 38 
7.7. 
Pharmacokinetic Analysis Set ........................................................................... 39 
7.8. 
DXA Scan Analysis Sets ................................................................................... 39 
7.8.1. 
Screened Scan Analysis Set .............................................................................. 39 
7.8.2. 
Scan Analysis Set .............................................................................................. 39 
7.8.3. 
Completers Scan Analysis Set .......................................................................... 40 
7.9. 
Protocol Deviations ........................................................................................... 40 
8. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS .............................. 41 
8.1. 
Hypothesis Testing ............................................................................................ 41 
8.2. 
General Methods ............................................................................................... 41 
8.3. 
Intercurrent Events and Missing Data ............................................................... 42 
8.3.1. 
Efficacy Data ..................................................................................................... 43 
8.3.2. 
Pharmacokinetic Data ....................................................................................... 47 
8.3.3. 
Safety Data ........................................................................................................ 47 
8.4. 
Visit Windows ................................................................................................... 47 
8.5. 
Subgroups .......................................................................................................... 48 
9. 
ANALYSIS OF DISPOSITION, DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS, AND MEDICATION ................................................. 51 
9.1. 
Subject Disposition and Withdrawals ............................................................... 51 
9.2. 
Demographic and Baseline Characteristics ....................................................... 52 
9.3. 
Medical History and Concomitant Diseases ..................................................... 52 
9.4. 
Prior and Concomitant Medications .................................................................. 53 
9.5. 
Treatment Exposure .......................................................................................... 54 
10. 
ANALYSIS OF EFFICACY DATA ................................................................ 56 
10.1. 
Primary Endpoint .............................................................................................. 56 
10.1.1. 
Primary Estimand .............................................................................................. 56 
10.1.2. 
Primary Analysis ............................................................................................... 56 
10.1.3. 
Summaries and Plots ......................................................................................... 57 


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10.1.4. 
Sensitivity Analyses .......................................................................................... 57 
10.1.5. 
Supplementary Analyses ................................................................................... 58 
10.1.6. 
Subgroup Analyses ............................................................................................ 59 
10.2. 
Secondary Endpoint .......................................................................................... 60 
10.2.1. 
Patient-Reported Outcomes Measurement Information System (PROMIS) 
Short Form – Functional Assessment of Chronic Illness Therapy (FACIT) 
Fatigue 13a ........................................................................................................ 60 
10.3. 
Exploratory Endpoints....................................................................................... 63 
10.3.1. 
30 Second Sit to Stand Test............................................................................... 63 
10.3.2. 
Pedometer Step Count ....................................................................................... 63 
10.3.3. 
Patient Global Impression of Severity (PGIS) Score - Muscle Symptoms and 
Fatigue Symptoms ............................................................................................ 64 
10.3.4. 
36 Item Short Form Survey (SF-36) ................................................................. 65 
10.3.5. 
Modified Fatigue Impact Scale (MFIS) – Total, Physical, Cognitive and 
Psychosocial Sub-scale Scores ......................................................................... 66 
10.3.6. 
Brief Pain Inventory (BPI) Short Form ............................................................. 67 
10.3.7. 
Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problems (WPAI: SHP) .................................................................................... 68 
10.3.8. 
Patient Global Impression of Change (PGIC) – Muscle Symptoms and Fatigue 
Symptoms ......................................................................................................... 68 
10.3.9. 
6-Minute Walk Distances (Derived from 12MWD) ......................................... 69 
10.3.10. 
PMM Phenotypic Description ........................................................................... 70 
10.4. 
Relationship of Endpoints ................................................................................. 70 
11. 
ANALYSIS OF PHARMACOKINETIC ENDPOINTS .................................. 71 
12. 
ANALYSIS OF SAFETY DATA ..................................................................... 72 
12.1. 
Adverse Events .................................................................................................. 72 
12.2. 
Laboratory Evaluations ..................................................................................... 74 
12.3. 
Dual Energy X-Ray Absorptiometry (DXA) Scan ........................................... 76 
12.4. 
Vital Signs ......................................................................................................... 76 
12.5. 
ECG ................................................................................................................... 77 


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12.6. 
Physical Examination ........................................................................................ 77 
12.7. 
Eye Examination ............................................................................................... 77 
12.8. 
COVID-19 Exposure and Vaccination Data ..................................................... 78 
13. 
INTERIM ANALYSES .................................................................................... 79 
14. 
CHANGES FROM PLANNED ANALYSES SPECIFIED IN THE 
PROTOCOL ..................................................................................................... 80 
15. 
REFERENCES .................................................................................................. 81 
APPENDIX 1 – SAS© CODE .............................................................................................. 82 
APPENDIX 2 – COUNTRY SPECIFIC PROTOCOL AMENDMENTS .......................... 86 
 


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1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
BCVA 
Best Corrected Visual Acuity 
BMD 
Bone Mineral Density 
BLQ 
Below the Limit of Quantification 
BMI 
Body Mass Index 
BPI 
Brief Pain Inventory 
BSAP 
Bone Specific Alkaline Phosphatase 
CK 
Creatine Kinase 
CPK 
Creatine Phosphokinase 
CPEO 
Chronic Progressive External Ophthalmoplegia 
CScAS 
Completers Scan Analysis Set 
CSR 
Clinical Study Report 
DXA 
Dual Energy X-ray Absorptiometry 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eDISH 
evaluation of Drug-Induced Serious Hepatotoxicity 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FAS 
Full Analysis Set 
FCS 
Fully Conditional Specification 
FDA 
Food and Drug Administration 
HDL 
High Density Lipoprotein 
IWRS 
Integrated Web-based Response System 
KSS 
Kearns-Sayre Syndrome 
LDL 
Low Density Lipoprotein 
LLOQ 
Lower Limit of Quantification 
LOCS III 
Lens Opacity Classification System III 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviation 
Description 
mFAS 
Modified Full Analysis Set 
MFIS 
Modified Fatigue Impact Scale 
MELAS 
Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-
Like Episodes  
MERF 
Myoclonic Epilepsy with Ragged Red Fibers  
MIDD 
Maternally Inherited Deafness and Diabetes 
MILS 
Maternally Inherited Leigh Syndrome 
MNGIE 
Mitochondrial Neurogastrointestinal Encephalopathy 
MMRM 
Mixed Effect Model for Repeated Measures 
NARP 
Neuropathy; Ataxia; and Retinitis Pigmentosa 
NTx 
Urine N-terminal telopeptide 
PCI 
Potentially Clinically Important 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PMM 
Primary Mitochondrial Myopathy 
PP 
Per Protocol 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PSOC 
Patient Screening Oversight Committee 
PK 
Pharmacokinetic 
PT 
Preferred Term 
QoL 
Quality of Life 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
ScAS 
Scan Analysis Set 
SD 
Standard Deviation 
SF-36 
36 Item Short Form Survey 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
TFLs 
Tables, Figures and Listings 


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Abbreviation 
Description 
ULN 
Upper Limit of Normal 
WPAI:SHP 
Work Productivity and Activity Impairment Questionnaire: Specific 
Health Problems 
12MWD 
12-minute Walk Distance 
12MWT 
12-minute Walk Test 
30STS 
30 Second Sit to Stand Test 
 


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2. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) details the statistical analyses for the REN001-201 
(STRIDE) study and the sub-study REN001-201-DXA. REN001-201 is a 24-week double 
blind, randomized placebo-controlled study, designed to assess the efficacy and safety of 
mavodelpar (REN001) in patients with Primary Mitochondrial Myopathy (PMM). 
REN001-201-DXA is an exploratory sub-study to REN001-201, designed to assess 
changes in bone mineral density (BMD), using Dual Energy X-ray Absorptiometry (DXA) 
scans, after 24 weeks of treatment with mavodelpar. 
The purpose of this SAP is to ensure that the data listings, summary tables and figures 
which will be produced, and the statistical methodologies that will be used, are 
comprehensive and appropriate for the assessment of study objectives specified in the 
study protocols. Changes from the analyses specified in the protocol will be identified in 
the SAP and any amendments to the SAP will be made prior to database lock. Any 
additional analyses not described in the final SAP or deviations from the final SAP will be 
documented in the clinical study report (CSR). 
The SAP has been developed based on REN001-201 Protocol Version 4.0, REN001-201-
DXA Protocol Version 2.0 and the latest CRF available (Version 5.0, Date 17 November 
2021). The subsequent country specific protocol amendments for REN001-201 (see 
Appendix 2) do not impact the SAP. 
The analysis of this study will occur after all subjects have had the ability to complete 
REN001-201 and the REN001-201-DXA sub-study (as applicable), the data has been 
cleaned and the database locked and unblinding has occurred. 
2.1. 
RESPONSIBILITIES 
Veristat is the Biostatistics vendor for these studies and is contracted to prepare the table, 
figures and listing (TFLs) shells based on this SAP. Shells to detail the format and layout 
of TFLs will be presented in a separate document to the SAP. Veristat will perform the 
statistical analyses and is responsible for the production and quality control of all TFLs.  


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3. 
STUDY OVERVIEW 
3.1. 
STUDY OBJECTIVES 
The study objectives for REN001-201 are listed below in Sections 3.1.1 to 3.1.5. The 
objective for the REN001-201-DXA sub-study is listed in Section 3.1.6. 
3.1.1. 
Primary Objective 
To evaluate the efficacy of REN001 in subjects with PMM treated for 24 weeks, assessed 
by the effect on exercise endurance. 
3.1.2. 
Secondary Objective 
To evaluate the efficacy of REN001 in subjects with PMM treated for 24 weeks, assessed 
by the effect on fatigue. 
3.1.3. 
Safety Objective 
To evaluate the safety and tolerability of REN001 in subjects with PMM during 24 weeks 
of treatment. 
3.1.4. 
Pharmacokinetic Objective 
To investigate the pharmacokinetics of REN001 in subjects with PMM. 
3.1.5. 
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 Quality of Life (QoL) of subjects with PMM after 
treatment for 24 weeks. 
3.1.6. 
REN001-201-DXA Sub-Study Objective 
To use DXA to supplement the bone health parameters already being assessed in a subset 
of PMM subjects who enter the parent REN001-201 STRIDE study. 
3.2. 
STUDY ENDPOINTS 
The study endpoints associated with the REN001-201 objectives detailed above in Section 
3.1 are listed below in Sections 3.2.1 to 3.2.5. The endpoints for the REN001-201-DXA 
sub-study are listed in Section 3.2.6.  


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3.2.1. 
Primary Endpoint 
Change from Baseline at Week 24 in distance walked during the 12-minute walk test 
(12MWT). 
3.2.2. 
Secondary Endpoint 
Change from Baseline at Week 24 in Patient-Reported Outcomes Measurement 
Information System (PROMIS) Short Form – Functional Assessment of Chronic Illness 
Therapy (FACIT) Fatigue 13a T-score. 
Note, the secondary endpoint has been changed from the protocol (refer to Section 14). 
3.2.3. 
Safety Endpoints 
• Incidence and severity of adverse events (AEs) 
• Absolute values, changes from Baseline and incidence of potentially clinically 
significant values for laboratory safety tests, electrocardiograms (ECGs), vital signs 
and eye assessments. 
3.2.4. 
Pharmacokinetic Endpoints 
Mavodelpar plasma concentrations collected pre-dose and 1, 2, 3 and 4 hours post-dose at 
Baseline, Week 12 and Week 24. 
3.2.5. 
Exploratory Endpoints 
• Changes from Baseline at Week 12 and 24 in:  
− number of sit to stands in 30 seconds using the sit to stand (STS) test 
− step count pedometer data 
− Patient Global Impression of Severity (PGIS) score for muscle symptoms 
and for fatigue symptoms   
− 36 Item Short Form Survey (SF-36) domain scores 
− MFIS Total, Physical, Cognitive and Psychosocial sub-scale scores 
− Brief Pain Inventory (BPI) Short Form pain severity and pain interference 
scores 
− Work Productivity and Activity Impairment questionnaire: Specific Health 
Problems (WPAI:SHP) scores 
− First 6-minute walk distance and last 6-minute walk distance* 
− Phenotypic description questions at Week 24 only*  
• PGIC score for muscle symptoms and for fatigue symptoms at the end of treatment 


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• PGIC score for muscle symptoms and for fatigue symptoms responder (‘Very 
Much Improved’ or ‘Moderately Improved’) at the end of treatment*. 
 * Note these endpoints were not defined in the protocol. 
3.2.6. 
REN001-201-DXA Sub-Study Endpoints 
Change from baseline to end of treatment in BMD, as measured by DXA, in the following: 
• Lumbar spine (L1 to L4) BMD 
• Total hip BMD and the femoral neck BMD (in the non-dominant hip) 
• Total hip, lumbar spine, and femoral neck T-scores and Z-scores. 
3.3. 
STUDY DESIGN 
3.3.1. 
REN001-201 Study 
REN001-201 is a pivotal global Phase 2b randomized, double-blind, placebo-controlled, 
parallel group, multi-center study in approximately 200 subjects with confirmed mtDNA 
PMM. Subjects will receive either mavodelpar 100 mg or matched placebo once daily for 
24 weeks. 
Each subject has a Screening visit to confirm eligibility to enter the study. The Screening 
visit must be completed within 8 weeks prior to the start of dosing and takes place at the 
study center. The Screening visit may be accomplished over more than 1 day. Subjects 
who are receiving prohibited medications for this study are required to suspend the 
medications and undergo sufficient washout during the screening period. Subjects may be 
re-screened once with prior approval from the Sponsor. An independent Patient Screening 
Oversight Committee (PSOC) assesses subjects to confirm the medical diagnosis of PMM 
prior to randomization. 
Subjects who successfully complete screening, and are approved by the PSOC, are 
randomized to receive either mavodelpar or placebo. Subjects have study visits at Weeks 2, 
4, 12, 18, 24 and, if applicable, follow-up. Visits at Weeks 2, 4, 18 and follow-up may be 
conducted at the subject’s home if more convenient and allowed by the site. Weeks 12 and 
24 are completed at the study center. A follow-up visit is completed 21-28 days after the 
last dose of study medication. The follow-up visit is not required for subjects who enrol 
directly into the mavodelpar open label extension study (REN001-202) at their Week 24 
visit. The schedule of assessments is detailed in Section 3.4. 
The planned maximum study duration for each subject is 36 weeks (assuming 8 weeks 
screening, 24 weeks treatment and 4 weeks follow up). 


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3.3.2. 
REN001-201-DXA Sub-Study 
The REN001-201-DXA sub-study is an exploratory sub-study, designed to assess changes 
in BMD, using DXA scans, after 24 weeks of treatment with mavodelpar. Due to 
regulatory and/or Institutional Review Board/Institutional Ethics Committee (IRB/IEC) 
concerns of radiation exposure, some sites are not participating in the sub-study. For those 
sites where it is approved the sub-study is offered to all prospective REN001-201 study 
subjects aged 25 or above. Subjects who consent to this sub-study undergo 2 DXA scans to 
assess BMD. The first DXA scan is at baseline and performed during the REN001-201 
screening period and the second follow-up DXA scan is performed at Week 24. If the 
subject discontinues treatment from REN001-201 after at least 20 weeks in the study, they 
will be asked to have a follow-up scan within 4 weeks of their last dose of study drug. Any 
subject who has not received 20 weeks dosing will not receive the follow-up DXA scan. 


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3.4. 
SCHEDULE OF ASSESSMENTS 
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 Consent20 
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 
 
Sites to provide appropriate 
snacks and lunch 
X 
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) 
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 
 
 
 
 
 
 
 
 
 
 
 
DXA Scan (REN001-201-DXA 
sub-study)21 
X 
 
 
 
 
 
 
 
 
X 
X 
 
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 post-menopausal females 45 years and older. Serum FSH test must be performed for all women who participate in the REN001-201-DXA sub-study who have not 
already had an FSH test as part of the parent REN001-201 study. 
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. 
20. A separate informed consent will be required for the REN001-201-DXA sub-study. 
21. Only conducted at sites, on eligible subjects, which are participating in the REN001-201-DXA sub-study. The screening DXA scan should be performed no more than 8 weeks prior to the 
start of dosing. If a subject discontinues study treatment after at least 20 weeks in the study they will be asked to have a follow-up, scan within 4 weeks of their last dose of study 
treatment. 


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3.5. 
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 versus 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, was 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 was determined as the 
appropriate sample size. 
The sample size for the DXA sub-study is not based on statistical justification. This sub-
study is exploratory in nature and limited to REN001-201 sites that have approval to 
conduct this sub-study. 
3.6. 
TREATMENT ASSIGNMENT AND BLINDING 
At Screening, all subjects are allocated a unique 6-digit study number by the Integrated 
Web-based Response System (IWRS), which is used throughout the study. The same 
subject identifier is used for both REN001-201 and REN001-201-DXA studies. The IWRS 
uses a computer-generated randomization schedule to assign subjects in a 1:1 allocation 
ratio to receive either mavodelpar 100 mg or placebo. The randomization is stratified by 
both mutational genotype (m.3243A>G or other mitochondrial DNA defects) and the 
screening 12-minute walk distance (≤ 500 meters or > 500 meters).  
A subject may be rescreened once with prior Sponsor approval; they will be given a new 
study number (their original study number will be recorded). 
To maintain the blind-blind conditions for the subject and Investigator, study medication is 
provided as visually matched capsules, and the capsules are supplied in identical bottles. 
3.7. 
ADMINISTRATION OF STUDY MEDICATION 
Subjects receive either 100 mg mavodelpar 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 is 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. 


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4. 
EFFICACY ASSESSMENTS 
The sections below detail the efficacy assessments including any derivations required to 
define the efficacy endpoints. The analyses of these endpoints are detailed in Section 10.  
4.1. 
12-MINUTE WALK TEST (12MWT) 
The primary endpoint is the change from baseline in distance walked during the 12MWT 
at Week 24. Subjects will perform the 12MWT at Screening, Baseline, Week 12 and Week 
24 visits. If applicable, the test will also be performed at the Early Termination visit. 
The test measures the distance a subject can walk on a flat, hard surface in a period of 12 
minutes. To reduce site variability, sites will be fully trained to administer the test 
according to the REN001-201 exercise manual. If the subject does not walk for the full 12 
minutes, the distance walked and the duration of time walked will be recorded, along with 
the reason for stopping prematurely.  
Handling of missing or incomplete 12MWT are detailed in Section 8.3.1. An independent 
blinded adjudication committee will review all reasons for missing or incomplete 12MWTs 
and adjudicate whether the reason was related to the subject’s PMM or study treatment. 
Subjects who walk further than 1000 meters at Screening will be excluded from the study. 
Subjects who walk ≤ 1000 meters at Screening but subsequently walk greater than 1000 
meters at Baseline will be allowed to continue into the study but will be excluded from the 
per protocol analysis. Baseline distance walked will be taken as the distance walked at the 
Baseline visit. 
For each visit changes from baseline and percent changes from baseline will be calculated.  
Additionally, the exploratory endpoints, distance walked in the first 6 minutes (from start 
of test up to 6 minutes) and the last 6 minutes (>6 minutes up to 12 minutes), will be 
derived. As only the number of completed laps are recorded each minute with the final 
minute recording any partial lap ongoing at the end of the 12 minutes, the distance walked 
in the first 6 minutes will be the total number of completed laps multiplied by the lap 
distance (20 meters). The distance walked in the last 6 minutes will then be the total 
distance walked minus the distance walked in the first 6 minutes. Note, in most cases, this 
will be an underestimate of the distance walked in the first 6 minutes and an over-estimate 
of the distance walked in the last 6 minutes.  
Pre and post exercise measurements for heart rate and blood pressures are collected. The 
changes (post – pre) will be calculated. 


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4.2. 
PATIENT-REPORTED OUTCOMES MEASUREMENT INFORMATION 
SYSTEM (PROMIS) SHORT FORM – FUNCTIONAL ASSESSMENT 
OF CHRONIC ILLNESS THERAPY (FACIT) FATIGUE 13A 
The PROMIS short form - FACIT Fatigue 13a is a set of person-centered measures that 
evaluates a range of fatigue symptoms, from mild subjective feelings of tiredness to an 
overwhelming, debilitating, and sustained sense of exhaustion that likely decreases a 
subject’s ability to execute daily activities and function normally in family or social roles. 
The fatigue short forms are universal rather than disease specific. All assess fatigue over 
the past 7 days.  
The PROMIS questionnaire will be used at Screening, Baseline, Week 4, Week 12, Week 
18 and Week 24 visits. If applicable, the test will also be performed at the Early 
Termination visit. 
There are 13 questions on a 5-point scale ranging from not at all (1) to very much (5). All 
questions, except Questions 7 and 8, are scaled so that higher score indicates a greater 
impact on fatigue. Questions 7 and 8 will be reversed prior to analysing. The total score is 
derived by summing the scores and will have a range from 13 to 65. If a subject has a 
missing response, then the total score will not be derived.  
The T-score will be determined using the HealthMeasures Scoring Service  
(https://www.assessmentcenter.net/ac_scoringservice) (PROMIS 2019). This service uses 
“response pattern scoring” (Expected A Posteriori estimation) and will also derive a 
T-score when there is missing data. Subject ID and Visit will be de-identified in the dataset 
prior to using this scoring service. The T-score rescales the total score into a standardized 
score, relative to the US general population, with a mean of 50 and a standard deviation of 
10. Therefore, an individual with a T-score of 60 is one standard deviation (SD) worse than 
the mean of the US general population. 
For each visit changes from baseline will be calculated for the T-score and total score. The 
T-score is a secondary endpoint. The total score data will only be listed. 
4.3. 
PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) – MUSCLE 
SYMPTOMS AND FATIGUE SYMPTOMS 
The subject is asked to rate both their change in PMM muscle symptoms and change in 
PMM fatigue symptoms at Week 24 (or, if applicable, the Early Termination visit). The 
PGIC has a 7-point scale from ‘Very Much Improved’ to ‘Very Much Worse’. This will be 
converted to a numeric scale from 3 (very much improved) to -3 (very much worse); hence 
a value of 0 will mean no change. These scores are exploratory endpoints. 


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Additionally, responder endpoints for both muscle symptoms and fatigue symptoms will 
be analysed, which is defined as a response of ‘Very Much Improved’ or ‘Moderately 
Improved’. The PGIC responder endpoints are also exploratory endpoints. 
4.4. 
30 SECOND SIT TO STAND TEST (30STS) 
The purpose of the 30 second sit-to-stand test (30STS) exploratory endpoint is to assess leg 
strength and endurance. Subjects are required to sit and rise to a full standing position as 
many times as they can in 30 seconds. A subject should only conduct the test if they are 
able to stand without using their arms to assist them out of the chair. A score of zero and a 
reason for not completing the test will be noted in the electronic Case Report Form (eCRF) 
in these circumstances. 
Subjects will perform the test at Baseline, Week 12 and Week 24 visits. If applicable, the 
test will also be performed at the Early Termination visit. 
For each visit changes from baseline will be calculated. 
4.5. 
PEDOMETER STEP COUNT  
Subjects are provided with a pedometer and access to an eDiary. Sites will train the subject 
on how and when to use the pedometer and to record their daily step count. Daily step 
counts should be recorded in the eDiary for 14 days during the screening period and for 7 
consecutive days within a 2-week window before each study visit (Weeks 4, 12, 18 and 
24).  
Note, collection of eDiary data is optional and only subjects who are able and willing to 
use a pedometer and record data in the eDiary will be included in the analyses. In addition, 
the Belgium site did not allow collection of pedometer data. Therefore, subjects that have 
no eDiary data collected will be excluded. 
If the subject forgets to reset the pedometer at the start of the day, then the step count from 
the previous day will be subtracted. If the data for the previous day is missing or if the step 
count for the previous day is greater than the step count recorded on this day, suggesting 
the pedometer was reset part way through the collection, then the value will not be used 
and will be set to missing.  
Two endpoints will be calculated; the median daily step count and the average daily step 
count over the non-missing eDiary data collected for the visit period. The average accounts 
for the whole week and takes into account changes in the daily activity patterns of subjects, 
whilst the median accounts for extreme values that may not represent the subject’s activity 
(e.g., forgetting to wear the pedometer).   
Ideally 7 consecutive days of step count data will be used to calculate these step count 
endpoints for each visit; however, if 7 consecutive days are not available then a minimum 


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of 4 days of data will be required for each visit. If there are 3 days or fewer of diary data 
for a visit, then the step count endpoints will be excluded from the analyses and identified 
in the data listing. The baseline will be calculated over the last 7 consecutive days of 
recordings prior to Day 1. If there are no 7 consecutive day periods with recordings, then 
the latest 7-day period with the most amount of completed days in the baseline period will 
be used. For post baseline visits (except Week 4) all diary data collected in the analysis 
visit window will be considered (refer to Section 8.4) and the 7 consecutive days finishing 
closest to the target visit date will be used. For Week 4 the lower limit of the analysis 
window will be widened to allow for the fact that the diary opens 2 weeks prior to the 
target visit date. If there are no 7 consecutive day periods with recordings, then the 7-day 
period with the most amount of completed days will be used. 
For each visit changes from baseline and percent changes from baseline will be calculated. 
4.6. 
PATIENT GLOBAL IMPRESSION OF SEVERITY (PGIS) SCORE - 
MUSCLE SYMPTOMS AND FATIGUE SYMPTOMS 
At Screening, Baseline, Week 4, Week 12, Week 18 and Week 24 visits, the subject will 
be asked to rate the severity of their PMM for muscle symptoms and for PMM fatigue 
symptoms over the past 7 days. If applicable, they will be asked the questions at the Early 
Termination visit. Both the PGIS muscle symptoms and PGIS fatigue symptoms are 
exploratory endpoints. 
The scale has 5 levels from ‘Absent’ to ‘Very Severe’. 
For each visit changes from baseline will be calculated for the two symptom scores. 
4.7. 
MODIFIED FATIGUE IMPACT SCALE (MFIS)  
The MFIS is a detailed tool that is completed by the subject. 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. The MFIS will be used at Screening, 
Baseline, Week 4, Week 12, Week 18 and Week 24 visits. If applicable, the test will also 
be performed at the Early Termination visit. 
During the conduct of the study, it has been identified that there was a translation error for 
the Netherlands site (site 2301) questionnaire, which incorrectly stated the recall period of 
4 weeks instead of 7 days. This affected several subjects at the site for some visits. As a 
result, a sensitivity analysis will be performed excluding data from subjects at this site. 
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 (9 items), cognitive (10 items) and psychosocial functioning (2 items). 
Physical functioning reflects motivation, effort, stamina and coordination. Cognitive 


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functioning concerns concentration, memory, thinking and organization of thoughts. 
Psychosocial functioning describes the impact of fatigue upon isolation, emotions, 
workload and coping. All items are scaled so that a higher score indicates a greater impact 
of fatigue. The below table shows how to calculate the 3 subscales and the total score: 
Subscale 
Items 
Range 
Physical 
4+6+7+10+13+14+17+20+21 
0 – 36 
Cognitive 
1+2+3+5+11+12+15+16+18+19 
0 – 40 
Psychosocial 
8+9 
0 – 8 
Total Score 
Physical + cognitive + psychosocial subscales 
0 – 84 
There is no recommended methodology for handling missing component scores for this 
questionnaire, however, to utilize all available data the following is proposed:  
• if 50% or more of the component scores are missing, then the subscale will not be 
derived and as a result the total score will not be derived. In this situation the 
subscale(s) with ≥50% missing component scores and the total score will be 
considered missing, and handled using the same methods described in Section 8.3.1  
for other MFIS missing data  
• if less than 50% of the component scores are missing then the average, rounded up 
to the nearest integer, of the non-missing scores for the subscale will be used to 
impute each missing value 
For each visit changes from baseline and percent changes from baseline will be calculated 
for each of the sub-scale scores and the total score. These scores are exploratory endpoints. 
4.8. 
36 ITEM SHORT FORM SURVEY (SF-36) 
The SF-36 version 2.0 Health Survey asks questions, with a one week recall period, which 
cover 8 health concepts: physical functioning, bodily pain, role limitations due to physical 
health problems, role limitations due to personal or emotional problems, mental health, 
social functioning, vitality (referred to in the protocol as energy/fatigue) and general health 
perceptions. It also includes a single item that provides an indication of perceived change 
in health. If mavodelpar is effective greater improvements are anticipated with vitality than 
the other health concepts. 
The SF-36 will be used at Baseline, Week 4, Week 12, Week 18 and Week 24 visits. If 
applicable, the test will also be performed at the Early Termination visit. 
All scale scores are exploratory endpoints and will be derived using QualityMetric Health 
Outcomes Scoring Software 5.0. This software generates standardized scores in 
accordance with the standards set by the developers of the survey. All items are scored so 


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that a high score defines a more favourable health state. In addition, each item is scored on 
a 0 to 100 range.  
For each visit changes from baseline will be calculated for each health concept scale. 
4.9. 
BRIEF PAIN INVENTORY (BPI) SHORT FORM 
The BPI Short Form rapidly assesses the severity of pain and its impact on functioning. 
The BPI questionnaire will be used at Baseline, Week 4, Week 12, Week 18 and Week 24 
visits. If applicable, the test will also be performed at the Early Termination visit. 
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. 
In addition, the average pain interference score will be derived as the average of the 
responses to the 7 components to Question 9 (Cleeland 2009). If there are 3 or fewer 
responses, then the pain interference score will not be calculated. The higher score 
indicates more pain interferes with daily functioning. 
For each visit changes from baseline will be calculated for the pain severity and pain 
interference scores. Both the pain severity score and the pain interference score are 
exploratory endpoints. 
4.10. 
WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT 
QUESTIONNAIRE: SPECIFIC HEALTH PROBLEMS (WPAI: SHP) 
The WPAI questionnaire is a validated instrument to measure impairments in work and 
activities. The questionnaire will be used at Baseline, Week 4, Week 12, Week 18 and 
Week 24 visits. If applicable, the test will also be performed at the Early Termination visit. 
Outcomes are expressed as impairment percentages, with higher numbers indicating 
greater impairment and less productivity, i.e., worse outcomes. There are 6 questions 
defined as: 
Questions 
Definition 
1 
currently employed (Yes/No) 
2 
hours missed because of problems associated with your PMM 
3 
hours missed because of other reasons 
4 
hours actually worked 
5 
how much did your PMM affect productivity while working (scale of 0 [no 
effect on my work] to 10 [completely prevented me from working]) 


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Questions 
Definition 
6 
how much did your PMM affect regular activities (scale of 0 [no effect on 
my daily activities] to 10 [completely prevented me from doing my daily 
activities]) 
 
The following 4 scores are exploratory endpoints and are calculated from the responses, 
the first 3 will only be calculated if the subject is employed: 
Score 
Equation 
Percent work time missed due to 
PMM 
100 × 
𝑄2
(𝑄2 + 𝑄4) 
 
Percent impairment while 
working due to PMM 
100 × 𝑄5
10 
Percent overall work impairment 
due to PMM 
100 × (
𝑄2
(𝑄2 + 𝑄4) + [(1 −(
𝑄2
(𝑄2 + 𝑄4))) × (𝑄5
10)]) 
 
Percent activity impairment due 
to PMM 
100 × 𝑄6
10 
 
 
Generally, if a response to a question used in the calculation of a score is missing, the score 
will be set to missing. The exception to this is the calculation of the percent overall work 
impairment due to PMM score; if all working hours are missed due to problems associated 
with PMM (i.e., Question 2≠0 and Q4=0)  then (1-(Q2/(Q2+Q4)))=0, and so it does not 
matter if  Question 5 (how much  did your PMM affect productivity while working) is 
missing or has a value.  Indeed, it is anticipated that the Question 5 response will be 
missing if they had not worked. In such situations the percent overall work impairment due 
to PMM will be entirely based on work time missed due to PMM i.e., 100%. 
For each visit changes from baseline for each score will be calculated. 
4.11. 
PMM PHENOTYPIC DESCRIPTION 
The phenotypic state of the subject’s disease is rated using 3 questions taken from the 
Newcastle Mitochondrial Disease Adult Scale. The questions will be completed at 
Baseline and Week 24 visits. If applicable, the test will also be performed at the Early 
Termination visit. Where possible the same physician should ask the questions on both 
occasions to ensure consistency of interpretation. 


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The 3 questions relate to exercise tolerance, gait stability and myopathy and asked in 
relation to the previous 4-weeks.  Each question has 6 levels (0 to 5) and higher scores 
indicate a worse rating. 
Changes from baseline to Week 24 will be calculated for the 3 phenotypic questions. 


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5. 
PHARMACOKINETIC ASSESSMENT 
Plasma mavodelpar concentrations will be determined from samples taken during the 
study. Samples may be analysed for metabolites, but any analysis of metabolite 
concentrations will not be part of the CSR and are not detailed in this SAP.  
Pre-dose and post-dose blood samples at 1, 2, 3 and optional 4 hours will be taken on Day 
1 and at the Week 12 and Week 24 visits. On the other visits, a single sample can be taken 
at any time post-dose. Sample collection times will be recorded. 
The data will be used for a population pharmacokinetic (PK) analysis which will be 
detailed in a separate population PK analysis plan and reported separately. 


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6. 
SAFETY ASSESSMENTS 
6.1. 
ADVERSE EVENT  
The incidence, causality and severity of treatment-emergent adverse events (TEAEs), 
including treatment-emergent serious adverse events (TESAEs) and adverse events of 
special interest (AESI), will be investigated.  
AESI are those of scientific and medical concern specific to mavodelpar and include: 
• Changes in laboratory parameters of muscle injury associated with clinically 
significant adverse events (AEs) 
• 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. 
• Occurrence of fractures after baseline 
AESI will be identified on the eCRF and will be reported in the same way as serious 
adverse events (SAEs). 
6.2. 
LABORATORY EVALUATIONS 
Laboratory evaluations are done throughout the study (as detailed in the schedule of 
assessments) and include: 
• Hematology parameters 
• Biochemistry parameters, including  
− the osteoblastic bone marker - bone specific alkaline phosphatase (BSAP) 
− calcium markers - parathyroid hormone and vitamin D 
• Urinalysis parameters, including: 
−  the osteoclastic bone marker - Urine N-terminal telopeptide (NTx), via a 
morning second void 
Changes from baseline will be calculated for each laboratory parameter for each scheduled 
visit. The last on-treatment measurement will also be identified. 
Laboratory values that are less than the lower limit of quantification (LLOQ) will be set to 
the LLOQ for the calculation of descriptive statistics. The original value will be displayed 
in listings. 
6.3. 
DUAL-ENERGY X-RAY ABSORPTIOMETRY (DXA) SCAN 
DXA scans will be performed on a subset of subjects at Screening and at Week 24, or the 
Early Termination visit provided the subject has received at least 20 weeks of study drug. 


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Baseline will be the measurement collected at Screening. The BMD, T-score and Z-score 
will be measured for 5 spine regions (L1-L4 and total) and for 2 hip regions (total and 
femoral neck).  
Changes from baseline and percent changes from baseline to end of treatment will be 
calculated for each parameter.  
6.4. 
VITAL SIGNS 
Changes from baseline will be calculated for each vital sign parameter for each scheduled 
visit. Change from baseline for systolic and diastolic blood pressure will be calculated 
irrespective of whether the arm used for the blood pressure assessment is the same at both 
visits. The last on-treatment measurement will also be identified. 
6.5. 
ECGS 
Changes from baseline will be calculated for each ECG parameter for each scheduled visit. 
The last on-treatment measurement will also be identified. 
6.6. 
PHYSICAL EXAMINATION 
Any physical examination abnormality considered clinically significant in the medical and 
scientific judgment of the Investigator (i.e., not related to progression of underlying 
disease), will be reported as an AE. 
6.7. 
EYE EXAMINATIONS 
Eye examination data will be performed during the study by an appropriately qualified 
professional. Any abnormality considered clinically significant, will be reported as an AE. 
Best corrected visual acuity (BCVA) can be assessed using the LogMAR scale, ETDRS 
letters or Snellen line. All results will be converted to the LogMAR scale before 
calculating changes from baseline at each visit for left and right eye BCVA (Roy 2003).  
Where the Snellen scale has data recorded as x/y the MAR value is calculated by dividing 
y by x and then the LogMAR is the base 10 logarithm of the MAR value [i.e., 
LogMAR=log10(MAR)]. Hence, higher scores indicate worse BCVA and increases from 
baseline indicate deterioration.  
A change of 0.02 in LogMAR is equivalent to 1 letter. Hence, a Snellen scores with ‘-z‘ or 
‘+z’ indicating z letters fewer, or z letters more, respectively, will require an adjustment to 
the LogMAR score; 0.02 will be added or subtracted, respectively, for each letter (z).  
e.g., 
20/15-1: LogMAR = Log10(15 divided by 20) + 0.02 = -0.105 


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20/15+1: LogMAR = Log10(15 divided by 20) - 0.02 = -0.145 
If the Snellen scale is not reported in x/y format or x/y±z format, then the conversion to 
logMAR will not be done. 
A change of 0.3 LogMAR (equivalent to 15 letters or 3-line change) is considered 
meaningful. 
Refraction error based on spherical equivalent will be derived for each eye using the 
following formula: 
Spherical Equivalent (diopters) = cylinder (diopters)/2 + sphere (diopters) 
Changes from baseline at each visit will be calculated. A change ≥0.75 diopters will be 
reported as an AESI. 
Cataract are classified and graded against the Lens Opacity Classification System III 
(LOCS III) for nuclear opalescence, nuclear colour, cortisol and posterior subcapsular 
cataracts. A change was made to the grading system used during the study. The original 
system was used at the screening visit for 30 subjects who were subsequently randomized. 
As the original data cannot be converted to the revised LOCS III grading system the data 
for these subjects (screening results recorded in the original format, and Week 12 and 
Week 24 results recorded in the new format) will only be listed and medically reviewed to 
identify any possible development of cataracts. Changes from baseline will be calculated 
for all other subjects. Higher scores equate to a deterioration in cataracts. The largest 
increase from baseline (or smallest decrease if both eyes show a reduction from baseline) 
across the eyes will be identified at each visit. 
6.8. 
COVID-19 EXPOSURE AND VACCINATION DATA 
Information on whether a subject has had exposure to COVID-19 or received a COVID-19 
vaccination is collected on a specific eCRF page. Further details of COVID-19 events will 
be recorded in either medical history or on an adverse event page, depending on the 
timing; and further details of COVID-19 vaccinations will be recorded on the concomitant 
page. 


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7. 
ANALYSIS SETS AND PROTOCOL DEVIATIONS 
7.1. 
SCREENED ANALYSIS SET 
The screened analysis set will include all subjects who signed the informed consent form 
and are screened for participation in this study. This analysis set will only be used for the 
purposes of describing subject disposition. 
7.2. 
RANDOMIZED ANALYSIS SET 
The randomized analysis set will include all randomized subjects. This analysis set will 
only be used for the purposes of describing subject disposition. 
7.3. 
SAFETY ANALYSIS SET 
The safety set will include all subjects who signed the informed consent form, completed 
screening and received at least one dose of study drug. The safety analysis set summaries 
will be based on the actual treatment received. The safety analysis set will be used for all 
baseline and safety analyses. 
7.4. 
FULL ANALYSIS SET 
The full analysis set (FAS) will include all subjects in the randomized set who received at 
least one dose of study drug and have not been subsequently discontinued from the study 
for failing eligibility criteria. Subjects will be analysed according to the treatment they 
were assigned at randomization. The FAS will be used for baseline analyses and will be 
the primary analysis set for efficacy. 
7.5. 
MODIFIED FULL ANALYSIS SET 
The modified full analysis set (mFAS) will include all subjects in the FAS who have at 
least one on-treatment measurement (excluding late baseline visit data) for the 12-minute 
walk distance (12MWD). This set is to be used for supplementary analyses. 
7.6. 
PER PROTOCOL ANALYSIS SET 
The per protocol (PP) analysis set will include 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 that meet any of the following criteria will be 
excluded from this analysis set:  
• Walk more than 1000m in the Baseline 12MWT 
• Violate any inclusion and/or exclusion criteria that may impact their efficacy 
assessment 


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• Receive the wrong study medication  
• Discontinue study treatment or are <80% compliant with study medication 
• Do not have valid Baseline or Week 24 12MWT assessments i.e., Baseline visit 
assessment must be prior to first dose and Week 24 visit assessment must be within 
7 days of last dose  
• Have a change in laboratory result during the study for amphetamines, opiates, 
cannabinoids, cocaine, barbiturates, benzodiazepines or methadone. The change in 
result alongside medications the subject received will be reviewed by the Reneo 
medical team to assess the potential impact on efficacy before excluding 
• Inconsistent use of orthotics for the 12MWT at Baseline and Week 24. The change 
in orthotic use will be reviewed by the Reneo medical team to assess the potential 
impact on efficacy before excluding. 
Precise reasons for excluding subjects from the PP set will be fully defined and 
documented prior to database lock. 
Subjects will be included in their ‘as treated’ treatment group. Note that this will be the 
same as the randomized treatment because receiving the wrong study medication is a major 
deviation and reason for exclusion.  
7.7. 
PHARMACOKINETIC ANALYSIS SET 
The PK set will include all subjects in the FAS who receive mavodelpar and have at least 
one evaluable (i.e., not impacted by any important protocol deviations or other events) 
post-dose PK measurement (even if below the limit of quantification). 
7.8. 
DXA SCAN ANALYSIS SETS 
There will be 3 analysis sets for the DXA sub-study: 
7.8.1. 
Screened Scan Analysis Set 
The screened scan analysis set will include all subjects who signed the informed consent 
form for the DXA sub-study and are screened for participation. This analysis set will only 
be used for the purposes of describing the subject disposition. 
7.8.2. 
Scan Analysis Set 
The scan analysis set (ScAS) will include all randomized subjects in the screened scan 
analysis set who received at least one dose of study drug and who have at least one valid 
DXA scan (i.e., with parameter measurements). The ScAS will be used for analysis of the 
DXA data. 


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7.8.3. 
Completers Scan Analysis Set 
The completers scan analysis set (CScAS) will include all subjects in the ScAS who have 
both screening and Week 24 valid DXA scans (i.e., with parameter measurements). The 
CScAS will be used for analysis of the DXA data. 
7.9. 
PROTOCOL DEVIATIONS 
Protocol deviations may be identified by site staff, study monitors and medical monitor 
reviewers. They may also be identified through programmable checks of the data. Site 
specific protocol deviations will be provided separately from the subject specific protocol 
deviations. 
Protocol deviations will be reviewed on an ongoing basis and categorized by Reneo 
Pharma Ltd. as either minor or major prior to database lock. Minor deviations are those 
that do not produce or have the potential to cause harm, do not impact the integrity of the 
trial, and cannot be avoided due to the subject’s schedule or natural events. In contrast, 
major deviations are events that may have a significant impact on subject’s rights or safety, 
or the integrity of the clinical study data. No subjects will be excluded from the safety set 
due to protocol deviations.  
All protocol deviations will be listed. The number of subjects reporting major deviations 
will be summarized overall and by deviation category. 


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8. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
8.1. 
HYPOTHESIS TESTING 
The null (H0) and alternative (H1) hypotheses can be expressed as: 
H0: mREN = mPLA 
H1: mREN ≠ mPLA 
where mREN and mPLA are the mavodelpar and Placebo responses, respectively. 
8.2. 
GENERAL METHODS 
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. To preserve the Type 1 error a fixed sequence testing procedure 
will be adopted. Testing will be on the FAS. The order of testing for the primary and 
secondary endpoints will be: 
1. Change from Baseline at Week 24 in distance walked during the 12MWT 
2. Change from Baseline at Week 24 in the PROMIS T-score 
Continuous variables will be summarized using the number of non-missing observations 
(n), mean, SD, median, minimum, and maximum. Categorical variables will be 
summarized using counts and percentages.   
Unless otherwise specified, the estimated mean and median for a set of values should be 
displayed to 1 more decimal place than the original values, and SD should be displayed to 
2 more decimal places than the original values. The minimum and maximum should be 
displayed to the same number of decimal places as the original values.  Deviations from 
this convention may arise to take account of the relevance of the precision (e.g., the 
distance walked in the 12MWT is reported to the nearest cm, but there is no relevance in 
presenting the mean to the nearest mm).  These deviations from convention will be 
documented in the relevant analysis sections below. 
Percentages will be displayed with 1 decimal place; except percentages will not be 
presented when the count is zero and 100% will be presented as an integer. Unless stated 
otherwise, percentages of subjects will be based on the number of subjects with non-
missing data in the analysis set used for the presentation. 
Baseline will be taken as the last available non-missing assessment prior to study drug 
administration (Day 1). Although the time of completion is not collected for QoL 
questionnaires (MFIS, PGIS, PROMIS, SF-36, BPI or WPAI:SHP), any completed on Day 
1 will be deemed suitable for baseline as the questionnaires are requested in the protocol to 


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be completed prior to dosing and, even if after dosing, there is no anticipated effect after a 
single dose.  
Unless stated otherwise, an on-treatment measurement will be any measurement collected 
(including scheduled and unscheduled visits) up to the date of last dose plus one day for 
safety endpoints and plus seven days for efficacy endpoints. Drug interruptions will not be 
considered, i.e., data will not be excluded during a drug interruption if the subject resumes 
study treatment.  
In by-visit summary tables, the baseline will be summarized using all available data, but 
also for each visit using only the baseline data from subjects with available data at the 
visit; hence the mean change from baseline will equal the mean observed visit value – 
mean baseline value.  
Throughout this document ‘change from baseline’ refers to the actual change from baseline 
(i.e., observed visit value – baseline value). 
Summary tables will be split by treatment group (REN001 100 mg and placebo). Baseline 
summary tables (disposition, demography, baseline characteristics, medical history and 
prior medications) will also include an overall summary. 
All data for randomized subjects, who receive at least one dose of study medication, will 
be listed. For screen failure subjects only disposition (including reason for screen failure), 
demographics and protocol deviations will be listed. 
Data listings will be ordered by treatment group and subject. A subject’s mutational 
genotype (m.3243A>G, m.8344A>G, mt deletion or Other) will be identified on the 
listings. Data listings will present study days in addition to dates, where study day is 
derived as per SDTM guidelines i.e., study day is derived as (assessment date – first day of 
dosing +1) after the start of dosing and as (assessment date – first day of dosing) before the 
start of dosing. Hence, the first day of dosing will be identified as Study Day 1. 
All statistical analyses will be performed using SAS® (Version 9.4 or higher, SAS Institute 
Inc., Cary, NC, USA).  
8.3. 
INTERCURRENT EVENTS AND MISSING DATA 
All possible efforts will be made to minimize missing data.  
Unless specified otherwise, screen values or pre-dose unscheduled measurements may be 
used as a baseline value in the event of missing Day 1 pre-dose measurements. 
The original data will always be presented in the listings. 


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8.3.1. 
Efficacy Data 
As missing data may potentially bias the outcome of the statistical analyses and the 
subsequent estimation of the magnitude of the treatment effect, different strategies will be 
applied to provide a balanced assessment of treatment efficacy. This section discusses 
intercurrent events and missing data in general, but details for each endpoint are discussed 
in Section 10. 
Intercurrent Events 
The following potential intercurrent events are currently identified:  
• Discontinuation of study treatment  
• Specifically, for the 12MWT and 30STS; unwilling or unable to perform the test or 
walk for the full 12 minutes due to reasons at least possibly related to PMM or 
study treatment  
Subjects who discontinue treatment will be encouraged, where appropriate, to continue in 
the study with a reduced assessment schedule at Weeks 12 and 24. As a minimum they will 
be requested to complete the 12MWT and MFIS efficacy assessments at these visits. This 
allows a treatment policy strategy to be used; for example, the distance walked at the 
relevant visit will be included in the analysis, regardless of whether the subject has 
previously discontinued study treatment.  
If the subject is unable to perform the 12MWT and/or 30STS at a visit, for reasons at least 
possibly related to their PMM, their data will be imputed as 0 meters and/or 0 sit to stands 
for each test, respectively. To assess the subject as unable to perform the 12MWT there 
must be clear evidence that the subject is not ambulatory at the time of the test.  
If the subject is still ambulatory, and therefore able to do the test, then consideration should 
be given to whether the subject is unwilling to perform the test, or prevented from (e.g., 
specialty clinic visit that prevents attending the study visit) performing the test due to 
reasons possibly related to PMM or study treatment. If the subject is still ambulatory but 
unwilling to perform the 12MWT, or prevented from doing the test, their distance will be 
imputed using a worst case imputation; unless the reason is unrelated to PMM or study 
treatment. The change from baseline distance will be imputed using a random draw from 
the normal distribution with a mean equal to the worst change from baseline reported over 
the study across both treatment groups, and the standard deviation for the raw changes 
from baseline at the relevant visit irrespective of treatment group. These values will only 
be determined from those assessments where subjects have walked for the full 12 minutes 
(i.e., those assessments where there were no intercurrent events). Twenty-five imputations 
will be made to match the multiple imputations mentioned below for missing data. The 
imputations will be restricted to ensure the value for the visit is ≥0 meters for the visit. 


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The same approach as detailed above in the previous paragraph, will be taken for subjects 
who discontinue study treatment and do not continue in the study; unless the reason for 
discontinuing from the study and withdrawing from the study are unrelated to their PMM 
or study treatment (e.g., site unable to continue having visits during pandemic). The special 
exception to this will be death; if a subject dies their 12MWD will be imputed as 0 meters. 
If the subject attempts the 12MWT or 30STS test but stops the test prematurely due to 
reasons at least possibly related to their PMM their data recorded will be used in all 
analyses. Examples of reasons for incomplete tests which will be considered related to the 
subject’s PMM include fatigue, weakness, tiredness, exhaustion or pain in limbs. In this 
situation it is assumed that the subject has walked as far as they could in the 12 minutes 
and the data is not regarded as missing. 
An independent blinded adjudication committee will review the 12MWT cases. The 
structure, function and operation of the adjudication committee will be detailed in a 
separate charter.  
Missing PROMIS T-scores as a result of an intercurrent event considered related to a 
subject’s PMM or study treatment will also be imputed using worst case imputation. A 
blinded Reneo team will adjudicate these cases. 
A blinded Reneo team will also adjudicate whether the subject stops their 30STS test 
prematurely for reasons at least possibly related to their PMM. 
Adjudication decisions will be made and documented prior to database locking and the 
randomization being unblinded.     
Missing data 
Missing data may arise for the following reasons: 
• Withdrawal from the study 
• Specifically, for the 12MWT and 30STS; unwilling or unable to perform the test or 
walk for the full 12 minutes due to reasons unrelated to their PMM or study 
treatment 
The reasons for not performing a test or stopping it prematurely will be collected. Only 
reasons which clearly indicate that it was unrelated to the subject’s PMM or study 
treatment will be assigned unrelated. The following are examples of why the reason may 
be regarded as unrelated to the subject’s PMM: 
• Site is unable to perform the test at the visit 
• Subject suffers an accidental injury prior to the visit with clear evidence the 
subject’s PMM and study treatment did not contribute to the injury 
• Unexpected fire alarm at the study center means the test has to be aborted 


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The independent blinded adjudication committee will review all reasons for missing or 
incomplete 12MWTs and adjudicate whether the reason was related to the subject’s PMM 
or study treatment. The committee will also adjudicate whether a subject is unable or 
unwilling to perform a test.     
Missing data assessed as unrelated to a subject’s PMM or study treatment will be 
considered missing at random (MAR). Missing scores (as opposed to intercurrent events) 
will be handled using either multiple imputation or through mixed effect models for 
repeated measures (MMRM). Where multiple imputations are used along with imputations 
for intercurrent events, the multiple imputation step will be performed prior to imputations 
for intercurrent events. Hence, the MAR imputations will be replaced with those for 
intercurrent events where applicable.  
The table below summarizes the imputation used for the intercurrent and missing data 
scenarios for the 12MWT: 
Type 
Case 
Handling of Data 
Intercurrent 
Event 
Discontinuation of study treatment only; 12MWT 
still completed 
No imputation 
required. Use 12MWD 
recorded 
Unable to perform the test for reasons possibly 
related to PMM or study treatment. Subject is not 
ambulatory at time of assessment. 
0 
Unable to walk the full 12 minutes for reasons 
possibly related to PMM or study treatment* 
Use 12MWD recorded 
Ambulatory subject unwilling to, or prevented from, 
performing the test for reasons possibly related to 
PMM or study treatment 
Worst case multiple 
imputation 
Withdrawal from study for reasons possibly related to 
PMM or study treatment 
Worst case multiple 
imputation 
Death 
0 
Missing 
Data 
Unable to perform the test, or walk the full 12 
minutes, for reasons unrelated to PMM or study 
treatment e.g., COVID-19 
 
 
Multiple imputation 
(MAR cases) 
Unwilling to perform the test for reasons unrelated to 
PMM or study treatment 
Withdrawal from study unrelated to PMM or study 
treatment 
* Note: This is the only adjudication decision where the distance walked for subject’s unable to walk the full 
12 minutes is used in the analyses. For all other decisions the distance is set to missing prior to analyses. 
 
 


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Multiple Imputation 
Missing values will be imputed with the SAS© MI procedure. Prior to imputation the 
missing data pattern will be assessed. To account for non-monotone missingness (i.e., for 
the 12MWT this would be where a subject has missing data for Week 12, but has data for 
Week 24), a Markov Chain Monte Carlo (MCMC) model will be used to impute the non-
monotone missing data, followed by a sequential regression model to impute the remaining 
data. Randomization seed numbers will be specified for each part of the imputation to 
ensure consistency and repeatability. 
In the non-monotone procedure, means and variances from the available data will be used 
to determine the MCMC starting values; imputed values will be selected with maximum 
likelihood methods. Initially, 200 MCMC runs will be generated before selecting the first 
imputed data set. An additional 24 data sets will be generated to reflect the uncertainty due 
to missing values. The 25 datasets will be separated by 100 iterations of the MCMC. The 
number of datasets may be increased if the analyses are not found to be sufficiently stable 
with respect to p-values. Stability will be determined if the p-values are the same to the 
second decimal place after 3 repetitions. These imputations will be performed separately 
within each treatment group. The imputation model will include the same covariates as for 
the analysis model and the value at each scheduled time point. Thus, for the primary 
endpoint the model will include the stratification mutation factor (in the event of a mis-
stratification, the actual value recorded on the database will be used) and the scheduled 
time points (Screening, Baseline, Week 12 and Week 24). Imputed values will be restricted 
to being plausible i.e., for the primary endpoint values will be restricted to ≥0 meters, and 
for the secondary endpoint PROMIS T-score will be restricted to ≥30.3 and ≤83.6. 
In the scenario where a subject has a missing baseline (either not collected or out of 
window) and the screening value is used as the baseline value, the multiple imputation 
model will preserve the time the data was collected. So in this scenario the screening value 
will be present and the baseline value will be missing and imputed. The imputed baseline 
values will only be used to facilitate the imputation of later visits and will not be used in 
the analyses. After imputation the imputed baseline values will be replaced with the 
observed screening value which will be used in the calculation of changes from baseline 
and analyses (e.g., as a covariate). 
The resulting 25 datasets will then be passed through the sequential regression models to 
impute for monotone missing data. If the non-monotone procedure is not required 25 
datasets will be generated from the monotone imputation.  
Each of the 25 datasets will be analysed and the results obtained will be combined using 
the SAS© MIANALYZE procedure, based on Rubin’s imputation rules (Rubin 19875), to 
produce pooled estimates of the treatment difference, along with their standard errors, 95% 
confidence intervals, and associated p-values. 


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The PGIC endpoints are discrete variables with 7 levels collected once at the end of the 
study, so for these endpoints an ordinal logistic regression model will be used to impute 
monotone missing data. The imputation model will include the same covariates as for the 
analysis model and 25 datasets will be imputed. Imputed values will be restricted to being 
plausible i.e., between -3 and 3.  
The PGIS endpoints are discrete variables with 5 levels collected at visits throughout the 
study, for these endpoints an ordinal logistic regression model will be used to impute 
missing data. If the data is non-monotone, then the Fully Conditional Specification (FCS) 
logistic regression method in SAS© MI procedure will be used. The imputation model will 
include the same covariates as for the analysis model and 25 datasets will be imputed. 
Imputed values will be restricted to being plausible i.e., between 1 and 5.  
8.3.2. 
Pharmacokinetic Data 
Missing data will not be imputed. 
Mavodelpar concentrations reported as below the limit of quantification (BLQ) will be 
taken as zero for linear plots, and equal to the LLOQ for log-linear plots. BLQ will be 
taken as zero for the computation of descriptive statistics. 
8.3.3. 
Safety Data 
AEs with missing classification should be queried prior to database lock. However, if there 
are missing classifications in the final data the following will be assumed: 
• missing causality will be taken as treatment related 
• missing severity will be taken as severe 
Missing seriousness will not be imputed. Such cases will be discussed in the CSR. 
Handling of missing dates/times for the start/stop of medications and adverse events are 
detailed in Sections 9.4 and 12.1 respectively.  
Laboratory values that are less than the LLOQ or greater than the upper limit of 
quantification (ULOQ) will be set to the LLOQ or ULOQ respectively, for the calculation 
of descriptive statistics. 
There will be no imputation for missing DXA data. 
8.4. 
VISIT WINDOWS 
Data will be assigned to ‘analysis’ visits using windowing (see table below). If more than 
one assessment (including the early termination or unscheduled assessments) falls within 
the same defined window, the on-treatment assessment closest to the target day with non-
missing data will be used for analysis. If the scheduled visit assessment is on-treatment and 


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within the analysis window, then this will be used irrespective of other unscheduled 
assessments within the analysis window. If two assessment dates are at the same distance 
from the target day, the latest on-treatment assessment with non-missing data will be used 
for analysis. Off-treatment assessments will only be assigned to a visit window in the 
absence of an on-treatment assessment within the analysis window. 
 
Visit 
Target Day 
Protocol Visit 
Window 
 
Analysis Window 
 
Analysis Interval 
Baseline 
1 
NA 
≤1* 
NA 
Week 2 
14 
±3 
8 - 20 
13 (±6) 
Week 4 
28 
±3 
21 – 35^ 
15 (±7) 
Week 12 
84 
±7 
63 -105 
43 (±21) 
Week 18 
126 
±7 
106 - 146 
41 (±20) 
Week 24 
168 
±7 
147 - 189 
43 (±21) 
* Baseline values must be prior to dosing if time of assessment is recorded. 
^  For pedometer data the lower limit of the analysis window will be widened to allow for the fact that the 
diary opens 2 weeks prior to the target visit date (Day 14 – 35). 
If an unscheduled or early termination visit is mapped to a scheduled visit, then the type of 
visit will be identified in the appropriate listing together with the visit that it has been 
mapped to. 
Any summaries of screening visit data will always be based on the data collected at the 
scheduled screening visit.  Consequently, if the subject does not have baseline data 
collected at the baseline visit then the screening data will be used for both the summary of 
the screening visit and the baseline visit. 
Follow-up visits by design are after the last dose of study drug and should not be allocated 
to on-treatment visits. 
Windowing will not be used for the DXA scan data as there is only one measurement post 
dose. 
Data collected outside these windows will not be attributed to an analysis window and will 
only be listed; unless specified otherwise in Section 10 and Section 10. Any scheduled visit 
outside the window will be identified on the appropriate listing. 
8.5. 
SUBGROUPS 
Subgroups will only be assessed for the purposes of exploring the consistency of effects. 
Data will be summarized for each treatment group and the differences between treatment 
groups within subject subgroups may be estimated along with 95% confidence intervals 


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and presented graphically using forest plots. Subgroup analyses are planned for the 
primary and secondary endpoints.  
The following subgroups have been defined: 
• Age: <65 years or ≥65 years 
• Sex: male or female 
• Race: black/African American, Asian, American Indian/Alaska Native, Native 
Hawaiian/Pacific Islander, white or other 
• Mutational genotype: there will be 2 subgroups, one which identifies the 
stratification groups (i.e., m.3243A>G or Other) and a second which further splits 
out the ‘other’ category genotype (i.e., m.3243A>G, m.8344A>G, mt deletion or 
Other). To split out the ‘other’ genotype category into these extended levels, first 
the m.8344A>G subjects will be identified from the other description free text 
field; then mt deletion subjects will be identified as subjects with a single large 
deletion gene defect; all remaining subjects will be categorized as Other.  In the 
event of a mis-stratification, the actual genotype recorded on the database will be 
used in analyses. 
• Syndromatic phenotype: as identified from the additional symptoms of PMM eCRF 
page.   
− chronic progressive external ophthalmoplegia (CPEO)  
− Kearns-Sayre syndrome (KSS) 
− Leigh and Leigh-like syndrome  
− maternally inherited deafness and diabetes (MIDD) 
− maternally inherited Leigh syndrome (MILS) 
− mitochondrial encephalomyopathy with lactic acidosis and stroke-like 
episodes (MELAS)  
− mitochondrial neurogastrointestinal encephalopathy (MNGIE)  
− myoclonic epilepsy with ragged red fibers (MERF)  
− neuropathy; ataxia; and retinitis pigmentosa (NARP)  
− Pearson syndrome (sideroblastic anemia and pancreatic dysfunction) 
− other 
• Baseline 12MWD: there will be 2 subgroups ≤500 m or >500 m and ≤650 m or 
>650 m 
• Country: all countries that randomized a subject 
• Region: North America (USA and Canada), Europe or Australia/New Zealand 


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• Clinically significant vitamin D deficiency at baseline defined as <30nmol/L: yes, 
no 
• Baseline PROMIS T-score: ≤60 or >60 
• Baseline 30STS able to perform test: yes or no  
• Long COVID (preferred term of post-acute COVID-19 syndrome) medical history 
status at baseline: yes, no  
• Menopausal status: males, pre-menopausal females or post-menopausal females. 
Post-menopausal females have a screening FSH value ≥ 23.0 IU/L and with either a 
date of last menstrual period > 1 year ago from date of first dose or a confirmed 
clinical history of sterility. Female subjects whose last menstrual period was > 1 
year ago but do not have a screening FSH value will also be assumed to be post-
menopausal. Female subjects who have a clinical history of sterility but do not have 
a screening FSH value cannot be classified. This subgroup will only be used for 
DXA and laboratory bone marker analyses. 
The number of subjects in each subgroup has been assessed using blinded baseline data. 
The review did not identify any subgroup categories to combine, however it has been 
agreed that only subgroup categories with 5 or more subjects will be summarized and only 
subgroup categories with 30 or more subjects will be analysed.  In addition to this the 
following decisions were made: 
• Race = other will not be summarized 
• Country and 30STS subgroups will only be summarized 
• All mutational genotype subgroup categories and baseline 12MWD categories will 
be summarized and analysed 
• Syndromatic phenotype subgroup category MERF will be analysed as well as 
summarized. 


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9. 
ANALYSIS OF DISPOSITION, DEMOGRAPHIC AND 
BASELINE CHARACTERISTICS, AND MEDICATION 
9.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
For the screened set the number of subjects screened, rescreened and randomized and the 
number who failed screening will be presented. For the randomized set the following 
number (%) of subjects will be presented: 
• Randomized and not treated 
• Randomized and dosed 
• Completed treatment 
• Discontinued from treatment and reason for discontinuation 
• Completed study (including subjects who complete the study or those who 
transition to mavodelpar open-label study at the Week 24 visit). This will be split 
by those completing at Week 24 (due to transitioning to the mavodelpar open label 
study) and those completing at follow-up 
• Withdrawn from study and reason for withdrawal 
• In each analysis set 
For each scheduled visit the following number (%) of subjects will be presented for the 
FAS: 
• For on-treatment those who: 
− attended the visit 
− missed the visit 
• For off-treatment (i.e., discontinued treatment prior to visit) those who: 
− attended the visit 
− missed the visit 
• Who withdrew from the study prior to the visit 
If a subject does not have a record for a visit and did not withdraw from the study, then the 
record will be counted as due to missing. For subjects who withdraw from the study then 
the date of study withdrawal will be used to assess whether the subject missed the visit. 
Any missing records prior to this date will be classed as missing and any missing records 
after this date will be classed as a withdrawal.  


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9.2. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demography (sex, race, ethnicity, age at consent [years], weight, height, body mass index 
(BMI) at screening and menopausal status) will be summarized. Age, weight, height and 
BMI will be summarized using summary statistics for continuous variables. Sex, 
categorical age (18 – 25 years, 26 - 45 years and 46 – 64 years and ≥ 65 years), race, 
ethnicity and menopausal status (men, pre-menopausal women and post-menopausal 
women) will be summarized as categorical variables.  
All subgroups defined in Section 8.5 will be summarized as categorical variables. In 
addition, screening 12MWD will be summarized categorically (≤500 m or >500 m and 
≤650 m or >650 m). In the event of a mis-stratification, the 12MWD screening categorical 
split will be based on the actual screening data.  
The following baseline endpoints will also be summarized as continuous variables: 
• 12MWD – screening and baseline distance 
• PROMIS T-score 
• MFIS scale – physical, cognitive, psychosocial and total score 
• 30 second sit to stand count 
• PGI-S – muscle and fatigue (note, summarized as categorical variables only) 
The duration of PMM symptoms (years) will be summarized using summary statistics for 
continuous variables. 
Duration of PMM symptoms (years) = Age at consent – Age at onset of PMM symptoms 
These data will be summarised for the safety, FAS, PP and CScAS sets. Menopausal status 
will only be summarized for the CScAS. If the SAF and FAS are the same only the one 
will be presented (as Safety/FAS). 
9.3. 
MEDICAL HISTORY AND CONCOMITANT DISEASES 
Medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) version 23.1.  
A separate summary of past and current medical history will be presented for the safety set 
by System Organ Class (SOC) and Preferred Term (PT) with counts and percentages. Each 
subject will be counted only once in each SOC or SOC/PT summary. In the summary 
tables, medical history will be presented by decreasing frequency of subjects overall within 
each SOC and then similarly by decreasing frequency of subjects overall within each PT. 
In cases of SOCs or PTs with equal frequencies, medical history will be sorted 
alphabetically.  


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Past medical history events are defined as events reported with an end date prior to Day 1 
and current medical history events are ongoing events on Day 1. If a partial end date is 
recorded, the following convention will be used to assign the event: 
• If a partial end date is missing a day and the month/year is the same, or after, the 
start date of dosing then the event will be assumed to be current; otherwise, it will 
be assumed to be a past event 
• If a partial end date is missing a month and only the year is present and the year is 
≤ the year that study dosing starts, then it will be assumed to be a past event. 
Medical history is collected at the screening visit and therefore events ending on or 
after the screening visit should be recorded with at least a month and year for the 
end date 
• If the end date is missing, then it will be assumed to be a current event. 
The following PTs, which are associated with the disease under study, will be listed but 
excluded from the summaries: 
• mitochondrial myopathy  
• progressive external ophthalmoplegia  
• MELAS syndrome,  
• myoclonic epilepsy and ragged-red fibres,  
• Kearns-Sayre syndrome,  
• gene mutation,  
• mitochondrial DNA deletion  
• mitochondrial encephalomyopathy  
9.4. 
PRIOR AND CONCOMITANT MEDICATIONS 
Prior and concomitant medications will be coded using World Health Organization (WHO) 
Drug Dictionary version WHODRUG GLOBAL B3 September 1, 2020.  
Prior medications will be defined as those medications started prior to the administration of 
study drug on Day 1. Concomitant medications will be defined as those medications taken 
following administration of study drug on Day 1. Hence medications started before 
receiving the study dose but continuing after will be considered as both prior and 
concomitant medications.  Concomitant medication summaries will be repeated for those 
medications that are taken whilst on-treatment (ignoring dosing interruptions) or started 
within 7 days after the last dose of study drug. 


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Medication will be summarised for the safety and the DXA CScAS by anatomic 
therapeutic chemical (ATC) level 2 (therapeutic main group) and ATC level 5 (PT 
medication name) with counts and percentages. Prior and concomitant medications will be 
presented by descending frequency in ATC and PT within ATCs over all subjects. A 
subject who takes more than one medication will be counted only once if these 
medications belong to the same extended ATC classification. These summaries will be 
repeated for medications that have an adverse impact or positive impact on the bones; a 
medical review of unique medications will be performed prior to database lock to identify 
these medications. 
All data will be listed for the safety set and a variable will be included to identify whether 
the medication is prior, concomitant or both prior and concomitant. The listing will also 
identify whether the start date of medication was after the date of last dose of study drug 
plus 7 days for those subjects who have discontinued treatment. 
If either the start or stop date of medication is missing, the most conservative case will be 
considered when assigning medications to categories. So, for a missing start date where 
stop date is after start date of dosing or missing, the date will be imputed as the dosing start 
date. For a missing start date where stop date is on or before the start date of dosing, the 
date will be imputed as the day before the stop date and the event will be classified as a 
prior medication; for a missing stop date the date will be imputed as the last study date. If a 
partial date is recorded, the following convention will be used to assign the medication: 
• If a partial date is missing a start day and the month/year is the same as the start 
date of dosing then use the dose start date if the stop date is after the dose start date 
or the stop date is missing, else ‘01’ will be used for the day; if a start date is 
missing a month and the year is the same as the start date of dosing then use the 
dose start date if the stop date is after the dose start date or the stop date is missing, 
else January will be used for the start month. 
• If a partial date is missing a stop day and month/year is same as last study date then 
use last study date, else last day of the given month will be used for the stop day; if 
a stop date is missing a month and the year is the same as last study date then use 
last study date, else December will be used for the stop month. 
Concomitant non-drug therapies will also be listed for the safety analysis set. 
9.5. 
TREATMENT EXPOSURE 
Duration of treatment, days on treatment, number of capsules taken, and treatment 
compliance, will be summarized for the FAS using descriptive statistics. Duration of 
treatment will also be summarized using 4-week categories (e.g., ≤4 weeks, >4 to ≤8 
weeks, …, >16 to ≤20 weeks, >20 weeks); and treatment compliance will also be 
summarized using the categories <80%, 80-120% and >120%.  


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• Duration of treatment in days is defined as (date of last dose minus date of first 
dose plus 1 day). Values will be presented to 1 decimal place. 
• Days on treatment is defined as the duration of treatment minus the number of days 
the subject is instructed to not take their medication (e.g., dose interruption due to 
AE) 
• Number of capsules expected to be taken is defined as the days on treatment 
multiplied by the number of capsules to be taken each day (2 per day) 
• Number of capsules taken is defined as number of capsules dispensed minus 
number of capsules returned 
• Treatment compliance (%) is defined as 100 * number of capsules taken / (number 
of capsules expected to be taken). Values will be presented to 1 decimal place. 
If study drug is not returned, the listing will present a compliance range; the lower limit 
will assume no study drug taken for the containers not returned and, the upper limit will 
assume all study drug taken for the containers not returned. The compliance listing will 
also include number of capsules dispensed and number of capsules returned.  
If study drug is not returned the summary will consider number of capsules taken as 
missing. However, for the treatment compliance categorical summary, the subject may be 
counted if their range falls entirely within one treatment compliance category (e.g., if the 
range is 40-60% they will be counted in the count for the <80% category). 


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10. 
ANALYSIS OF EFFICACY DATA 
All analysis models used for the efficacy endpoints will have their model assumptions 
checked by evaluating model residuals.  
Sample SAS© code for the analysis models used are provided in Appendix 1.  
All analyses will be based on the FAS unless stated otherwise. The primary comparison for 
all analyses will be at Week 24. 
10.1. 
PRIMARY ENDPOINT 
10.1.1. 
Primary Estimand 
The primary estimand of interest for this study involves a treatment policy strategy. Using 
this treatment policy strategy, the primary estimand for the primary endpoint 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. 
10.1.2. 
Primary Analysis 
Intercurrent events and missing data will be handled using the methodology described in 
Section 8.3.1. For the primary endpoint the missing values will be imputed using the 
technique of multiple imputations; this includes incomplete tests considered unrelated to 
their PMM, which will be set to missing prior to imputation. The multiple imputation step 
will be performed prior to any imputations for intercurrent events. 
Changes from baseline will be analysed 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 matrix will be used for the repeated 
visits within a subject and the model will allow the covariance matrix to differ between 
treatment groups. If this analysis fails to converge, then an analysis of covariance 
(ANCOVA) will be used which will analyse the change from baseline at Week 24 and at 
Week 12 separately. The ANCOVA model will include a fixed term for treatment and the 
mutation stratification factor and continuous baseline distance walked during the 12MWT 
as covariates. The Kenward-Rogers approximation will be used to estimate the 
denominator degrees of freedom (Kenward 1997). The treatment comparison (mavodelpar 
100mg - placebo) for the change from baseline at both Week 12 and Week 24 will be 
estimated. The estimates, standard errors, 95% confidence intervals and associated 
p-values will be presented for each of the multiple imputation analyses as well as the 
pooled values. 


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10.1.3. 
Summaries and Plots 
Observed, change from baseline and percent change from baseline values will be 
summarized by visit, both including and excluding imputed values. The imputed summary 
statistics will be based on Rubin’s methodology (Rubin 19875) to combine the means and 
standard errors from the imputed data sets. The associated 95% confidence intervals for the 
observed, change from baseline and percent change from baseline means will also be 
presented. 
Mean plots for observed, change from baseline and percent change from baseline values, 
with 95% confidence intervals, will be presented by treatment group with visit on the x-
axis. A reference line for no change (i.e., y=0) will be included in the change from baseline 
and percent change from baseline plots.  
Spaghetti plots for the changes from baseline will be plotted over time. The plots will be 
split by treatment group. The y-axis will be uniform across the plots to allow comparisons. 
A reference line for no change (i.e., y=0) will be included. 
A plot of the proportion of subjects achieving no change or an increase in 12MWD at 
Week 24 will be presented by treatment group. The x-axis will present the change in 
12MWD at Week 24 (starting at 0m to maximum change achieved at Week 24) and the y-
axis will present the proportion of subjects who achieve this change as a percentage. A 
corresponding summary table will present proportion of subjects achieving no change or 
an increase in 12MWD at Week 24 at incremental cut points of 20m. This plot and table 
will use the average values for subjects across the imputed datasets (including imputations 
for intercurrent events).  
The number of stops and the number of falls will be summarized by visit. If a subject does 
not walk for the full 12 minutes, then this will be counted as an additional stop when 
summarizing. 
All data will be listed together with changes from baseline, percent change from baseline   
and assessments imputed due to being at least possibly related to the subject’s PMM will 
be identified. The pre and post exercise measurement for heart rate, blood pressure and 
RPP scale score will be listed separately, along with their changes from pre-test.  
12MWD values, mean, median, minimum and maximum will all be presented to 2 decimal 
places and SD will be presented to 3 decimal places.  
10.1.4. 
Sensitivity Analyses 
The following sensitivity analyses will be performed for the primary endpoint with the 
FAS: 


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1. Pattern mixture multiple imputation. This will assume that missing data after 
treatment discontinuation (i.e., date of last dose of study drug) in either treatment 
group will be assumed to follow a similar trajectory to those in the placebo group. 
All missing data including missing data due to intercurrent events will be handled 
using the same methodology described in Section 8.3.1, the MNAR statement 
together with the MODEL option from the SAS© MI procedure will be used to 
impute missing data based on the placebo treatment group only. 
The same model used for the primary analysis will then be applied to the imputed 
datasets. 
For this sensitivity analysis the data including imputed values, and associated 
change from baseline and percent change from baseline values will be summarized 
by visit. 
2. Tipping point analysis (O’Kelly 2014). This will assume that the missing values at 
least possibly related to a subject’s PMM deviate by a certain amount, delta, in a 
worsening direction. All values will be imputed using multiple imputation (i.e., 
MAR) and then a sequential series of analyses will be performed where a value 
delta is subtracted from the imputed values for those possibly related to PMM. The 
range of delta will be applied in increments of 5. If it exists, the delta that turns the 
conclusion from favouring one group to favouring the other is called the tipping 
point. 
A check will be made to ensure the adjusted imputed value is plausible i.e., ≥ 0, 
and if not, the value will be fixed at zero. The same model used for the primary 
analysis will then be applied to the imputed datasets. 
For this analysis, a table giving results for each progressively increasing delta value 
will be produced for Weeks 12 and 24. A forest plot of the estimate of the treatment 
difference and associated 95% confidence interval for each delta incremental value 
will also be presented for Weeks 12 and 24. 
3. ANCOVA. If the primary analysis model described above does not converge then 
ANCOVA will be used as the main analysis. However, if the model does converge 
then as an additional sensitivity analysis the ANCOVA approach will be used to 
analyse the change from baseline at Week 12 and Week 24 separately. As above, 
the ANCOVA model will include a fixed term for treatment and the mutation 
stratification factor and continuous baseline distance walked during the 12MWT as 
covariates.  
 
10.1.5. 
Supplementary Analyses 
The following supplementary analyses will be performed for the primary endpoint: 
1. Per protocol analysis. The primary analysis will be repeated for the PP analysis set. 


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2. While on-treatment strategy. Only on-treatment values (up to 7 days after the 
subject's last dose of study drug) will be considered for analysis; consequently, only 
subjects in the mFAS will be included. For this strategy the estimand is defined as 
the difference in means between the treatments in the target population for the 
change from baseline in 12MWD, while the subject continues to receive study drug 
(plus 7 days).  
The last on-treatment change from baseline in 12MWD will be analysed using an 
ANCOVA. The model will include 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.    
3. Treatment period restricted analysis. On-treatment values will be analysed for the 
mFAS. This analysis restricts the observation time of interest to the time of last 
dose of study drug plus 7 days. For this strategy the estimand is defined as the 
difference in means between the treatments in the target population for the change 
from baseline at Week 24 in 12MWD, while the subject continues to receive study 
drug (plus 7 days).  
The same model used for the primary analysis will be applied. All missing data will 
be assumed MAR and predicted from the MMRM model without multiple 
imputation. 
4. Worst case imputation. This will impute all missing data irrespective of cause using 
a worst case imputation as described in Section 8.3.1. The same model used for the 
primary analysis will then be applied to the imputed datasets. The data including 
imputed values, and associated change from baseline and percent change from 
baseline values will be summarized by visit. 
5. Non-parametric analysis. All missing data including missing data due to 
intercurrent events will be handled using the same methodology described in 
Section 8.3.1. A Hodges-Lehmann estimate (‘Interval midpoint’) and asymptotic 
standard error will be calculated for change from baseline, taking account of the 
variables; stratification mutation factor and categorical baseline distance walked 
during the 12MWT. The estimates will then be combined across the imputations to 
give a pooled estimate of treatment effect which will be presented together with the 
asymptotic standard error, 95% confidence interval and associated p-value. 
A review of baseline blinded data revealed that the number of subjects in the 
≤500 m baseline 12MWD is small.  Consequently, to improve the balance of 
subjects across the strata groups in the analysis the categories for baseline 12MWD 
will be ≤650 m and >650 m. 
10.1.6. 
Subgroup Analyses 
The impact of all subgroups (specified in Section 8.5) on the primary endpoint will also be 
investigated descriptively. Summaries will be presented by subgroup and the imputed 


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datasets generated for the primary analysis will be analysed by subgroup using the primary 
analysis model. A forest plot of the estimate of the treatment difference and associated 
95% confidence interval for each subgroup will be presented for Weeks 12 and 24. 
10.2. 
SECONDARY ENDPOINT 
10.2.1. 
Patient-Reported Outcomes Measurement Information System 
(PROMIS) Short Form – Functional Assessment of Chronic 
Illness Therapy (FACIT) Fatigue 13a 
Intercurrent events and missing data will be handled using the methodology described in 
Section 8.3.1. Missing values will be imputed using the technique of multiple imputations. 
Missing data as a result of an intercurrent event which is considered related to a subject’s 
PMM will be imputed using worst case imputation. The multiple imputation step will be 
performed prior to any imputations for intercurrent events. 
Changes from baseline in T-score will be analysed 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 score and 
continuous baseline distance walked during the 12MWT as covariates. An unstructured 
covariance structure will be used, and the model will allow the covariance matrix to differ 
between treatment groups. If this analysis fails to converge, then an analysis of covariance 
(ANCOVA) will be used which will analyse the change from baseline at each post-
baseline visit separately. The ANCOVA model will include a fixed term for treatment and 
the mutation stratification factor, continuous baseline score and continuous baseline 
distance walked during the 12MWT as covariates. The Kenward-Rogers approximation 
will be used to estimate the denominator degrees of freedom. 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 
estimates, standard errors, 95% confidence intervals and associated p-values will be 
presented for each of the multiple imputation analyses as well as the pooled values. 
Observed and change from baseline values will be summarized by visit, both including and 
excluding imputed values. The imputed summary statistics will be based on Rubin’s 
methodology (Rubin 1987) to combine the means and standard errors from the imputed 
data sets. The associated 95% confidence intervals for the observed and change from 
baseline means will also be presented. 
Mean plots of observed and changes from baseline values, with 95% confidence intervals, 
will be presented by treatment group with visit on the x-axis. A reference line for no 
change (i.e., y=0) will be included in the change from baseline plot. 


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Spaghetti plots for the changes from baseline will be plotted over time. The plots will be 
split by treatment group. The y-axis will be uniform across the plots to allow comparisons. 
A reference line for no change (i.e., y=0) will be included. 
Categorical shift tables of change from baseline showing improvement (at least a 5-point 
decrease in score), no change (less than a 5-point change in either direction) or worsening 
(at least a 5-point increase in score) at each visit will be summarized. The table will 
include categories for withdrawn and missing. Percentages will not be presented for the 
withdrawn and missing rows, and the percentages presented will use the number of non-
missing values as the denominator. In addition, to account for subjects at the extreme ends 
of the scale, the shift table will also include the percent improving or worsening based on 
those subjects who have the potential to improve or worsen respectively. 
Sensitivity Analyses 
A pattern mixture multiple imputation and tipping point analysis similar to the primary 
analysis will also be performed.  
1. Pattern mixture multiple imputation. This will assume that missing data after 
treatment discontinuation in either treatment group will be assumed to follow a 
similar trajectory to those in the placebo group. 
Missing data will be imputed using multiple imputation as defined in Section 8.3.1, 
the MNAR statement together with the MODEL option from the SAS© MI 
procedure will be used to impute missing data based on the placebo treatment 
group only. The same model used above will then be applied to the imputed 
datasets and the SAS© MIANALYZE procedure will be used to produce pooled 
estimates of the treatment difference, along with their standard errors, 95% 
confidence intervals, and associated p-values.  
For this sensitivity analysis the data including imputed values, and associated 
change from baseline will be summarized by visit. 
2. Tipping point analysis. This method assumes that the missing values at least 
possibly related to a subject’s PMM deviate a certain amount, delta, in a worsening 
direction. Missing data will be imputed using multiple imputation (i.e., MAR) as 
defined in Section 8.3.1; then a sequential series of analyses will be performed 
where a value delta is added to the imputed values for those related to PMM. The 
delta will be applied in increments of 5 which is equivalent to half a standard 
deviation based on a US population. If it exists, the delta that turns the conclusion 
from favouring one group to favouring the other is called the tipping point. 
A check will be made to ensure the adjusted imputed value is plausible i.e., ≥30.3 
and ≤83.6, and if not, the value will be fixed at either 30.3 or 83.6 respectively. The 
same model used for the main analysis above will then be applied to the imputed 
datasets. 


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For this analysis, a table giving results for each progressively increasing delta value 
will be produced for each visit. A forest plot of the estimate of the treatment 
difference and associated 95% confidence interval for each delta incremental value 
will also be presented for each visit. 
3. ANCOVA. If the primary analysis model described above does not converge then 
ANCOVA will be used as the main analysis. However, if the model does converge 
then as an additional sensitivity analysis the ANCOVA approach will be used to 
analyse the change from baseline at each post-baseline visit separately. The 
ANCOVA model will include a fixed term for treatment and the mutation 
stratification factor, continuous baseline score and continuous baseline distance 
walked during the 12MWT as covariates. 
Supplementary Analyses 
The following supplementary analyses will be performed: 
1. Per protocol analysis. The analysis will be repeated for the PP analysis set. 
2. While on-treatment strategy. Only on-treatment values (up to 7 days after the 
subject's last dose of study drug) will be considered for analysis; consequently, only 
subjects in the mFAS will be included. This analysis will take the last value prior to 
discontinuation of study treatment.  
The last on-treatment change from baseline will be analysed using an ANCOVA. 
The model will include a fixed term for treatment and the mutation stratification 
factor, continuous baseline score 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.    
3. Treatment period restricted analysis. On-treatment values will be analysed for the 
mFAS. The same model used for the main analysis will be applied. All missing 
data will be assumed MAR and predicted from the MMRM model without multiple 
imputation. 
4. Non-parametric analysis. All missing data including missing data due to 
intercurrent events will be handled using the same methodology described in 
Section 8.3.1. A Hodges-Lehmann estimate (‘Interval midpoint’) and asymptotic 
standard error will be calculated for change from baseline, taking account of the 
variables: 
a. Stratification mutation factor 
b. Categorical baseline T-score (≤ 60 and > 60)  
The estimates will then be combined across the imputations to give a pooled 
estimate of the treatment effect which will be presented together with the 
asymptotic standard error, 95% confidence interval and associated p-value.   


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As for the primary endpoint, the impact of all subgroups (specified in Section 8.5) will also 
be investigated descriptively. Summaries will be presented by subgroup and the imputed 
datasets generated for the main analysis will be analysed by subgroup using the main 
analysis model. A forest plot of the estimate of the treatment difference and associated 
95% confidence interval for each subgroup will be presented for Weeks 12 and 24 only. 
10.3. 
EXPLORATORY ENDPOINTS 
10.3.1. 
30 Second Sit to Stand Test 
Changes from baseline will be analysed 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 sit to stand score and 
continuous baseline distance walked during the 12MWT as covariates. An unstructured 
covariance structure will be used, and the model will allow the covariance matrix to differ 
between treatment groups. If the analysis fails to converge, then an ANCOVA will be 
used, which will analyse the change from baseline at Week 24 and at Week 12 separately. 
The ANCOVA model will include a fixed term for treatment and the mutation 
stratification factor, continuous baseline sit to stand score and continuous baseline distance 
walked during the 12MWT as covariates. The Kenward-Rogers approximation will be 
used to estimate the denominator degrees of freedom. 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.  
Observed and change from baseline values will be summarized by visit, both including and 
excluding predicted values, using descriptive statistics. Predicted values for a subject will 
be the predicted values from the MMRM analysis. The associated 95% confidence 
intervals for the observed and change from baseline means will also be presented. In 
addition, the number of subjects with an imputed count of 0 at the visit will be 
summarized. 
Mean plots of observed and change from baseline values, with 95% confidence intervals, 
will be presented by treatment group with visit on the x-axis. A reference line for no 
change (i.e., y=0) will be included in the change from baseline plot. 
10.3.2. 
Pedometer Step Count  
Only subjects who have at least one median and average daily step count derived for a visit 
will be analysed. Changes from baseline for each endpoint will be analysed 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, sex, continuous 
baseline pedometer count, age as a continuous variable and continuous baseline distance 
walked during the 12MWT as covariates. An unstructured covariance structure will be 


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used, and the model will allow the covariance matrix to differ between treatment groups. If 
the analysis fails to converge, then a Toeplitz structure will be used. The Kenward-Rogers 
approximation will be used to estimate the denominator degrees of freedom. 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.  
Observed, change from baseline and percent change from baseline values will be 
summarized by visit, both including and excluding predicted values. Predicted values for a 
subject will be the predicted values from the MMRM analysis. The associated 95% 
confidence intervals for the observed, change from baseline and percent change from 
baseline means will also be presented. In addition, the number of subjects with a daily step 
count <500 or ≥20,000 at the visit will be summarized.  
Mean plots of observed value, change from baseline and percent change from baseline 
values, with 95% confidence intervals, will be presented by treatment group with visit on 
the x-axis. A reference line for no change (i.e., y=0) will be included in the change from 
baseline and percent change from baseline plots. 
Spaghetti plots of the individual median and average daily step count change from baseline 
and percent change from baseline will be plotted over time. The plots will be split by 
treatment group. The y-axis will be uniform across the plots to allow comparisons. A 
reference line for no change (i.e., y=0) will be included. 
Median and average daily step count values mean, median, minimum and maximum will 
all be presented to 0 decimal places and SD will be presented to 1 decimal places.  
10.3.3. 
Patient Global Impression of Severity (PGIS) Score - Muscle 
Symptoms and Fatigue Symptoms 
Missing values will be imputed using the technique of multiple imputations. Ordinal 
regression will be used to impute the monotone missing data.  Week 12 and Week 24 data 
will then be analysed separately using ordinal logistic regression analysis for each 
symptom. The model will include a fixed term for treatment. The model will also include 
the stratification mutation factor, baseline score and baseline distance walked during the 
12MWT as covariates. If there are few counts in one or more of the response categories 
causing issues with model convergence then categories will be combined in a logical way 
(e.g., only adjacent categories will be combined) to reduce the number of categories. The 
proportional odds assumption will be checked using the Score test; if the assumption does 
not hold then a partial or non-proportional model will be considered. The estimated odds 
ratios, p-values and 2-sided 95% confidence intervals for the odds ratios will be presented.  


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Categorical shift tables from baseline at each visit will be summarized including marginal 
totals.  The table will include categories for withdrawn and missing. Percentages will not 
be presented for the withdrawn and missing rows, and the percentages presented will use 
the number of non-missing values as the denominator. In addition, to account for subjects 
at the extreme ends of the scale, the shift table will be repeated for improvement, no 
change or worsening from baseline at each visit, based on those subjects who have the 
potential to improve or worsen, respectively.  
Stacked bar charts will be presented for the proportion of subjects at each of the PGIS 
scores by visit for each of the treatment groups. The categories will include each of the 
PGIS levels and missing and withdrawn. 
10.3.4. 
36 Item Short Form Survey (SF-36) 
Changes from baseline for the 8 scale scores will be analysed 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 scale score 
and continuous baseline distance walked during the 12MWT as covariates. An 
unstructured covariance structure will be used, and the model will allow the covariance 
matrix to differ between treatment groups. If the analysis fails to converge, then a Toeplitz 
structure will be used. The Kenward-Rogers approximation will be used to estimate the 
denominator degrees of freedom. 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.  
Observed and change from baseline values will be summarized at each visit both including 
and excluding predicted values using descriptive statistics for the 8 scale scores. Predicted 
values for a subject will be the predicted values from the MMRM analysis. The associated 
95% confidence intervals for the observed and change from baseline means will also be 
presented.  
Mean plots of observed and change from baseline values, with 95% confidence intervals, 
will be presented by treatment group with visit on the x-axis. A reference line for no 
change (i.e., y=0) will be included in the change from baseline plot. 
Categorical shift tables of change from baseline for each scale score showing improvement 
(at least a 4-point increase in score), no change (less than a 4-point change in either 
direction) or worsening (at least a 4-point decrease in score) at each visit will be 
summarized. The table will include categories for withdrawn and missing. Percentages will 
not be presented for the withdrawn and missing rows, and the percentages presented will 
use the number of non-missing values as the denominator. In addition, to account for 
subjects at the extreme ends of the scale, the shift table will also include the percent 
improving or worsening based on those subjects who have the potential to improve or 


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worsen respectively. Where a 4-point change in score indicates an improvement or 
worsening, subjects with the potential to improve will have a baseline score of 96 or 
below; similarly, for those with a potential to worsen they will have a baseline score of 4 
or more. 
Scale scores and changes from baseline will be listed separately from the raw data.  
Scale score values will be presented to 0 decimal places. 
10.3.5. 
Modified Fatigue Impact Scale (MFIS) – Total, Physical, 
Cognitive and Psychosocial Sub-scale Scores 
Changes from baseline will be analysed using a MMRM for each of the scores. 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 score 
and continuous baseline distance walked during the 12MWT as covariates. An 
unstructured covariance structure will be used, and the model will allow the covariance 
matrix to differ between treatment groups. If the analysis fails to converge, then a Toeplitz 
structure will be used. The Kenward-Rogers approximation will be used to estimate the 
denominator degrees of freedom. 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.  
Observed, change from baseline and percent change from baseline values will be 
summarized by visit both including and excluding predicted values using descriptive 
statistics. Predicted values for a subject will be the predicted values from the MMRM 
analysis. The associated 95% confidence intervals for the observed and change from 
baseline means will also be presented.  
Mean plots of observed, change from baseline and percent change from baseline values, 
with 95% confidence intervals, will be presented by treatment group with visit on the x-
axis. A reference line for no change (i.e., y=0) will be included in the change from baseline 
and percent change from baseline plots. 
Spaghetti plots for the changes from baseline will be plotted over time. The plots will be 
split by treatment group. The y-axis will be uniform across the plots to allow comparisons. 
A reference line for no change (i.e., y=0) will be included. 
Categorical shift tables of change from baseline showing improvement (at least a 4-point 
decrease in score), no change (less than a 4-point change in either direction) or worsening 
(at least a 4-point increase in score) at each visit will be summarized. The table will 
include categories for withdrawn and missing. Percentages will not be presented for the 
withdrawn and missing rows, and the percentages presented will use the number of non-
missing values as the denominator. In addition, to account for subjects at the extreme ends 


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of the scale, the shift table will also include the percent improving or worsening based on 
those subjects who have the potential to improve or worsen respectively. 
As a sensitivity analysis the main analysis will be repeated excluding subjects from the 
Netherlands site to assess if there was an impact due to the incorrect recall period being 
included on the questionnaire for subjects at this site. 
Total and sub-scale scores and changes from baseline will be listed separately from the raw 
data.  
10.3.6. 
Brief Pain Inventory (BPI) Short Form 
Changes from baseline for pain severity and pain interference will be analysed 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 score and continuous baseline distance walked during the 12MWT as covariates. 
An unstructured covariance structure will be used, and the model will allow the covariance 
matrix to differ between treatment groups. If the analysis fails to converge, then a Toeplitz 
structure will be used. The Kenward-Rogers approximation will be used to estimate the 
denominator degrees of freedom. 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.  
Observed and change from baseline values will be summarized at each visit both including 
and excluding predicted values using descriptive statistics for the pain severity and pain 
interference scores. Predicted values for a subject will be the predicted values from the 
MMRM analysis. The associated 95% confidence intervals for the observed and change 
from baseline means will also be presented. 
Mean plots of observed and change from baseline values, with 95% confidence intervals, 
will be presented by treatment group with visit on the x-axis. A reference line for no 
change (i.e., y=0) will be included in the change from baseline plot. 
Categorical shift tables of change from baseline for pain severity and pain interference 
showing improvement (at least a 1.5-point decrease in score), no change (less than a 1.5-
point change in either direction) or worsening (at least a 1.5-point increase in score) at 
each visit will be summarized. The table will include categories for withdrawn and 
missing. Percentages will not be presented for the withdrawn and missing rows, and the 
percentages presented will use the number of non-missing values as the denominator. In 
addition, to account for subjects at the extreme ends of the scale, the shift table will also 
include the percent improving or worsening based on those subjects who have the potential 
to improve or worsen respectively. 


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The summary and MMRM analysis may be repeated excluding subjects who have a 
baseline pain severity score <4. 
Pain severity and pain interference scores and changes from baseline will be listed with the 
raw data. 
10.3.7. 
Work Productivity and Activity Impairment Questionnaire: 
Specific Health Problems (WPAI: SHP) 
Changes from baseline for WPAI scores, except percent activity impairment, will be 
analysed using a MMRM for subjects who were employed at baseline. 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 score and 
continuous baseline distance walked during the 12MWT as covariates. An unstructured 
covariance structure will be used, and the model will allow the covariance matrix to differ 
between treatment groups. If the analysis fails to converge, then a Toeplitz structure will 
be used. The Kenward-Rogers approximation will be used to estimate the denominator 
degrees of freedom. 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 analysis will be repeated for percent of 
activity impairment which will be based on all subjects. 
WPAI scores, except percent activity impairment, will only be summarized for those 
subjects who are employed. Observed and change from baseline values will be 
summarized by visit both including and excluding predicted values using descriptive 
statistics for the 4 WPAI scores. Predicted values for a subject will be the predicted values 
from the MMRM analysis. The associated 95% confidence intervals for the observed and 
change from baseline means will also be presented. 
Mean plots of observed and change from baseline values, with 95% confidence intervals, 
will be presented by treatment group with visit on the x-axis. A reference line for no 
change (i.e., y=0) will be included in the change from baseline plot. 
WPAI score values will be presented to 0 decimal places. 
10.3.8. 
Patient Global Impression of Change (PGIC) – Muscle 
Symptoms and Fatigue Symptoms 
PGIC is only assessed at the end of study treatment (Week 24 or early termination). Data 
will be included regardless of the duration between the subject’s last dose of study 
medication and the assessment. 
Subjects with no PGIC assessment will be considered as missing unless the incidence of 
missing PGIC data exceeds 5%. If more than 5% of subjects do not complete the PGIC at 


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Week 24 or the early termination visit, multiple imputation, using ordinal logistic 
regression (refer to Section 8.3.1) will be adopted to account for their missing data. 
Subjects who die prior to their PGIC assessment will be imputed as ‘very much worse’.  
Both PGIC numeric scores will be analysed using ANCOVA. The model will include 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.  
A supplementary analysis will also be performed using a while on treatment strategy. In 
this analysis only assessments within 7 days of the last dose of study treatment will be 
included. The numeric score will be analysed using ANCOVA using the same model as 
stated above. 
A logistic regression analysis will be performed on the responder exploratory endpoints. 
Subjects who early terminate with no PGIC assessment will be assumed to be a non-
responder. The model will include a fixed term for treatment and the mutation stratification 
factor and continuous baseline distance walked during the 12MWT as covariates. The 
estimated odds ratios, 95% confidence intervals and associated p-value for the odds ratios 
will be presented, together with the exponentiated least squares means treatment estimates 
and standard errors. 
In addition, both PGIC scores will be summarized as a categorical variable for the FAS. 
The table will include categories for withdrawn (if the subject withdraws prior to the Week 
24 visit and does not complete the PGIC at an Early Termination visit) and missing. 
Percentages will not be presented for the withdrawn and missing rows, and the percentages 
presented will use the number of non-missing values as the denominator.  
10.3.9. 
6-Minute Walk Distances (Derived from 12MWD) 
The first and last 6-minute walk distances derived from the 12MWD will be analysed in 
the same way as the primary analysis. 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. 
The baseline 6-minute walk distance will not be included in the model as a covariate as 
this will be correlated with the baseline 12MWD already included in the model. Note that 
if a subject’s 12MWD is incomplete but they walk for longer than 6 minutes then only the 
last 6-minute period will be classified as incomplete and imputation rules applied. For 
example if a subject walks for 10 minutes and the walk is adjudicated as ‘ambulatory 
subject unwilling to, or prevented from, performing the test for reasons possibly related to 
PMM or study treatment’ then the worst case imputation will only apply to the last 6 
minutes.  


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In addition to the summary presentation, mean plots for observed, change from baseline 
and percent change from baseline values, with 95% confidence intervals, will be presented 
by treatment group and 6-minute time period with visit on the x-axis. A reference line for 
no change (i.e., y=0) will be included in the change from baseline and percent change from 
baseline plots. 
The first and last 6-minute walk distance values, mean, median, minimum and maximum 
will all be presented to 2 decimal places and SD will be presented to 3 decimal places. 
10.3.10. 
PMM Phenotypic Description 
Categorical shift tables from baseline to Week 24 will be summarized, including marginal 
totals, for the 3 phenotypic questions.  The table will include categories for withdrawn and 
missing. Percentages will not be presented for the withdrawn and missing rows, and the 
percentages presented will use the number of non-missing values as the denominator. 
10.4. 
RELATIONSHIP OF ENDPOINTS 
To assess the relationship of the primary endpoint to other efficacy endpoints, scatter plots 
will be generated for the changes from baseline in 12MWD at Week 12 and Week 24 
versus changes from baseline for the secondary endpoint PROMIS T-score and the 
exploratory endpoints, 30 second sit to stand, MFIS (physical, cognitive, psychosocial and 
total), the 8 scales for SF-36 and BPI (pain severity and pain interference). The plots will 
identify treatment group and the visit week. The Pearson correlation coefficients for each 
treatment group at Week 12 and for Week 24 will also be presented in the footnote of the 
plots. 
For PGIC muscle symptoms and PGIC fatigue symptoms a box plot of change from 
baseline in 12MWD will be presented for each response level and treatment group at Week 
12 and at Week 24 separately. The plot will be repeated for the 2 PGIS symptoms with the 
response levels of improvement, no change and worsening from baseline. 


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11. 
ANALYSIS OF PHARMACOKINETIC ENDPOINTS 
The mavodelpar concentrations will be evaluated using the PK set. mavodelpar 
concentrations will be summarized at each scheduled time point on Day 1 and Weeks 12 
and 24 using descriptive statistics. For post-dose samples, only concentrations collected 
within a 10% window of the protocol specified post dose time point will be included. 
Similarly, pre-dose concentrations will only be included if the samples were taken prior to 
dosing on the day. The number of subjects with a BLQ value will also be tabulated. 
Linear and log-linear individual concentration profile spaghetti plots against time will be 
produced for Day 1 and Weeks 12 and 24. All subjects will be displayed on the same plot 
and mutational genotype (m.3243A>G, m.8344A>G, mt deletion or Other) will be 
identified. The actual sampling time will be used on the x-axis with pre-dose fixed at zero 
for all subjects.  
Linear and log-linear median concentration profile plots against time will be produced for 
Day 1 and Weeks 12 and 24. The nominal sampling time will be used on the x-axis. Lines 
will be included for all subjects and by mutational genotype. 
A listing of all concentration data will be presented. The actual time post dose, deviation 
and percent deviation from nominal post dose time will also be listed for the post dose 
samples on Day 1 and Weeks 12 and 24. For all other visits the actual time relative to dose 
the sample was collected will be listed. 
Concentration values will be presented to 3 significant figures. 


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12. 
ANALYSIS OF SAFETY DATA 
All safety evaluations will be performed using the safety analysis set unless specified 
otherwise. 
12.1. 
ADVERSE EVENTS 
AEs will be coded using MedDRA version 23.1. 
AEs will be considered treatment-emergent (TE) unless there is a clear indication that the 
event occurred prior to the first dose of study drug. AEs with missing start dates will be 
taken as TE unless the end date occurs before Day 1. If there is a partial start date, then the 
AE will be taken as TE unless suggested otherwise by the partial information provided and 
the end date. Events that occur after informed consent and prior to the first study dose are 
to be reported as pre-treatment AEs. Therefore, only TEAEs are to be reported on the 
adverse event eCRF page. Onset dates will be checked against the first dose date to ensure 
there is no conflict in this designation. 
If an adverse event has a missing start date (where stop date is after the dosing date or 
missing) the date will be imputed as the dosing start date and for a missing start date 
(where stop date is before the start date of dosing) the date will be imputed as the day of 
informed consent and the event will be classified as a pre-treatment AE; for a missing stop 
date the TEAE will be considered as ongoing at the last visit date. If a partial date is 
recorded, the following convention will be used to assign the AE: 
• If a start date is missing the day information and month/year is the same as the 
dosing start date then use the dose start date, else ‘01’ will be used for the day; if a 
start date is missing the day/month and the year is the same as the dosing start date 
then use the dose start date, else January will be used for the start month. 
• If a stop date is missing the day information and month/year is same as last study 
date then use last study date, else last day of the given month will be used for the 
stop day; if a stop date is missing the day/month and year is the same as last study 
date then use last study date, else December will be used for the stop month. 
Only TEAEs will be included in the summary tables. Summaries will be generated for all 
TEAEs and for TEAEs that are emergent no more than 7 days after the last dose of study 
drug. The latter approach is to exclude any AEs reported by subjects when there is no 
likely systemic presence of mavodelpar – this is made even more possible by the 
encouragement of subjects to remain in the study if they discontinue study treatment 
prematurely. Those specific summaries generated for both all TEAEs and those not more 
than 7 days after the last dose are identified below; all other summaries will only be 
generated for all TEAEs. 


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An overall summary (for all TEAEs and those not more than 7 days after the last dose) will 
present the number and percentage of subjects with: 
• any TEAE 
• any TEAE considered as related to study drug (evaluated by the investigator as 
Possibly Related or Related) 
• any TESAE 
• any TESAE considered as related to study drug  
• any AESI 
• Maximum severity TEAE of mild, moderate or severe; i.e. a subject with TEAEs at 
different intensities will be summarized at the most severe intensity 
• Maximum severity for TEAE considered as related to study drug 
• any TEAE leading to study drug discontinuation  
• any TEAE leading to death 
The table will include the total number of TEAEs reported. The total number of unique 
terms within subjects will also be presented, counting each TEAE PT only once within 
each subject. 
The number and percentage of subjects with TEAEs will be presented (for all TEAEs and 
those not more than 7 days after the last dose) by System Organ Class (SOC) and PT. 
Subjects with multiple TEAEs within a SOC or SOC/PT combination will be counted only 
once for that SOC or SOC/PT combination. Similar summaries will be presented for 
related TEAEs, AESI and TESAEs.   
In addition, the AESI of refraction disorders will be summarized by lower-level term. The 
lower-level term will identify the direction of diopter change. 
SOC and PT summaries of TEAEs by maximum severity (mild, moderate or severe) will 
be presented.   
All summaries will be ordered by descending frequency of total number of subjects within 
each SOC and then similarly by decreasing frequency of total number of subjects within 
each PT, in the mavodelpar treatment group. In cases of SOCs or PTs with equal 
frequencies, AEs will be sorted alphabetically. 
All AEs will be listed with their onset and end study days. AE duration (stop date/time – 
start date/time or [stop date – start time + 1] for AEs with no time information) will be 
included in the listing for those AEs no longer ongoing; where applicable imputed data 
will be used for the calculation of AE duration, but the original date/time information will 
be presented in the listing. For ongoing AEs the duration will be calculated using the 


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subject’s last study date and will be presented prefixed by ‘>’. The listing will identify 
treatment emergent AEs, AESI and SAEs. TEAEs that occur more than 7 days after the 
last dose of study drug for those subjects who have discontinued treatment will also be 
identified.  
A separate listing of TESAEs, TEAESI and TEAEs leading to study drug discontinuation 
will also be generated. If there are any deaths a listing will include the date of death and 
the adverse event(s) associated with death.  
12.2. 
LABORATORY EVALUATIONS 
Observed and change from baseline clinical laboratory data (hematology, biochemistry and 
continuous urinalysis parameters) will be summarized by visit and for the last on-treatment 
measurement using descriptive statistics. 
Observed, change from baseline and percent change from baseline values for BSAP, 
parathyroid hormone, vitamin D and urine NTx will be summarized by visit and for the 
last on-treatment measurement using descriptive statistics. The summary will also be split 
by sex and menopausal status (i.e., men, pre-menopausal women and post-menopausal 
women). For NTx only subjects who have a second void collected at the visit will be 
included in the summary presentations (including the plots specified below). 
Urinalysis categorical data will also be summarized by visit. Descriptive statistics will be 
used for continuous data and counts and percentages for categorical data. A shift table 
from baseline to visit, of normal, abnormal low, abnormal high and missing records will 
also be summarised for hematology, chemistry and urinalysis data, with marginal totals, 
using counts and percentages. If the reference range does not have a lower bound (e.g., 
reference range is 0 to x), the low columns/rows will be presented as ‘-‘, rather than a 
count of zero.  
Box plots of changes from baseline by visit and treatment group will be presented for the 
clinical laboratory parameters hemoglobin, HbA1c, high density lipoprotein (HDL) and 
low density lipoprotein (LDL) on-treatment values. The whiskers will display the 5th and 
95th percentiles and outliers (i.e., outside the 5th to 95th percentile) will be identified on the 
plot with subject ID.  The number of observations contributing to each visit will be 
included on the plot. The box plot will be repeated for the parameters BSAP and urine N-
terminal telopeptide (NTx) however these plots will be presented overall and by sex and 
menopausal status (i.e., men, pre-menopausal women and post-menopausal women).  
Subjects who satisfy the criteria for values of potential clinical importance (PCI), identified 
in the table below, will be summarized and listed. The summary will present the number of 
subjects with at least one on-treatment post baseline value (including unscheduled visits) 
satisfying the criteria. The listing will have a similar layout to the overall laboratory listing 


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but will only include those subjects who satisfy the criteria for a specific parameter. The 
records satisfying the criteria will be identified on the listing. The criteria are: 
Category 
Parameter 
Criteria 
Chemistry 
Creatine kinase (CK) 
Normal baseline value and post ≥ 5 x ULN 
> ULN baseline value and post ≥ 5 x baseline 
level 
Aldolase 
Normal baseline value and post > ULN 
Troponin I 
> ULN 
Potential Hy’s Law (ALT, 
AST, total bilirubin and 
alkaline phosphatase) 
ALT or AST > 3 x ULN and 
Total bilirubin > 2 x ULN and 
Alkaline Phosphatase ≤ 2 x ULN 
An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will be generated. 
The plot will include all post baseline data and will present ALT relative to the upper limit 
of normal (ULN) on the x-axis and total bilirubin relative to the ULN on the y-axis using a 
log scale for both axes. Reference lines for Hy’s law thresholds, i.e., ALT = 3 x ULN and 
total bilirubin = 2 x ULN, will be added. The plot will identify treatment group and 
mutational group and separate plots will be done for on-treatment and off-treatment 
records. 
A spaghetti plot for the changes from baseline in creatine kinase (CK referred to in the 
protocol as creatine phosphokinase [CPK]) over time will be presented. The actual 
sampling day will be used on the x-axis (baseline will be set to day 1). A solid line will be 
used to connect measurements; however, if the measurement was collected after the last 
dose of study drug plus one day, then a dotted line will be used. Treatment group will be 
identified on the plot. The plot will be repeated for aldolase and troponin I. 
Individual CK, aldolase, ALT, AST and troponin I values relative to the ULN will be 
plotted over time (i.e., one plot per subject) and treatment group and mutation type will be 
identified. The actual sampling day will be used on the x-axis (baseline will be set to day 
1). The day of last dose of study drug will be identified on the plot with a vertical reference 
line. 
All individual central laboratory results will be listed. The listing will include change from 
baseline values and values relative to the ULN. The last on-treatment measurements and 
values outside the laboratory reference range will be identified.  
Local laboratory results will not be summarized and will be listed separately from central 
laboratory results. 


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12.3. 
DUAL ENERGY X-RAY ABSORPTIOMETRY (DXA) SCAN 
Observed, change from baseline values and percent changes from baseline values for the 
DXA endpoints will be summarized for the DXA ScAS. The summary will be presented 
overall within the treatment group and by sex and menopausal status (i.e., men, pre-
menopausal women and post-menopausal women). 
A box and whisker plot will be presented for each of the parameters measuring the total 
spine and the 2 hip regions (total and femoral neck), for the DXA CScAS. The whiskers 
will display the 5th and 95th percentiles and outliers will be identified on the plot with 
subject ID. The plot will present the 2 visits alongside one another for each treatment 
group. The plot will be repeated by sex and menopausal status. 
For the DXA CScAS, the study day of the follow-up DXA scan will be summarized using 
descriptive statistics. In addition, the number and percentage of subjects will be presented 
for the following relating to when they have their scan: 
• whilst on treatment in REN001-201 (within 7 days of their last dose) and have not 
yet transitioned to the mavodelpar open-label study 
• after discontinuing treatment in REN001-201, but having transitioned to the 
mavodelpar open-label study 
• after discontinuing treatment in REN001-201 (> 7 days after their last dose) and not 
transitioned to the mavodelpar open-label study 
12.4. 
VITAL SIGNS 
Observed and change from baseline values will be summarized by visit and for the last on-
treatment measurement using descriptive statistics.  
Box plots of change from baseline by visit and treatment group will be presented for on-
treatment measurements. The whiskers will display the 5th and 95th percentiles and 
outliers will be identified on the plot with subject ID. The number of observations 
contributing to each visit box plot will be included. 
The number and percentage of subjects with an increase or decrease from baseline in on-
treatment systolic blood pressure of <10 mmHg, ≥10 to <20mmHg, ≥20 to <30 mmHg or 
≥30 mmHg will be summarized by visit. The denominator for percentages will be the 
number of subjects still on-treatment. This summary will be repeated for diastolic blood 
pressure using the following categories <5 mmHg, ≥5 to <10 mmHg, ≥10 to <15 mmHg, 
≥15 to <20 mmHg, ≥20 to <25 mmHg or ≥25 mmHg. 
Observed and change from baseline values will be listed. The listing will identify the 
increase or decrease from baseline categories detailed above for systolic and diastolic 
blood pressure. The last on-treatment measurements will be identified. 


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12.5. 
ECG 
Observed and change from baseline values will be summarized by visit and for the last on-
treatment measurement using descriptive statistics.   
A shift table from baseline to on-treatment visit, for overall ECG interpretation (normal, 
abnormal not clinically significant, abnormal clinically significant and missing) will be 
summarised with marginal totals, using counts and percentages.  
A shift table from baseline to the maximum post baseline QTcF value will be summarized 
according to the categories specified in the table below. The maximum will be taken from 
all scheduled and unscheduled on-treatment values.  
Parameter 
Criteria 
QTcF 
< 450 msec 
≥ 450 msec and < 480 msec* 
≥ 480 msec and < 500 msec* 
≥ 500 msec* 
QTcF increase from baseline 
< 30 msec 
≥ 30 msec and < 60 msec* 
≥ 60 msec* 
* Values of PCI. 
 
Observed and change from baseline values will be listed. The listing will identify the last 
on-treatment measurement and QTcF values of PCI (identified in the above table).  
12.6. 
PHYSICAL EXAMINATION 
Physical examination data will be listed. 
12.7. 
EYE EXAMINATION 
Observed and change from baseline values for 4 cataract gradings in LOCS III (nuclear 
opalescence, nuclear colour, cortical and posterior subcapsular cataracts) will be 
summarized by visit using descriptive statistics. The summary will be across both eyes 
(i.e., each subject will contribute 2 values if they have a left and right eye reading at the 
visit) and repeated for the worst change at each visit.  
Subjects with at least one change in spherical equivalent of ≥0.75 diopters in either eye 
will be listed separately and will include all the subject’s spherical equivalent data reported 
during the study.  
Eye examination data will be listed. There will be 7 separate eye examination listings - 
refraction, BCVA, pinhole visual acuity, slit lamp examination, cataract grading, 


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tonometry and irido-corneal drainage angle assessment. Subjects who had their cataracts 
assessed at screening using a different grading system will have their data listed separately 
from the remaining subjects to facilitate a medical review of this data. 
BCVA (LogMAR scale) values will be presented to 1 decimal place and spherical 
equivalent refraction error values will be presented to 2 decimal places. 
12.8. 
COVID-19 EXPOSURE AND VACCINATION DATA 
The following COVID-19 exposure and vaccination information will be summarized. The 
number (%) of subjects will be presented: 
• Number of vaccination doses received at the time of screening, Baseline, Week 12 
and Week 24 
• Documented COVID-19 prior to first dose and during the study 
All data will be listed. 


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13. 
INTERIM ANALYSES 
No interim analysis is planned. 
An independently chaired Safety Review Committee (SRC) will review unblinded safety 
data at specified intervals for the duration of the study. The structure, function and 
operation of the SRC is detailed in the REN001-201 SRC charter. Reneo personnel and site 
Investigators and study teams will remain blinded for the duration of the study. 


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14. 
CHANGES FROM PLANNED ANALYSES SPECIFIED IN 
THE PROTOCOL 
• The secondary endpoints have been updated following FDA advice.  The PROMIS 
T-score has been promoted to a secondary endpoint and MFIS physical sub-scale 
score and PGIC (muscle symptoms) have been moved to exploratory endpoints. 
The order of testing of endpoints has also been updated to align with this change. 
• As the PGIC is assessed at the end of study treatment (Week 24 or Early 
Termination) a while on treatment strategy was proposed in the protocol. However, 
with some subjects not completing their PGIC assessment until more than a week 
after their last dose of study medication the strategy has been changed. The primary 
analysis will include all recorded data, regardless of the duration between the 
subject’s last dose of study medication and the assessment. Given some subjects 
will have been off treatment for more than 7 days before recording PGIC, this 
analysis will no longer be referred to as a ‘while on treatment’ strategy; instead, 
this is a ‘treatment policy’ strategy. Subjects with no PGIC assessment will be 
considered as missing unless the incidence of missing PGIC data exceeds 5%. If 
the incidence exceeds 5% a multiple imputation approach will be used. A ‘while on 
treatment’ strategy has also been included as a supplementary analysis, where only 
assessments within 7 days of the last dose of study treatment will be included. 
• A responder endpoint has been defined for the PGIC muscle symptoms and PGIC 
fatigue symptoms in addition to the 7-point scale endpoints. 
• Two additional exploratory endpoints based on the 12MWD have been defined to 
further support the primary analysis.  The endpoints are the first and last 6-minute 
periods of the 12MWD and aim to investigate whether there is a difference in 
treatment effect in these two periods. 
• The supplementary analysis for the primary endpoint using a while on treatment 
strategy has been updated to an ANCOVA following review comments from the 
FDA. The original while on treatment analysis proposed in the protocol is now 
referred to as a treatment period restricted analysis. 
• Added the exploratory endpoint for the phenotypic description questions (exercise 
tolerance, gait stability and myopathy) which are asked at Baseline and Week 24. 
 
 


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15. 
REFERENCES 
Cleeland CS. The Brief Pain Inventory User Guide. 2009:1-66. Published at: 
https://www.mdanderson.org/documents/Departments-and-Divisions/Symptom-
Research/BPI_UserGuide.pdf.  
Kenward MG, Roger JH. Small Sample Inference for Fixed Effects from Restricted 
Maximum Likelihood. Biometrics. 1997(53):983–997. 
Roy W. Beck, et al. A Computerized Method of Visual Acuity Testing: Adaptation of the 
Early Treatment of Diabetic Retinopathy Study Testing Protocol. American Journal of 
Ophthalmology February 2003. 
O’Kelly M, Ratitch B. Clinical Trials with Missing Data: A Guide for Practitioners. 
Wiley; 2014. 
Patient-Reported Outcomes Measurement Information System. Published February 28, 
2019. 
https://staging.healthmeasures.net/images/PROMIS/manuals/PROMIS_Fatigue_Scoring_
Manual.pdf 
Rubin DB. Multiple Imputation for Nonresponse in Surveys. Wiley; 1987. 
 
 


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APPENDIX 1 – SAS© CODE 
Primary Endpoint Analyses  
 
1:  Repeated measures mixed model analysis (MMRM). 
 
proc mixed data=<dataset>; 
 class treatment(ref=’Placebo’) visit subject mutation(ref=’Other’); 
 model chg=mutation baseline treatment visit treatment*visit / ddfm=kr 
solution; 
 repeated visit / subject=subject type=un group=treatment; 
 lsmeans treatment*visit / cl diff; 
 estimate 'REN001 - Placebo: W24' treatment 1 -1 trt*visit 0 1 0 -1/cl; 
 estimate 'REN001 - Placebo: W12' treatment 1 -1 trt*visit 1 0 -1 0/cl; 
run; 
 
Assumptions: 
• treatment is 2 levels e.g. 1=REN001; 2=Placebo 
• visit is 2 levels e.g. 1=Week 12; 2=Week 24 
• mutation is 2 levels e.g. 1=m.3243>G; 2=Other 
• chg is change from baseline; baseline is baseline score 
• An unstructured covariance matrix is specified using type=un. If this 
analysis fails to converge, then an ANCOVA approach will be used instead. 
 
2:  Non-monotone multiple imputation. 
 
proc mi data=<dataset> seed=<seednumber> nimpute=25 
out=<outmidataset1> minimum=(. 0 0 0 0);  
 by treatment; 
 var mutation scrn bl w12 w24; 
 mcmc impute=monotone chain=multiple nbiter=200 niter=100; 
run; 
 
Assumptions: 
• Dataset has one record per subject in a horizontal structure for observed 
values at each visit 
• Observed values for endpoint at each visit are contained in the variables -
scrn=screening, bl=baseline, w12=week 12, w24=week 24  
• If a subject has a missing baseline (either not collected or out of window) 
then the screening value will be used as baseline. However, for the multiple 
imputation model the time the data was collected will be preserved so the 
scrn variable will be the screening value and the bl variable will be missing 
and imputed. The imputed baseline values will only be used to facilitate the 
imputation of later visits but will not be used in the analyses. 
• mutation is 2 levels e.g. 1=m.3243>G; 2=Other 
• treatment is 2 levels e.g. 1=REN001; 2=Placebo 


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3:  Monotone multiple imputation. 
 
proc mi data=<outmidataset1> seed=<seednumber> nimpute=1  
        out=<outmidataset2> minimum=(. 0 0 0 0); 
by treatment _imputation_; 
var mutation scrn bl w12 w24; 
 monotone reg; 
run; 
 
Assumptions: 
• Dataset is the output dataset from the non-montone MI step, and already 
contains the 25 imputations for each subject denoted in the dataset by the 
variable _imputation_ 
• Observed values for endpoint at each visit are contained in the variables -
scrn=screening, bl=baseline, w12=week 12, w24=week 24  
• If a subject has a missing baseline (either not collected or out of window) 
then the screening value will be used as baseline. However, for the multiple 
imputation model the time the data was collected will be preserved so the 
scrn variable will be the screening value and the bl variable will be missing 
and imputed. The imputed baseline values will only be used to facilitate the 
imputation of later visits but will not be used in the analyses. 
• mutation is 2 levels e.g. 1=m.3243>G; 2=Other 
• treatment is 2 levels e.g. 1=REN001; 2=Placebo 
 
4: Combining multiple imputation analyses using MIANALYZE. 
 
ODS OUTPUT PARAMETERESTIMATES=<outestdataset>; 
proc mianalyze data=<diffsdataset>;  
 by visit; 
 modeleffects estimate; 
 stderr stderr; 
run; 
  
Assumptions: 
• Convert the resulting MI dataset to a vertical structure and analyse using 
MMRM (SAS code point 1) by imputation. Output the dataset of estimates 
(ODS OUTPUT DIFFS=<diffsdataset>;) keeping the visit comparisons of 
interest. Use this dataset in the MIANALYZE procedure. 
 
 
 


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Secondary Endpoint Analyses  
 
5: PROMIS T-score - Repeated measures mixed model analysis (MMRM). 
 
proc mixed data=<dataset>; 
 class treatment(ref=’Placebo’) visit subject mutation(ref=’Other’); 
 model chg=mutation base12mwd baseline treatment visit treatment*visit / 
ddfm=kr solution; 
 repeated visit / subject=subject type=un group=treatment; 
 lsmeans treatment*visit / cl diff; 
 estimate 'REN001 - Placebo: W4' treatment 1 -1 treatment*visit 1 0 0 0 -
1 0 0 0/cl; 
 estimate 'REN001 - Placebo: W12' treatment 1 -1 treatment*visit 0 1 0 0 
0 -1 0 0/cl; 
 estimate 'REN001 - Placebo: W18' treatment 1 -1 treatment*visit 0 0 1 0 
0 0 -1 0/cl; 
 estimate 'REN001 - Placebo: W24' treatment 1 -1 treatment*visit 0 0 0 1 
0 0 0 -1/cl; 
run; 
 
Assumptions: 
• treatment is 2 levels e.g. 1=REN001; 2=Placebo 
• visit is 4 levels e.g. 1=Week 4; 2=Week 12; 3=Week 18; 4=Week 24 
• mutation is 2 levels e.g. 1=m.3243>G; 2=Other 
• chg is change from baseline; baseline is baseline score 
• base12mwd is the Baseline 12MWD 
• An unstructured covariance matrix is specified using type=un. If this 
analysis fails to converge, then an ANCOVA approach will be used instead. 
 
Exploratory Endpoint Analyses  
 
6:  PGIC - ANCOVA. 
 
proc mixed data=<dataset>; 
 class treatment mutation(ref=’Other’); 
 model pgic=mutation base12mwd treatment / ddfm=kr solution; 
 lsmeans treatment / cl diff; 
 estimate 'REN001 - Placebo' treatment 1 -1/cl; 
run; 
 
Assumptions: 
• treatment is 2 levels e.g. 1=REN001; 2=Placebo 
• mutation is 2 levels e.g. 1=m.3243>G; 2=Other 
• pgic is the numeric score 
• base12mwd is the Baseline 12MWD 
 
 
 


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7:  PGIC – Logistic regression. 
 
proc logistic data=<dataset>; 
 class treatment mutation/param=glm; 
 model pgic=mutation base12mwd treatment/expb; 
 lsmeans treatment / cl exp diff; 
 estimate 'REN001 - Placebo' treatment 1 -1/exp cl; 
run; 
 
Assumptions: 
• treatment is 2 levels e.g. 1=REN001; 2=Placebo 
• mutation is 2 levels e.g. 1=m.3243>G; 2=Other 
• pgic is 2 levels responder endpoint e.g. 1=yes; 2=no 
• base12mwd is the Baseline 12MWD 
 
8:  PGIC – monotone multiple imputation. 
 
proc mi data=<dataset> seed=<seednumber> out==<outmidataset1> nimpute=25; 
  by treatment; 
  class pgic mutation; 
  monotone logistic(pgic=mutation base12mwd / details); 
  var mutation base12mwd pgic; 
run; 
 
Assumptions: 
• Dataset has one record per subject in a horizontal structure  
• pgic is the numeric ordinal score (range of -3 to 3) 
• mutation is 2 levels e.g. 1=m.3243>G; 2=Other 
• treatment is 2 levels e.g. 1=REN001; 2=Placebo 
• base12mwd is the Baseline 12MWD 
 
 
 
 


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APPENDIX 2 – COUNTRY SPECIFIC PROTOCOL AMENDMENTS 
The following country specific protocol amendments have been approved for REN001-
201: 
Country 
Amendment, Version (Date) 
Canada 
Amendment 3, Version 4.0 (21 March 2021)  
France 
Amendment 3, Version 4.0 (1 April 2021) 
Germany 
Amendment 3, Version 4.0 (20 May 2021) 
Canada 
Amendment 4, Version 5.0 (29 June 2022)  
France 
Amendment 4, Version 5.0 (29 June 2022) 
Germany 
Amendment 4, Version 5.0 (29 June 2022) 
There are no country specific protocol amendments for REN001-201-DXA sub-study. 
 


Electronic Signature Page: Statistical Analysis Plan - REN001-201 SAP
REN001-201
Statistical Analysis Plan - REN001-201 SAP
VV-CLIN-000103 V2.0
Approved
16-Nov-2023 19:28:08 GMT+0000
Approved
17-Nov-2023 19:14:44 GMT+0000
Approved
18-Nov-2023 02:37:27 GMT+0000