Conditions: Primary Mitochondrial Myopathy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 155
Healthy volunteers: no

Brief summary:
This study is designed to evaluate the long-term safety and tolerability of REN001 administered once daily to subjects with PMM due to mitochondrial DNA mutations (mtDNA-PMM) or nuclear DNA mutations (nDNA-PMM). Subjects with mtDNA mutations will have previously completed Study REN001-201 or participated in Study REN001-101. Subjects with nDNA mutations who enroll in this study will be REN001- naïve.

Detailed description:
This study is designed to evaluate the long-term safety and tolerability of REN001 administered once daily to subjects with PMM due to mitochondrial DNA mutations (mtDNA=PMM) or nuclear DNA mutations (nDNA-PMM). Subjects with mtDNA mutations will have previously completed Study REN001-201 (which is referred to as the STRIDE study) or participated in Study REN001-101. Subjects with nDNA mutations who enroll in this study will be REN001- naïve.

Eligible subjects will be treated with REN001 100mg orally, once daily for 24 months. Following the baseline visit there are planned visits at at defined time points. A final follow-up telephone call will be made by the study centre to the subject approximately 30 days after the last dose of study drug.

Arms:
arm 1: 100 mg once daily

Interventions: intervention 1: REN001
Intervention descriptions: intervention 1: Once daily dosing

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Title: An Open-label, Multi-centre Study to Evaluate the Long-term Safety and Tolerability of 
REN001 in Subjects With Primary Mitochondrial Myopathy (PMM) 
NCTID: NCT05267574
Document Date: 7 August 2023


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CLINICAL STUDY PROTOCOL 
AN OPEN-LABEL, MULTI-CENTRE STUDY TO EVALUATE THE LONG-TERM 
SAFETY AND TOLERABILITY OF REN001 IN SUBJECTS WITH PRIMARY 
MITOCHONDRIAL MYOPATHY (PMM) 
Sponsor: 
Reneo Pharma Ltd. 
Innovation House, Discovery Park 
Ramsgate Road  
Sandwich 
Kent CT13 9FF 
United Kingdom 
Clinical Research Organisation (CRO): 
Emmes BioPharma UK Ltd (Formerly 
Orphan Reach Ltd) 
The Old School 
Newport Road 
Woughton Park 
Milton Keynes MK6 3AP 
United Kingdom 
Sponsor Protocol No.: 
REN001-202 
EudraCT No.: 
2021-003471-34 
IND No.: 
Not applicable 
Study Drug Name: 
REN001 
Development Phase: 
Phase 2b 
Date of Protocol: 
07 August 2023 
Protocol version: 
Version 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. 
Notice of Confidential and Proprietary Information: 
This document is confidential. It contains proprietary information of Reneo Pharma Ltd. 
and/or Reneo Pharmaceuticals, Inc. Such information may be used solely for the purpose of 
reviewing or performing this study. Any viewing or disclosure of such information that is not 
authorized in writing by Reneo Pharma Ltd. is strictly prohibited. 
CONFIDENTIAL 


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SIGNATURE PAGE
Declaration of Sponsor Chief Medical Officer
Title: An open-label, multi-centre study to evaluate the long-term safety and tolerability 
of REN001 in subjects 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.
_____________________________________
{See Electronic Signature Page}
Institution: Reneo Pharma Ltd.


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SIGNATURE PAGE 
 
Declaration of the National Co-ordinating Investigator (use as appropriate) 
 
Title: An open label, multi-centre study to evaluate the long-term safety and tolerability 
of REN001 in subjects with primary mitochondrial myopathy (PMM) 
 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence. This documentation includes this study 
protocol, Investigator's Brochure, Case Report Forms, and other scientific data. 
 
The study will not commence without the prior written approval of a properly constituted 
Independent Ethics Committee (IEC). No changes will be made to the study protocol without 
the prior written approval of the Sponsor and the IEC, except where necessary to eliminate an 
immediate hazard to the subjects. 
 
I have read and understood and agree to abide by all the conditions and instructions contained 
in this protocol. 
 
 
National Co-ordinating Investigator  
 
Country_________________________ 
 
 
 
Signature:  ______________________________ 
 
PLEASE PRINT NAME and TITLE___________________________________________ 
 
 
 


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PROTOCOL SYNOPSIS 
Title: 
AN OPEN-LABEL, MULTI-CENTRE STUDY TO 
EVALUATE THE LONG-TERM SAFETY AND 
TOLERABILITY OF REN001 IN SUBJECTS WITH 
PRIMARY MITOCHONDRIAL MYOPATHY (PMM) 
Sponsor Study No: 
REN001-202 
Compound: 
REN001 
Phase: 
Phase 2b 
Sponsor: 
Reneo Pharma Ltd. 
Design: 
This study is designed to evaluate the long-term safety and 
tolerability of REN001 administered once daily to subjects 
with PMM due to mitochondrial DNA mutations (mtDNA-
PMM) or nuclear DNA mutations (nDNA-PMM). Subjects 
with mtDNA mutations will have previously completed 
Study REN001-201 (which is referred to as the STRIDE 
study) or participated in Study REN001-101.  Subjects with 
nDNA mutations who enrol in this study will be REN001-
naïve.  nDNA-PMM subjects will not be enrolled in France.   
Eligible subjects will be treated with REN001 100 mg orally, 
once daily for 48 months. Following the baseline visit there 
are 10 planned visits at Months 1, 3, 6, 12, 18, 24, 30, 36, 42 
and 48. To satisfy a regulatory agency request for subjects to 
be assessed every three months for the first 18 months, 
subjects in Germany will have two additional visits at Month 
9 and 15, making it a total of 12 planned visits.  A final 
follow-up telephone call will be made by the study centre to 
the subject approximately 30 days after the last dose of study 
drug. A final follow-up telephone call will not be required if 
mavodelpar has been approved within the country and the 
subject switches to commercially available medication. 
As the subjects with nDNA mutations will not have 
participated in another REN001 study, an independent 
Patient Screening Oversight Committee (PSOC) will review 
their screening criteria to ensure they have the appropriate 
PMM diagnosis for entering this study. The structure, 
function and operation of the PSOC are detailed in the 
REN001-202 PSOC Charter. 
A Safety Review Committee (SRC) will review safety data 
during the study. The structure, function, and operation of the 
SRC is detailed in the REN001-202 SRC Charter. Interim 
data cuts may be taken, and summaries prepared to support 
regulatory submissions or external communications such as 
publications. 


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Objectives: 
Primary: 
To evaluate long-term safety and tolerability of REN001 in 
subjects with PMM. 
Secondary: 
To assess subjects with mtDNA-PMM who are receiving 
long-term treatment with REN001 in terms of PMM 
associated symptoms, pain severity and interference, exercise 
endurance, quality of life (QoL), patient global impression of 
change (PGIC) and patient global impression of severity 
(PGIS) for muscle and fatigue, and work productivity. 
Pharmacokinetic (PK): 
To further characterise the PK profile of REN001 in subjects 
with PMM receiving long-term treatment 
Exploratory:  
To evaluate the effect of long-term treatment with REN001 
on bone health. 
To assess subjects with nDNA-PMM who are receiving long-
term treatment with REN001 in terms of PMM associated 
symptoms, pain severity and interference, exercise 
endurance, quality of life (QoL), patient global impression of 
change (PGIC) and patient global impression of severity 
(PGIS) for muscle and fatigue, and work productivity. 
Endpoints 
Primary: 
For mtDNA and nDNA subjects: 
 Number and severity of Adverse Events (AE) 
 Number of AEs leading to study drug discontinuation 
 Number of serious adverse events (SAE) 
 Number of adverse events of special interest (AESI) 
 Number of AEs leading to death 
Secondary: 
For mtDNA and nDNA subjects: 
 Absolute values, changes from baseline, and 
incidence of potentially clinically significant changes 
in: 
o Laboratory safety tests 
o Electrocardiograms (ECG) 
o Supine vital signs 
o Eye assessments 
For mtDNA subjects: 
 Absolute values and changes from baseline in: 
o Distance walked during the 12-Minute Walk 
Test (12MWT)*  
o Modified Fatigue Impact Scale (MFIS) total 
scores and sub-scale scores* 


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o Patient Global Impression of Severity (PGIS) 
scores for fatigue and muscle symptoms 
o Brief Pain Inventory (BPI) pain severity and 
pain interference scores* 
o Patient Reported Outcomes Measurement 
Information System (PROMIS) Short Form-
Functional Assessment of Chronic Illness 
Therapy (FACIT) Fatigue 13a scores* 
o 36-item Short Form Health Survey (SF-36) 
domain scores (7-day recall)* 
o Work Productivity and Activity Impairment 
Questionnaire: Specific Health Problem 
(WPAI:SHP) scores* 
o First 6-minute walk distance and last 6-minute 
walk distance* 
o Phenotypic description question* 
 Patient Global Impression of Change (PGIC) scores 
(muscle and fatigue symptoms). 
Pharmacokinetic (PK): 
REN001 plasma concentrations and parameters.* 
Exploratory: 
For mtDNA and nDNA subjects: 
 Change from baseline to end of treatment in bone 
mineral density (BMD) as measured by dual-energy 
x-ray absorptiometry (DXA), in the following: 
o Lumbar spine (L1 to L4) BMD 
o Total hip BMD and the femoral neck BMD (in 
the non-dominant hip) 
o Total hip, lumbar spine and femoral neck T-
scores and Z-scores 
For nDNA subjects: 
 Absolute values and changes from baseline in: 
o Distance walked during the 12-Minute Walk 
Test (12MWT)*  
o Modified Fatigue Impact Scale (MFIS) total 
scores and sub-scale scores* 
o Patient Global Impression of Severity (PGIS) 
scores for fatigue and muscle symptoms 
o Brief Pain Inventory (BPI) pain severity and 
pain interference scores* 
o Patient Reported Outcomes Measurement 
Information System (PROMIS) Short Form-
Functional Assessment of Chronic Illness 
Therapy (FACIT) Fatigue 13a scores* 


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o 36-item Short Form Health Survey (SF-36) 
domain scores (7-day recall)* 
o Work Productivity and Activity Impairment 
Questionnaire: Specific Health Problem 
(WPAI:SHP) scores* 
o First 6-minute walk distance and last 6-minute 
walk distance* 
o Phenotypic description questions* 
 Patient Global Impression of Change (PGIC) scores 
(muscle and fatigue symptoms). 
*collected up to Month 24 only 
Number of Subjects: 
Recruitment of subjects with mtDNA mutations will be 
limited to those subjects who participated in the STRIDE 
study (applicable only for countries where this study is being 
conducted) or Study REN001-101. It is estimated that 
approximately 150 mtDNA subjects will be enrolled. 
Additionally, up to 50 REN001-naïve subjects with nDNA 
mutations will be recruited. 
Treatment: 
Supplies of REN001 will be available as 50mg capsules. 
Subjects will take REN001, 100mg (2 capsules) once daily 
with food (preferably with morning meal). Subjects will be 
treated in the study for 48 months. The study will be 
considered completed with the last follow-up telephone call of 
the last subject, unless the subject switches to commercially 
available medication in which case the follow-up phone call 
is not required. 
Eligibility Criteria: 
Inclusion Criteria for all Subjects: 
1. mtDNA-PMM subjects: Completed treatment in the 
STRIDE study or participated in Study REN001-101, and 
in the opinion of the Investigator and Sponsor have been 
compliant with the study requirements.   
Or  
 
nDNA-PMM subjects: Subjects aged 18 years or older 
with known nuclear (nDNA) pathogenic variants with a 
major muscle phenotype consisting of objective 
myopathy with poor exercise tolerance.  Proof of 
pathogenicity must be provided. Must be able to walk at 
least 100m in the screening 12MWT and the limitations 
in walk test must be primarily due to the energy deficit 
and not due to ataxia or any other condition.  For subjects 
under 25 years old only: confirmation of bone growth 
plate closure by wrist radiograph. 
2. Have PMM which continues to be primarily characterized 
by exercise intolerance or active muscle pain. 


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3. Willing and able to swallow the REN001 gelatin 
capsules. 
4. Concomitant medications (including supplements) 
intended for the treatment of PMM or other co-
morbidities likely to remain stable throughout 
participation in the study where clinically possible. 
5. Signed and dated informed consent document indicating 
that the subject has been informed of all pertinent aspects 
of the study. 
6. Females should be either of non-child-bearing potential 
or must agree to use highly effective methods of 
contraception from baseline through to approximately 30 
days after the last dose of study drug. Males with partners 
who are women of childbearing potential (WOCBP) must 
also use contraception from baseline through to 14 weeks 
after the last dose of study drug.  If subjects are 
transferred to a commercial supply of REN001 they must 
be advised to adhere to the contraceptive requirements.  
 
Exclusion Criteria for all subjects: 
Subjects who present with any of the following will not be 
included in the study: 
1. Anticipated to need a peroxisome proliferator-activated 
receptor (PPAR) agonist other than REN001 during the 
study. 
2. Anticipated to need drugs during the study with a narrow 
therapeutic index and Breast Cancer Resistant Protein 
(BCRP) mediated absorption, distribution, metabolism 
and excretion (ADME) (See Table 1).  
3. Intent to donate blood, or blood components during the 
study or within one month after completion of the study.  
4. Current drug dependency. Use of opiates/cannabis for 
medical reasons is acceptable with prescription evidence 
 
5. Current alcohol dependency. 
6. Any medical, psychiatric or laboratory condition that may 
increase the risk associated with study participation or 
interfere with the interpretation of study results and, in 
the judgment of the Investigator and Medical Monitor, 
would make the subject inappropriate for entry into this 
study. 
7. Pregnant or nursing females. 
Subjects with mtDNA mutations can enroll at STRIDE Week 
24 visit, STRIDE-FU visit, after exiting from STRIDE or 
after exiting REN001-101 (UK only). Subjects enrolling after 
exiting from either of the 2 feeder mtDNA studies and all 


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subjects with nDNA mutations will be required to fulfil 
additional exclusion criteria during their additional screening 
visit.  This is required for the mtDNA-PMM subjects due to 
the gap in study drug treatment and period of time without 
study assessments.  The additional exclusion criteria are:  
1. Clinically significant kidney disease or impairment, with 
an eGFR less than 60ml/min/1.73m2 using the CKD-EPI 
creatinine equation at baseline. German sites - see 
alternative criteria below. 
2. 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 baseline. (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 
 
3. Uncontrolled diabetes and/or a glycosylated hemoglobin 
. German sites - see alternative criteria 
below. 
4. 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 are acceptable 
provided the symptoms and medications would not be 
predicted to compromise safety or interfere with the tests 
and interpretations of this study). 
5. Clinically significant cardiac disease and/or clinically 
significant ECG abnormalities including a baseline QTcF 
tachyarrhythmia or unstable arrythmia that in the opinion 
of the Investigator should exclude the subject from study 
completion. 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 their safety in this 
study. 
6. Treatment with an investigational drug, other than 
REN001, within 3 months or 5 drug half-lives, whichever 
is longer, prior to Day 1. 
7. Have been hospitalized within the 3 months prior to 
screening for any major medical condition (as deemed by 
the Investigator). 


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8. Subject with poor nutritional status as determined by the 
Investigator. 
9. Subjects with positive hepatitis B surface antigen 
(HBsAg) and hepatitis B core antibody (HBcAb) or 
positive hepatitis C or human immunodeficiency virus 
(HIV) at screening. German sites - see alternative criteria 
below. 
10. Subjects who are not eligible or have a contraindication 
for cataract surgery. 
11. Any condition possibly reducing drug absorption (e.g., 
gastrectomy or increased gastrointestinal motility). 
12. History of cancer (except basal cell carcinoma). 
13. For subjects from REN001-101 study and nDNA-PMM 
subjects only, a history of fragility/stress fractures or an 
osteoporosis concomitant condition which has not been 
adequately addressed. 
For subjects at sites in Germany  
For additional criteria 1, 3 and 9, the following alternative 
criteria apply:  
1. Clinically significant kidney disease or impairment, with 
an eGFR less than 60ml/min/1.73m2 using the CKD-EPI 
creatinine equation. 
3. Uncontrolled diabetes and/or a glycosylated hemoglobin 
part of the Week 18 visit in the Stride Study. 
Nevertheless, the Week 18 blood draw may be used to 
obtain the test provided the subjects has given the 
appropriate consent). 
9. Subjects with positive hepatitis B surface antigen 
(HBsAg) and hepatitis B core antibody (HBcAb) or 
positive hepatitis C or human immunodeficiency virus 
(HIV). (NOTE:  these tests are not obtained as part of the 
Week 18 or 24 visits in the Stride Study. Nevertheless, 
the Week 18 or 24 blood draws may be used to obtain the 
test provided the subjects has given the appropriate 
consent). 
These criteria will require screening assessments to be 
completed within the 8 weeks prior to the start of dosing in 
this study.  
For subjects wishing to start dosing immediately after the 
STRIDE Week 24 visit, their STRIDE Week 18 blood tests 
may be used as the screening assessments; additional blood 
tests will need to be collected for HbA1c and serology. For 
mtDNA-PMM subjects wishing to start dosing in this study 
immediately after the STRIDE -FU visit, their STRIDE 


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Week 24 blood tests may be used as the screening 
assessments; additional blood sample will need to be 
collected for serology.  
 
Study Visits: 
It is expected that most STRIDE subjects will enrol at the 
STRIDE Week 24 visit with the baseline visit for this study 
coinciding with the STRIDE Week 24 visit. Enrolment at the 
STRIDE follow-up (FU) visit will require additional baseline 
assessments. Subjects who wish to take part in this study 
after leaving the STRIDE study (i.e., after their STRIDE FU 
visit), subjects who participated in Study REN001-101, and 
all nDNA subjects will require additional screening and 
baseline visits, dependent on when the subject enrols in the 
study: 
 Option 1: Enrolment at the STRIDE Week 24 visit: 
Most of the STRIDE Week 24 assessments will be 
regarded as the baseline assessments for this study. 
Additional assessments will be performed as noted in 
Section 6.1.1. 
 Option 2: Enrolment at the STRIDE FU visit: The 
STRIDE FU visit will be regarded as the baseline visit 
for this study with additional assessments performed as 
noted in Section 6.1.2. If a washout period for any 
prohibited medication started since the STRIDE Week 
24 visit, the subject will exit the STRIDE study and 
will require additional screening and baseline visits to 
enter the STRIDE AHEAD Study (Option 3 enroller). 
 Option 3: Enrolment after exiting Study REN001-101 
or STRIDE (mtDNA-PMM subjects): separate 
screening and baseline visits will be required, with 
assessments performed as noted in Section 6.1.3.  
 Option 4: Enrolment of nDNA-PMM subjects: separate 
screening and baseline visits will be required, with 
assessments performed as noted in Section 6.1.4.   
nDNA-PMM subjects will not be enrolled in France.  
Prior to dosing, the PSOC will assess if nDNA-PMM 
subjects have the appropriate diagnosis for entry into this 
study. 
After the baseline visit each subject will have 10 scheduled 
visits over a period of 48 months (12 for subjects at sites in 
Germany). The final follow-up will be conducted by a 
telephone call approximately 30 days after the last dose of 
study drug. A final follow-up telephone call will not be 
required if mavodelpar has been approved within the country 
and the subject switches to commercially available 
medication. 


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Where sites permit, a concierge service will be available to 
subjects to arrange hotel accommodation and transport to and 
from the study centre and reimburse any subject study 
expenses, if applicable. Subjects may be asked to have a 
negative COVID-19 test prior to undertaking scheduled visits 
to the study centre. 
All protocol assessments are detailed in the study Schedule of 
Activities (Table 3).  
Statistical Methods: 
No formal statistical testing is planned.  
Endpoints will be summarized by STRIDE treatment 
(REN001 or Placebo) from the start of STRIDE for mtDNA-
PMM subjects. Endpoints will also be summarized from the 
start of REN001-202, and from the start of REN001 
treatment for mtDNA-PMM subjects. Subjects with nDNA-
PMM  will be summarized from the start of REN001-202.   
Treatment-emergent adverse events (TEAEs) will be 
summarized by System Organ Class (SOC) and preferred 
term, in accordance with the Medical Dictionary for 
Regulatory Activities (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 AESI and SAEs 
will also be tabulated. 
Absolute values and changes from baseline in clinical 
laboratory test, vital signs, ECG and eye examination data 
will be summarized using descriptive statistics by visit.  
Absolute values and changes from baseline in 12 Minute 
Walk Distance (12MWD) and other secondary and 
exploratory endpoints will be summarized and plotted over 
time. 
 


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LIST OF STUDY PERSONNEL 
Sponsor 
Reneo Pharma Ltd, 
Innovation House, Discovery Park, 
Ramsgate Road, Sandwich, 
Kent CT13 9FF 
United Kingdom 
 
 
 
 
 
 
 
 
  
 
 
Contract Research Organisation 
Emmes BioPharma UK Ltd 
The Old School 
Newport Road 
Woughton Park 
Milton Keynes MK6 3AP 
United Kingdom 
 
Telephone: +44 (0)1908 251 480 
 
Medical Monitor 
Email: medicalmonitor202@emmes.com 
 
Serious Adverse Event Reporting to 
Pharmacovigilance Team 
Bionical Emas 
Suite 209, Spirella Building 
Bridge Road, 
Letchworth Garden City, 
Hertfordshire 
SG6 4ET 
 
Email: Drug.safety@bionical-emas.com 
Fax: +44 (0) 1462 600 456 
 
Statistician  
 
  
ParamStat Limited 
 
 
 
 


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TABLE OF CONTENTS 
LIST OF STUDY PERSONNEL .......................................................................................... 13 
1 
INTRODUCTION.......................................................................................................... 21 
1.1 
Indication .............................................................................................................. 21 
1.2 
Background .......................................................................................................... 21 
1.3 
Study Rationale .................................................................................................... 22 
1.4 
Risk-Benefit Assessment ...................................................................................... 22 
1.4.1 Benefits ......................................................................................................... 22 
1.4.2 Risks .............................................................................................................. 23 
1.4.3 Safety Data Review....................................................................................... 25 
1.5 
Dose Selection Rationale...................................................................................... 25 
2 
STUDY OBJECTIVES .................................................................................................. 27 
2.1 
Primary Objective ................................................................................................ 27 
2.2 
Secondary Objectives........................................................................................... 27 
2.3 
Pharmacokinetic (PK) Objectives ...................................................................... 27 
2.4 
Exploratory Objectives ........................................................................................ 27 
3 
OVERALL DESIGN AND PLAN OF THE STUDY ................................................. 28 
3.1 
Overview ............................................................................................................... 28 
3.2 
Endpoints .............................................................................................................. 30 
3.2.1 Primary Endpoints ........................................................................................ 30 
3.2.2 Secondary Endpoints .................................................................................... 30 
3.2.3 PK Endpoints ................................................................................................ 31 
3.2.4 Exploratory Endpoints .................................................................................. 31 
3.3 
Justification of the Study Design ........................................................................ 32 
3.4 
Termination or Suspension of Study .................................................................. 32 
3.5 
Termination or Suspension of Investigational Sites ......................................... 32 
3.6 
Conditions for Individual Subject Withdrawal from the Study ...................... 32 
3.7 
Strategy for Potential Withdrawal due to Laboratory Test Abnormalities ... 33 
3.7.1 Safety Monitoring for Muscle Injury ............................................................ 33 
3.7.2 Safety Monitoring for Liver: Management and Stopping Rules .................. 35 
3.7.3 Safety Monitoring for Kidney: Management and Stopping Rules ............... 37 
3.8 
Replacement of Subjects...................................................................................... 37 
3.9 
Temporary Discontinuations .............................................................................. 37 
3.10 Review of Screening Eligibility Data for nDNA-PMM subjects ...................... 37 
3.11 Safety Review Committee (SRC) ........................................................................ 37 
4 
STUDY POPULATION ................................................................................................ 38 
4.1 
Protocol Criteria for All Subjects ....................................................................... 38 
4.1.1 Inclusion Criteria .......................................................................................... 38 
4.1.2 Exclusion Criteria ......................................................................................... 38 
4.2 
Additional Exclusion Criteria ............................................................................. 39 
4.3 
Alternative Exclusion Criteria for Subjects in Germany ................................. 40 
4.4 
Additional Criteria for Subjects at Sites where DXA Scans are Approved ... 40 
4.5 
Planned Sample Size and Study Centres ........................................................... 41 


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4.6 
Study Completion................................................................................................. 41 
5 
STUDY DRUG ............................................................................................................... 42 
5.1 
Study Drug Identity ............................................................................................. 42 
5.2 
Management of Study Drug ................................................................................ 42 
5.3 
Administration ..................................................................................................... 42 
5.4 
Packaging, Labelling and Storage ...................................................................... 42 
5.5 
Excessive Pharmacological Effects ..................................................................... 42 
5.6 
Drug Accountability............................................................................................. 42 
5.7 
Compliance ........................................................................................................... 43 
5.8 
Contraceptive Requirements .............................................................................. 43 
5.8.1 Females ......................................................................................................... 43 
5.8.2 Males who are considered fertile and with partners who are WOCBP ........ 44 
5.9 
Concomitant Medications ................................................................................... 44 
5.9.1 Statins ............................................................................................................ 44 
5.9.2 Sensitive BCRP substrates with narrow therapeutic indices ........................ 45 
5.9.3 Treatment with moderate or strong inhibitors or inducers of cytochrome 
P450 (CYP)2C8 ............................................................................................ 45 
6 
STUDY CONDUCT ....................................................................................................... 47 
6.1 
Screening and Baseline Visits ............................................................................. 47 
6.1.1 Option 1: Enrolment at STRIDE Week 24 ................................................... 47 
6.1.2 Option 2: Enrolment at STRIDE FU ............................................................ 49 
6.1.3 Option 3: Enrolment of mtDNA-PMM subjects from Study REN001-101 or 
after exiting STRIDE .................................................................................... 50 
6.1.4 Option 4: Enrolment of nDNA-PMM subjects ............................................. 52 
6.2 
Month 1 (Day 28) ................................................................................................. 54 
6.3 
Month 3 (Day 84) ................................................................................................. 55 
6.4 
Month 6 (Day 168) ............................................................................................... 56 
6.5 
Month 9 (Day 252)  German sites only............................................................. 57 
6.6 
Month 12 (Day 336) ............................................................................................. 57 
6.7 
Month 15 (Day 420)  Germany only ................................................................. 58 
6.8 
Month 18 (Day 504) ............................................................................................. 59 
6.9 
Month 24 (Day 672) or Early Withdrawal Visit (Prior to Month 24) ............. 60 
6.10 Month 30 (Day 840) ............................................................................................. 61 
6.11 Month 36 (Day 1008) ........................................................................................... 62 
6.12 Month 42 (Day 1176) ........................................................................................... 62 
6.13 Month 48 (Day 1344) or Early Withdrawal Visit (Post Month 24) ................. 63 
6.14 Follow-up Telephone Contact ............................................................................. 64 
6.15 Unscheduled Visits ............................................................................................... 64 
7 
PARAMETERS AND METHODS OF ASSESSMENT ............................................ 68 
7.1 
Safety Parameters ................................................................................................ 68 
7.1.1 Adverse Events ............................................................................................. 68 
7.1.2 Clinical Laboratory Safety Tests .................................................................. 73 
7.1.3 Physical Examination (including weight and height) ................................... 75 
7.1.4 Vital Signs ..................................................................................................... 75 


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7.1.5 Electrocardiogram (ECG) Recording ........................................................... 75 
7.1.6 Eye Examination ........................................................................................... 75 
7.1.7 Dual-energy X-ray absorptiometry (DXA) Scans ........................................ 76 
7.2 
Exercise Endurance ............................................................................................. 76 
7.2.1 12-Minute Walk Test (12MWT) ................................................................... 76 
7.3 
Quality of Life PROs ........................................................................................... 76 
7.3.1 Modified Fatigue Impact Scale (MFIS) ........................................................ 76 
7.3.2 Patient Global Impression of Severity (PGIS): Muscle and Fatigue ............ 77 
7.3.3 Patient Global Impression of Change (PGIC): Muscle and Fatigue ............. 77 
7.3.4 PROMIS Short Form 13a (FACIT-Fatigue) ................................................. 78 
7.3.5 36-item Health Survey V2.0® (SF-36) .......................................................... 78 
7.4 
Work Productivity PRO ...................................................................................... 78 
7.5 
Pain Severity and Interference PRO .................................................................. 79 
7.6 
PMM Phenotypic Description ............................................................................. 79 
7.7 
PK Blood Samples ................................................................................................ 80 
8 
STATISTICAL METHODS ......................................................................................... 81 
8.1 
Study Subjects ...................................................................................................... 81 
8.1.1 Disposition of Subjects ................................................................................. 81 
8.1.2 Protocol Deviations ....................................................................................... 81 
8.1.3 Analysis Populations ..................................................................................... 81 
8.2 
General Considerations ....................................................................................... 82 
8.2.1 Statistical Hypotheses ................................................................................... 82 
8.2.2 Determination of Sample Size ...................................................................... 82 
8.2.3 Data Summaries ............................................................................................ 82 
8.3 
Demographics, Baseline Characteristics and Concomitant Medications ....... 82 
8.4 
Treatment Compliance ........................................................................................ 82 
8.5 
Efficacy Analyses ................................................................................................. 83 
8.6 
Safety Analyses ..................................................................................................... 83 
8.7 
PK Analysis........................................................................................................... 83 
9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS .................................... 84 
9.1 
Data Quality Assurance ....................................................................................... 84 
9.2 
Electronic Case Report Forms (eCRF) and Source Documentation............... 84 
9.3 
Access to Source Data .......................................................................................... 84 
9.4 
Data Processing .................................................................................................... 84 
9.5 
Archiving Study Records .................................................................................... 85 
9.6 
Good Clinical Practice (GCP) ............................................................................. 85 
9.7 
Confidentiality ...................................................................................................... 85 
9.8 
Informed Consent ................................................................................................ 85 
9.9 
Protocol Approval and Amendment .................................................................. 86 
9.10 Premature Termination of the Study ................................................................. 86 
9.11 Liability and Insurance ....................................................................................... 86 
9.12 Publication Policy................................................................................................. 86 
10 REFERENCES ............................................................................................................... 87 
11 APPENDICES ................................................................................................................ 89 


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Appendix 1:
International Workshop on PMM ..................................................... 89 
Appendix 2:
Modified Fatigue Impact Scale (MFIS) ............................................. 90 
Appendix 3:
PROMIS Short Form-13a(FACIT-Fatigue) ..................................... 92 
Appendix 4:
Work Productivity and Activity Impairment (WPAI): PMM ........ 93 
Appendix 5:
 Brief Pain Inventory (Short Form) ................................................... 95 
Appendix 6:
Sample Schedules for Study Visit ...................................................... 97 
Appendix 7:
Global Protocol Amendment v2.0, Summary of Changes ............. 100 
Appendix 8:  
Global Protocol Amendment v3.0, Summary of Changes ............. 113 
 
 
 


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LIST OF TABLES 
Table 1: Prohibited Medication .........................................................................................46 
Table 2: Screening and Baseline Visits .............................................................................65 
Table 3: Schedule of Activities ...........................................................................................67 
Table 4: Safety Laboratory Parameters ...........................................................................74 
Table 5: Approximate Blood Volume Required for Study .............................................74 
 
LIST OF FIGURES 
Figure 1: Study Design .........................................................................................................30 
Figure 2: CK Algorithm .......................................................................................................35 


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List of Abbreviations and Definitions of Terms 
ADR 
Adverse Drug Reaction 
ADME 
Absorption, Distribution, Metabolism and Excretion 
AE 
Adverse event 
AESI 
Adverse Event of Special Interest 
AP 
Alkaline Phosphatase 
AST 
Aspartate aminotransferase  
ATP 
Adenosine triphosphate 
AUC 
Area Under the Curve 
 
AUC calculated over the dosing interval 
BCRP 
Breast Cancer Resistant Protein 
BID 
Bis in die  twice daily 
BMD 
Bone Mineral Density 
BMI 
BPI 
Body Mass Index 
Brief Pain Inventory 
CA 
Competent Authorities 
CFR 
Code of Federal Regulations 
CK 
Creatine phosphokinase 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum observed concentration 
Ctrough 
Observed concentration from sample collected prior to dosing 
CoQ10 
Coenzyme Q10 
COVID -19 
Corona Virus Disease 2019 
CRO 
Clinical Research Organisation 
DNA 
Deoxyribonucleic acid 
DSUR 
Drug Safety Update Report 
DXA 
Dual-energy X-ray Absorptiometry 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
eGFR 
Estimated Glomerular Filtration Rate 
EIA 
Enzyme immunoassay 
FAO 
Fatty Acid Oxidation 
FAS 
Full Analysis Set 
FU 
Follow-up visit 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HbA1c 
Glycosylated haemoglobin 
HBcAb 
Hepatitis B core Antibody 
HBsAg 
Hepatitis B surface Antigen 
hCG 
Human Chorionic Gonadotropin 
HDL 
High Density Lipoprotein 
HDPE 
High Density Polyethylene 
hr 
hour 
ICH GCP 
International Council on Harmonisation Good Clinical Practice 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 


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IWRS 
Integrated Web-based Response System 
kg 
Kilogram 
LDL 
Low Density Lipoprotein 
LFT 
Liver Function Test 
LOQ 
Level of Quantification 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFIS 
Modified Fatigue Impact Scale 
mg 
milligrams 
mL 
milliliter 
mmHg 
millimetres of mercury 
msec 
millisecond 
mtDNA 
mitochondrial Deoxyribonucleic Acid 
nDNA 
nuclear Deoxyribonucleic Acid 
OLE 
Open Label Extension 
OXPHOS 
Oxidative phosphorylation 
PDF 
Portable Document Format 
PGIC 
PGIS 
Patient Global Impression of Change 
Patient Global Impression of Severity 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic 
PMM 
Primary mitochondrial myopathy 
PPAR 
peroxisome proliferator-activated receptor 
PRO 
Patient Reported Outcome 
PSOC 
Patient Screening Oversight Committee 
PTE 
Pre-treatment Events 
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 
 
RR 
The interval between the successive R waves 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
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 
Tmax 
Time to maximum plasma concentration 
ULN 
Upper Limit of Normal 
WOCBP 
Women of childbearing potential 
WPAI:SHP 
Work Productivity and Activity Impairment Questionnaire: Specific 
Health Problem 
12MWD 
12-minute walk distance 
12MWT 
12-minute walk test 
 
 


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1 
INTRODUCTION 
1.1 
Indication 
Primary mitochondrial myopathies (PMM) are genetic disorders associated with pathogenic 
variants in the mitochondrial or nuclear genes that can lead to oxidative phosphorylation 
(OXPHOS) dysfunction or other disturbances of mitochondrial structure and function. PMM 
predominantly, but not exclusively, affect the skeletal muscle and present with motor 
function deficits and poor endurance (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. Marked clinical variation can be 
seen in patients and this 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 and nDNA 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 can 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). PMM 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 or nuclear 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). 
PMM represents an area of significant unmet medical need; there is currently no available 
disease-modifying therapy for patients with PMM.  
1.2 
Background  
. 
involved in cellular metabolic processes such as glucose homeostasis, fatty acid synthesis and 
 in several 
metabolically active tissues including liver, muscle, and fat. It is the most abundant PPAR 
isoform in skeletal muscle and has a higher expression in oxidative type I muscle fibers 
compared with glycolytic type II muscle fibers. REN001 potently and selectively activates 
the treatment of patients with mitochondrial myopathies. 
Full details of the REN001 chemistry, pre-clinical and clinical data can be found in the 
current 
.  


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1.3 
Study Rationale 
There is a strong rationale for the use of REN001, a selective 
, in patients with 
PMM. The PPAR  receptor is a nuclear receptor primarily found in skeletal muscle. Patients 
with PMM caused by genetic mutations in the mitochondrial or nuclear genomes have 
impaired oxidative phosphorylation. Selective PPAR agonists may ameliorate the cellular 
energy deficit in patients with these mutations by: 
 Increasing fatty acid oxidation (FAO) and OXPHOS activity resulting in enhanced 
mitochondrial adenosine triphosphate (ATP) generating capacity. 
 In mtDNA-PMM, 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. 
 Increasing mitochondrial biogenesis and thereby increasing residual OXPHOS 
activity, which would enhance the cellular ATP synthesis capacity. 
 
The information collected will support the long-term safety evaluations of REN001 in the 
total PMM population. Enrolment of PMM patients with nDNA mutations in the REN001-
202 OLE study offers the opportunity to rapidly gain safety, tolerability and exploratory 
efficacy data on the effect of REN001 in these patients. The information obtained will then be 
used to support further clinical development of REN001 in this population. 
This protocol amendment expands the duration of the study to 48 months, to enable subjects 
who have perceived  benefit from therapy to continue to receive REN001.  
1.4 
Risk-Benefit Assessment 
1.4.1 Benefits 
In Study REN001-101, an open label Phase 1b study in subjects with mtDNA PMM, oral 
REN001 dosed at 100mg 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, most subjects experienced improvement in the outcome 
measures of distance walked in the 12MWT and symptoms of fatigue and pain evaluated with 
Patient Reported Outcome (PRO) measures. The study was terminated early in 2020 due to 
the operational obstacles created by the Corona Virus Disease 2019 (COVID-19) pandemic. 
Subjects who were ongoing in the study when Study REN001-101 was terminated will be 
given the opportunity for further treatment with REN001 in this study. 
The STRIDE study is an ongoing double-blind, placebo-controlled, Phase 2b study to 
evaluate the efficacy and safety of 24 weeks treatment with REN001, dosed at 100mg per 
day, in mtDNA PMM subjects.  This long-term safety study will offer the opportunity for 
extended active treatment for those subjects randomized to REN001 in STRIDE, and active 
treatment for subjects who were randomized to placebo. Neither subjects nor sites will be 
aware of the allocated treatment in STRIDE when rolling directly into this study, and the 
Sponsor will remain blinded to this information until the STRIDE database is locked and 
treatment allocation unblinded. 
Patients with nDNA mutations will not have previously participated in studies in the REN001 
program (due to eligibility criteria designed to maintain a homogenous population). However, 
the potential for REN001 to provide benefit for PMM patients is based on the myopathic 
phenotype, rather than specific genetic cause. Therefore, after gaining experience in the 


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mtDNA-PMM population, this protocol was amended (Version 2.0) to widen enrollment to 
include adult PMM patients with nDNA mutations This will provide long-term safety data on 
the total PMM patient population and provide evidence of potential efficacy in the nDNA-
PMM population.   
This amendment increases the duration of the study from 24 months to 48 months.  The 
duration of the study has been increased to continue the collection of long-term safety and 
also to enable access to REN001 therapy to those subjects who may be benefiting from 
REN001 treatment. 
1.4.2 Risks 
 
Subjects with PMM may have asymptomatic benign raised baseline creatine kinase (CK) 
levels as part of the PMM disease. Even among healthy individuals CK levels rise transiently 
after exercise or intense physical activity. In patients with PMM, serum CK levels may 
increase to as much as 30 times the ULN within 24 hours after 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-
limited and resolved with no intervention despite continued treatment with REN001 and 
, including exercise. In all 
clinical trials of 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 as a precautionary measure CK levels will be assessed 
throughout the study. 
 
A 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 predicated that the changes observed in 
the 6-month rat study are rat strain specific. Nevertheless, following this observation, taking a 
conservative approach, ophthalmology examinations are being included in all REN001 trials. 
Slit lamp eye examinations will be conducted together with assessments of best corrected 
visual acuity during this study. 
 
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 CYP3A4 is considered low but cannot yet 
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. 
There are few commonly used CYP3A4 substrates with a narrow therapeutic index which are 
not already prohibited by the protocol (Table 1). It is standard clinical practice to evaluate 
every patient as an individual with their own context of comorbid conditions and concurrent 


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medications. In order to ensure Investigators are checking the most up-to-date references for 
potential drug-drug interactions, they are referred to their own national medical prescribing 
guidance if available and to the Flockhart Table1 maintained by the University of Indiana 
available at https://drug-interactions.medicine.iu.edu/ if they are in any doubt about the status 
of a proposed concomitant medication. 
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. 
 
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 while taking the study drug and for 
approximately 30 days after stopping study drug (at least one menstrual cycle after drug 
exposure).  If subjects are transferred to a commercial supply of REN001 they must be 
advised to adhere to the contraceptive requirements. Serum pregnancy testing will be 
completed at screening for mtDNA-PMM subjects enrolling after exiting one of the two 
feeder studies and for nDNA-PMM subjects. Urine pregnancy tests will be carried out at 
baseline and monthly thereafter until completion of the study for all WOCBP regardless of 
when they enrolled. 
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. As a precautionary measure, women taking 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 of study drug (Section 5.8). 
 
Carcinogenicity studies have been initiated but are not yet completed. Animal carcinogenicity 
data in rodents suggest that some, but not all, PPAR agonists have carcinogenicity potential. 
The mechanism by which implicated compounds produce tumors in rodents is not well 
understood and the relevance of these findings for other classes of PPAR agonists, if any, to 
humans is unknown. Subjects with a history of cancer, except in situ basal cell carcinoma in 
the skin, are excluded from participation in the study.  
                                                 
1 Flockhart DA, Thacker, D., McDonald, C., Desta, Z. The Flockhart Cytochrome P450 Drug-Drug Interaction 
Table. Division of Clinical Pharmacology, Indiana University School of Medicine (Updated 2021). https://drug-
interactions.medicine.iu.edu/. [Accessed 23 March 2022]. 


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A finding of premature bone plate closure was observed in toxicology studies in one species 
of rat. This finding was not seen in the non-human primate studies. As a precaution, 
treatment-naïve nDNA-PMM subjects under 25 years of age will have a wrist x-ray prior to 
enrolment to confirm skeletal maturity. 
Currently it is not known if REN001 (a 
nist) will have any impact on bone mineral density (BMD). Nonetheless, 
given the requirements for walk tests and taking a conservative approach, the Sponsor 
excluded subjects with a history of fragility/stress fractures or an osteoporosis concomitant 
condition which has not been addressed from the STRIDE study, and will monitor markers of 
bone turnover during this study. Any reports of bone fracture will be captured as an AESI. 
Any change in BMD over the course of the study will be assessed using DXA scans where 
available. 
1.4.3 Safety Data Review 
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 in aggregate by the 
Safety Review Committee (SRC) at pre-defined milestones. See Section 3.11. The safety 
profile of REN001 to date supports further development in clinical studies subject to 
appropriate subject selection and safety monitoring.  
1.5 
Dose Selection Rationale 
The dose of 100mg once daily used in this study is the same dose used in the 2 feeder studies 
for mtDNA-PMM subjects: Study REN001-101 (a UK only study) and the STRIDE study. 
To date a total of 163 subjects have been enrolled and 106 subjects received REN001 in four 
completed clinical trials pertinent to this indication (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 48 weeks, repeat dose in mtDNA-PMM subjects; 
treatment received for up to 40 weeks due to curtailment of study during the COVID-19 
pandemic). In the single dose study, doses ranged from 25mg to 250mg, doses in the 14-day 
study ranged from 50mg to 200mg QD or 100mg BID, in the 28-day study the dose was 
100mg BID and in the 48-week study the dose was 100mg 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, most subjects with mtDNA-PMM who received REN001 at an oral 
dose of 100mg once daily for 12 weeks improved 12MWD, 30 second sit to stand, VO2 max 
and gait analysis with these physical function measures being supported by the PRO data. 
PRO data also reported a reduction in muscle related symptoms and fatigue. Pharmacological 
activity of the REN001 at 100mg per day was also shown in Phase 1 studies in other 
indications (see Investigator Brochure for details).  
The safety and the pharmacodynamic effects observed in these four completed studies 
support the 100mg QD dose level in the primary mitochondrial myopathy population 
evaluated in both the STRIDE study and in this long-term safety study. Although, there is no 
prior history of REN001 exposure in patients with nDNA mutations, the safety profile of 
REN001 in this population is not expected to differ significantly from patients with mtDNA 
mutations. nDNA-PMM patients enrolling in this study must meet similar screening safety 


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requirements as the naïve mtDNA-PMM patients who previously enrolled in the STRIDE 
study or in the REN001-101 study. 
For completeness, Phase Ib clinical trials have also been completed in Fatty Acid Oxidation 
Disorder, n= 24 subjects, 50mg or 100mg dose once daily; and McArdle Disease, n= 17 
 
 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To evaluate long-term safety and tolerability of REN001 in subjects with PMM. 
2.2 
Secondary Objectives 
To assess subjects with mtDNA-PMM who are receiving long-term treatment with REN001 
in terms of PMM associated symptoms, pain severity and interference, exercise endurance, 
quality of life (QoL), patient global impression of change (PGIC) and patient global 
impression of severity (PGIS) for muscle and fatigue, and work productivity. 
2.3 
Pharmacokinetic (PK) Objectives 
To further characterise the PK profile of REN001 in subjects with PMM receiving long-term 
treatment. 
2.4 
Exploratory Objectives 
To evaluate the effect of long-term treatment with REN001 on bone health. 
To assess subjects with nDNA-PMM who are receiving long-term treatment with REN001 in 
terms of PMM associated symptoms, pain severity and interference, exercise endurance, 
quality of life (QoL), patient global impression of change (PGIC) and patient global 
impression of severity (PGIS) for muscle and fatigue, and work productivity. 


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3 
OVERALL DESIGN AND PLAN OF THE STUDY 
3.1 
Overview 
This is a long-term safety study for subjects who have completed treatment in the STRIDE 
study, subjects who participated in the REN001-101 study and nDNA-PMM subjects. At sites 
with the IEC and regulatory approvals, eligible subjects will be treated for 48 months. A SRC 
will review safety data during the study. The structure, function, and operation of the SRC is 
detailed in the REN001-202 SRC Charter. Interim data cuts may be taken, and summaries 
prepared to support regulatory submissions or external communications such as publications. 
Subjects with mtDNA mutations enrolling from the STRIDE study will be switching from 
taking blinded REN001 or placebo in the STRIDE study to open label REN001 in this study. 
At the time of enrolment into this long-term study, prior treatment allocation in the STRIDE 
study will be unknown. Subjects who are nearing completion of the STRIDE study will be 
invited to discuss continuing into this long-term safety study and provide informed consent 
prior to any study activities. It is expected that most subjects transferring from the STRIDE 
study will do so at the STRIDE Week 24 visit to prevent an interruption in dosing and reduce 
the number of study visits and assessments. Subjects who are enrolled at the STRIDE Week 
24 visit will not need to complete the STRIDE follow-up (FU) visit. 
Alternative exclusion criteria (Section 4.3) apply to subjects who will be enrolled from sites 
in Germany. These criteria will require screening blood tests within 8 weeks prior to the start 
of dosing in this study. For those subjects wishing to start dosing immediately after the 
STRIDE Week 24 visit, their STRIDE Week 18 blood tests may be used as the screening 
assessments. However, additional blood samples will need to be collected for HbA1c and 
serology. See section 6.1.1 for details. 
Enrolment at the STRIDE FU visit will require additional baseline assessments. For subjects 
at the German sites wishing to start dosing in this study immediately after the STRIDE FU, 
their STRIDE Week 24 blood tests may be used as the screening assessments; additional 
blood samples will need to be collected for serology. See Section 6.1.2 for details. 
Subjects who wish to take part in this study after leaving the STRIDE study (i.e., after their 
STRIDE FU visit), who participated in Study REN001-101 (UK only), and nDNA-PMM 
subjects will require additional screening and baseline visits; details of enrolment options are 
provided in Section 6.1 and Table 2. 
The PSOC will assess if nDNA-PMM subjects have the appropriate diagnosis for entry into 
the study prior to dosing.  Subjects who successfully complete screening and are approved by 
the PSOC will then undergo a Baseline Visit.  
After the baseline visit, each subject will have study visits at Months 1, 3, 6, 12, 18,  24, 30, 
36, 42 and 48 (and Month 9 and 15 for German subjects). As a final follow-up there will be a 
telephone call from the study centre to the subject approximately 30 days after the last dose 
of study drug. A final follow-up telephone call will not be required if mavodelpar has been 
approved within the country and the subject switches to commercially available medication. 
Where the site permits, a concierge service will be available to subjects to arrange hotel 
accommodation and transport to and from study centre visits and to reimburse any subject 
study expenses, if applicable. If a study centre requires it, subjects may be asked to have a 
negative COVID-19 test prior to undertaking scheduled visits at the study centre. 
It is expected that most mtDNA-PMM subjects will enrol at the STRIDE Week 24 visit to 
prevent an interruption in dosing and reduce the number of study assessments. The 
requirement for screening and baseline visits will be dependent on when the subject enrols in 


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the study: 
 Option 1: Enrolment at the STRIDE Week 24 visit: Most of the STRIDE Week 24 
assessments will be regarded as the baseline assessments for this study. Additional 
assessments will be performed as noted in Section 6.1.1. 
 Option 2: Enrolment at the STRIDE FU visit: The STRIDE FU visit will be regarded as 
the baseline visit for this study with additional assessments performed as noted in 
Section 6.1.2. If a washout period for any prohibited medication started since the 
STRIDE Week 24 visit, the subject will exit the STRIDE study and will require 
additional screening and baseline visits to enter the STRIDE AHEAD Study (Option 3 
enroller). 
 Option 3: Enrolment after exiting Study REN001-101 or STRIDE (mtDNA-PMM 
subjects): separate screening and baseline visits will be required, with assessments 
performed as noted in Section 6.1.3.  
 Option 4: Enrolment of nDNA-PMM subjects: separate screening and baseline visits 
will be required, with assessments performed as noted in Section 6.1.4. nDNA-PMM 
subjects will not be enrolled in France. 
The study design is shown in Figure 1 below. Full details of assessments required for the 
enrolment options is given below and shown in Table 2. 
 
 


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Figure 1: 
Study Design 
SUBJECT SOURCE: 
 
    
 
           
LONG-TERM SAFETY STUDY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.2 
Endpoints 
3.2.1 Primary Endpoints 
For mtDNA and nDNA subjects: 
 Number and severity of adverse events (AEs) 
 Number of AEs leading to study drug discontinuation 
 Number of serious adverse events (SAEs)  
 Number of adverse events of special interest (AESI) 
 Number of AEs leading to death 
3.2.2 Secondary Endpoints  
For mtDNA and nDNA subjects: 
REN001-201 (STRIDE Study) 
Double blind, randomized study 
(mtDNA-PMM subjects) of REN001, 
100mg daily for 24 weeks  
OR 
Matched placebo for 24 weeks 
REN001-202 (STRIDE AHEAD Study) 
Long-term safety and tolerability study of 
open label REN001, 100mg daily for 48 
Months 
REN001-101  
Open label study (mtDNA-PMM 
subjects) of REN001, 100mg daily 
for 12 weeks (Part A), followed by 
optional treatment extension (Part B). 
The study was stopped early due to 
COVID-19 pandemic. 
nDNA-PMM Subjects 
REN001-naïve subjects who have 
PMM of nDNA origin 


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 Absolute values, changes from baseline, and incidence of potentially clinically 
significant changes in: 
o Laboratory safety tests 
o Electrocardiograms (ECG) 
o Supine vital signs 
o Eye assessments 
For mtDNA subjects: 
 Absolute values and changes from baseline in: 
 Distance walked during the 12MWT* 
 MFIS total scores and sub-scale scores* 
Patient Global Impression of Severity (PGIS) scores for fatigue and muscle symptoms 
 Brief pain inventory (BPI) pain severity and pain interference scores* 
 Patient Reported Outcomes Measurement Information System (PROMIS) Short 
Form- Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue 13a 
scores* 
 36-Item Short Form Health Survey (SF-36) domain scores (7-day recall)*  
 Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem (WPAI:SHP) scores* 
 First 6-minute walk distance and last 6-minute walk distance* 
 Phenotypic description questions* 
 Patient Global Impression of Change (PGIC) scores for fatigue and muscle symptoms 
3.2.3 PK Endpoints 
REN001 plasma concentrations will be measured at each study visit*. The following 
parameters will be calculated for subjects recruited under Protocol Version 1.0: Ctrough, Cmax, 
Tmax and Area Under Curve (AUC) . The REN001 plasma concentrations may be included in 
a population PK analysis which will be reported separately to the Clinical Study Report for 
this study. REN001 metabolite concentrations may also be analyzed and reported. 
3.2.4 Exploratory Endpoints 
For mtDNA and nDNA subjects: 
 Change from baseline to end of treatment in bone mineral density (BMD), as 
measured by dual energy x-ray absorptiometry (DXA), in the following: 
o Lumbar spine (L1 to L4) BMD 
o Total hip BMD and the femoral neck BMD (in the non-dominant hip) 
o Total hip, lumbar spine, and femoral neck T-scores and Z-scores 
For nDNA subjects: 
 Absolute values and changes from baseline in: 
 Distance walked during the 12-Minute Walk Test (12MWT)*  
 Modified Fatigue Impact Scale (MFIS) total scores and sub-scale scores* 
Patient Global Impression of Severity (PGIS) scores for fatigue and muscle symptoms 
 Brief Pain Inventory (BPI) pain severity and pain interference scores* 


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 Patient Reported Outcomes Measurement Information System (PROMIS) Short 
Form-Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue 13a 
scores* 
 36-item Short Form Health Survey (SF-36) domain scores (7-day recall)* 
 Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem (WPAI:SHP) scores* 
 First 6-minute walk distance and last 6-minute walk distance* 
 Phenotypic description questions* 
 Patient Global Impression of Change (PGIC) scores (muscle and fatigue symptoms). 
*collected up to Month 24 only 
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. The STRIDE study is designed 
to assess the efficacy and safety of REN001 in patients with PMM caused by mtDNA gene 
mutations treated over a 24-week period.    
This long-term safety study is designed to evaluate the safety and tolerability of long-term 
treatment with REN001 in subjects with PMM. In addition, valuable data regarding PMM 
associated symptoms, exercise endurance, quality of life and work productivity will be 
captured. This study will also give the opportunity to evaluate the effects of REN001 on 
safety and tolerability, any effects of REN001 on other outcome measures, and on quality- of- 
life measures in PMM subjects with nDNA mutations. 
This study will also generate data to support the evaluation of the PK profile of REN001 over 
time.  
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: 
 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. 
 Occurrence of local or global events (e.g., pandemic) that would impact the safety of 
subjects in the study. 
 A decision by the Sponsor to suspend or discontinue development of the drug for the 
PMM indication. 
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 as otherwise 
permitted by the contractual agreement. 
3.6 
Conditions for Individual Subject Withdrawal from the Study 
The primary reason for subject withdrawal from the study should be recorded in the 
electronic Case Report Form (eCRF). Individual subjects may be withdrawn from the study 
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 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. 
 Use of a prohibited concomitant medication. 
 Major protocol deviation e.g., the discovery after administration of the first dose of 
study drug 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 
 
 Lost to follow-up. The subject does not return to the study centre and attempts to 
contact the subject are unsuccessful. Attempts to contact the subject must be 
documented. 
 Evidence of pregnancy during the treatment period of the study. 
 Clinically significant changes from baseline in ECG considered treatment-related 
including an increase from baseline to an absolute heart rate corrected QT interval 
500 millisecond (msec). Single ECGs 
should be repeated at 5-minute intervals 3 times to confirm any increased QT interval 
values. In the event of increased QTcF, the subject must be monitored until the value 
returns to below 500 msec. 
 Clinically significant muscle injury including test abnormalities (e.g., CK) as defined 
in Section 3.7.1. 
 Clinically significant liver toxicity including test abnormalities (e.g., ALT/AST) as 
defined in Section 3.7.2. 
 Clinically significant kidney toxicity including test abnormalities (e.g., creatinine 
levels) as defined in Section 3.7.3. 
 A TEAE that could result in a 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. 
 Voluntary withdrawal. The subject wishes to discontinue study drug and 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., 
category).  
If a subject is prematurely withdrawn from the study drug, the Investigator must make every 
effort to perform the evaluations described for the Early Withdrawal visit and a further 
Follow-up contact approximately 30 days after the last does of study drug (if required, see 
Section 6.14). If the subject is withdrawing consent for continuing in the study and/or further 
contact no further assessments will be performed. 
3.7 
Strategy for Potential Withdrawal due to Laboratory Test Abnormalities 
3.7.1 Safety Monitoring for Muscle Injury 
Patients with PMM often present with mild to moderate baseline elevations in CK and can 
experience transient episodes of significantly elevated CK induced by acute illness, vigorous 
exercise, and other conditions. These elevations are not associated with symptoms or signs 
and the patients are typically well. CK elevations are generally of the skeletal muscle 


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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 clinically significant 
rhabdomyolysis. Similarly, elevations in serum aminotransferases and uric acid can 
accompany CK elevations and may not be indicative of liver disease.  
True, clinically significant, 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 a triggering event and may be 
associated with dark pigmentation of the urine (Nance & Mammen, 2015). Acute kidney 
injury is a 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 
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. 
 
 


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Figure 2: 
CK Algorithm 
 
 
 
 
For the purpose of the different enrollment options, baseline is considered the visit where the 
subject starts drug. 
3.7.2 Safety Monitoring for Liver: Management and Stopping Rules 
Subjects with clinically significant liver disease or impairment have been excluded. It would 
be inappropriate to exclude all subjects with milder elevations in LFTs out of the normal 
range because subjects 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 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: 
 For subjects who enrol 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. 


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 For subjects who enrol 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. 
 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).  
 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. 
 
 Repeated ALT, AST, ALP, and total bilirubin tests two or three times weekly.  
 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. 
 Obtain a more detailed history of symptoms and prior or concurrent diseases. 
 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. 
 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.  
 Obtain a history of exposure to environmental chemical agents. 
 Obtain additional tests to evaluate liver function, as appropriate (e.g., International 
normalized ratio (INR) or Prothrombin time (PT), direct bilirubin). 
 Consider gastroenterology or hepatology consultations. 
 
Discontinuation or interruption of study drug should be considered, in consultation with the 
Medical Monitor and the Sponsor where possible, if: 
 ALT or AST > 8xULN. 
 ALT or AST > 5xULN for more than 2 weeks. 
 ALT or AST > 3xULN and total bilirubin > 2xULN or INR >1.5. 
 ALT or AST > 3xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
 
Discontinuation of study drug should occur and close monitoring continued, if: 
 ALT or AST > 8xULN. 
 ALT or AST > 5xULN for more than 2 weeks. 
 ALT or AST > 3xULN and total bilirubin > 2xULN or INR >1.5. 


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 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: Management and Stopping Rules 
If subjects develop a creatinine elevation > 2xULN and more than 2x baseline value: 
 Monitor creatinine 2 times per week, or as clinically indicated, until recovery. 
 For subjects with > 3xULN the study drug should be withheld, and the subject should 
continue to be followed closely.  
 In the event of either of the above continued participation in the study should be 
discussed with the Medical Monitor. 
 
Discontinuation of study drug should be considered, in consultation with the Medical 
Monitor and the Sponsor where possible, if: 
 A > 3xULN creatinine elevation is sustained or deteriorating. 
 The subject is unwell and has hyperkalemia. 
 
Study drug must be discontinued if: 
 A > 3xULN creatinine elevation is sustained or deteriorating. 
 The subject is unwell and has hyperkalemia. 
3.8 
Replacement of Subjects 
Replacement of subjects is not applicable in this 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 (Section 5.7). 
3.10 Review of Screening Eligibility Data for nDNA-PMM subjects  
An independent Patient Screening Oversight Committee with experts in the diagnosis of 
PMM will review screening data to ensure nDNA-PMM subjects have the appropriate 
diagnosis for entry into the study. Details regarding the structure, function and operation of 
the PSOC are detailed in the REN001-202 PSOC Charter. nDNA-PMM subjects will not be 
enrolled in France.  
3.11 Safety Review Committee (SRC) 
Review of subject safety data (including AEs, ECGs, laboratory safety tests, vital signs, and 
eye examinations) from this long-term open-label safety study will be performed by the SRC 
in accordance with the REN001-202 SRC Charter. Safety reviews will be conducted 
throughout the study 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 other study modifications based on these reviews. 


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4 
STUDY POPULATION 
Protocol inclusion and exclusion criteria in Section 4.1 are intended for all subjects enrolling 
into the study. These are the only criteria to be assessed for mtDNA-PMM subjects enrolling 
at the STRIDE Week 24 or STRIDE FU visits. Additional eligibility criteria will need to be 
met for those mtDNA-PMM subjects enrolling after exiting from either of the 2 feeder 
studies and nDNA-PMM subjects (Section 4.2). In addition, nDNA-PMM subjects will have 
some screening data independently reviewed by the PSOC to confirm eligibility. nDNA-
PMM subjects will not be enrolled in France. 
4.1 
Protocol Criteria for All Subjects 
4.1.1 Inclusion Criteria 
Subjects must meet the following inclusion criteria to be eligible for the study: 
1. mtDNA-PMM subjects: Completed treatment in the STRIDE study or participated in 
Study REN001-101, and in the opinion of the Investigator and the Sponsor have been 
compliant with the study requirements  
 
Or 
 
nDNA-PMM subjects: Subjects aged 18 years or older with known nuclear (nDNA) 
pathogenic variants with a major muscle phenotype consisting of objective myopathy 
with poor exercise tolerance.  Proof of pathogenicity must be provided. Must be able to 
walk at least 100m in the screening 12MWT and the limitations in walk test must be 
primarily due to the energy deficit and not due to ataxia or any other condition.  For 
subjects under 25 years old only: confirmation of bone growth plate closure by wrist 
radiograph. 
2. Have PMM which continues to be primarily characterized by exercise intolerance or 
active muscle pain. 
3. Willing and able to swallow gelatin capsules. 
4. Concomitant medications (including supplements) intended for the treatment of PMM or 
other co-morbidities likely to remain stable throughout participation in the study where 
clinically possible. 
5. Signed and dated informed consent document indicating that the subject has been 
informed of all pertinent aspects of the study. 
6. Females should be either of non-child-bearing potential or must agree to use highly 
effective methods of contraception from baseline through to approximately 30 days after 
last dose of study drug. Males with partners who are WOCBP must also use contraception 
from baseline through to 14 weeks after last dose of study drug. 
4.1.2 Exclusion Criteria 
Subjects presenting with any of the following will not be included in the study: 
1. Anticipated to need a PPAR agonist other than REN001 during the study. 
2. Anticipated to need drugs during the study with a narrow therapeutic index and Breast 
Cancer Resistant Protein (BCRP) mediated absorption, distribution, metabolism and 
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3. Intent to donate blood, or blood components during the study or within one month after 
completion of the study. 
4. Current drug dependency. Use of opiates/cannabis for medical reasons is acceptable with 
prescription evidence or at the Investigator s discretion. 
5. Current alcohol dependency. 
6. Any medical or psychiatric condition or laboratory abnormality that may increase the risk 
associated with study participation or interfere with the interpretation of study results and, 
in the judgment of the Investigator and Medical Monitor, would make the subject 
inappropriate for entry into this study. 
7. Pregnant or nursing females. 
4.2 
Additional Exclusion Criteria  
Subjects with mtDNA-PMM enrolling after exiting from either of the 2 feeder studies and 
subjects who have nDNA-PMM will be required to fulfil these additional exclusion criteria: 
1. Clinically significant kidney disease or impairment, with an eGFR less than 
60ml/min/1.73m2 using the CKD-EPI creatinine equation at baseline. German sites - see 
alternative criteria below in Section 4.3. 
2. 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 
baseline. (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 
 
3. 
 German 
sites - see alternative criteria below in Section 4.3. 
4. 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, are acceptable provided the 
symptoms and medications would not be predicted to compromise safety or interfere with 
the tests and interpretations of this study.) 
5. Clinically significant cardiac disease and/or clinically significant ECG abnormalities 
nd degree heart block, symptomatic 
tachyarrhythmia or unstable arrythmia that in the opinion of the Investigator should 
exclude the subject from study completion. 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 their safety in this study. 
6. Treatment with an investigational drug, other than REN001, within 3 months or 5 drug 
half-lives, whichever is longer, prior to Day 1. 
7. Have been hospitalized within the 3 months prior to Screening for any major medical 
condition (as deemed by the Principal Investigator). 
8. Subjects with poor nutritional status as determined by the Investigator. 
9. Subjects with positive hepatitis B surface antigen (HBsAg) and hepatitis B core antibody 
(HBcAb), or positive hepatitis C or human immunodeficiency virus (HIV) at screening. 
German sites  see alternative criteria below in Section 4.3. 
10. Subjects who are not eligible or have a contraindication for cataract surgery. 
11. Any condition possibly reducing drug absorption (e.g., gastrectomy or increased 
gastrointestinal motility). 
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13. For subjects exiting REN001-101 study  and nDNA- PMM subjects  a history of 
fragility/stress fractures or an osteoporosis concomitant condition which has not been 
adequately addressed. 
4.3 
Alternative Exclusion Criteria for Subjects in Germany  
For additional exclusion criteria 1, 3 and 9, the following alternative criteria apply: 
1. Clinically significant kidney disease or impairment, with an eGFR less than 
60ml/min/1.73m2 using the CKD-EPI creatinine equation. 
3. 
HbA1c is not obtained as part of the Week 18 visit in the Stride Study. Nevertheless, the 
Week 18 blood draw may be used to obtain the test provided the subjects has given the 
appropriate consent). 
9. Subjects with positive hepatitis B surface antigen (HBsAg) and hepatitis B core antibody 
(HBcAb) or positive hepatitis C or human immunodeficiency virus (HIV). (NOTE:  these 
tests are not obtained as part of the Week 18 or 24 visits in the Stride Study. Nevertheless, 
the Week 18 or 24 blood draws may be used to obtain the test provided the subjects has 
given the appropriate consent). 
Assessment of these criteria will require screening blood tests within 8 weeks prior to their 
start of dosing in this study. For those subjects wishing to start dosing immediately after the 
STRIDE Week 24, their STRIDE Week 18 blood tests may be used as the screening 
assessments. However, additional blood samples will need to be collected for HbA1c and 
serology. 
For mtDNA-PMM subjects wishing to start dosing immediately after the STRIDE FU visit 
their STRIDE Week 24 blood tests may be used as the screening assessments. However, 
additional blood samples will need to be collected for serology. 
 
4.4 
Additional Criteria for Subjects at Sites where DXA Scans are Approved 
A separate DXA sub-study was set up to collect DXA scans alongside the STRIDE study. In 
countries and sites where the DXA sub-study was approved by IEC/Regulators, and subjects 
have a DXA scan at the STRIDE Week 24 time point, this will be taken as baseline for this 
study and a DXA will be performed at Month 24, and at Month 48, or early withdrawal from 
this study. 
Subjects who did not enter the DXA sub-study during the STRIDE study at sites where the 
DXA sub-study was approved, subjects who participated in Study REN001-101 and nDNA-
PMM subjects must meet the following enrolment criteria. If eligible, these subjects will have 
a baseline DXA scan on entry to this study and then a DXA scan at Month 24, and one at 
Month 48 or at early withdrawal.  DXA scans are considered optional for all subjects.  
Criteria to be eligible for the DXA scan for subjects who did not enter the STRIDE DXA 
sub-study:  
 Must have at least one hip free of metal. 
 Signed consent for DXA scan. 
Subjects presenting with any of the following will not be eligible for a DXA scan: 
 Positive pregnancy test, or possibility of being pregnant. 


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 Gastrointestinal contrast agents or radionuclides administered within 14 days of the 
scan, where DXA cannot be rescheduled. 
 Severe degenerative changes or fracture deformity in the spine and either fractures in 
both hips, or double hip replacement. 
 Implants, hardware, devices, or other foreign material in both measurement areas. 
 Subjects fitted with an implantable cardioverter defibrillator. Pacemakers are 
permitted. 
 Subject unable to attain correct position for both measures and/or remain motionless 
for the measurement (maximum of 5 minutes scan time, 20 minutes for the entire 
procedure). 
 Absolute weight >136kg (or 300lb). 
4.5 
Planned Sample Size and Study Centres  
Recruitment will be limited to those mtDNA-PMM subjects who participated in the STRIDE 
study (applicable only for countries where this study is being conducted) or Study REN001-
101 (UK only), and nDNA-PMM subjects. It is estimated that approximately 150 mtDNA-
PMM and 50 nDNA-PMM subjects may be enrolled. Recruitment will be from across a 
minimum of 30 centres. nDNA-PMM subjects will not be enrolled in France. 
4.6 
Study Completion 
The study will be considered completed with the last follow-up telephone call of the last 
subject. A final follow-up telephone call will not be required if mavodelpar has been 
approved within the country and the subject switches to commercially available medication. 
 


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5 
STUDY DRUG 
5.1 
Study Drug Identity 
Study drug is presented as orange, hard gelatin capsules, manufactured by Xcelience LLC, a 
Lonza company. The dosage strength of REN001 capsules is 50mg. Capsules are packaged in 
200mL high-density polyethylene (HDPE) bottles, with a heat induction seal and child-
resistant lids, containing 100 capsules of 50mg REN001. Labels will contain batch number 
and expiration date. 
5.2 
Management of Study Drug 
Study drug will be managed using an Integrated Web-Based Response System (IWRS). 
Sufficient bottles will be supplied to ensure subjects have at least enough capsules to 
maintain dosing between study centre visits. 
5.3 
Administration 
Subjects will receive once daily 100mg REN001 as 2 x 50mg capsules for oral administration 
for the duration of the study. Study drug should be taken with food at a convenient time to the 
subject (ideally in the morning). Subjects will be supplied with a dose record card and will be 
requested to record the date and time of dosing for all study visit days. 
At the Month 3 visit, PK samples will be taken pre and post study drug administration over a 
4-hour period (Section 6.3). At this visit the subject should take the study drug at the study 
centre with food when instructed to do so by the site staff. 
5.4 
Packaging, 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. 
Until dispensed to the subjects, the study drug (REN001 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 drug has been dispensed to subjects, it should be stored refrigerated (2-8oC) at 
drug does not need to be kept refrigerated during transport to and 
study centre. Subjects should only open and use one bottle of 
study drug at a time. Study drug should be kept away from children. 
5.5 
Excessive Pharmacological Effects 
No specific antidotes for REN001 are available and standard supportive measures should be 
used in the case of excessive pharmacological effects. 
5.6 
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. 
The subject must bring all study drug (including empty bottles) to the study centre at each 
visit to monitor compliance, reconciliation, and quarantine of any expired study drug ahead 
of destruction. Any study drug remaining at the end of study will be returned to the Sponsor 


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or their representative or destroyed locally on behalf of the Sponsor (with written permission 
of the Sponsor) and the destruction fully documented. 
5.7 
Compliance 
At all study visits subject compliance with the study drug regimen will be monitored by 
capsule counts. If a subject consistently fails to take their study drug, the Investigator should 
alert the site monitor, Medical Monitor and Sponsor and a decision will be made as to 
whether the subject should be withdrawn for non-compliance. 
5.8 
Contraceptive Requirements 
In countries where the regulatory authority allows, WOCBP will be allowed to enrol into this 
long-term safety study provided they continue to agree to use adequate contraceptive 
requirements as outlined for their participating site. 
Contraceptive requirements for the study have been defined using the recent 
recommendations of the Clinical Trials Facilitation Group, Rome September 2014 meeting 
(Clinical Trials Facilitation Group, 2014 and 2020) and also the International Council on 
Harmonisation (ICH) M3(R2) guidance (European Medicines Agency, 2009).  
5.8.1 Females 
Females of child-bearing potential must agree to use highly effective methods of 
contraception from baseline to approximately 30 days (one menstrual cycle) after the last 
dose of study drug. Highly effective methods are: 
 combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation administered by oral or intravaginal route. 
 oral, injectable or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation. 
 intrauterine device. 
 intrauterine hormone-releasing system. 
 bilateral tubal occlusion. 
 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. 
 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. 
Caution with co-administration of REN001 and hormonal contraceptives is advised due to the 
potential for drug-drug interaction (Section 1.4). In addition to highly effective hormonal 
contraception, WOCBP at risk of pregnancy are advised to also use an additional effective 
non hormonal method of contraception. Effective methods are male condom, female condom, 
cervical cap, diaphragm, contraceptive sponge. 
Females are considered to be of non-child-bearing potential if they fulfil at least one of the 
following criteria: 
 Post-menopausal, defined as 45 years or older and amenorrhoeic for at least 1 year 
PLUS have a serum follicle stimulating hormone (FSH) 
reference range for postmenopausal women, at screening or baseline visit. 
 Have undergone a documented hysterectomy and/or bilateral oophorectomy. 


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5.8.2 Males who are considered fertile and with partners who are WOCBP 
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 drug. A condom is 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. 
5.9 
Concomitant Medications 
Any medication other than the study drug is considered a concomitant medication. The 
following information must be recorded in the eCRF for each concomitant medication: 
generic name, route of administration, dose, start and stop date (and whether it is a prior 
medication) and indication.  
At baseline, 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. If the subject is enrolled at the STRIDE Week 24 or FU visits, then their ongoing 
concomitant medications at the time of transition from one study to the other will be recorded 
for both studies. For those mtDNA-PMM subjects enrolling from Study REN001-101 (UK 
only), or after exiting the STRIDE study, and nDNA-PMM subjects, any medications taken 
prior to the start of dosing will be documented as prior medications. 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 is allowed only once and requires prior approval by the Sponsor.  
If a mtDNA-PMM subject who wishes to enrol at the STRIDE FU visit has started taking 
prohibited medications between their Week 24 and FU visits, they will not be allowed to start 
dosing until they have had a sufficient washout of the medications (Table 1). The subject will 
exit the STRIDE study and have a screening and baseline visit for this study. Subjects may 
not use the medications and treatments listed in Table 1 and these medications must be 
withheld for the duration of the study. 
5.9.1 Statins 
Concomitant statin therapy should be initiated based on a consideration of risk-benefit, given 
the inherent risk of myopathy from statin treatment. 
Potential identified individual risk factors for statin-induced myopathy include age, sex, race 
and clinical co-morbidities (history of elevated CK, family history of muscle symptoms 
induced by lipid lowering therapy, hypothyroidism, McArdle disease, diabetes mellitus, 
current infection, renal disease, hyperuricemia, alcohol overconsumption, trauma and intense 
physical activity). Identified pharmacodynamic genetic markers that appear to increase statin 
risk for myopathy include CPT2, COQ2 and RYR2 (Feng et al. 2012). 
In addition, pharmacokinetic interactions, arising from concomitant drug therapy or genetic 
polymorphisms in enzymes and transporters that decrease statin elimination by mechanisms 
including metabolism and transport by CYP3A4, SLCO1B1, OAT3, P-gp and BCRP, are risk 
factors for statin-induced myopathy. The contribution of each of these is dependent on the 
individual statin with the dose intensity of the statin being a high predictor of risk.  
Mavodelpar does not appear to be an inhibitor of any of the above processes with perhaps the 
exception of BCRP. Therefore, a clinical study to examine the impact of mavodelpar on a 
single 20mg rosuvastatin dose, the statin predicted to be most affected by mavodelpar, was 
conducted in healthy subjects. Based on preliminary data from the study, a chronic 100 mg 


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daily regimen resulted in a weak interaction, increasing the AUCinf by 58% (90% CI; 40% to 
78%) and Cmax by 81% (90% CI; 61% to 103%); i.e., 1.58 and 1.81-fold increase 
respectively. These data indicate that this weak interaction is likely to be inhibition of BCRP 
in the intestine, leading to a small increase in the extent of rosuvastatin absorption. Based on 
the pharmacokinetic changes alone, rosuvastatin use may be considered.   
Additional physiologically-based pharmacokinetic (PBPK) modelling was conducted with a 
model that predicted the changes in rosuvastatin and applied to predict pharmacokinetic changes 
that mavodelpar might have on atorvastatin and pravastatin. Based on the findings from this 
model, no significant PK drug-drug interactions are anticipated for these statins as well. 
Therefore, these statins could also be used based on pharmacokinetic changes. The use of any of 
these statins in this population should be initiated based on consideration of risk-benefit.   
5.9.2 Sensitive BCRP substrates with narrow therapeutic indices 
Based on in vitro data and a clinical drug-drug interaction study with the index BCRP 
substrate, rosuvastatin, mavodelpar is a weak inhibitor of BCRP. Therefore, drugs with 
narrow therapeutic indices and whose dispositions are affected by BCRP should not be used 
(Table 1). 
5.9.3 Treatment with moderate or strong inhibitors or inducers of cytochrome P450 
(CYP)2C8  
Approximately half of mavodelpar clearance is estimated to be mediated by oxidative 
metabolism, mediated primarily by CYP2C8.  In a clinical drug-drug interaction study with 
gemfibrozil, a strong index CYP2C8 inhibitor, mavoldelpar exposure (AUCinf) was increased 
(preliminary data) by 257 (90% CI; 216% to 305%). Also, steady-state carbamazepine, an 
identified PXR and CAR activator responsible for induction of various CYP enzymes, on 
mavodelpar exposure was also investigated in a clinical drug-drug interaction study. 
Carbamazepine reduced (preliminary data) mavodelpar exposure (AUCinf) by 60%. The AUC 
ratio of mavodelpar + carbamazepine compared to mavodelpar alone was 39% (90% CI; 37% to 
42%). . Such a decrease might result in loss of efficacy. Therefore, the use of moderate or strong 
inhibitors of CYP2C8 and PXR/CAR inducers are prohibited (See Table 1). 


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Table 1: 
Prohibited Medication 
Medication 
Washout period (Prior to Day 1)1 
Statins (including simvastatin and lovastatin)2 
1 week 
Anticoagulants2  
1 week or 5 half-lives: (whichever 
longer) 
Bezafibrate and other PPAR agonists 
4 weeks 
Cyclosporine and other immunosuppressive drugs 
4 weeks 
Oral or systemic steroids2 
4 weeks 
Investigational drugs (other than REN001) 
3 months or 5 half-lives 
(whichever longer) 
Moderate or strong CYP2C8 inhibitors and 
CAR/PXR activators, including clopidogrel, 
deferasirox, gemfibrozil, teriflunomide, trimethoprim, 
tucatinib, rifampin, carbamazepine 
3 months or 5 half-lives 
(whichever 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 (section 4.1.2) 
                                                 
1 Only applies to mtDNA-PMM subjects enrolling at STRIDE FU, after exiting STRIDE or Study REN001-101, and nDNA-
PMM subjects 
2 pravastatin, atorvastatin and rosuvastatin may be used after careful consideration of the benefit/risk assessment.  Other 
statins, anticoagulants and steroids may be allowed if considered medically appropriate following discussion with the 
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6 
STUDY CONDUCT 
Depending on IEC and regulatory approvals, this study may be conducted at a minimum of 
30 study sites. Details of study assessments are provided in Section 7. 
Following baseline, visits should occur within the scheduled timeslot for the visit; see Table 
3, Schedule of Activities. Where possible, visits should occur on the target visit day in 
relation to the first day of study drug dosing. 
Site staff will provide subjects with meals and snacks at appropriate times during the visit so 
that study drug is taken with food and to ensure subjects have enough energy prior to 
completing the exercise tests as required. 
All PROs should, where possible, be completed prior to the 12MWT, and the 12MWT should 
be performed at least 2 hours after a snack. The 12MWT should be conducted at the same 
time of day on every occasion where possible.  
Where a study centre requires, subjects may be asked to have a negative COVID-19 test prior 
to undertaking scheduled visits at the study centre. 
6.1 
Screening and Baseline Visits 
It is expected that most mtDNA-PMM subjects will enrol at the STRIDE Week 24 visit to 
prevent an interruption in dosing and reduce the number of study assessments. The 
requirement for screening and baseline visits will be dependent on when the subject enrols in 
the study: 
 Option 1: Enrolment at the STRIDE Week 24 visit: Most of the STRIDE Week 24 
assessments will be regarded as the baseline assessments for this study. Additional 
assessments will be performed as noted in Section 6.1.1. 
 Option 2: Enrolment at the STRIDE FU visit: The STRIDE FU visit will be regarded as 
the baseline visit for this study with additional assessments performed as noted in 
Section 6.1.2. If a washout period for any prohibited medication started since the 
STRIDE Week 24 visit, the subject will exit the STRIDE study and will require 
additional screening and baseline visits to enter the STRIDE AHEAD Study (Option 3 
enroller). 
 Option 3: Enrolment after exiting Study REN001-101 or STRIDE (mtDNA-PMM 
subjects): separate screening and baseline visits will be required, with assessments 
performed as noted in Section 6.1.3.  
 Option 4: Enrolment of nDNA-PMM subjects: separate screening and baseline visits 
will be required, with assessments performed as noted in Section 6.1.4. nDNA-PMM 
subjects will not be enrolled in France. 
Full details of assessments required for the enrolment options is given below and shown in 
Table 2. 
6.1.1 Option 1: Enrolment at STRIDE Week 24  
As a subject nears completion of the STRIDE study, the possibility of participation in this 
long-term safety study should be discussed with the subject and the approved patient 
information sheet supplied to the subject. 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 informed consent from each subject prior 
to commencing any specific study related activities or assessments. Subjects who are enrolled 
at the STRIDE Week 24 visit will not need to complete the STRIDE FU visit. 


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Subjects enrolling in Germany will require screening blood tests within 8 weeks prior to the 
start of dosing in this study. For subjects wishing to start dosing immediately after the 
STRIDE Week 24 visit, their STRIDE Week 18 blood tests may be used as the screening 
assessments. However, additional blood samples will need to have been collected for HbA1c 
and serology with results available for review prior to dosing in this study. 
Medical histories and demography reported in STRIDE will be transferred to this study. The 
following procedures taking place at STRIDE Week 24 will be regarded as baseline 
assessments for this long-term safety study: 
 Second morning void urine sample for: 
o Urine NTX bone markers 
o Urinalysis and drugs of abuse testing 
o Urine pregnancy testing (WOCBP) 
 Blood samples for: 
o Haematology and biochemistry (including HbA1c)  
o Bone and calcium markers 
o Pre-dose plasma sample for PK analysis of REN001 
 Review of ongoing concomitant medications and non-drug treatments. 
 Review of ongoing AEs. 
 Physician completion of subject s PMM phenotypic description. 
 Physical examination (including weight). 
 ECG. 
 Vital signs (including temperature). 
 Patient Reported Outcome (PRO) Questionnaires 
o MFIS 
o PGIS  muscle symptoms and fatigue symptoms 
o PROMIS Short Form  13a (FACIT Fatigue) 
o SF-36 
o WPAI:SHP 
o BPI 
 12MWT. 
 Eye examination.  
 DXA Scan (if participating in DXA sub-study of STRIDE study). 
Additional procedures required specifically for enrolment into this long-term safety study at 
Week 24 of STRIDE are: 
 Obtain written informed consent. In Germany written informed consent should be 
obtained prior to the additional screening samples for HbA1c and serology tests taken 
within 8 weeks prior to baseline, these may be done at STRIDE Week 18 visit. 
 Optional DXA Scan (if not performed as part of the STRIDE DXA sub-study in those 
countries and sites where this is permitted). It should be scheduled as close as possible 
to this baseline visit, however if this is not feasible, then it must be performed within 
the 4 weeks after the baseline visit. Subjects must be checked against the Additional 
Criteria for Sites with approvals for DXA Scans (Section 4.3). All WOCBP must have 


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a negative pregnancy test prior to the scan. All female subjects will require an FSH 
test if not confirmed as post-menopausal on the STRIDE Study. Details of how the 
DXA scan will be performed can be found in the DXA Manual. 
 
s post-menopausal in 
the STRIDE study and if not already conducted at Week 24 STRIDE visit. 
 Dispense study drug, first dose to be taken the following day with food at home. 
Subject should be instructed on study drug dosing requirements and reminded of the 
study restrictions. Study centre will telephone the subject the day after this baseline 
visit to confirm administration of first dose of study drug (Day 1) and record any 
change in AEs or concomitant medications (ongoing or new) since leaving the study 
centre on the previous day. Additional telephone contact will be made with the subject 
until first administration of study drug is confirmed. The contact and the first dose 
date will be reported in the eCRF. 
 
6.1.2 Option 2: Enrolment at STRIDE FU  
Subjects will be required to attend the study centre for the STRIDE FU visit to allow the 
additional assessments required for enrolment into this study.  
Subjects enrolling in Germany will require screening blood tests within 8 weeks prior to the 
start of dosing in this study. For subjects wishing to start dosing immediately after the 
STRIDE FU visit, their STRIDE Week 24 blood tests may be used as the screening 
assessments. However, additional blood samples will need to have been collected for 
serology with results available for review prior to dosing in this study. 
Subjects who plan to roll over at the STRIDE FU visit should be provided with a urine 
collection cup and instructions for collecting a second morning void, at the STRIDE Week 24 
visit.  This is provided in case the subject has their second morning void before attending the 
study centre at their next study visit.  
Medical histories and demography reported in STRIDE will be transferred to this study. The 
following procedures taking place at the Week 24 or the FU visit for the STRIDE study will 
be regarded as baseline assessments for this long-term study: 
 Review of ongoing AEs (part of STRIDE FU assessments). 
 Vital signs (including temperature, part of STRIDE FU assessments). 
 Urine pregnancy testing (WOCBP, part of STRIDE FU assessments). 
 Eye examination (part of Week 24 assessments) 
 DXA Scan (if participating in DXA sub-study of STRIDE study, part of Week 24 
assessments) 
 Review of ongoing concomitant medications and non-drug treatments (part of 
STRIDE FU assessments).  
Additional procedures required specifically for enrolment into this long-term safety study at 
the STRIDE FU visit are: 
 Obtain written informed consent. In Germany written informed consent should be 
obtained prior to the additional screening samples for serology tests taken within 8 
weeks prior to baseline, these may be done at STRIDE Week 24 visit. 
If subject started on any prohibited medications (Table 1) since STRIDE Week 24, a 
washout period will be required and the subject will need to exit the STRIDE study and 
return for screening and baseline visits after the washout period, as an Option 3 enroller; 


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the screening visit should be scheduled as soon as possible after the washout period.  
For subjects who do not need a washout period of prohibited medications the following 
procedures should be carried out at the STRIDE FU visit: 
 Second morning void urine sample for: 
o Bone marker  NTX 
o Urinalysis, drugs of abuse testing 
 Blood samples for: 
o Haematology and biochemistry (including HbA1c) 
o Bone and calcium metabolism markers 
o Serum FSH testing for all females (aged 45 years) who were not confirmed 
as post-menopausal in the STRIDE study 
o Pre-dose plasma sample for PK analysis of REN001 
 Physician completion of subject s PMM phenotypic description. 
 Full physical examination (including weight and height). 
 ECG. 
 Patient Reported Outcome (PRO) Questionnaires 
o MFIS 
o PGIS  muscle symptoms and fatigue symptoms 
o PROMIS Short Form  13a (FACIT Fatigue) 
o SF-36 
o WPAI:SHP 
o BPI 
 12MWT. 
 Optional DXA Scan (in those countries and sites where this is permitted), if not 
performed as part of the STRIDE DXA sub-study. It should be scheduled as close as 
possible to this baseline visit, however if this is not feasible, then it must be 
performed within the 4 weeks after the baseline visit. Subjects must be checked 
against the Additional Criteria for Sites with approvals for DXA Scans (Section 4.4). 
All WOCBP must have a negative pregnancy test prior to the scan. All female 
subjects will require an FSH test if not confirmed as post-menopausal on the STRIDE 
Study. Details of how the DXA scan will be performed can be found in the DXA 
Manual. 
 Dispense study drug, first dose to be taken at the site with food under the supervision 
of study staff. The time of dosing will be recorded. Subject should be instructed on 
study drug dosing requirements and reminded of the study restrictions.  
6.1.3 Option 3: Enrolment of mtDNA-PMM subjects from Study REN001-101 or after 
exiting STRIDE 
Separate screening and baseline visits are required when enrolling mtDNA-PMM subjects 
into this study after exiting from either of the 2 feeder mtDNA-PMM studies, as screening 
blood and urine test results must be available at the baseline visit for clinical review. Subjects 
who are receiving prohibited medication must suspend the medication if this can safely and 
appropriately be done. If a washout period is required for any prohibited medications this 
may extend the time between the screening and baseline visits (Table 1). The assessments to 
be carried out at each visit are as follows: 


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 Obtain written informed consent. 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 specific study related activities or assessments. 
 Subject Demography. 
 Complete Medical History (including prescription and non-prescription 
drugs/treatment, non-drug treatments, topical products, vitamins and dietary 
supplements taken in the last 4 weeks, alcohol, drugs of abuse and tobacco use. (See 
Table 1 for prohibited medication and washout times). 
 Review of ongoing concomitant medications and non-drug treatments. If subject is on 
any prohibited medications (Table 1), a washout period will be required and the 
baseline visit should be scheduled after the washout period.  
 Review of pre-treatment events (Section 7.1.1.1). 
 Full physical examination (including weight and height). 
 ECG. 
 Vital signs (including temperature). 
 Urinalysis and drugs of abuse testing. 
 Blood samples for: 
o Haematology and biochemistry (including HbA1c, HIV/Hepatitis B/C 
serology) 
o Serum pregnancy test (WOCBP) 
o Serum FSH testing for all females (
45 years) enrolling from Study REN001-
101 (UK only) or not confirmed as post-menopausal in the STRIDE study 
 Eye examination (may be completed between Screening and Baseline visits). Eye 
examinations will not be repeated if within 6 months of a previous test within 
STRIDE.   
 Optional DXA Scan (in those countries and sites where this is permitted). It should be 
scheduled as close as possible to the baseline visit, however if this is not feasible, then 
it must be performed within the 4 weeks after the baseline visit. Subjects must be 
checked against the Additional Criteria for Sites with approvals for DXA Scans 
(Section 4.4).  All WOCBP must have a negative pregnancy test prior to the scan.  All 
female subjects will require an FSH test if not confirmed as post-menopausal on the 
STRIDE Study. A STRIDE subject will not have a baseline DXA in this study if they 
had a Week 24 DXA in the STRIDE study. Details of how the DXA scan will be 
performed can be found in the DXA Manual. DXA scans will not be repeated if 
within 6 months of a previous scan within STRIDE. 
 Provide a urine collection cup and instructions for collecting a second morning void 
for next study visit. This is provided in case the subject has their second morning void 
before attending the study centre at their next study visit.  
 
This should be scheduled when results from all screening tests are available for clinical 
review against the protocol criteria. Maximum time between screening and baseline visits 
should be 8 weeks. Re-screening of subjects is allowed only once and requires prior approval 
by the Sponsor, for instance, if the wash out of prior medication is longer than 8 weeks.  


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The following assessments should be performed: 
 Second morning void urine sample for: 
o Bone marker  NTX 
o Urinalysis and drugs of abuse testing 
o Pregnancy testing (WOCBP) 
 Blood samples for: 
o Haematology and biochemistry (including HbA1c) 
o Bone and calcium metabolism markers 
o Plasma sample for PK analysis of REN001 
 Review of concomitant medication including contraception and non-drug treatments. 
 Review of pre-treatment events (Section 7.1.1.1). 
 Physician completion of subject s PMM phenotypic description. 
 Full physical examination (including weight). 
 ECG. 
 Vital signs (including temperature). 
 Patient Reported Outcome (PRO) Questionnaires 
o MFIS 
o PGIS  muscle symptoms and fatigue symptoms 
o PROMIS Short Form  13a (FACIT Fatigue) 
o SF-36 
o WPAI:SHP 
o BPI 
 12MWT.  
 Dispense study drug. First dose to be taken with food at the site under the supervision 
of site staff. The time of the first dose will be recorded. Subject should be instructed 
on study drug dosing requirements and reminded of the study restrictions. 
6.1.4 Option 4: Enrolment of nDNA-PMM subjects 
Separate screening and baseline visits are required when enrolling nDNA-PMM subjects, as 
screening blood and urine test results must be available at the baseline visit for clinical 
review. There must be a minimum of 4 weeks between the screening 12MWT and the 
baseline 12MWT. Subjects who are receiving prohibited medication must suspend the 
medication if this can safely and appropriately be done. If a washout period is required for 
any prohibited medications this may extend the time between the screening and baseline visit 
(Table 1). The assessments to be carried out at each visit are as follows: 
 
 Obtain written informed consent. 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 specific study related activities or assessments. 
 Subject Demography. 
 Complete Medical History (including prescription and non-prescription 
drugs/treatment, non-drug treatments, topical products, vitamins and dietary 


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supplements taken in the last 4 weeks, alcohol, drugs of abuse and tobacco use. (See 
Table 1 for prohibited medication and washout times). 
 Review of ongoing concomitant medications and non-drug treatments. If subject is on 
any prohibited medications (Table 1), a washout period will be required, and the 
baseline visit should be scheduled after the washout period.  
 Full physical examination (including weight and height). 
 ECG. 
 Vital signs (including temperature). 
 Urinalysis and drugs of abuse testing. 
 Blood samples for: 
o Haematology and biochemistry (including HbA1c, HIV/Hepatitis B/C 
serology) 
o Serum pregnancy test (WOCBP) 
o Serum FSH testing for all females (
45 years) 
 Eye examination (may be completed between Screening and Baseline visits). 
 For subjects <25 years old (only) a wrist radiograph will be required to confirm bone 
growth plate closure. 
 Optional DXA Scan (in those countries and sites where this is permitted). It should be 
scheduled as close as possible to the baseline visit, however if this is not feasible, then 
it must be performed within the 4 weeks after the baseline visit. Subjects must be 
checked against the Additional Criteria for Sites with approvals for DXA Scans 
(Section 4.4).  All WOCBP must have a negative pregnancy test prior to the scan.  All 
female subjects, regardless of child-bearing potential, must have an FSH test.  Details 
of how the DXA scan will be performed can be found in the DXA Manual. 
 12MWT. Subjects must be able to walk at least 100m in the screening 12MWT and 
the limitations in walk test must be primarily due to the energy deficit and not due to 
ataxia or any other condition. 
 Provide a urine collection cup and instructions for collecting a second morning void 
for next study visit. This is provided in case the subject has their second morning void 
before attending the study centre at their next study visit.  
 Input of the Pro-forma Screening data into eCRF for PSOC approval.  Provided the 
subject fulfils all the inclusion and none of the exclusion criteria, and the PSOC has 
confirmed their agreement, the subject may enter the study and proceed with the 
Baseline Visit. 
 
This should be scheduled when results from all screening tests are available for clinical 
review against the protocol criteria. Maximum time between screening and baseline visits 
should be 8 weeks. Re-screening of subjects is allowed only once and requires prior approval 
by the Sponsor, for instance, if the wash out of prior medication is longer than 8 weeks.  
The following assessments should be performed: 
 Second morning void urine sample for: 
o Bone marker  NTX 
o Urinalysis and drugs of abuse testing 
o Pregnancy testing (WOCBP) 


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 Blood samples for: 
o Haematology and biochemistry 
o Bone and calcium metabolism markers 
o Plasma sample for PK analysis of REN001 
 Review of concomitant medication including contraception and non-drug treatments. 
 Review of pre-treatment events (Section 7.1.1.1). 
 
 
 Full physical examination (including weight). 
 ECG. 
 Vital signs (including temperature). 
 Patient Reported Outcome (PRO) Questionnaires 
o MFIS 
o PGIS  muscle symptoms and fatigue symptoms 
o PROMIS Short Form  13a (FACIT Fatigue) 
o SF-36 
o WPAI:SHP 
o BPI 
 12MWT  
 Dispense study drug. First dose to be taken with food at the site under the supervision 
of site staff. The time of the first dose will be recorded. Subject should be instructed 
on study drug dosing requirements and reminded of the study restrictions. 
6.2 
Month 1 (Day 28) 
Visits should be scheduled relative to the first day of study drug administration (Day 1). The 
following assessments will be carried out at the first post baseline visit:  
 The subject should take their study drug with food at their usual dosing time. The 
actual time of dosing should be recorded by the patient on a dosing card. 
 Review concomitant medications, non-drug treatments and study drug compliance 
including capsule counts of remaining study drug. 
 Review of AEs. 
 Vital signs (including temperature). 
 Obtain blood samples for: 
o Haematology and biochemistry 
o Single plasma sample for PK analysis of REN001, time to be recorded 
o FSH t
 who were not confirmed as post-
menopausal in the STRIDE study or at the STRIDE AHEAD Screening visit, 
and/or if menopausal symptoms develop. 
 Urinalysis and drugs of abuse testing. 
 Urine pregnancy testing (WOCBP). 
 PRO Questionnaires: 
o MFIS 
o PGIS  muscle symptoms and fatigue symptoms 


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o PROMIS Short Form  13a (FACIT Fatigue) 
o SF-36 
o WPAI:SHP 
 Provide home pregnancy testing kits for WOCBP for use after 2 months of dosing. 
Study centre will telephone the subject and remind them of the need to complete the 
test and confirm the test has been carried out. The date of test and result will be 
recorded in the eCRF. 
 Provide a urine collection cup and instructions for collecting a second morning void 
for next study visit. This is provided in case the subject has their second morning void 
before attending the study centre at their next study visit.  
 Subject should be instructed on study drug dosing requirements and reminded of the 
study restrictions. Subject should be reminded that the study drug should be taken at 
the study centre for the Month 3 visit after a pre-dose blood sample for PK is taken. 
6.3 
Month 3 (Day 84) 
Site staff will provide subjects with meals and snacks at appropriate times during the visit. 
Where possible and applicable the 12MWT should be performed at the same time of day as in 
the Week 24 Visit of the STRIDE study. A sample Schedule for Study Visit is in Appendix 5. 
The urine and blood samples should be carried out prior to dosing: 
 Obtain urine sample for: 
o Urinalysis (and pregnancy testing if WOCBP) 
 Obtain blood samples for: 
o Pre-dose plasma sample for PK analysis of REN001 
o Haematology and biochemistry 
o FSH test for females (if menopausal symptoms develop) 
Following these tests, the study drug should be administered with food under the supervision 
of clinical staff and the time of dosing recorded. 
 Plasma samples for PK analysis of REN001 will be taken at 1, 2, and 4 hours post 
dose. Other assessments below should be scheduled in between blood samples. Exact 
time of collection of all blood samples to be recorded.  
Other assessment to be performed at this visit: 
 Review concomitant medications, non-drug treatments and study drug compliance 
including capsule counts of remaining study drug. 
 Review of AEs. 
 Brief physical examination (including weight). 
 ECG. 
 Vital signs (including temperature). 
 PRO Questionnaires (to be completed prior to exercise testing) 
o MFIS 
o PGIS  muscle symptoms and fatigue symptoms 
o PROMIS Short Form  13a (FACIT Fatigue) 
o SF-36 
o WPAI:SHP 


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 12MWT (to be completed at the same time of day as previously). 
 Eye examination (may be completed ± 14 days of the visit if required). 
 Provide home pregnancy testing kits for WOCBP for use at Months 4 and 5 of dosing. 
Study centre will telephone the subject and remind them of the need to complete the 
test and confirm the test has been carried out. The date of test and result will be 
recorded in the eCRF. 
 Provide a urine collection cup and instructions for collecting a second morning void 
for next study visit. This is provided in case the subject has their second morning void 
before attending the study centre at their next study visit.  
 Dispense study drug and remind subject of study drug dosing requirements and study 
restrictions. 
6.4 
Month 6 (Day 168) 
Site staff will provide subject with meals and snacks at appropriate times during the visit. The 
following assessments will be carried out: 
 The subject should take their study drug with food at their usual dosing time. The 
actual time of dosing should be recorded by the patient on a dosing card. 
 Obtain second morning void urine sample for: 
o Bone marker  NTX 
o Urinalysis and drugs of abuse testing 
o Urine pregnancy testing (WOCBP)  
 Obtain blood samples for: 
o Haematology and biochemistry 
o Bone and calcium metabolism markers 
o 2 plasma samples for PK analysis of REN001, sample 1 to be taken on arrival 
at site, sample 2 to be taken at end of visit. Time of samples to be recorded. 
o FSH test for females (if menopausal symptoms develop) 
 Review concomitant medications, non-drug treatments and study drug compliance 
including capsule counts of remaining study drug.  
 Review of AEs. 
 Physician completion of subject s PMM phenotypic description. 
 Brief physical examination (including weight). 
 ECG. 
 Vital signs (including temperature). 
 PRO Questionnaires (to be completed prior to exercise testing) 
o MFIS 
o PGIS  muscle symptoms and fatigue symptoms 
o PROMIS Short Form  13a (FACIT Fatigue) 
o SF-36 
o WPAI:SHP 
 12MWT (to be completed at same time of day as previously). 
 Eye examination (may be completed ± 14 days of the visit if required). 
 Provide home pregnancy testing kits for WOCBP to enable monthly pregnancy 


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testing. Study centre will telephone the subject and remind them of the need to 
complete the test and confirm the test has been carried out each month. The date of 
test and result will be recorded in the eCRF. 
 Provide a urine collection cup and instructions for collecting a second morning void 
for next study visit. This is provided in case the subject has their second morning void 
before attending the study centre at their Month 12 study visit.  
 Dispense study drug and remind subject of study drug dosing requirements and study 
restrictions. 
6.5 
Month 9 (Day 252)  German sites only 
Site staff will provide subject with meals and snacks at appropriate times during the visit. The 
following assessments will be carried out: 
 The subject should take their study drug with food at their usual dosing time. The 
actual time of dosing should be recorded by the patient on a dosing card.  
 Urinalysis and drugs of abuse testing 
 Urine pregnancy testing (WOCBP)  
 Obtain blood samples for:  
o Haematology and biochemistry 
o FSH test for females (if menopausal symptoms develop) 
 Review concomitant medications, non-drug treatments and study drug compliance 
including capsule counts of remaining study drug.  
 Review of AEs. 
 Brief physical examination (including weight). 
 ECG. 
 Vital signs (including temperature). 
 Provide home pregnancy testing kits for WOCBP to enable monthly pregnancy 
testing. Study centre will telephone the subject and remind them of the need to 
complete the test and confirm the test has been carried out each month. The date of 
test and result will be recorded in the eCRF. 
6.6 
Month 12 (Day 336) 
Site staff will provide subjects with meals and snacks at appropriate times during the visit. 
The following assessments will be carried out:  
 The subject should take their study drug with food at their usual dosing time. The time 
of dosing should be recorded by the patient on a dosing card. 
 Obtain second morning void urine sample for: 
o Bone marker  NTX 
o Urinalysis and drugs of abuse testing  
o Urine pregnancy testing (WOCBP) 
 Obtain blood samples for: 
o Haematology and biochemistry (including HbA1c) 
o Bone and calcium metabolism markers 
o 2 plasma samples for PK analysis of REN001, sample 1 to be taken on arrival 
at site, sample 2 to be taken at end of visit. Time of sample collection to be 


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recorded.  
o FSH test for females (if menopausal symptoms develop) 
 Review concomitant medications, non-drug treatments and study drug compliance 
including capsule counts of remaining study drug. 
 Review of AEs. 
 Physician completion of subject s PMM phenotypic description. 
 Brief physical examination (including weight). 
 ECG. 
 Vital signs (including temperature). 
 PRO Questionnaires (to be completed prior to exercise testing) 
o MFIS 
o PGIS  muscle symptoms and fatigue symptoms 
o PROMIS Short Form  13a (FACIT Fatigue) 
o SF-36 
o WPAI:SHP 
o PGIC muscle and fatigue symptoms 
o BPI 
 12MWT (to be completed at same time of day as previously). 
 Eye examination (may be completed ± 14 days of the visit if required). 
 Provide home pregnancy testing kits for WOCBP to enable monthly pregnancy 
testing. Study centre will telephone the subject and remind them of the need to 
complete the test and confirm the test has been carried out each month. The date of 
test and result will be recorded in the eCRF. 
 Provide a urine collection cup and instructions for collecting a second morning void 
for next study visit. This is provided in case the subject has their second morning void 
before attending the study centre at their Month 18 study visit. 
 Dispense study drug and remind subject of study drug dosing requirements and study 
restrictions. 
6.7 
Month 15 (Day 420)  Germany only 
Site staff will provide subject with meals and snacks at appropriate times during the visit. The 
following assessments will be carried out: 
 The subject should take their study drug with food at their usual dosing time. The 
actual time of dosing should be recorded by the patient on a dosing card. 
 Urinalysis and drugs of abuse testing 
 Urine pregnancy testing (WOCBP)  
 Blood samples for: 
o  Haematology and biochemistry 
o FSH test for females (if menopausal symptoms develop) 
 Review concomitant medications, non-drug treatments and study drug compliance 
including capsule counts of remaining study drug.  
 Review of AEs. 


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 Brief physical examination (including weight). 
 ECG. 
 Vital signs (including temperature). 
 Provide home pregnancy testing kits for WOCBP to enable monthly pregnancy 
testing. Study centre will telephone the subject and remind them of the need to 
complete the test and confirm the test has been carried out each month. The date of 
test and result will be recorded in the eCRF. 
 
6.8 
Month 18 (Day 504) 
Site staff will need to provide subject with meals and snacks at appropriate times during the 
visit. The following assessments will be carried out: 
 The subject should take their study drug with food at their usual dosing time. The time 
of dosing should be recorded by the patient on a dosing card. 
 Obtain second morning void urine sample for: 
o Bone marker  NTX 
o Urinalysis and drugs of abuse testing 
o Pregnancy testing (WOCBP) 
 Obtain blood samples for: 
o Haematology and biochemistry 
o Additional bone and calcium metabolism markers 
o 2 plasma samples for PK analysis of REN001, sample 1 to be taken on arrival 
at site, sample 2 to be taken at end of visit. Time of samples to be recorded. 
o FSH test for females (if menopausal symptoms develop) 
 Review concomitant medications, non-drug treatments and study drug compliance 
including capsule counts of remaining study drug.  
 Review of AEs. 
 Brief physical examination (including weight). 
 ECG. 
 Vital signs (including temperature). 
 PRO Questionnaires (to be completed prior to exercise testing): 
o MFIS 
o PGIS  muscle symptoms and fatigue symptoms 
o PROMIS Short Form  13a (FACIT Fatigue) 
o SF-36 
o WPAI:SHP 
 12MWT (to be completed at same time of day as previously). 
 Eye examination (may be completed ± 14 days of the visit if required). 
 Provide home pregnancy testing kits for WOCBP to enable monthly pregnancy 
testing. Study centre will telephone the subject and remind them of the need to 
complete the test and confirm the test has been carried out each month. The date of 
test and result will be recorded in the eCRF. 


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 Provide a urine collection cup and instructions for collecting a second morning void 
for next study visit. This is provided in case the subject has their second morning void 
before attending the study centre at their next study visit. 
 Dispense study drug and remind subject of study drug dosing requirements and study 
restrictions. 
6.9 
Month 24 (Day 672) or Early Withdrawal Visit (Prior to Month 24) 
Site staff will provide subjects with meals and snacks at appropriate times during the visit.  
If the subject discontinues study treatment prior to Month 24 they will be withdrawn from the 
study.  If they discontinue study treatment between visits, they will be required to attend an 
early withdrawal visit as soon as possible after their last dose of REN001.  If their withdrawal 
is prior to the Month 24 visit, the below assessments should be carried out:   
The following assessments will be carried out: 
 The subject should take their study drug with food at their usual dosing time. The 
actual time of dosing should be recorded by the patient on a dosing card. 
 Obtain second morning void urine sample for: 
o Bone marker  NTX 
o Urinalysis and drugs of abuse testing 
o  Pregnancy testing (WOCBP) 
 Obtain blood samples for: 
o Haematology and biochemistry (including HbA1c) 
o Bone and calcium metabolism markers 
o 2 plasma samples for PK analysis of REN001, sample 1 to be taken on arrival 
at site, sample 2 to be taken at end of visit. Time of samples to be recorded. 
o FSH test for females (if menopausal symptoms develop) 
 Review concomitant medications, non-drug treatments and study drug compliance 
including capsule counts of remaining study drug. 
 Review of AEs.  
 Physician completion of subject s PMM phenotypic description. 
 Brief physical examination (including weight). 
 ECG. 
 Vital signs (including temperature). 
 PRO Questionnaires (to be completed prior to exercise testing) 
o MFIS 
o PGIS  muscle symptoms and fatigue symptoms 
o PROMIS Short Form  13a (FACIT Fatigue) 
o SF-36 
o WPAI:SHP 
o PGIC muscle and fatigue symptoms 
o BPI 
 12MWT (to be completed at same time of day as previous visits). 
 Eye examination (may be completed ± 14 days of the visit if required). 


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 Optional DXA Scan 
o Eligible subjects must have had a DXA scan at baseline, either as part of the 
STRIDE study or at entry into this long-term safety study. If subject is an 
Early Withdrawal, a scan will only be performed if there has been at least 20 
weeks of dosing following the baseline scan. All female subjects not 
confirmed as post-menopausal should have an FSH test performed. All 
WOCBP must have a negative pregnancy test prior to the scan. Where 
possible, the same scanner should be used at this visit as at the baseline visit. 
Details can be found in the DXA Manual. 
The following items must be completed for subjects continuing dosing beyond Month 24: 
 Provide home pregnancy testing kits for WOCBP to enable monthly pregnancy 
testing. Study centre will telephone the subject and remind them of the need to 
complete the test and confirm the test has been carried out each month. The date of 
test and result will be recorded in the eCRF. 
 Provide a urine collection cup and instructions for collecting a second morning void 
for next study visit. This is provided in case the subject has their second morning void 
before attending the study centre at their Month 30 study visit. 
 Dispense study drug and remind subject of study drug dosing requirements and study 
restrictions. 
6.10 Month 30 (Day 840) 
Site staff will need to provide subject with meals and snacks at appropriate times during the 
visit. The following assessments will be carried out: 
 The subject should take their study drug with food at their usual dosing time. The time 
of dosing should be recorded by the patient on a dosing card. 
 Obtain second morning void urine sample for: 
o Bone marker  NTX 
o Urinalysis and drugs of abuse testing 
o Pregnancy testing (WOCBP) 
 Obtain blood samples for: 
o Haematology and biochemistry 
o Additional bone and calcium metabolism markers 
o FSH test for females (if menopausal symptoms develop) 
 Review concomitant medications, non-drug treatments and study drug compliance 
including capsule counts of remaining study drug.  
 Review of AEs. 
 Brief physical examination (including weight). 
 ECG. 
 Vital signs (including temperature). 
 PRO Questionnaire: 
PGIS  muscle symptoms and fatigue symptoms 
 Eye examination (may be completed ± 14 days of the visit if required). 
 Provide home pregnancy testing kits for WOCBP to enable monthly pregnancy 
testing. Study centre will telephone the subject and remind them of the need to 


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complete the test and confirm the test has been carried out each month. The date of 
test and result will be recorded in the eCRF. 
 Provide a urine collection cup and instructions for collecting a second morning void 
for next study visit. This is provided in case the subject has their second morning void 
before attending the study centre at their Month 36 study visit. 
 Dispense study drug and remind subject of study drug dosing requirements and study 
restrictions. 
6.11 Month 36 (Day 1008) 
Site staff will need to provide subject with meals and snacks at appropriate times during the 
visit. The following assessments will be carried out: 
 The subject should take their study drug with food at their usual dosing time. The time 
of dosing should be recorded by the patient on a dosing card. 
 Obtain second morning void urine sample for: 
o Bone marker  NTX 
o Urinalysis and drugs of abuse 
o Pregnancy testing (WOCBP) 
 Obtain blood samples for: 
o Haematology and biochemistry 
o Additional bone and calcium metabolism markers 
o FSH test for females (if menopausal symptoms develop) 
 Review concomitant medications, non-drug treatments and study drug compliance 
including capsule counts of remaining study drug.  
 Review of AEs. 
 Brief physical examination (including weight). 
 ECG. 
 Vital signs (including temperature). 
 PRO Questionnaire: 
PGIS  muscle symptoms and fatigue symptoms 
o PGIC  muscle symptoms and fatigue symptoms 
 Eye examination (may be completed ± 14 days of the visit if required). 
 Provide home pregnancy testing kits for WOCBP to enable monthly pregnancy 
testing. Study centre will telephone the subject and remind them of the need to 
complete the test and confirm the test has been carried out each month. The date of 
test and result will be recorded in the eCRF. 
 Provide a urine collection cup and instructions for collecting a second morning void 
for next study visit. This is provided in case the subject has their second morning void 
before attending the study centre at their Month 42 study visit. 
 Dispense study drug and remind subject of study drug dosing requirements and study 
restrictions. 
6.12 Month 42 (Day 1176) 
Site staff will need to provide subject with meals and snacks at appropriate times during the 
visit. The following assessments will be carried out: 


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 The subject should take their study drug with food at their usual dosing time. The time 
of dosing should be recorded by the patient on a dosing card. 
 Obtain second morning void urine sample for: 
o Bone marker  NTX 
o Urinalysis and drugs of abuse 
o Pregnancy testing (WOCBP) 
 Obtain blood samples for: 
o Haematology and biochemistry 
o Additional bone and calcium metabolism markers 
o FSH test for females (if menopausal symptoms develop) 
 Review concomitant medications, non-drug treatments and study drug compliance 
including capsule counts of remaining study drug.  
 Review of AEs. 
 Brief physical examination (including weight). 
 ECG. 
 Vital signs (including temperature). 
 PRO Questionnaire: 
PGIS  muscle symptoms and fatigue symptoms 
 Eye examination (may be completed ± 14 days of the visit if required). 
 Provide home pregnancy testing kits for WOCBP to enable monthly pregnancy 
testing. Study centre will telephone the subject and remind them of the need to 
complete the test and confirm the test has been carried out each month. The date of 
test and result will be recorded in the eCRF. 
 Provide a urine collection cup and instructions for collecting a second morning void 
for next study visit. This is provided in case the subject has their second morning void 
before attending the study centre at their Month 48 study visit. 
 Dispense study drug and remind subject of study drug dosing requirements and study 
restrictions. 
 
6.13 Month 48 (Day 1344) or Early Withdrawal Visit (Post Month 24) 
Site staff will need to provide subject with meals and snacks at appropriate times during the 
visit.  
If the subject discontinues study treatment prior to Month 48 they will be withdrawn from the 
study.  If they discontinue study treatment between visits, they will be required to attend an 
early withdrawal visit as soon as possible after their last dose of REN001.  If their withdrawal 
is after the Month 24 visit, the below assessments should be carried out.  The following 
assessments will be carried out: 
 The subject should take their study drug with food at their usual dosing time. The time 
of dosing should be recorded by the patient on a dosing card. 
 Obtain second morning void urine sample for: 
o Bone marker  NTX 
o Urinalysis and drugs of abuse 


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o Pregnancy testing (WOCBP) 
 Obtain blood samples for: 
o Haematology and biochemistry 
o Additional bone and calcium metabolism markers 
o FSH test for females (if menopausal symptoms develop) 
 Review concomitant medications, non-drug treatments and study drug compliance 
including capsule counts of remaining study drug.  
 Review of AEs. 
 Brief physical examination (including weight). 
 ECG. 
 Vital signs (including temperature). 
 PRO Questionnaires: 
o PGIS  muscle symptoms and fatigue symptoms 
o PGIC  muscle symptoms and fatigue symptoms 
 Eye examination (may be completed ± 14 days of the visit if required). 
 Optional DXA Scan 
o Eligible subjects must have had a DXA scan at baseline and/or at the Month 
24 visit. If subject is an Early Withdrawal after M24, a scan will only be 
performed if there has been at least 20 weeks of dosing following the M24 
scan. All female subjects not confirmed as post-menopausal should have an 
FSH test performed. All WOCBP must have a negative pregnancy test prior to 
the scan. Where possible, the same scanner should be used at this visit as at 
the baseline and Month 24 visits. Details can be found in the DXA Manual. 
 Provide home pregnancy testing kit for WOCBP for final pregnancy test prior to the 
follow-up telephone contact at approximately 30 days after the last dose of study 
drug. 
6.14 Follow-up Telephone Contact 
If subject has completed 48 Months treatment or is an Early Withdrawal from the study, there 
will be a FU telephone contact from the study centre to the subject approximately 30 days 
after their last dose of study drug. If the Early Withdrawal visit is 21 or more days after the 
last dose of study drug, then the FU telephone contact is not needed.  The following activities 
will be completed: 
 Review of any AEs that were ongoing at the final study centre visit or Early 
Withdrawal visit. 
 Document result of pregnancy testing (WOCBP only). 
Any clinically significant abnormalities noted at the final treatment visit should be followed 
up until resolved or stabilized. 
The follow up phone call is not required if mavodelpar has been approved within the country 
and the subject switches to commercially available medication. 
6.15 Unscheduled Visits 
Unscheduled visits may also be arranged at any time at the discretion of the investigator as 
clinically indicated.  These visits should be recorded on the unscheduled study visit pages in 
the electronic Case Report Form (eCRF).


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Table 2: 
Screening and Baseline Visits 
Assessments 
Option 1 
Enrolment at 
STRIDE Week 241 
Option 2 
Enrolment at 
STRIDE FU2 
Option 3 
mtDNA-PMM subjects from 
REN001-101  or after exiting 
STRIDE3 
Option 4 
 nDNA-PMM subjects3  
Baseline 
Baseline 
Screening 
Baseline 
Screening 
Baseline 
Informed Consent 
X 
X 
X 
 
X 
 
Demography 
STRIDE Baseline 
STRIDE Baseline 
X 
 
X 
 
Medical History 
STRIDE Baseline 
STRIDE Baseline 
X 
 
X 
 
Physician completion of PMM Phenotype 
STRIDE Week 24 
X 
 
X 
 
X 
Physical Exam (inc weight and height)4  
STRIDE Week 24 
X 
X 
X 
X 
X 
ECG 
STRIDE Week 24 
X 
X 
X 
X 
X 
Vital signs 
STRIDE Week 24 
STRIDE FU  
X 
X 
X 
X 
Safety labs 
STRIDE Week 24 
X 
X 
X 
X 
X 
HbA1c5 
STRIDE Week 24 
X 
X 
X 
X 
X 
HEP B/C/HIV6 
 
 
X 
 
X 
 
Blood for bone and calcium markers 
STRIDE Week 24 
X 
 
X 
 
X 
PK blood sample for REN001 
STRIDE Week 247 
X 
 
X 
 
X 
Urinalysis, inc pregnancy testing8  
STRIDE Week 24 
STRIDE FU 
X 
 
X 
Serum pregnancy testing 
 
 
X 
 
X 
 
Urine drugs of abuse9 
STRIDE Week 24 
X 
X 
X 
X 
X 
Serum FSH 
 
X10 
X 
 
X 
 
Urine NTX bone markers 
STRIDE Week 24 
X 
 
X 
 
X 
PROs 
STRIDE Week 24 
X 
 
X 
 
X 
12MWT 
STRIDE Week 24 
X 
 
X 
X 
X11 
                                                 
1 Most of baseline data will be STRIDE Week 24 data. Additional assessments to be carried out on the same day (Section 6.1.1). 
2 Baseline tests to be carried out at the STRIDE FU visit.  
3 Separate screening and baseline visits required (Section 6.1.3).  nDNA subjects will not be recruited in France. 
4 Height only collected at screening/baseline visits 
5 Subjects enrolling in Germany require a HbA1c to be performed 8 weeks prior to baseline. For subjects enrolling at STRIDE Week 24 or FU these samples could coincide with STRIDE Week 
18 or 24 visits respectively.  Informed consent must be obtained prior to these samples being taken. 
6 Subjects enrolling in Germany require a Hepatitis B/C/HIV to be performed 8 weeks prior to baseline. For subjects enrolling at STRIDE Week 24 or FU these samples could coincide with 
STRIDE Week 18 or 24 visits respectively.  Informed consent must be obtained prior to these samples being taken.  
7 Data will only be reported in the REN001-201 CSR 
8 Urine pregnancy testing will be carried out at all visits, excluding the option 3 & option 4 screening 
pregnancy test at the STRIDE Week 24 visit in lieu of an FSH test which will be conducted at Month 1, if required.   
9 
cretion for alcohol/drug dependency.  Use for medical reason is acceptable with prescription evidence. 
10 FSH for females aged 45 years not confirmed as post-menopausal in the STRIDE study (FSH not conducted at STRIDE Week 24 visit, see footnote 5). 
11 There must be a minimum of 4 weeks between the screening and baseline 12MWT. 


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Eye examination 
STRIDE Week 24 
STRIDE Week 24 
X1 
 
X1 
 
Wrist radiograph2 
 
 
 
 
X 
 
DXA Scan3 
STRIDE Week 24 
STRIDE Week 24 
STRIDE Week 24 
 
X 
 
Concomitant Medication review 
STRIDE Week 24 
STRIDE FU 
X 
X 
X 
X 
AE Review4 
STRIDE Week 24 
STRIDE FU 
X 
X 
 
X 
Dispense Study Drug 
X 
X 
 
X 
 
X 
First dose of study drug5 
X 
X 
 
X 
 
X 
                                                 
1 Eye examination can be done at any time between the screening and baseline visit for scheduling reasons. 
2 Subjects <25 years old. 
3 Optional. Only conducted at sites which participated in the DXA sub-study. If a DXA scan was performed at STRIDE Week 24 it will be regarded as the baseline. Sites with approvals in place 
should review all subjects against the additional protocol criteria (Section 4.3) and perform DXA if subject eligible and not performed in STRIDE. 
4 Review of pre-treatment events for subjects enrolling at option 3 and option 4: after exiting STRIDE or REN001-101, and nDNA-PMM subjects. 
5 Subject enrolling at STRIDE Week 24 should take the first dose the day after the Baseline visit, this will be confirmed with a telephone call from site the next day. Subject enrolling at STRIDE 
FU or after exiting STRIDE or Study REN001-101, and nDNA-PMM subjects should take the first dose at the study centre baseline visit. 
 


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Table 3: 
Schedule of Activities 
Assessments/Time* 
Screening
/ 
Baseline 
Visits1 
 
Month 1 
(Day 
28) 
Month 3 
(Day 84) 
Month 6 
(Day 168) 
Month 9 
(Day 252) 
Germany 
only 
Month 12 
(Day 336) 
Month 15 
(Day 420) 
Germany 
only 
Month 18 
(Day 504) 
Month 24 
(Day 672) or 
pre M24 
Early 
Withdrawal2 
Month 30 (Day 
840), M36 (Day 
1008), M42 
(Day 1176) 
Month 48 
(Day 1344) or 
post M24 
Early 
Withdrawal2 
Window for visit 
 
±3 days 
±7 days 
±7 days 
±21days 
±21days 
±21days 
±21 days 
±21 days 
±21 days 
±21 days 
Physician-PMM phenotypic description 
 
 
 
X 
 
X 
 
 
X 
X 
X 
Physical exam3 (inc. weight) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety bloods haematology/biochemistry 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c 
 
 
 
 
 
X 
 
 
X 
X 
X 
Blood for bone and calcium markers 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
PK blood sample for REN0014 
 
X 
X 
X 
 
X 
 
X 
X 
 
 
Urinalysis inc. pregnancy testing5  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine drugs of abuse 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum FSH6 
 
X7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine NTX bone markers 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
PROs8 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
12MWT 
 
 
X 
X 
 
X 
 
X 
X 
 
 
Eye examination 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
DXA Scan9 
 
 
 
 
 
 
 
 
X 
 
X 
Dispense Study Drug 
 
 
X 
X 
 
X 
 
X 
X 
X 
 
Concomitant medication review 
X------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
AE review 
X------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
Dosing of study drug 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
                                                 
1 See Table 2. It is expected that most subjects will enrol at the STRIDE Week 24 visit with the baseline visit for this study coinciding with the STRIDE Week 24 visit. With additional 
assessments subjects can also enrol at the STRIDE FU visit, or at any time after exiting Study REN001-101 or STRIDE, and nDNA-PMM subjects (Table 2 and Section 6.1). 
2 If subject discontinues study drug, they will be required to attend an early withdrawal visit as soon as possible after their last dose of study drug. A FU telephone call by the site approx. 30 (±7) 
days after last dose of study drug is required unless subject transfers to commercially available mavodelpar. Clinically significant abnormalities should be followed up until resolved/stabilized. 
3 Brief symptom directed physical exam can be done post baseline. 
4 PK samples (1 or 2) will be collected at all visits except Month 3 when 4 PK samples will be collected at 0,1,2,4 hrs post dose. 
5 Urine home pregnancy test kits will be supplied to WOCBP to enable monthly pregnancy testing. The study centre must contact the subject to confirm the pregnancy test results. The final test 
will be performed prior to the follow-up telephone contact approximately 30 days after the last dose of study drug. 
6 FSH test should be done during study if menopausal symptoms develop. 
7 
-menopausal. 
8 PROs include MFIS, PGIS and PGIC (muscle and fatigue symptoms), SF-36, PROMIS, WPAI:SHP, BPI.  BPI will be carried out at Month 12 and Month 24 only.  After the M24 visit, only 
the PGIS will be conducted at each visit.  The PGIC will be carried out at Month 12, 24, 36 and 48 only.   
9 Optional DXA scan will only be conducted at sites which participated in the DXA sub-study. Eligible subjects must have had a DXA scan at baseline. 
*Additional unscheduled visits may be arranged at any time at the discretion of the investigator as clinically required. 


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7 
PARAMETERS AND METHODS OF ASSESSMENT 
7.1 
Safety Parameters 
7.1.1 Adverse Events 
 
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 
drug; it does not necessarily have to have a causal relationship with study participation. 
Hence, occurrences between the screening and baseline visits for those mtDNA-PMM 
subjects enrolling from REN001-101 (UK only), or after exiting the STRIDE study, and 
nDNA-PMM subjects will be reported as PTEs. For those mtDNA-PMM subjects who 
transition to this study immediately from STRIDE, only ongoing adverse events at the time of 
enrolling in this study will be reported as a PTE (see Section 7.1.1.3). 
Adverse Event (AE): 
 An AE is any untoward medical event that occurs in a subject who has received study 
drug and does not necessarily have a causal relationship with study treatment. An AE 
can therefore be any unfavourable 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 TEAE 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 investigational medicinal product 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 an AE(s). 
 
Changes in laboratory values or ECG parameters are only considered to be AEs if they are 
judged to be clinically significant (i.e., if some action or intervention is required or if the 
Investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory re-test and/or continued monitoring of an abnormal value are not considered an 
intervention. In addition, repeated or additional non-invasive 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 an AE. 


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For STRIDE subjects the handling of pre-existing conditions (present at the time of signing of 
informed consent) will be dependent on their reporting in the STRIDE study and when the 
subject is enrolled into this study. 
If the subject is enrolled at the STRIDE Week 24 or FU visits the following will apply: 
 If the condition was reported as an ongoing AE at the end of the STRIDE study then 
the details concerning the AE will be transferred to a PTE eCRF page in this study 
and followed up during this study. 
 If the condition was reported as pre-existing in the STRIDE study (i.e., present at the 
time of signing STRIDE informed consent) then it would have been reported in 
medical history for STRIDE. Such information 
database and may be updated (e.g., end date provided). 
For mtDNA-PMM subjects enrolled from Study REN001-101 or after exiting STRIDE, and 
nDNA-PMM subjects, then the following will apply: 
 Baseline evaluations (e.g., laboratory tests, ECG, X-rays etc.) should NOT be 
recorded as PTEs. 
 Pre-existing conditions (present at the time of signing REN001-202 informed consent) 
are considered concurrent medical conditions and should be recorded as medical 
history. They should NOT be 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., 
 For example, 
o episodic conditions asthma or epilepsy: if episodes become more frequent, 
serious or severe in nature, the AE term recorded should capture the change in 
the condition from baseline (e.g., 
 
o degenerative concurrent conditions (e.g., cataracts): if the worsening of the 
condition occurs to a greater extent to that which would be expected the AE 
term recorded should captures the change in the condition from baseline (e.g., 
. 
 
If the subject experiences a worsening or complication of PTE or an AE after starting the 
study drug in this study, 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.
 
 
AESI 
ongoing monitoring and rapid communication by the Investigator to the Sponsor may be 
warranted. These events require further investigation to fully characterize. Based on this 
assessment, the Sponsor plans to include AESI as follows: 
 Changes in laboratory parameters of muscle injury associated with clinically 
significant AEs  
 Changes observed after baseline in formation or exacerbation of cataracts.  
 Occurrence of fractures after baseline 


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While an AESI may not meet the definition of an SAE, it should be reported in the same 
manner as SAE (See Section 7.1.1.9). This allows the event 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 suspected unexpected serious adverse reactions 
(SUSARs). 
 
Each AE will be assessed by the Investigator with regard to the following categories. 
7.1.1.6.1 Seriousness 
An SAE (or serious ADR or unexpected SAE) is defined as any untoward medical occurrence 
that at any dose: 
 Results in death. 
 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). 
 Requires inpatient hospitalisation or prolongs existing hospitalisation. 
 Results in persistent or significant disability or incapacity. 
 Is a congenital anomaly or birth defect. 
 Is an important medical event(s) that may not be immediately life-threatening or result 
in death or hospitalisation 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 hospitalisation, or 
the development of drug dependency or drug abuse. 
Note: Cases of potential drug-
 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 
 In this clinical study, the term SAE 
s. 
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 AE must be assessed by the Investigator using one of the following 
categories, and recorded in the eCRF: 
 Mild: An AE that does not interfere with usual activities. 
 Moderate: An AE that interferes with usual activities. 
 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. 
 
Relationship (causality) to study procedures should be determined for all AEs. 


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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. 
 
7.1.1.8.1 PTE and AE Collection Periods 
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 drug (Day 1) 
or until screen failure. 
Collection of AEs will commence from the time that the subject is first administered study 
drug (Day 1). Routine collection of AEs will continue until the follow-up telephone contact 
(if required, see Section 6.14) approximately 30 days after the last study drug dose. 
7.1.1.8.2 PTE and AE Reporting 
AEs at the end of the STRIDE study for subjects enrolled at the STRIDE Week 24 or FU 
visits that are still present at the time the subject signs the informed consent to participate in 
this study should be followed up in this study and recorded in the eCRF as PTEs. 
At each study visit, the Investigator will assess whether any subjective AEs have occurred. A 
 
Subjects may report AEs occurring at any other time during the study. 
All subjects experiencing AEs, whether considered associated with the use of the study drug 
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/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 drug. The 
following information will be documented for each event: 
 Event term 
 Start and stop date {and time} 
 Severity
 Investigator s opinion of the causal relationship between the event and administration 
of study drug 
o If no, provide alternative aetiology or explanation 
 
 opinion of the causal relationship to study procedure(s), including the 
details of the suspected procedure 
 Action concerning study drug 
 Outcome of event 
 Seriousness. 
 
All SAEs that occur during the study from the signing of the informed consent and up to 
approximately 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: 
 Sender of report (name, address of Investigator) 


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 Subject identification (screening number, initials, NOT subject name) 
 Protocol number 
 Description of SAE and reason why the event is categorized as serious 
 Causality assessment, if possible 
As far as possible all points on the SAE form should be covered in the initial report and the 
completed SAE form faxed to the PV 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 information to be sent to PV Team: 
Bionical Emas 
Spirella Building 
Bridge Road 
Letchworth Garden City, Hertfordshire 
SG6 4ET 
United Kingdom 
Email: Drug.safety@bionical-emas.com 
Fax: +44 (0) 1462 600 456 
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. 
 
Although pregnancy should not be considered as an SAE per se, any pregnancies occurring in 
a study subject between baseline and the end of the contraception requirements (14 weeks 
after last dose for males, 30 days (approximately 1 menstrual cycle) 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, the subject 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 of study drug should also 
 
All reported pregnancies will be followed up to final outcome, using the paper pregnancy 
follow-up 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 using the Pregnancy 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 was participating in a clinical study at the time she became pregnant 
and provide details of treatments the subject received. 
 
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 the Sponsor, or 
until there is a satisfactory explanation for the changes observed, or until the subject is lost to 
follow-up. 


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The Sponsor will be responsible for reporting all SUSARs and any other applicable SAEs to 
regulatory authorities, Investigators and IECs, as applicable, in accordance with national or 
regional regulations in the countries where the study is conducted. Day zero is the first day of 
SUSARs will be submitted 
within 7 days for fatal and life-threatening events and within 15 days for other SUSARs, 
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 the study drug or that would be sufficient to consider changes in 
the study drug 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 IECs 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 regulatory 
authority and IEC 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 REN001-202 Laboratory 
Manual. Sites will be provided with laboratory kits from the central laboratory. Details of 
parameters to be tested are listed in Table 4. Approximate volume of blood to be taken from 
each subject during the study is detailed in Table 5. Additional blood may be required for 
repeats of safety laboratory tests. 


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Table 4: 
Safety Laboratory Parameters 
Biochemistry 
Albumin, Alanine aminotransferase (ALT), Aldolase 
Alkaline phosphatase (AP), Aspartate aminotransferase (AST) 
Bilirubin (Total, direct and indirect) 
Calcium, Cholesterol (Total, LDL and HDL), C-reactive protein 
Creatinine, Creatine Kinase (CK)  
eGFR using CKD-EPI 
Gamma glutamyl transferase (GGT), Glucose (non-fasted) 
Lipase 
Magnesium 
Phosphate, Potassium, Protein (Total) 
Sodium 
Triglycerides,  
Urea, Uric acid 
Bone and Calcium Markers
Bone Specific alkaline phosphatase (BSAP) 
Parathyroid Hormone 
Vitamin D 
Endocrine and biomarker assays 
FSH (females 
not confirmed as post-menopausal, or if 
menopausal symptoms develop) 
Human chorionic gonadotropin (hCG) (WOCBP only) 
Troponin 1 
Haematology 
Basophils 
Eosinophils 
Haemoglobin 
Haematocrit (Packed cell 
volume) 
Large unstained cells 
Lymphocytes  
Mean corpuscular volume 
(MCV) 
Monocytes 
Neutrophils 
Platelet count 
Red cell count 
Reticulocytes 
White cell count 
HbA1c 
Serological Markers 
HBsAg, HBcAb, Anti-hepatitis C virus serology (by multi-antigen enzyme immunoassay (EIA), 
HIV 
Urinalysis 
-Blood, Glucose, Ketone, Protein, pH, Specific Gravity, Nitrite, Leukocytes, Bilirubin and 
Urobilinogen. Any significant abnormalities should be investigated via microscopy  
-Pregnancy Testing: hCG. Urine home pregnancy test kits will be supplied to allow monthly testing 
between study centre visits.  
-Testing for drugs of abuse: cocaine, cannabinoids, opiates, barbiturates, benzodiazepines, 
methadone, and amphetamines.  
Urine Biomarker assay 
-Urine N-terminal telopeptide (NTX).  
Laboratory tests 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 AE. The Investigator should assess 
the possible relationship to study drug as is the case for all other AEs. 
Table 5: 
Approximate Blood Volume Required for Study 
Test 
No. samples after 
baseline over 48 
months1 
Vol 
(ml) 
Total (ml) 
Haematology (including HbA1c)2 
10 
2 
20 
Biochemistry (including aldolase, troponin I, FSH and hCG as 
applicable)3 
10 
5 
50 
PK samples 
14 
4 
56 
                                                 
1Two additional samples needed for screening and baseline safety bloods if enrolment of mtDNA-PMM subjects is after 
participating in Study REN001-101 or after exiting STRIDE, and nDNA-PMM subjects (maximum of 14 ml extra taken 
over the screening and baseline period).   
2 There will be an additional 2 Haematology samples collected for German subjects (8 samples rather than 6), totaling 16ml 
3 There will be an additional 2 Biochemistry samples collected for German subjects (8 samples rather than 6), totaling 40ml 


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Test 
No. samples after 
baseline over 48 
months1 
Vol 
(ml) 
Total (ml) 
Bone and calcium markers (including BSAP, PTH, and 
vitamin D) 
9 
4 
36 
Total volume over study (mL) 
 
 
162 
7.1.3 Physical Examination (including weight and height) 
All physical examinations will be carried out by a qualified person. Subjects enrolling at 
STRIDE Week 24 will have had a symptom-directed physical examination in STRIDE. 
Subjects with mtDNA-PMM enrolling at STRIDE FU or from study REN001-101 (UK only), 
or after exiting STRIDE, and nDNA-PMM subjects will have a full physical examination at 
baseline, to include an assessment of head, neck, heart, lungs, abdomen, skin (including hair 
and nails), peripheral circulation, joints, general appearance, and a neurological examination. 
Post baseline, 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 AEs reported. 
Height collected at screening/baseline visits only. Subjects should have weight and height 
measured while wearing indoor clothing and with shoes off.   
7.1.4 Vital Signs 
Blood pressure (systolic and diastolic mmHg) will be measured after subject has been supine 
for at least 5 minutes. The subject
, where possible should be used throughout 
the study (and, where applicable, the same arm as used in the STRIDE study) and recorded to 
the nearest mmHg. Pulse (beats per minute) should be measured in the brachial/radial artery 
for at least 30 seconds. Body temperature will be recorded at all visits using a digital 
thermometer. Any results <35oC should be repeated to ensure correct placement of the 
thermometer. 
7.1.5 Electrocardiogram (ECG) Recording 
Single ECG measurements will be taken after the subject has rested for at least 10 minutes in 
a supine position using a 12-lead ECG machine.  
To ensure safety of the subjects, a qualified individual at the site will evaluate all ECGs.  If 
the QTcF is 500 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 (>500 msec), as a 
precautionary measure, the subject will discontinue treatment.  If a machine read QTcF value 
is prolonged, as defined above, repeat measurement may not be necessary, provided a 
qualified physician 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 EC abnormality. ECGs may be sent to an ECG vendor 
for centralised reading at a later date if deemed necessary. 
7.1.6 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 in both the STRIDE study and in this long-term safety study. If the 
lens is clear, that should be recorded. If a cataract is identified, the cataract should be 


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classified and graded against the Lens Opacity Classification System III, (Chylack et al, 
1993). 
In addition, best corrected distance visual acuity (including refraction) should be assessed.  
For scheduling reasons, the above assessments may be conducted ± 14 days of the visit 
window given for the eye assessments. 
In addition, any subject who experiences any visual symptoms during the study should have 
an additional eye examination as appropriate. 
Eye examinations will not be repeated if within 6 months of a previous test within STRIDE.   
7.1.7 Dual-energy X-ray absorptiometry (DXA) Scans 
Eligible subjects can choose to have a DXA scan (in those countries and sites where this is 
permitted), of the non-dominant hip and spine. If the non-dominant hip is unsuitable for 
scanning (e.g., fractures, hip replacement etc.) then the dominant hip can be used instead. 
The same DXA scanner should be used for all scans on an individual subject to aid 
interpretation of the scans. Subject weight and height are required for scan data, further 
details can be found in the DXA Scanning Manual. Scans which are not of sufficient quality, 
as determined by an independent assessor, will not be included in the database.  
DXA scans will not be repeated if within 6 months of a previous test within STRIDE.   
7.2 
Exercise Endurance 
7.2.1 12-Minute Walk Test (12MWT) 
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 centres and that the test is conducted at the same time of the day at each visit. Time of 
the test will be recorded in the eCRF. Further details are given in the REN001-202 Exercise 
Manual.  
Note: nDNA-PMM subjects must be able to walk at least 100m in the screening 12MWT and 
the limitations in walk test must be primarily due to the energy deficit and not due to ataxia or 
any other condition. There must be a minimum of 4 weeks between the screening 12MWT 
and the baseline 12MWT. 
7.3 
Quality of Life PROs 
7.3.1 Modified Fatigue Impact Scale (MFIS) 
The MFIS is a 21-item scale, the score reflects functional limitation due to fatigue 
experienced within the previous 7 days rather than a measure of the 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 


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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. See Appendix 2.
7.3.2
Patient Global Impression of Severity (PGIS): Muscle and Fatigue
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
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
7.3.3
Patient Global Impression of Change (PGIC): Muscle and Fatigue 
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 in this open label study, 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?
a.
Very much improved
b.
Moderately improved
c.
Minimally improved
d.
No change


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e.
Minimally worse
f.
Moderately worse
g.
Very much worse
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 in this open label study, 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
7.3.4
PROMIS Short Form 13a (FACIT-Fatigue)
The PROMIS® Short Form-13a Functional Assessment of Chronic Illness FACIT-Fatigue 
items assess a range of self-reported symptoms, from mild subjective feelings of tiredness to 
an overwhelming, debilitating, and sustain
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 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 3.
7.3.5
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.
7.4
Work Productivity PRO
The Work Productivity and Activity Impairment: Specific Health Problem (WPAI:SHP) 
questionnaire is a well validated instrument to measure impairments in work and activities 
due to a specific disease over the last 7 days. 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


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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. 
7.5 
Pain Severity and Interference PRO  
The Brief Pain Inventory (BPI) Short Form rapidly assesses the severity of pain and its 
impact on functioning. It is well used in research and clinical settings.  
Four severity items will be investigated by the responses to the worst, least and average pain 
in the 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 5.  
7.6 
PMM Phenotypic Description 
To enable comparative descriptions of the phenotypic state of each subject  disease, 3 
questions, taken from the Newcastle Mitochondrial Disease Adult Scale (NMDAS) will be 
completed by the physician. 
While the questions do not need to be read verbatim, the subject should be questioned to 
determine t
interpretation the same physician (where possible) should assess subjects on all occasions. 
Rate function over the preceding 4-week period, according to patient and/or caregiver 
interview only. The physician
into account. 
Question 1  Exercise Tolerance 
0 
Normal 
1 
Unlimited on flat  symptomatic on inclines or stairs. 
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 


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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. 
7.7 
PK Blood Samples 
Blood samples for determination of REN001 concentrations and possibly REN001 metabolite 
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 PK analysis, will be collected into 
a labelled tube. Sample handling instructions are provided in the REN001-202 Laboratory 
Manual. The plasma samples will be stored at the central laboratory prior to analysis. Plasma 
samples will be transferred to the bioanalytical laboratory on dry ice to maintain frozen 
conditions. Analysis of REN001 concentrations in plasma will be performed using a validated 
analytical method. 
Subjects will be supplied with a dose record card and will be requested to record the date and 
time of dosing for all study visit days. At each of the Baseline and Month 1 visits a single PK 
sample will be taken. At Months 6, 12, 18 and 24 two plasma samples will be taken for PK 
analysis of REN001, sample 1 to be taken on arrival at site, sample 2 to be taken at end of 
visit. At the Month 3 visit, PK samples will be taken pre and post study drug administration 
over a 4-hour period (pre-dose and at 1, 2 and 4 hours post dose (Section 6.3); The subject 
should take the study drug at the study centre with food when instructed to do so by the site 
staff, time of dose and time of all PK samples should be recorded.  


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8 
STATISTICAL METHODS 
A formal Statistical Analysis Plan (SAP) will be 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 Clinical Study Report. 
As this study is the open-label extension study to STRIDE, the two studies will be reported 
together.  In addition to data being presented from the start of REN001-202, the data will also  
be presented from the start of STRIDE and from the start of REN001 treatment for mtDNA-
PMM subjects. This will allow the assessment of long-term safety and efficacy from the start 
of dosing in STRIDE for those who received REN001 in STRIDE, as well as from the start of 
REN001 in this study.  
Presentations from the start of REN001-202 will include all mtDNA-PMM subjects who 
receive at least one dose of REN001 in this study.  The presentations will be split by the 
various options for entering the study, and by the STRIDE treatment group (REN001, 
Placebo) for those subjects who participated in STRIDE. nDNA-PMM subjects will also be 
summarized from the start of REN001-202. 
Presentations from the start of STRIDE will include all mtDNA-PMM subjects who receive 
at least one dose of study drug in the STRIDE study. These will be split by the STRIDE 
treatment groups (REN001, Placebo). For those subjects who are enrolled into this study after 
exiting STRIDE only the data collected in STRIDE will be summarized in these 
presentations. 
Presentations from the start of REN001 treatment will summarize the data emergent during 
treatment with REN001.   These summaries will include all mtDNA-PMM subjects who 
receive REN001 in STRIDE and/or this study.  
8.1 
   Study Subjects 
8.1.1 Disposition of Subjects 
The number and percentage of subjects entering and completing the study will be presented 
by treatment group, where treatment groups will be detailed in the SAP. 
Reasons for withdrawal will also be summarized.   
8.1.2 Protocol Deviations 
. Full details of the 
handling of protocol deviations can be found in the Protocol Deviation Management Plan. 
Deviations will be assessed regularly and finalized prior to database lock. 
8.1.3 Analysis Populations 
Separate safety and full analysis sets will be identified for the different approaches to 
summarizing the data (start of REN001-202, start of STRIDE or start of REN001 treatment). 
Precise details of the analysis sets are dependent on the approach and will be defined further 
in the SAP, but the general definitions are:    
Screened Set 
All subjects who sign the informed consent form. 
Safety Set/Full Analysis 
Set (FAS) 
All subjects who receive at least one dose of study 
treatment . 
PK Set 
All subjects in the FAS who have at least 1 evaluable 
post-


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Quantification (LOQ)) in this study. 
Scan Set 
All subjects in the FAS who have evaluable post-
baseline DXA endpoint data. 
    
Safety and efficacy analyses will be based upon the Safety and FAS analysis sets, 
respectively. 
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 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 
No formal statistical testing is planned. 
8.2.2 Determination of Sample Size 
Recruitment of mtDNA-PMM subjects will be limited to those who participated in the 
STRIDE study (applicable only for countries where this study is being conducted) or Study 
REN001-101. It is estimated that approximately 150 mtDNA-PMM subjects will be enrolled. 
Up to 50 nDNA-PMM subjects will be recruited. 
8.2.3 Data Summaries 
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). 
For both safety and efficacy analyses, data used as a baseline measurement will be dependent 
on the approach to summarizing the data: 
 For presentations from the start of REN001-202, baseline will be taken as the last 
measurement prior to dosing in this study. 
 For presentations from the start of STRIDE, baseline will be taken as the last 
measurement prior to dosing in STRIDE.  
 For presentations from the start of REN001 treatment, baseline will be taken as the 
last measurement prior to REN001 dosing.  This will be prior to REN001 dosing in 
this study for all subjects except those who receive REN001 in STRIDE, where it will 
be the last measurement prior to dosing in STRIDE. 
8.3 
Demographics, Baseline Characteristics and Concomitant Medications 
Demographics, baseline characteristics, and concomitant medication data will be 
summarized. Prior medications will also be summarized. 
The WHO Drug coding dictionary will be used for the concomitant medications. 
8.4 
Treatment Compliance 
Treatment compliance will be assessed through capsule counts and will be summarized.  


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8.5 
Efficacy Analyses 
Absolute values and, where applicable, changes from baseline in 12MWD and other 
secondary endpoints will be summarized and may be plotted over time.  
8.6 
Safety Analyses 
No imputation will be used for handling missing data, with the exception of conservative 
approaches taken for missing AE information (e.g., intensity). Details of such conventions 
will be documented in the SAP.  
Treatment-emergent adverse events will be summarized 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 AESIs will also be tabulated. 
Changes from baseline in laboratory parameters (including bone and calcium markers), vital 
signs, ECG and eye examinations data will be summarized by visit. 
The incidence of potentially clinically significant laboratory and ECG values (e.g., increase in 
 
 
Absolute values and changes from baseline for the DXA endpoints will be summarized. 
Summaries will be presented over all subjects and for the following demographic sub-groups: 
 Men 
 Pre-menopausal women 
 Post-menopausal women 
8.7 
PK Analysis 
REN001 plasma concentrations will be summarized over time. Individual and median 
concentration over time profile plots will be presented for concentrations measured from 
samples collected at the Month 3 visit. Both linear-linear and linear-log plots will be 
presented. 
PK parameters will be calculated from the Month 3 plasma concentrations for subjects who 
had their Month 3 visit completed under Protocol Version 1.0.  The parameters will include 
Ctrough, Cmax, Tmax and AUC . These parameters will be summarized. 
The data may be used for a population PK analysis which will be reported as a standalone 
report to the Clinical Study Report. 


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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 
subje
). 
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
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 study, a monitor will make site visits to review protocol compliance, compare 
eCRFs and individual subject
cords, 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
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 the CRO and the Sponsor of the necessary support at 
all times. 
9.4 
Data Processing 
The site will be supplied with a web browser address for an EDC system 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. Clinical Research Associates and Data Managers will review 
eCRFs 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 system. 


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Designated Investigator site staff are required to respond to queries and make any necessary 
changes to the data. Details of the data correction process will be specified in the Data 
Management Plan. After database lock, the Investigator will receive a CD-ROM of the 
 eCRFs (portable document format [PDF]) for archiving at the investigational site. 
An audit trail of all changes to the database, including the date, reason for the data change and 
who made the change, will be maintained within the clinical 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 ICFs, drug 
dispensing records, AE 
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 (e.g., retention period in Canada is 25 
years). 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 (GCP) 
The procedures set out in this study protocol are designed to ensure that the Sponsor and 
Investigator abide by the principles of ICH GCP and 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 the CRO by their subject number and/or birth year, 
not by name. Documents 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., 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 a copy retained by the Investigator as part of the study 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 


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approved by the appropriate IEC 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 and 
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 IEC and CA approval prior to 
implementation (if appropriate). All amendments will be distributed to all protocol recipients, 
with appropriate instructions. 
9.10 Premature Termination of the Study 
If the Investigator, the Sponsor, or the Medical Monitor becomes aware of conditions or 
events that suggest a possible hazard to subjects if the study continues, the study may be 
terminated after appropriate consultation between the relevant parties. The study may also be 
. 
Conditions that may warrant termination include, but are not limited to: 
 The discovery of an unexpected, significant, or unacceptable risk to the subjects 
enrolled in the study. 
 A decision on the part of the Sponsor to suspend or discontinue development of the 
drug. 
9.11 Liability and Insurance 
The Sponsor will obtain 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. 
The Sponsor will arrange for subjects participating in this study to be insured against 
financial loss due to personal injury caused by the pharmaceutical products 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 Principal 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 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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10 REFERENCES 
Chylack LT Jr., Wolfe JK, Singer DM, et al. The Lens Opacities Classification System III. 
The Longitudinal Study of Cataract Study Group. Arch Ophthalmol. 1993;111(6):831-836. 
Clinical Trials Facilitation Group. Recommendations related to contraception and pregnancy 
testing in clinical trials. CTFG; 2014. 
Clinical Trials Facilitation Group. Recommendations related to contraception and pregnancy 
testing in clinical trials version 1.1. CTFG; 2020. 
European Commission. Clinical trials - Directive 2001/20/EC; 2001, April 1. Retrieved from 
European Commission: https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
1/dir_2001_20/dir_2001_20_en.pdf. 
European Medicines Agency: EMA/CPMP/ICH/286/1995 - ICH guideline M3(R2) on non-
clinical safety studies for the conduct of human clinical trials and marketing authorisation for 
pharmaceuticals. 2009 December. Retrieved from the European Medicines Agency: 
https://www.ema.europa.eu/en/documents/scientific-guideline/ich-guideline-m3r2-non-
clinical-safety-studies-conduct-human-clinical-trials-marketing-authorisation_en.pdf. 
European Union. Commission Directive 2003/94/EC; 2003, October 8. Retrieved from 
Official Journal of the European Union: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
1/dir_2003_94/dir_2003_94_en.pdf. 
Feng Q, Wilke RA, Baye TM. Individualized risk for statin-induced myopathy: current 
knowledge, emerging challenges and potential solutions. Pharmacogenomics. 
2012;13(5):579-594.  
Gorman GS, Chinnery, PF, DiMauro, S, et al. Mitochondrial Diseases. Nat Rev Dis Primers. 
2016;2:1-22. Published 2016 Oct 20. 
Government of Canada. Guidance Document: Considerations for Inclusion of Women in 
Clinical Trials and Analysis of Sex Differences; 2013. Retrieved from the Government of 
Canada: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- 
products/applications-submissions/guidance-documents/clinical- trials/considerations-
inclusion-women-clinical-trials-analysis-data-sex- differences.html. Accessed 18 March 
2021. 
Lippi, G, Schena F, Salvagno GL, et al. Acute variation of biochemical markers of muscle 
damage following a 21-km, half marathon run. Scand J Clin & Lab Invest. 2008;68(7):667-
672. 
Mancuso M, McFarland R, Klopstock T, Hirano, M; consortium on Trial Readiness in 
Mitochondrial Myopathies. International 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. 
2017;27(12):1126-1137. 
Moghadam-Kia S, Oddis CV, Aggarwal R. Approach to asymptomatic creatine kinase 
elevation. Cleve Clin J Med. 2016;83(1):37-42. 
Nance JR, Mammen AL. Diagnostic evaluation of rhabdomyolysis. Muscle Nerve. 
2015;51(6):793-810.  


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Parikh S., Goldstein A, Koenig MK, et al. Diagnosis and management of mitochondrial 
disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 
2015;17(9):689-701.  
Pfeffer G, Chinnery PF. Diagnosis and treatment of mitochondrial myopathies. Ann Med. 
2013;45(1):4-16. 
Tarnopolsky MA. Metabolic Myopathies. Continuum (Minneap Minn). 2016;22(6, Muscle 
and Neuromuscular Junction Disorders):1829-1851. 
US Code of Federal Regulations 21CFR211.165 Retrieved from 
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=211.165 
US Code of Federal Regulations 21CFR312.6 Retrieved from 
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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Title: An Open-label, Multi-centre Study to Evaluate the Long-term Safety and Tolerability of 
REN001 in Subjects With Primary Mitochondrial Myopathy (PMM) 
NCTID: NCT05267574
Document Date: 24 November 2023


Statistical Analysis Plan
Confidential 
Page 1 of 77 
Sponsor Name: 
Reneo Pharma Ltd.
Protocol 
Numbers, Titles, 
Version and 
Dates*: 
REN001-202  
An open-label, multi-centre study to evaluate the long-term safety 
and tolerability of REN001 in subjects With Primary 
Mitochondrial Myopathy (PMM) 
Version/Dates: 
1.0 (4 August 2021) 
2.0 (21 December 2022) 
3.0 (7 August 2023) 
Feeder study: 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) 
Author(s): 
 
SAP Version/Date: Final v2.0 / 24 November 2023 
* Country specific protocol amendments are listed in Appendix 1 for both studies. 
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. 


Mavodelpar (REN001)
Reneo Pharma Ltd.
REN001-201 & REN001-202
Statistical Analysis Plan
Version 2.0
Confidential
Page 2 of 77
Signature Page
Protocol 
Numbers:  
REN001-201 & REN001-202
Protocol Titles:
REN001-202 - An open-label, multi-centre study to evaluate the 
long-term safety and tolerability of REN001 in subjects with Primary 
Mitochondrial Myopathy (PMM)
Feeder study 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:
Final v2.0
Version Date:
24 November 2023
I confirm that I have reviewed this document and agree with the content.
Author
__
_______________
__________________
ParamStat Limited
Date (MM-DD-YY)
Approvals
___
______________
__________________
 ParamStat Limited
Date (MM-DD-YY)
___
_______
__________________
 
Date (MM-DD-YY)
 Reneo Pharma Ltd.


Mavodelpar (REN001)
Reneo Pharma Ltd.
REN001-201 & REN001-202
Statistical Analysis Plan
Version 2.0
Confidential
Page 3 of 77
Signature Page (continued 1)
Protocol 
Numbers:  
REN001-201 & REN001-202
Protocol Titles:
REN001-202 - An open-label, multi-centre study to evaluate the 
long-term safety and tolerability of REN001 in subjects with Primary 
Mitochondrial Myopathy (PMM)
Feeder study 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:
Final v2.0
Version Date:
24 November 2023
I confirm that I have reviewed this document and agree with the content.
 Veramed
Date (MM-DD-YYYY)


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TABLE OF CONTENTS 
1. 
GLOSSARY OF ABBREVIATIONS .............................................................. 11 
2. 
INTRODUCTION ............................................................................................. 13 
2.1. 
Responsibilities ................................................................................................. 15 
3. 
STUDY OVERVIEW ....................................................................................... 16 
3.1. 
Study Objectives ............................................................................................... 16 
3.1.1. 
Primary Objective ............................................................................................. 16 
3.1.2. 
Secondary Objectives ........................................................................................ 16 
3.1.3. 
Pharmacokinetic Objective ............................................................................... 16 
3.1.4. 
Exploratory Objective ....................................................................................... 16 
3.2. 
Study Endpoints ................................................................................................ 16 
3.2.1. 
Primary Endpoints ............................................................................................. 16 
3.2.2. 
Secondary Endpoints ......................................................................................... 16 
3.2.3. 
Pharmacokinetic Endpoints ............................................................................... 17 
3.2.4. 
Exploratory Endpoints....................................................................................... 18 
3.3. 
Study Design ..................................................................................................... 18 
3.4. 
Schedule of Assessments .................................................................................. 20 
3.5. 
Determination of Sample Size........................................................................... 23 
3.6. 
Treatment Assignment and Blinding................................................................. 23 
3.7. 
Administration of Study Medication ................................................................. 23 
3.8. 
Approach to Combining REN001-201 Data ..................................................... 23 
4. 
EFFICACY ASSESSMENTS ........................................................................... 29 
4.1. 
12-Minute Walk Test (12MWT) ....................................................................... 29 
4.2. 
Patient-Reported Outcomes Measurement Information System (PROMIS) 
Short Form  Functional Assessment of Chronic Illness Therapy (FACIT) 
Fatigue 13a ........................................................................................................ 30 
4.3. 
Patient Global Impression of Change (PGIC)  Muscle Symptoms and Fatigue 
Symptoms ......................................................................................................... 30 
4.4. 
Patient Global Impression of Severity (PGIS) score - muscle symptoms and 
fatigue symptoms .............................................................................................. 31 


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4.5. 
Modified Fatigue Impact Scale (MFIS) ............................................................ 31 
4.6. 
36 Item Short Form Survey (SF-36) ................................................................. 32 
4.7. 
Brief Pain Inventory (BPI) Short Form ............................................................. 32 
4.8. 
Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problems (WPAI: SHP) .................................................................................... 33 
4.9. 
PMM Phenotypic Description ........................................................................... 34 
5. 
PHARMACOKINETIC ASSESSMENT .......................................................... 36 
6. 
SAFETY ASSESSMENTS ............................................................................... 37 
6.1. 
Adverse Events .................................................................................................. 37 
6.2. 
Laboratory Evaluations ..................................................................................... 37 
6.3. 
Dual-Energy X-Ray Absorptiometry (DXA) Scan ........................................... 38 
6.4. 
Vital Signs ......................................................................................................... 38 
6.5. 
ECGs ................................................................................................................. 39 
6.6. 
Physical Examination ........................................................................................ 39 
6.7. 
Eye Examinations .............................................................................................. 39 
6.8. 
COVID-19 Exposure and Vaccination Data ..................................................... 40 
7. 
ANALYSIS SETS AND PROTOCOL DEVIATIONS .................................... 41 
7.1. 
Screened Analysis Set ....................................................................................... 41 
7.2. 
Safety Analysis Sets .......................................................................................... 41 
7.3. 
Full Analysis Sets .............................................................................................. 41 
7.4. 
Pharmacokinetic Analysis Set ........................................................................... 42 
7.5. 
DXA Scan Analysis Set .................................................................................... 42 
7.6. 
Protocol Deviations ........................................................................................... 42 
8. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS .............................. 43 
8.1. 
Hypothesis Testing ............................................................................................ 43 
8.2. 
General Methods ............................................................................................... 43 
8.3. 
Missing Data ..................................................................................................... 45 
8.3.1. 
Efficacy Data ..................................................................................................... 45 
8.3.2. 
Pharmacokinetic Data ....................................................................................... 46 


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8.3.3. 
Safety Data ........................................................................................................ 46 
8.4. 
Visit Windows ................................................................................................... 46 
8.5. 
Subgroups .......................................................................................................... 48 
8.6. 
Baseline Definition ............................................................................................ 49 
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 ..................................................... 53 
9.4. 
Prior and Concomitant Medications .................................................................. 54 
9.5. 
Treatment Exposure .......................................................................................... 55 
10. 
ANALYSIS OF EFFICACY DATA ................................................................ 57 
10.1. 
12-Minute Walk Test (12MWT) ....................................................................... 57 
10.1.1. 
6-Minute Walk Distance (Derived from 12MWD) ........................................... 58 
10.2. 
Modified Fatigue Impact Scale (MFIS) ............................................................ 58 
10.3. 
Patient Global Impression of Change (PGIC)  Muscle Symptoms and Fatigue 
Symptoms ......................................................................................................... 59 
10.4. 
Patient Global Impression of Severity (PGIS) Score - Muscle Symptoms and 
Fatigue Symptoms ............................................................................................ 59 
10.5. 
Patient-Reported Outcomes Measurement Information System (PROMIS) 
Short Form  Functional Assessment of Chronic Illness Therapy (FACIT) 
Fatigue 13a ........................................................................................................ 59 
10.6. 
36 Item Short Form Survey (SF-36) ................................................................. 60 
10.7. 
Brief Pain Inventory .......................................................................................... 61 
10.8. 
Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problems (WPAI: SHP) .................................................................................... 61 
10.9. 
PMM Phenotypic Description ........................................................................... 61 
11. 
ANALYSIS OF PHARMACOKINETIC ENDPOINTS .................................. 63 
12. 
ANALYSIS OF SAFETY DATA ..................................................................... 64 
12.1. 
Adverse Events .................................................................................................. 64 


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12.2. 
Laboratory Evaluations ..................................................................................... 66 
12.3. 
Dual Energy X-Ray Absorptiometry (DXA) Scan ........................................... 68 
12.4. 
Vital Signs ......................................................................................................... 68 
12.5. 
ECG ................................................................................................................... 69 
12.6. 
Physical Examination ........................................................................................ 69 
12.7. 
Eye Examination ............................................................................................... 69 
12.8. 
COVID-19 Exposure and Vaccination Data ..................................................... 70 
13. 
INTERIM ANALYSES .................................................................................... 71 
14. 
CHANGES FROM PLANNED ANALYSES SPECIFIED IN THE 
PROTOCOL ..................................................................................................... 72 
15. 
REFERENCES .................................................................................................. 73 
APPENDIX 1  COUNTRY SPECIFIC PROTOCOL AMENDMENTS .......................... 74 
APPENDIX 2  REN001-201 SCHEDULE OF ASSESSMENTS ..................................... 75 
 


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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 
CPEO 
Chronic Progressive External Ophthalmoplegia 
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 
HDL 
High Density Lipoprotein 
KSS 
Kearns-Sayre Syndrome 
LDL 
Low Density Lipoprotein 
LLOQ 
Lower Limit of Quantification 
LOCS III 
Lens Opacity Classification System III 
MedDRA 
Medical Dictionary for Regulatory Activities 
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 


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Abbreviation 
Description 
MNGIE 
Mitochondrial Neurogastrointestinal Encephalopathy 
mtDNA 
mitochondrial DNA mutations 
NARP 
Neuropathy; Ataxia; and Retinitis Pigmentosa 
nDNA  
nuclear DNA mutations 
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 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PK 
Pharmacokinetic 
PSOC 
Patient Screening Oversight Committee 
PT 
Preferred Term 
QoL 
Quality of Life 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
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 
ULN 
Upper Limit of Normal 
ULOQ 
Upper Limit of Quantification 
WPAI:SHP 
Work Productivity and Activity Impairment Questionnaire: Specific 
Health Problems 
WHO 
World Health Organization 
12MWD 
12-minute Walk Distance 
12MWT 
12-minute Walk Test 


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2. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) details the statistical analyses for the REN001-202 
Open Label study. REN001-202 is an open label long term (48 months) safety study in 
subjects with Primary Mitochondrial Myopathy (PMM) due to mitochondrial DNA 
mutations (mtDNA-PMM) or nuclear DNA mutations (nDNA-PMM). Subjects with 
mtDNA-PMM will have previously completed treatment in Study REN001-201 or 
participated in Study REN001-101. Subjects with nDNA-PMM who enrol in this study 
will be mavodelpar (REN001) naïve. As this study is an open label extension study to 
REN001-201 the two studies will be reported together for the REN001-202 clinical study 
report (CSR). Therefore, this SAP also details the planned integrated analysis for these two 
studies from a safety perspective and, the planned analysis will provide long term safety 
data of up to 54 months exposure to mavodelpar for mtDNA subjects who receive 
mavodelpar in REN001-201.   
Figure 1 below shows the different pathways a subject can enter REN001-202 and the 5 
distinct reporting groups.  These groups provide the following assessments for mavodelpar 
100mg once daily: 
 Long-term safety data  
 Long-term tolerability  
 Bridging data (safety and efficacy) between nDNA-PMM subjects and mtDNA 
subjects 
While efficacy data will be presented, these should be interpreted in a descriptive manner 
since the design of this open label study, does not enable obtaining either reliable or fully 
interpretable confirmatory evidence of efficacy, including 'durability of effect'.  These 
limitations regarding long-term efficacy assessments are due to several key issues: the lack 
of a randomized comparator group, the lack of blinding when assessing effects on effort-
dependent outcome measures, and the potential impact of meaningfully informative 
missing data. 


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Figure 1
Subject Reporting Groups
The data will be presented in different ways:
from the start of REN001-202. These data presentations will focus on all 5 
reporting groups and only consider data collected in REN001-202. This will allow 
the assessment of mtDNA-PMM and nDNA-PMM over 48 months of mavodelpar
treatment. It will also provide an assessment of:
o
the continued safety of mavodelpar for subjects who received mavodelpar
for 6 months in REN001-201;
o
the introduction of mavodelpar for subjects who received placebo for 6 
months in REN001-201;
o
the re-introduction of mavodelpar for subjects who had a break in 
mavodelpar treatment in studies REN001-101 or REN001-201; and 
o
the introduction of mavodelpar for mavodelpar-naïve nDNA subjects.
from the start of REN001-201. These presentations will focus on reporting Groups 
1, 2, 3 and 4a and include data collected in both REN001-201 and REN001-202, 
except Group 4a, where only REN001-201 data will be included. This will continue 
to acknowledge the randomization to treatment groups at the start of the REN001-
201. It will provide an insight on the influence of a 6-month delay in beginning 
mavodelpar on subject safety and efficacy outcomes. Importantly, this will 
summarize the data for all subjects randomized and dosed in REN001-201.
from the start of REN001 treatment. These presentations will focus on reporting 
Groups 1, 2, 3 and 4 and include data collected in both REN001-201 and REN001-
202 depending on when mavodelpar is initiated. This provides an overall summary 
of emergent data following the initiation of mavodelpar treatment to mtDNA-PMM 


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subjects. This is particularly important with respect to safety data (e.g., overall 
incidence of AEs with mavodelpar treatment). 
For further details on the reporting groups refer to Section 8.2. 
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 protocol. 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. The SAP will be 
the point of reference for the analyses performed for the CSR. Any additional analyses not 
described in the final SAP or deviations from the final SAP will be documented in the 
CSR. 
The SAP has been developed based on REN001-202 Protocol Version 3.0 and the latest 
CRF available (Version 6.0, Date 24 April 2023) and REN001-201 Protocol Version 4.0. 
The subsequent country specific protocol amendments for REN001-202 (see Appendix 1) 
do not impact the SAP. 
An interim synoptic CSR will be prepared for this study which will be included in the 
regulatory submission package. The data cut will be the date of the last subject last visit in 
REN001-201 and the data will be extracted from the database after REN001-201 database 
has been locked. This CSR will include REN001-202 data up to the data cut date and best 
efforts will be made to clean data up to this data cut date. In addition, there will be a set of 
safety outputs generated after submission for the 120-day safety update which is required 
as part of the submission package. The final CSR will be generated after all subjects have 
completed participation in REN001-202 and the database is locked. 
2.1. 
RESPONSIBILITIES 
Veramed is the Biostatistics vendor for this study and is contracted to prepare the table, 
figures and listing (TFLs) shells based on this SAP. These shells will detail the format and 
layout of TFLs and will be presented in a separate document to the SAP. Veramed 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 
3.1.1. 
Primary Objective 
To evaluate long-term safety and tolerability of REN001 in subjects with PMM. 
3.1.2. 
Secondary Objectives 
To assess subjects with mtDNA-PMM who are receiving long-term treatment with 
REN001 in terms of PMM associated symptoms, pain severity and interference, exercise 
endurance, quality of life (QoL), patient global impression of change (PGIC) for muscle 
and fatigue, and work productivity. 
3.1.3. 
Pharmacokinetic Objective 
To further characterise the PK profile of REN001 in subjects with PMM receiving long-
term treatment. 
3.1.4. 
Exploratory Objective 
To evaluate the effect of long-term treatment with REN001 on bone health. 
To assess subjects with nDNA-PMM who are receiving long-term treatment with REN001 
in terms of PMM associated symptoms, pain severity and interference, exercise endurance, 
quality of life (QoL), patient global impression of change (PGIC) for muscle and fatigue, 
and work productivity. 
3.2. 
STUDY ENDPOINTS 
3.2.1. 
Primary Endpoints 
 Number and severity of Adverse Events (AE) 
 Number of AEs leading to study drug discontinuation 
 Number of serious adverse events (SAE) 
 Number of adverse events of special interest (AESI) 
 Number of AEs leading to death 
3.2.2. 
Secondary Endpoints 
 Absolute values, changes from Baseline and incidence of potentially clinically 
significant changes in:  


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 Laboratory safety tests 
 Electrocardiograms (ECGs) 
 Vital signs  
 Eye assessments 
For mtDNA-PMM subjects  
 Absolute values and changes from Baseline in:  
 Distance walked during the 12-minute walk test (12MWT)* 
 Modified Fatigue Impact Scale (MFIS) Total scores and sub-scale scores* 
 Patient Global Impression of Severity (PGIS) score for fatigue and muscle 
symptoms   
 Brief Pain Inventory (BPI) pain severity and pain interference scores*  
 Patient-Reported Outcomes Measurement Information System (PROMIS) 
Short Form  Functional Assessment of Chronic Illness Therapy (FACIT) 
Fatigue 13a scores* 
 36 Item Short Form Survey (SF-36) domain scores (7-day recall)* 
 Work Productivity and Activity Impairment questionnaire: Specific Health 
Problem (WPAI:SHP) scores* 
 First 6-minute walk distance and last 6-minute walk distance*  
 Phenotypic description questions 
 Patient Global Impression of Change (PGIC) scores (muscle and fatigue 
symptoms)  
*Collected up to Month 24 only. 
3.2.3. 
Pharmacokinetic Endpoints 
 Mavodelpar plasma concentrations collected pre-dose and 1-, 2-, 4-, 6-, 8-, 12-, and 
24-hours post-dose at Month 3 for subjects recruited under Protocol Version 1.0. 
For subjects recruited under Protocol Version 2.0 plasma concentrations are only 
collected pre-dose and 1-, 2-, and 4-hours post-dose. 
 PK parameters, including Ctrough, Cmax, Tmax and AUC , calculated from the Month 
3 mavodelpar plasma concentrations of subjects recruited under Protocol Version 
1.0. 


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3.2.4. 
Exploratory Endpoints 
For mtDNA and nDNA subjects: 
 Change from baseline to end of treatment in bone mineral density (BMD), as 
measured by Dual Energy X-ray Absorptiometry (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. 
For nDNA-PMM subjects  
 Absolute values and changes from Baseline in:  
 Distance walked during the 12-minute walk test (12MWT)* 
 MFIS Total scores and sub-scale scores* 
 Patient Global Impression of Severity (PGIS) score for fatigue and muscle 
symptoms   
 Brief Pain Inventory (BPI) pain severity and pain interference scores* 
 Patient-Reported Outcomes Measurement Information System (PROMIS) 
Short Form  Functional Assessment of Chronic Illness Therapy (FACIT) 
Fatigue 13a scores* 
 36 Item Short Form Survey (SF-36) domain scores* 
 Work Productivity and Activity Impairment questionnaire: Specific Health 
Problem (WPAI:SHP) scores* 
 First 6-minute walk distance and last 6-minute walk distance* 
  Phenotypic description questions 
 PGIC scores (muscle and fatigue symptoms)  
*Collected up to Month 24 only. 
3.3. 
STUDY DESIGN 
REN001-202 is a global Phase 2b open label long-term safety study initially set up for 
mtDNA-PMM subjects who complete treatment in REN001-201 or who were participating 
in REN001-101 (a UK only study) when it was ended due to the COVID-19 pandemic. 
Subjects will receive mavodelpar 100 mg once daily for 48 months.  
Protocol Version 2.0 extended recruitment to subjects with nDNA-PMM and increased the 
predicted sample size. These subjects will enter the study naïve to mavodelpar. 


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Subjects enrolling from REN001-201 will be switching from taking blinded mavodelpar or 
placebo in the randomized controlled REN001-201 study to open label mavodelpar in 
REN001-202. At the time of enrolment into this long-term study, prior treatment allocation 
in REN001-201 will be unknown. Subjects who are nearing completion of their 
participation in REN001-201 will be invited to discuss continuing into this long-term 
safety study.  
Hence, subjects may enter REN001-202 via the following pathway options: 
1. At REN001-201 Week 24 (REN001-201 W24). Consequently, these subjects will 
not need to complete the REN001-201 FU visit. 
2. At REN001-201 Follow-up (REN001-201 FU).  
3.  (a)  After leaving REN001-201, following their completion of REN001-201 
(REN001-201 Exit). This will result in a break in study participation where the 
subject is off study drug and not monitored in either study. 
(b) After leaving study REN001-101. REN001-101 completed in March 2020 and 
therefore subjects will have not received mavodelpar for more than 2 years at the 
time of entry to REN001-202. 
4. Recruitment of mavodelpar naïve nDNA-PMM subjects. A Patient Screening 
Oversight Committee (PSOC) will assess these subjects to confirm the medical 
diagnosis of nDNA-PMM prior to enrolment.  
It is expected that most subjects transferring from REN001-201 will do so at the REN001-
201 Week 24 visit to prevent an interruption in dosing and reduce the number of study 
visits and assessments. Their Week 24 REN001-201 visit will also be used as their 
Baseline visit for REN001-202. 
Enrolment at the REN001-201 FU visit will require additional baseline assessments. 
Enrolment after exiting REN001-201, after participating in Study REN001-101 and for 
nDNA-PMM subjects, will require an additional screening visit to complete eligibility 
checks prior to enrolment. Note, all subjects enrolling from German sites will also need to 
satisfy additional eligibility checks irrespective of when they roll over from REN001-201. 
After the baseline visit, subjects will have study visits at Months 1, 3, 6, 12, 18, 24, 30, 36, 
42 and 48 (subjects at the German sites will also have visits at Month 9 and 15) from the 
start of REN001-202. At a final follow up there will be a telephone call from the study 
centre to the subject approximately 30 days after the last dose of study drug. A final 
follow-up telephone call will not be required if mavodelpar has been approved within the 
country and the subject switches to commercially available medication. The schedule of 
assessments for REN001-202 is detailed in Section 3.4 and the REN001-201 schedule of 
assessments is included in Appendix 2. 


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Screening and Baseline Visits 
1
2
3
3
4
 
7
8
9
10
11
12
12
13
14
15
16
1 
2 
3 
4 
5 


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6 
7
8 
9 
10 
11 
12 
13 
14 
15 
16 


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Post Baseline Visits 
1 
2 
3 
4
5
6 
7 
8 
9 


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3.5. 
DETERMINATION OF SAMPLE SIZE 
The sample size for this study is not based on statistical justification. Recruitment of 
mtDNA-PMM subjects will be limited to those subjects who participated in REN001-201 
or REN001-101, and reside in countries where this long-term safety study is approved. It is 
estimated that approximately 150 mtDNA-PMM subjects will be enrolled. 
It is anticipated that up to 50 nDNA-PMM subjects may also be enrolled. 
3.6. 
TREATMENT ASSIGNMENT AND BLINDING 
REN001-202 is an open label study with all subjects receiving mavodelpar 100 mg once 
daily. Prior treatment allocation in REN001-201 will remain blinded until database lock of 
REN001-201. 
Subjects enrolling from REN001-201 will be assigned the same subject ID they were 
allocated in REN001-201. Subjects enrolling from study REN001-101 and nDNA-PMM 
subjects will be assigned a new unique 6-digit subject ID. 
A subject, enrolling under pathway options 3 or 4 (Section 3.3), may be rescreened once 
with prior Sponsor approval and will be given a new subject ID (their original subject ID 
will be recorded). 
3.7. 
ADMINISTRATION OF STUDY MEDICATION 
Subjects will receive 100 mg mavodelpar orally once daily. Study drug should be taken 
with food at a convenient time to the subject (ideally in the morning). The exceptions to 
this are: 
 at the Baseline visit for subjects enrolled under pathway options 2-4 (Section 3.3) 
the first dose will be taken with food at the site under the supervision of site staff.  
Subjects enrolled under pathway option 1 are expected to have taken their last dose 
of REN001-201 study medication that morning prior to their REN001-201 Week 
24 (REN001-202 Baseline) visit, in which case their first dose of mavodelpar in 
REN001-202 should be taken the following day.   
 at the Month 3 visit, where the subject should take the study drug at the study 
centre with food, when instructed to do so by the site staff. 
3.8. 
APPROACH TO COMBINING REN001-201 DATA 
For mtDNA-PMM subjects, the data from REN001-202 will be combined with data from 
its feeder study, REN001-201. The combined data will be presented from the start of 
REN001-201 and from the start of REN001 treatment. Presentations from the start of 
REN001-201 will include all mtDNA-PMM subjects who receive at least one dose of 


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study drug in REN001-201 and will continue to acknowledge the randomization to 
treatment groups at the start of REN001-201. 
Presentations from the start of REN001 treatment will summarize the data emergent during 
treatment with mavodelpar. These summaries will include all mtDNA-PMM subjects who 
receive mavodelpar in REN001-201 and/or REN001-202. In addition to these summaries, 
data from REN001-202 alone will be reported which will include mtDNA-PMM and 
nDNA-PMM subjects. These datasets will provide long-term safety, as well as descriptive 
information on efficacy measures.  
As described in Section 3.3 there are 4 pathway options in which subjects can enter 
REN001-202. The pathway options are described in more detail below: 
1. REN001-201 W24 
The majority of subjects enrolling in REN001-202 will enroll at REN001-201 
Week 24. This will prevent an interruption in dosing and reduce the number of 
study visits and assessments for subjects.  
The REN001-201 Week 24 visit will also be the REN001-202 Baseline visit; data 
in the REN001-201 database for this visit will be copied across programmatically 
to the REN001-202 database to avoid sites having to re-enter the data. Any data 
from REN001-201 database repeated in the REN001-202 database will be removed 
from the tables, listings and analysis datasets prior to reporting the combined data 
from the two studies. For example, any ongoing AEs or medications at the 
REN001-201 Week 24 visit will be copied across to the REN001-202 database, 
where they may be updated if there is any status change (e.g., end date being 
available); hence the latest information on these events recorded in REN001-202 
database will be used for reporting. 
Dosing in REN001-202 will start the day after the REN001-201 Week 24 visit. 
However, to allow for scheduling of eye examinations and DXA scans these 
REN001-201 Week 24 assessments can occur up to 14 and 28 days respectively, 
after the first dose of study drug in REN001-202. 
The schematic below details how subjects transition between the 2 studies and the 
visit naming convention throughout the 2 studies: 
 


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Statistical Analysis Plan
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REN001-
201
Treatment
Group
REN001-201 
REN001-202
Sc
BL
W2
W4
W12
W18
W24
BL
M1
M3
M6
M12
M18
M24
M48
REN001
REN001
REN001
Sc
BL
M0.5
M1
M3
M4.5
M6
M7
M9
M12
M18
M24
M30
M54
Placebo
Placebo
REN001
Sc
BL
M0.5
M1
M3
M4.5
M6
M7
M9
M12
M18
M24
M30
M54
*BL
*M1
*M3
*M6
*M12
*M18
*M24
*M48
Footnote: Sc=Screening; BL=Baseline; FU=Follow-up; W=Week; M=Month.
* Baseline visit and nominal visits from start of REN001 treatment.
In REN001-202 visits occur every 6 months between Month 24 and Month 48 (i.e., Months 30, 36 and 42). Where applicable, a
final follow up telephone call will occur approximately 30 days after the last dose of study drug.
2. REN001-201 FU  
Subjects who enroll at the REN001-201 FU visit will have had an interruption in 
study drug from the time of the REN001-201 Week 24 visit to the time of the 
combined REN001-201 FU and REN001-202 Baseline visits. This gap in study 
treatment is expected to be approximately 4 weeks. For reporting purposes, the 
nominal study visits in REN001-202 will be considered as a continuation from 
REN001-201 Week 24.
The REN001-202 Baseline visit data will either be collected at the visit or come 
from the REN001-201 FU visit if the assessment is performed at the FU visit. The 
exception to this is the eye examinations and DXA scans which will be taken from 
REN001-201 Week 24 visit; however, to allow for scheduling of eye examinations 
and DXA scans these REN001-201 Week 24 assessments can occur after the first 
dose of study drug in REN001-202. As above for REN001-201 W24 rollover 
subjects, data in the REN001-201 database for the FU visit will be copied across 
programmatically to the REN001-202 database to avoid sites having to re-enter the 
data. Any data from REN001-201 database repeated in the REN001-202 database 
will be removed from the tables, listings and analysis datasets prior to reporting the 
combined data from the two studies. For example, any ongoing AEs or medications 
at the REN001-201 FU visit will be copied across to the REN001-202 database, 
where they may be updated if there is any status change (e.g., end date being 
available); hence the latest information on these events recorded in the REN001-
202 database will be used for reporting.
Dosing in REN001-202 will start on the day of the REN001-202 Baseline visit.
The schematic below details how subjects transition between the 2 studies and the 
visit naming convention throughout the 2 studies:


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Statistical Analysis Plan
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REN001-
201
Treatment
Group
REN001-201 
REN001-202
Sc
BL
W2
W4
W12
W18
W24
FU
BL
     M1
M3
M6
M12
M18
M24
M48
REN001
REN001
REN001
Sc
BL
M0.5
M1
M3
M4.
5
M6
M7
M9
M12
M18
M24
M30
M54
Placebo
Placebo
REN001
Sc
BL
M0.5
W4
W12
W18
W24
M7
M9
M12
M18
M24
M30
M54
*BL
*M1
*M3
*M6
*M12
*M18
*M24
*M48
Footnote: Sc=Screening; BL=Baseline; FU=Follow-up; W=Week; M=Month.
* Baseline visit and nominal visits from start of REN001 treatment.
In REN001-202 visits occur every 6 months between Month 24 and Month 48 (i.e., Months 30, 36 and 42). Where applicable, a
final follow up telephone call will occur approximately 30 days after the last dose of study drug.
3. (a) REN001-201 Exit 
Enrolment after exiting REN001-201 will result in a break in study participation of 
variable duration where the subject is off study drug and not monitored in either 
study. Due to the gap in monitoring and dosing, for reporting purposes, the 
will be considered as two separate subjects and data in 
REN001-202 will not be considered as a continuation from REN001-201.
These subjects will need to complete Screening and Baseline visits in REN001-202 
to check eligibility prior to enrolment. If the subject had a DXA scan in REN001-
201, then the REN001-201 Week 24 visit can be used as the Baseline assessment if 
there is 6 months or less since the assessment. Similarly, the REN001-201 Week 24 
eye examination can be used as the Baseline assessment if there is a gap of 6 
months or less.
Dosing in REN001-202 will start on the day of the REN001-202 Baseline visit.
The schematic below details how subjects transition between the 2 studies:


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Statistical Analysis Plan
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REN001-
201
Treatment
Group
REN001-201 
REN001-202
Sc
BL
W2
W4
W12
W18
W24
FU
Sc
BL
M1
M3
M6
M12
M18
M24
M48
REN001
REN001
REN001^
Sc
BL
M0.5
M1
M3
M4.5
M6
FU
Sc
BL
M1
M3
M6
M12
M18
M24
M48
Placebo
Placebo
REN001
Sc
BL
M0.5
W4
W12
W18
W24
FU
Sc
BL
M1
M3
M6
M12
M18
M24
M48
Footnote: Sc=Screening; BL=Baseline; FU=Follow-up; W=Week; M=Month.
^ Data from REN001-202 will not be considered a continuation of REN001-201 but will be reported as a separate subject.
In REN001-202 visits occur every 6 months between Month 24 and Month 48 (i.e., Months 30, 36 and 42). Where 
applicable, a final follow up telephone call will occur approximately 30 days after the last dose of study drug.
3. (b) REN001-101
REN001-101 completed in March 2020 and therefore subjects will not have 
received mavodelpar for more than 2 years at the time of entry to REN001-202. For 
reporting purposes, only data from the start of REN001-202 will be considered.
Subjects will need to perform Screening and Baseline visits in REN001-202 to 
check eligibility prior to enrolment. 
Dosing in REN001-202 will start on the day of the REN001-202 Baseline visit.
The schematic below details the subject visits:
REN001-
201
Treatment
Group
REN001-201 
REN001-202
Sc
BL
W2
W4
W12
W18
W24
FU
Sc
BL
M1
M3
M6
M12
M18
M24
M48
NA
Not Applicable
REN001
Sc
BL
M1
M3
M6
M12
M18
M24
M48
Footnote: Sc=Screening; BL=Baseline; FU=Follow-up; W=Week; M=Month; NA=Not Applicable.
In REN001-202 visits occur every 6 months between Month 24 and Month 48 (i.e., Months 30, 36 and 42).
Where applicable, a final follow up telephone call will occur approximately 30 days after the last dose of study 
drug.
4. nDNA-PMM Subjects
Subjects enrolled with nDNA-PMM will not have received mavodelpar previously 
so only data from the start of REN001-202 will be available to report.
Subjects will need to perform Screening and Baseline visits in REN001-202 to 
check eligibility prior to enrolment. Dosing in REN001-202 will start on the day of 
the REN001-202 Baseline visit.


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The schematic below details the subject visits:
REN001-
201
Treatment 
Group
REN001-201 
REN001-202
Sc
BL
W2
W4
W12
W18
W24
FU
Sc
BL
M1
M3
M6
M12
M18
M24
M48
NA
Not Applicable
REN001
Sc
BL
M1
M3
M6
M12
M18
M24
M48
Footnote: Sc=Screening; BL=Baseline; FU=Follow-up; W=Week; M=Month; NA=Not Applicable.
In REN001-202 visits occur every 6 months between Month 24 and Month 48 (i.e., Months 30, 36 and 42).
Where applicable, a final follow up telephone call will occur approximately 30 days after the last dose of 
study drug.


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4. 
EFFICACY ASSESSMENTS 
The sections below detail the efficacy assessments, including any derivations required for 
the efficacy secondary endpoints. The descriptive presentations of data regarding these 
endpoints are detailed in Section 10.  
Details concerning the baseline used in the derivation of changes from baseline are 
provided in Section 8.6. 
4.1. 
12-MINUTE WALK TEST (12MWT) 
In REN001-201 subjects will perform the 12MWT at Screening, Baseline, Week 12 
(Month 3) and Week 24 (Month 6). In REN001-202 subjects will be assessed at Baseline, 
Months 3, 6, 12, 18 and 24; which from the start of REN001-201 are equivalent to Months 
6, 9, 12, 18, 24 and 30. It will also be assessed at an early termination visit if the subject 
withdraws from the study. In addition, nDNA-PMM subjects will have a screening 
12MWT assessment. 
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 REN001-202 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.  
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 
evaluate a range of fatigue symptoms, from mild subjective feelings of tiredness to an 
overwhelming, debilitating, and sustained sense of exhaustion that likely decreases a 
 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.  
In REN001-201 the PROMIS questionnaire will be used at Screening, Baseline, Week 4 
(Month 1), Week 12 (Month 3), Week 18 (Month 4.5) and Week 24 (Month 6). In 
REN001-202 subjects will be assessed at Baseline, Months 1, 3, 6, 12, 18 and 24; which 
from the start of REN001-201 are equivalent to Months 6, 7, 9, 12, 18, 24 and 30. It will 
also be assessed at an early termination visit if the subject withdraws from the study. 
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 a higher score indicates a greater 
impact on fatigue. Answers to 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 
(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 
total score data will only be listed. 
4.3. 
PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC)  MUSCLE 
SYMPTOMS AND FATIGUE SYMPTOMS 
In REN001-201 the subject is asked to rate their change in PMM muscle symptoms and 
their PMM fatigue symptoms at Week 24 (Month 6). In REN001-202 subjects will be 
assessed at Months 12, 24, 36 and 48; which from the start of REN001-201 are equivalent 
to Months 18, 30, 42 and 54. It will also be assessed at an early termination visit if the 
subject withdraws from the study. 


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The PGIC has a 7-
 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 in muscle symptoms.  
4.4. 
PATIENT GLOBAL IMPRESSION OF SEVERITY (PGIS) SCORE - 
MUSCLE SYMPTOMS AND FATIGUE SYMPTOMS 
In REN001-201 the PGIS will be used at Screening, Baseline, Week 4 (Month 1), Week 12 
(Month 3), Week 18 (Month 4.5) and Week 24 (Month 6). In REN001-202 subjects will be 
assessed at Baseline, Months 1, 3, 6, 12, 18, 24, 30, 36, 42 and 48; which from the start of 
REN001-201 are equivalent to Months 6, 7, 9, 12, 18, 24, 30, 36, 42, 48 and 54. It will also 
be assessed at an early termination visit if the subject withdraws from the study. 
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. The scale has 5 levels 
 
For each visit changes from baseline will be calculated for the two symptom scores. 
4.5. 
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.  
In REN001-201 subjects will perform the MFIS at Screening, Baseline, Week 4 (Month 1), 
Week 12 (Month 3), Week 18 (Month 4.5) and Week 24 (Month 6). In REN001-202 
subjects will be assessed at Baseline, Months 1, 3, 6, 12, 18 and 24; which from the start of 
REN001-201 are equivalent to Months 6, 7, 9, 12, 18, 24 and 30. It will also be assessed at 
an early termination visit if the subject withdraws from the study. 
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 
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 


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Subscale 
Items 
Range 
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 
considered missing 
 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. 
4.6. 
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 REN001 is effective greater improvements are anticipated with vitality than 
the other health concepts. 
In REN001-201 the SF-36 will be used at Baseline, Week 4 (Month 1), Week 12 (Month 
3), Week 18 (Month 4.5) and Week 24 (Month 6). In REN001-202 subjects will be 
assessed at Baseline, Months 1, 3, 6, 12, 18 and 24; which from the start of REN001-201 
are equivalent to Months 6, 7, 9, 12, 18, 24 and 30. It will also be assessed at an early 
termination visit if the subject withdraws from the study. 
All scale scores 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 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. 
4.7. 
BRIEF PAIN INVENTORY (BPI) SHORT FORM 
The BPI Short Form assesses the severity of pain and its impact on functioning.  


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Statistical Analysis Plan  
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In REN001-201 the BPI questionnaire will be used at Baseline, Week 4 (Month 1), Week 
12 (Month 3), Week 18 (Month 4.5) and Week 24 (Month 6). In REN001-202 subjects will 
be assessed at Baseline, Month 12 and Month 24; which from the start of REN001-201 are 
equivalent to Months 6, 18, and 30. It will also be assessed at an early termination visit if 
the subject withdraws from the study. 
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. 
4.8. 
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.  
In REN001-201 the questionnaire will be used at Baseline, Week 4 (Month 1), Week 12 
(Month 3), Week 18 (Month 4.5) and Week 24 (Month 6). In REN001-202 subjects will be 
assessed at Baseline, Months 1, 3, 6, 12, 18 and 24; which from the start of REN001-201 
are equivalent to Months 6, 7, 9, 12, 18, 24 and 30. It will also be assessed at an early 
termination visit if the subject withdraws from the study. 
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]) 
 
Subjects are asked to answer Questions 2 to 6 with respect to the past 7 days.  
The following 4 scores 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 
 
 
Percent impairment while 
working due to PMM 
 
 
Percent overall work impairment 
due to PMM 
 
 
Percent activity impairment due 
to PMM 
 
 
 
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 
-(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. 
4.9. 
PMM PHENOTYPIC DESCRIPTION 
The phenotypic presentation 
the Newcastle Mitochondrial Disease Adult Scale. The 3 questions relate to exercise 


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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. 
In REN001-201 the questionnaire will be used at Baseline and Week 24 (Month 6). In 
REN001-202 subjects will be assessed at Baseline, Months 6, 12, 18, 24, 36 and 48; which 
from the start of REN001-201 are equivalent to Months 12, 18, 24, 30, 42 and 54. It will 
also be assessed at an early termination visit if the subject withdraws from the study. 
Where possible the same physician should ask the questions on each occasion to ensure 
consistency of interpretation. 
For each visit changes from baseline for each question will be calculated. 
 


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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.  
At Month 1 in REN001-202 a single sample will be taken and at Months 6, 12, 18 and 24 
two samples will be taken, one on arrival at site, and the second taken at the end of the 
visit. At Month 3 the timing of samples is dependent on the version of the protocol being 
used when the subject was recruited: 
 Protocol Version 1: pre-dose and 1, 2, 4, 6, 8, 12 and 24 hours post-dose 
 Protocol Version 2: pre-dose and 1, 2 and 4 hours post-dose  
PK parameters will be calculated from the Month 3 plasma concentrations, for those 
subjects enrolled under Protocol Version 1.0, by an external vendor using a non-
compartmental approach with WinNonlin© software (version 8.3 or higher). Details 
concerning the derivation of parameters will be documented in a separate non-
compartmental analysis plan. The PK parameters estimated will include, but may not be 
limited to: 
Ctrough 
Observed plasma concentration at 24-hours post dose (just prior to next 
dose) 
Cmax 
Maximum observed plasma concentration over the dosing interval 
Tmax 
Time of the maximum measured plasma concentration over the dosing 
interval. If the maximum value occurs at more than one time point, Tmax is 
defined as the first time point with this value. 
AUC  
The area under the plasma concentration versus time curve, over the dosing 
interval (i.e., 0-24 hours), as calculated using the linear trapezoidal method 
when concentrations are increasing and the logarithmic trapezoidal method 
when concentrations are decreasing 
The data will also 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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Statistical Analysis Plan  
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6. 
SAFETY ASSESSMENTS 
The primary purpose of this study is to assess the long-term safety and tolerability of 
dosing with mavodelpar 100 mg once daily. The sections below detail the safety 
assessments, including any derivations required. The analyses of the safety endpoints are 
detailed in Section 10.  
Details concerning the baseline used in the derivation of changes from baseline are 
provided in Section 8.6. 
Subjects attending sites in Germany will have additional safety assessments at Month 9 
and Month 15. These safety assessments include ECGs, vital signs, safety laboratory 
evaluation and physical examinations. The data from these assessments will not be 
included in any by visit  summaries but will be listed and will be considered in summaries 
of results of potential clinical importance.  
6.1. 
ADVERSE EVENTS  
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.  
 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).  
Note in Protocol Versions 1.0 and 2.0, a 
(regardless of changes in lens clarity) was also considered an AESI and reported on the 
eCRF. However, since the implementation of Protocol Version 3.0 these are no longer 
routinely reported as AESIs. 
6.2. 
LABORATORY EVALUATIONS 
Laboratory safety samples are collected throughout the 2 studies and will be used to 
determine the following: 
 Hematology parameters 
 Biochemistry parameters, including:  
 the osteoblastic bone marker - bone specific alkaline phosphatase (BSAP) 


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 calcium markers - parathyroid hormone and vitamin D 
 Urinalysis parameters, including: 
  the osteoclastic bone marker - Urine N-terminal telopeptide (NTx), via a 
morning second urinary void 
Changes from baseline will be calculated for each laboratory parameter at each scheduled 
visit. 
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 recorded 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 Week 24 (Month 6) 
in REN001-201; and in REN001-202 at Baseline, Month 24 and Month 48. Therefore, 
subjects who have DXA scans throughout the 2 studies will have a total of 4 scans at 
Screening, Month 6, Month 30 and Month 54 from the start of REN001-201. For subjects 
who withdraw from the study, it will be performed at an early termination provided the 
subject has received at least 20 weeks of study drug.  
To allow for scheduling of the DXA scans the REN001-201 Week 24 (Month 6) 
assessment can occur up to 28 days after the visit. Hence, this assessment could occur after 
the start of administration of mavodelpar in REN001-202; this period is not considered 
sufficient time to have an impact on DXA results. Therefore, for those mtDNA-PMM 
subjects who received placebo in REN001-201, enrolled in REN001-202 at REN001-201 
Exit, enrol from study REN001-101 or for nDNA-PMM subjects this record will still be 
considered the baseline record relative to the start of REN001, provided it occurs within 28 
days of the first dose of mavodelpar. 
Baseline DXA scans will not be required for REN001-201 Exit subjects if within 6 months 
of the last REN001-201 scan. 
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 (systolic and 
diastolic blood pressure, pulse, weight and temperature) for each scheduled visit. Change 


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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.  
6.5. 
ECGS 
Changes from baseline will be calculated for each ECG parameter (heart rate, QRS 
duration, PR interval QT interval and QTcF interval) for each scheduled visit.  
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. 
To allow for scheduling of the eye examinations the REN001-201 Week 24 (Month 6) 
assessment can occur up to 14 days after the visit. Hence, this examination could occur 
after the start of administration of mavodelpar in REN001-202; this period is not 
considered sufficient time to have an impact on eye examination results. Therefore, for 
those mtDNA-PMM subjects who received placebo in REN001-201, enrolled in REN001-
202 at REN001-201 Exit, enrol from study REN001-101 or for nDNA-PMM subjects this 
record will still be considered the baseline record relative to the start of mavodelpar 
provided it occurs within 14 days of the first dose of mavodelpar. 
Baseline eye examinations will not be required for REN001-201 Exit subjects if the 
screening visit is within 6 months of the last REN001-201 examination. 
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.  
-
the LogMAR score; 0.02 will be added or subtracted, respectively, for each letter (z).  
e.g., 


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20/15-1: LogMAR = Log10(15 divided by 20)+0.02 = -0.105 
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.  
Cataract are classified and graded against the Lens Opacity Classification System III 
(LOCS III) for nuclear opalescence, nuclear colour, cortisol and posterior subcapsular 
cataracts. Changes from baseline will be calculated. 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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REN001-201 & REN001-202 
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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 REN001-202 informed 
consent form and are screened for participation in REN001-202. 
7.2. 
SAFETY ANALYSIS SETS 
There will be a separate safety set for each of the approaches for summarizing the data. 
 from the start of REN001-202  will include all REN001-202 subjects who signed 
the REN001-202 informed consent form, completed screening and received at 
least one dose of mavodelpar study medication in REN001-202. 
 From the start of REN001-201  will include all subjects who signed the 
REN001-201 informed consent form, completed screening and received at least 
one dose of study medication in REN001-201. 
 from the start of REN001 treatment  will include all subjects who signed the 
informed consent form (REN001-201 form for mavodelpar REN001-201 subjects 
and REN001-202 form for REN001-201 placebo subjects), completed screening 
and received at least one dose of mavodelpar study medication in either REN001-
201 (mavodelpar subjects in REN001-201) or REN001-202 (placebo subjects in 
REN001-201).  
The 
REN001-201 safety analysis set summaries will be based on the 
actual treatment received. The safety analysis sets will be used for all baseline and safety 
analyses. 
A listing safety analysis set will be used for listings. This will include all subjects who 
signed the informed consent form and received at least one dose of study medication in 
either REN001-201 or REN001-202. 
7.3. 
FULL ANALYSIS SETS 
There will be a separate full analysis set (FAS) from the start of REN001-202 and from the 
start of REN001-201 approaches for summarizing the data. 
 from the start of REN001-202  will include all REN001-202 subjects who signed 
the REN001-202 informed consent form, completed screening, received at least 
one dose of mavodelpar study medication in REN001-202 and have not been 
subsequently discontinued from the study for failing eligibility criteria. 
 from the start of REN001-201  will include all subjects who signed the REN001-
201 informed consent form, completed screening, received at least one dose of 


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REN001-201 & REN001-202 
Statistical Analysis Plan  
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study medication in REN001-201 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 REN001-201 
randomization 
REN001-201
. The FAS will be the 
primary analysis set for efficacy. 
7.4. 
PHARMACOKINETIC ANALYSIS SET 
The PK set will include all subjects in the safety set who receive mavodelpar in REN001-
202 and have at least one evaluable (i.e., not impacted by any important protocol 
deviations or other events) PK measurement (even if below the limit of quantification) in 
REN001-202. 
Note, intense PK sampling will not be performed on all subjects if it is deemed that 
sufficient data (i.e., full sampling in approximately 20 -30 subjects) has been collected. 
7.5. 
DXA SCAN ANALYSIS SET 
The DXA scan set will include all subjects in the safety set who have a valid REN001-202 
Month 24 or Month 48 (or Early Termination) DXA scan (i.e., with parameter 
measurements). The DXA scan set will be used for analysis of the DXA data. 
7.6. 
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 
ule or natural events. In contrast, 
, 
or the integrity of the clinical study data. No subjects will be excluded from the safety set 
due to protocol deviations.  
Only protocol deviations from REN001-202 will be listed; the REN001-201 protocol 
deviations will be listed in the REN001-201 CSR. The number of subjects reporting major 
deviations in either study will be summarized overall and by deviation category. 


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8. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
8.1. 
HYPOTHESIS TESTING 
No formal statistical testing is planned. 
8.2. 
GENERAL METHODS 
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. 
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. Drug 
interruptions will not be considered, i.e., data will not be excluded during a drug 
interruption if the subject resumes study treatment; this includes the follow-up period for 
subjects who enrol in REN001-202 at the REN001-201 FU.  
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.  
(i.e., observed visit value  baseline value). The baseline definitions are detailed in Section 
8.6. 
There will be 3 approaches to summarising the data and, unless stated otherwise, all 
presentations will be presented for each approach. Figure 1 in Section 2 shows the different 
pathway options a subject can enter REN001-202 and the 5 distinct reporting groups these 


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subjects represent. These 5 reporting groups are referenced in square brackets alongside 
the descriptions below. The summaries are: 
 From the start of REN001-202 Summaries will be presented by mutation group 
(REN001 100 mg mtDNA-PMM [Groups 1 to 4] and REN001 100 mg nDNA-
PMM [Group 5]). The mtDNA-PMM group will also be split by: 
o Placebo > REN001 100 mg [Group 1]  subjects who received placebo in 
REN001-201 and enrolled at REN001-201 W24, FU or after exit. 
o REN001 100 mg > REN001 100 mg [Group 2]  subjects who received 
mavodelpar in REN001-201 and enrolled at REN001-201 W24 visit.  
o REN001 100 mg >FU> REN001 100 mg [Group 3]  subjects who received 
mavodelpar in REN001-201 and enrolled at REN001-201 FU visit. 
o REN001 100 mg >Exit> REN001 100 mg [Groups 4a and 4b]  subjects 
who received mavodelpar in REN001-201 and enrolled after exiting 
REN001-201 or subjects who took part in REN001-101 study.  
Summaries will extend out to Month 48, where applicable. 
 From the start of REN001-201 which will be split by REN001-201 treatment group 
(REN001 100 mg [Groups 2, 3 and 4a] and placebo [Group 1]). Subjects who enrol 
in REN001-202 at REN001-201 Exit will only have their REN001-201 data 
included in these summaries. Baseline summary tables (disposition, demography, 
baseline characteristics, medical history and prior medications) will also include an 
overall summary. 
Summaries will extend out to Month 54, where applicable, for all subjects who 
complete both studies. 
 From the start of REN001 treatment [Groups 1, 2, 3 and 4]. Subjects who enrol in 
REN001-202 at REN001-201 Exit and receive mavodelpar in REN001-201 [Group 
4a] will be counted as 2 separate subjects. Summaries will be presented over all 
subjects (REN001 100 mg). 
Summaries will extend out to Month 54, where applicable, for subjects who receive 
mavodelpar in REN001-201 and enrol in REN001-202 at REN001-201 W24 or FU; 
for all other subjects summaries will extend to Month 48. 
In addition, for summaries from the start of REN001 there is only Week 2 (Month 0.5), 
Week 18 (Month 4.5), Month 1 (Month 7) and Month 3 (Month 9) for subjects who 
receive mavodelpar in REN001-201 and therefore this visit will not be included in the by 
visit summaries. Refer to Section 3.8 for diagram of visit assignment. 


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All data for subjects included in at least one safety analysis set will be listed. For screen 
failures, only REN001-202 screen failure subjects will have data listed, and this will be 
limited to disposition (including reason for screen failure), demographics and protocol 
deviations. 
Data listings will be ordered by REN001-201 treatment group (REN001 100 mg, Placebo, 
Not Applicable), REN001-202 enrolment (REN001-201 W24, REN001-201 FU, REN001-
201 Exit, REN001-101 or nDNA-PMM subjects) and subject. For those subjects who do 
not enter REN001-202 their REN001-202 enrolment will be identified 
Study data from both REN001-201 and REN001-202 will be listed unless stated otherwise, 
and the listing will indicate the study source of the data. The visit listed will be the original 
visit for the associated study. A subject s mutational genotype (m.3243A>G, m.8344A>G, 
mt deletion or Other) will be identified on the listings for mtDNA-PMM subjects. In 
addition to dates, data listings will present study days relative to: 
 Start of REN001-201 dosing (if applicable) 
 Start of REN001-202 dosing (if applicable) 
Study day will be 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. 
Changes from baseline will be included in listings. More than one change from baseline 
will be presented if more than one baseline is used (Refer to Section 8.6). All statistical 
analyses will be performed using SAS® (Version 9.4 or higher, SAS Institute Inc., Cary, 
NC, USA).  
8.3. 
MISSING DATA 
All possible efforts will be made to minimize missing data.  
Unless specified otherwise, screening 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. 
8.3.1. 
Efficacy Data 
This is a long-term safety study; since efficacy is a secondary objective and only 
descriptive presentations of efficacy will be generated there will be no imputation for 
missing efficacy data.  However, all 12MWTs which were stopped prematurely (i.e., 
before completing 12 minutes) will be reviewed by an adjudication committee to consider 
If 
deemed at least possibly related, then their data recorded will be used in analyses; if 


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unrelated the data will be considered missing. The adjudication for the REN001-201 
12MWTs will have been conducted as part of the REN001-201 reporting and so these 
decisions will be used for this study as well. As the descriptive presentation of long-term 
efficacy data is a secondary objective for this study and treatment is open-label the 
adjudication of the REN001-202 12MWTs will be performed by Reneo. 
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 except for the geometric mean 
and geometric CV%, where they will be set to the LLOQ.  
8.3.3. 
Safety Data 
AEs with missing classification will 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 
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 
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. 


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This is the same approach as used in the REN001-201 SAP and therefore the REN001-201 
data will have the same analysis visit windowing assigned as per the REN001-201 CSR.  
To assess whether a REN001-202 visit is within the analysis window the day relative to the 
start of REN001-202 will be used. This will mean that for subjects who enrol at REN001-
201 FU the interruption in study drug during the REN001-201 FU period will be ignored. 
Study  
 
Original 
Visit 
Visit Name for 
Combined Study 
Summaries 
Target 
Day1 
Protocol 
Visit 
Window 
 
Analysis 
Window1 
 
Analysis 
Interval 
REN001-201 
Baseline 
Baseline  
1 
NA 
 
NA 
Week 2 
Month 0.5 
14 
±3 
8  20 
13 (±6) 
Week 4 
Month 1 
28 
±3 
21  35 
15 (±7) 
Week 12 
Month 3 
84 
±7 
63  105 
43 (±21) 
Week 18 
Month 4.5 
126 
±7 
106  146 
41 (±20) 
Week 24 
Month 6 
168 
±7 
147  189 
43 (±21) 
REN001-202 
Baseline 
Month 6 
1 
NA 
 
NA 
Month 1 
Month 7 
28 
±3 
21  35 
15 (±7) 
Month 3 
Month 9 
84 
±7 
63  105 
43 (±21) 
Month 6 
Month 12 
168 
±7 
147  189 
43 (±21) 
Month 9^ 
Month 15^ 
252 
±21 
211  293 
83 (±41) 
Month 12 
Month 18 
336 
±21 
294  378 
85 (±42) 
Month 15^ 
Month 21^ 
420 
±21 
379  461 
83 (±41) 
Month 18 
Month 24 
504 
±21 
462  546 
85 (±42) 
Month 24 
Month 30 
672 
±21 
630  714 
85 (±42) 
Month 30 
Month 36 
840 
±21 
798  882 
85 (±42) 
Month 36 
Month 42 
1008 
±21 
966  1050 
85 (±42) 
Month 42 
Month 48 
1176 
±21 
1134  1218 
85 (±42) 
Month 48 
Month 54 
1344 
±21 
1302  1386 
85 (±42) 
NA=not applicable. 
1 Target day and analysis windows are relative to start of each study. 
* Baseline values must be prior to dosing if time of assessment is recorded. 
^ Month 9 and Month 15 (original) visits are only applicable for German sites. 
Subjects can have more than one baseline defined depending on which reporting group is 
used. Section 8.6 provides more details on the baseline definitions.  


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REN001-202 follow-up visit, by design, is after the last dose of study drug and should not 
be allocated to on-treatment visits.  Similarly, REN001-201 follow-up visit should not be 
assigned to an on-treatment visit in REN001-202. 
Windowing will not be used for the DXA scan data. Subjects can have a maximum of 4 
DXA scans across the studies and these will be assigned to the nominal scheduled visits. 
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. In addition, 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. 
Subgroup analyses are planned for adverse events, 12-minute Walk Distance (12MWD) 
and DXA endpoints. For these analyses only subgroup categories with 5 or more subjects 
will be summarized. The subgroups that will be used for each endpoint are defined in the 
table below, the remaining subgroups will only be used in the summary of baseline 
characteristics. 
Endpoint 
Subgroups 
Adverse events 
Age, sex, race (excluding Other race category) 
12MWD 
Mutational genotype (both subgroups defined below), baseline 
12MWD 
DXA 
Menopausal status 
 The subgroups are defined as: 
 
 
 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
gory genotype (i.e., m.3243A>G, m.8344A>G, mt deletion or 
Other)
ategory into these extended levels, first 
the m.8344A>G subjects will be identified from the other description free text 


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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.   
 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 
 
>650 m  
 Country: all countries that randomized a subject 
 Region: North America (USA and Canada), Europe or Australia/New Zealand 
 Clinically significant vitamin D deficiency at baseline, defined as <30nmol/L: yes, 
no 
 Baseline PROMIS T-score: 60 or >60 
 Menopausal status: males, pre-menopausal females or post-menopausal females. 
Post-
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. 
8.6. 
BASELINE DEFINITION 
Subjects will have up to 2 baselines for endpoints: 


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 The last available non-missing assessment prior to study drug administration in 
REN001-201 (Day 1). This baseline will be used for analyses from the start of 
REN001-201 and, for those who receive mavodelpar in REN001-201, from the 
start of REN001 treatment analyses. 
 The last available non-missing assessment prior to study drug administration in 
REN001-202. This baseline will be used for analyses from the start of REN001-
202, and from the start of REN001 treatment for those subjects who: 
o  received placebo in REN001-201 
o enter REN001-202 having exited REN001-201  
o enter REN001-202 having exited REN001-101 
o have nDNA-PMM 
For those subjects who enter REN001-202 from REN001-201 at the REN001-201 
W24 or FU visits the baseline should be from the assessments at those visits. 
Questionnaires collected on the first day of dosing in either study will be considered as a 
baseline assessment within the context of the above definitions. 
Note, to allow for scheduling of the eye examinations and DXA scans the REN001-201 
Week 24 (Month 6) assessment can occur up to 14 days or 28 days respectively, after the 
visit. Hence, this assessment could occur after the start of administration of mavodelpar in 
REN001-202; this period is not considered sufficient time to have an impact on the results. 
Therefore, these assessments can still be considered a baseline record provided it occurs 
within 14 days for eye examinations or 28 days for DXA scans, of the first dose of 
mavodelpar.  


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REN001-201 & REN001-202 
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9. 
ANALYSIS OF DISPOSITION, DEMOGRAPHIC AND 
BASELINE CHARACTERISTICS, AND MEDICATION 
9.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
To account for all pathways into REN001-202 a summary including REN001-201 and 
REN001-202 disposition will be generated. For REN001-201 the summary will be split by 
REN001-201 treatment groups and present the number (%) of subjects who were: 
 Dosed in REN001-201 (% not required) 
 Discontinued treatment in REN001-201 (along with reasons) 
 Completed treatment in REN001-201 and did not enrol in REN001-202  
Percentages will be based on the number of subjects dosed in REN001-201. 
For REN001-202 the summary will be split by REN001-101 subjects, nDNA-PMM 
subjects, and the 6 REN001-201 enrolment pathway options: 
1. REN001-201 REN001 enrolled at W24 visit 
2. REN001-201 REN001 enrolled at FU visit 
3. REN001-201 REN001 enrolled after exiting 
4. REN001-201 Placebo enrolled at W24 visit 
5. REN001-201 Placebo enrolled at FU visit 
6. REN001-201 Placebo enrolled after exiting.  
The summary will present the number (%) of subjects who were: 
 Screened (for subjects who enrolled after exiting REN001-201, REN001-101 
subjects or nDNA-PMM subjects) 
 Rescreened (applicable for subjects who enrolled after exiting REN001-201, 
REN001-101 subjects or nDNA-PMM subjects)a 
 Not dosed in REN001-202a  
 Dosed in REN001-202a 
 Completed REN001-202b 
 Withdrew from REN001-202 (along with reasons)b 
 Ongoing in REN001-202 (applicable for interim analyses of REN001-202)b 
 In each analysis set (safety, FAS, PK and DXA)b 


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REN001-201 & REN001-202 
Statistical Analysis Plan  
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a Percentages will be based on the number of subjects in the REN001-202 screened set 
for subjects who enrolled after exiting REN001-201, REN001-101 subjects or nDNA-
PMM subjects.  
b Percentages will be based on the number of subjects dosed in REN001-202. 
The number (%) of subjects in the FAS and safety analysis sets will also be summarized 
from the start of REN001-201 and the number (%) in the safety analysis set from the start 
of REN001 treatment. The denominator will be based on the number of subjects dosed in 
REN001-201 and the number of subjects dosed with mavodelpar respectively. 
For each scheduled visit the following number (%) of subjects will be presented for each 
safety analysis set: 
 Who attended the visit 
 Who 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.  
For interim reporting some subjects will still be ongoing in REN001-202 at the time of the 
data cut, so in addition to the above categories the number of subjects with the potential to 
reach a REN001-202 visit will be included; and therefore, the number who attended, 
missed or were withdrawn prior to visit will be based on those with the potential to reach 
the REN001-202 visit. Subjects will be assessed as to whether they have the potential to 
reach a REN001-202 visit using the duration from the first dose in REN001-202 to the date 
of the data cut. If the duration is greater than the target visit day, then the subject will be 
deemed to have the potential to reach the REN001-202 visit. If the subject attends a visit 
they will automatically be categorized as having the potential to reach the visit. 
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  
 race, 
ethnicity, and menopausal status (men, pre-menopausal women and post-menopausal 
women) will be summarized as categorical variables.  


Mavodelpar (REN001)  
 
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REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
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The appropriate baseline will need to be used for the subject dependent on their starting 
position (REN001-201 or REN001-202). For example, the summary of age at consent from 
the start of REN001 treatment will take their REN001-201 age at consent for subjects who 
received mavodelpar in REN001-201 and their REN001-202 age at consent for all other 
subjects. 
All subgroups defined in Section 8.5 will be summarized as categorical variables. In 
addition, the following baseline endpoints will be summarized as continuous variables: 
 12MWD  baseline distance 
 PROMIS T-score 
 MFIS scale  physical, cognitive, psychosocial and total score 
 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 and DXA scan sets. Menopausal status will 
only be summarized for the DXA scan set.  
9.3. 
MEDICAL HISTORY AND CONCOMITANT DISEASES 
Medical history for subjects who enrol at REN001-201 W24 or FU will come from 
REN001-201. The only changes to their medical history will be the updating of 
information (e.g., provision of an end date).   
Medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) version 23.1.  
Medical history will be presented for each 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.  
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  


Mavodelpar (REN001)  
 
Reneo Pharma Ltd. 
REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
Page 54 of 77 
 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 and concomitant medications are defined in the table below based on the 
summary being presented. 
Presentation 
Prior Medicationa 
Concomitant Medicationa 
from start of 
REN001-201 
Medications started prior to the 
first administration of study drug 
in REN001-201 
Medications taken following first 
administration of study drug in 
REN001-201. Medications will be 
attributed to a treatment period 
(REN001-201 or REN001-202) if 
they start or continue into the 
treatment period.  
from start of 
REN001  
Medications started prior to the 
first administration of 
mavodelparb 
Medications taken following first 
administration of mavodelpar.  
From start of 
REN001-202 
Medications started prior to first 
administration of study drug in 
REN001-202b   
Medications taken following first 
administration of study drug in 
REN001-202   
a Medications started before receiving the study dose but continuing after will be considered as both prior and 
concomitant medications.  
b  For subjects who participated in REN001-201 only ongoing medications at the time of starting dosing in 
REN001-202 will be considered as prior medications. Note, from start of REN001 this is relevant only to 
REN001-201 placebo subjects. 
Medication will be summarised for each safety set and the DXA scan set 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 


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REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
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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, and variables will be included to identify the phase of the study 
when the medication starts and ends (prior, REN001-201 or REN001-202). 
If either the start or stop date of medication is missing, the most conservative case will be 
considered when assigning medications to categories. 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 the study that the medication was reported in. 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 the study it was reported in, 
For a missing stop date the date will be imputed as the last study date for REN001-202, 
except for medications recorded in REN001-201 where the subject enrols after exiting 
REN001-201; in these cases the last study date in REN001-201 will be used. If a partial 
date is recorded, the following convention will be used to assign the medication based on 
the database that the medication was recorded in: 
 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
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 and the associated phases (prior, 
REN001-201 or REN001-202) will be included. 
9.5. 
TREATMENT EXPOSURE 
Duration of mavodelpar treatment, days on mavodelpar treatment, number of mavodelpar 
capsules taken, and mavodelpar treatment compliance, will be summarized for each safety 
analysis set using descriptive statistics. Duration of treatment will also be summarized 
using 1 month categories up to 3 months and then 3 monthly (84 days) categories (e.g., 1 
month, >1 
2 months, >2 to 3 months, 3 month, >3 
6 months
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Mavodelpar (REN001)  
 
Reneo Pharma Ltd. 
REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
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months, >54 months); and treatment compliance will also be summarized using the 
categories <80%, 80-120% and >120%.  
 Duration of treatment in days is defined as (date of last mavodelpar dose minus 
date of first mavodelpar 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 mavodelpar medication (e.g., dose 
interruption due to AE); this will also include the gap in study medication for 
subjects enrolling at REN001-201 FU 
 Number of capsules expected to be taken is defined as the days on mavodelpar 
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 for mavodelpar treatment period 
 Treatment compliance (%) is defined as 100 * number of mavodelpar capsules 
taken / (number of REN001 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 for 
mavodelpar treatment period. If study drug is not returned the summary will consider 
number of capsules taken as missing, and so the subject will be excluded. 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). 
As the study will be ongoing at the time of the interim synoptic CSR only duration of 
treatment and days on treatment will be presented.  For ongoing subjects, the date of last 
dose will be assigned the date of last contact up to the date of the data cut. 
Only mavodelpar dosing across the 2 studies will be listed. 


Mavodelpar (REN001)  
 
Reneo Pharma Ltd. 
REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
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10. 
ANALYSIS OF EFFICACY DATA 
All analyses will be based on the FAS for the groups from the start of REN001-202 and 
from the start of REN001-201 unless stated otherwise. 
Missing data will be handled using the complete case methodology described in 
Section 8.3.1.  
As the nDNA-PMM subjects will only be recruited from a subset of the REN001-202 sites, 
summaries may also be presented only including mtDNA-PMM subjects from the same 
sites. Two separate sets of subjects may be used: the subjects who received mavodelpar in 
REN001-201 with their data from the start of REN001-201, and the subjects who received 
placebo in REN001-201 from the start of REN001-202. Consideration will be given to the 
duration of exposure for nDNA-PMM subjects when summarising the data from the 
mtDNA-PMM subjects (e.g., if the duration of exposure of nDNA-PMM subjects is up to 6 
months, only the first 6 months of data for the mtDNA-PMM subjects will be used).  
10.1. 
12-MINUTE WALK TEST (12MWT) 
Observed, change from baseline and percent change from baseline values will be 
summarized by visit using descriptive statistics. The associated 95% confidence intervals 
for the observed, change from baseline and percent change from baseline means will also 
be presented. The number of subjects withdrawn prior to the visit or with missing data will 
also be presented. Note missing data will include those subjects who prematurely stop the 
12MWT and their reason for stopping is adjudicated as not being possibly related to the 
 
Mean plots for observed, change from baseline and percent change from baseline values, 
with 95% confidence intervals will be presented by 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 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. 
The impact of the subgroups (specified in Section 8.5) on the 12MWD will also be 
investigated descriptively. Summaries will be presented by subgroup.  
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 (from start of REN001-202 and 
from start of REN001-201) and corresponding percent changes from baseline. Assessments 


Mavodelpar (REN001)  
 
Reneo Pharma Ltd. 
REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
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which were prematurely stopped and adjudicated as being at least possibly related to the 
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. 
10.1.1. 
6-Minute Walk Distance (Derived from 12MWD) 
The first and last 6-minute walk distances derived from the 12MWD will be presented in 
the same way as the 12MWD
for longer than 6 minutes then only the last 6-minute period will be classified as 
incomplete.  
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 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. 
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. 
10.2. 
MODIFIED FATIGUE IMPACT SCALE (MFIS)  
Observed, change from baseline and percent change from baseline values will be 
summarized by visit using descriptive statistics, for the subscale scores and total score. The 
associated 95% confidence intervals for the observed, change from baseline and percent 
change from baseline means will also be presented. The number of subjects withdrawn 
prior to the visit or with missing data 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 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. 
Spaghetti plots for the changes from baseline will be plotted over time. The plots will be 
split by 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-


Mavodelpar (REN001)  
 
Reneo Pharma Ltd. 
REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
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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. 
10.3. 
PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC)  MUSCLE 
SYMPTOMS AND FATIGUE SYMPTOMS 
PGIC muscle symptoms and fatigue symptoms scores will be summarized by visit as a 
categorical variable. 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. 
Stacked bar charts will be presented for the proportion of subjects at each of the PGIC 
scores by visit for each of the groups. The categories will include each of the PGIC levels 
and missing and withdrawn. 
10.4. 
PATIENT GLOBAL IMPRESSION OF SEVERITY (PGIS) SCORE - 
MUSCLE SYMPTOMS AND FATIGUE SYMPTOMS 
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 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 groups. The categories will include each of the PGIS levels 
and missing and withdrawn. 
10.5. 
PATIENT-REPORTED OUTCOMES MEASUREMENT INFORMATION 
SYSTEM (PROMIS) SHORT FORM  FUNCTIONAL ASSESSMENT 
OF CHRONIC ILLNESS THERAPY (FACIT) FATIGUE 13A 
Observed and change from baseline values will be summarized by visit using descriptive 
statistics for the T-score. The associated 95% confidence intervals for the observed and 
change from baseline means will also be presented. The number of subjects withdrawn 
prior to the visit or with missing data will also be presented. 
Mean plots of observed and change from baseline values for the T-score, with 95% 
confidence intervals will be presented by 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. 


Mavodelpar (REN001)  
 
Reneo Pharma Ltd. 
REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
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Spaghetti plots for the changes from baseline will be plotted over time. The plots will be 
split by 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 for T-score 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. 
10.6. 
36 ITEM SHORT FORM SURVEY (SF-36) 
Observed and change from baseline values will be summarized at each visit using 
descriptive statistics for the 8 scale scores. The associated 95% confidence intervals for the 
observed and change from baseline means will also be presented. The number of subjects 
withdrawn prior to the visit or with missing data will also be presented. 
Mean plots of observed and change from baseline values, with 95% confidence intervals 
will be presented by 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 
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. 


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REN001-201 & REN001-202 
Statistical Analysis Plan  
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10.7. 
BRIEF PAIN INVENTORY 
Observed and change from baseline values will be summarized at each visit using 
descriptive statistics for the pain severity and pain interference scores. The associated 95% 
confidence intervals for the observed and change from baseline means will also be 
presented. The number of subjects withdrawn prior to the visit or with missing data will 
also be presented. 
Mean plots of observed and change from baseline values, with 95% confidence intervals 
will be presented by 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. 
Pain severity and pain interference scores and changes from baseline will be listed with the 
raw data. 
10.8. 
WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT 
QUESTIONNAIRE: SPECIFIC HEALTH PROBLEMS (WPAI: SHP) 
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 using descriptive statistics for the 4 WPAI scores. The associated 95% 
confidence intervals for the observed and change from baseline means will also be 
presented. The number of subjects withdrawn prior to the visit or with missing data will 
also be presented. 
Mean plots of observed and change from baseline values, with 95% confidence intervals 
will be presented by 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. 
10.9. 
PMM PHENOTYPIC DESCRIPTION 
Categorical shift tables from baseline at each visit will be summarized, including marginal 
totals, for the 3 phenotypic questions.  The table will include categories for withdrawn and 


Mavodelpar (REN001)  
 
Reneo Pharma Ltd. 
REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
Page 62 of 77 
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.  


Mavodelpar (REN001)  
 
Reneo Pharma Ltd. 
REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
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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 Month 3 scheduled time point using descriptive 
statistics, including the additional summary statistics geometric mean and geometric CV%. 
The summary will be repeated for subjects who have completed the 24 h profile. 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 Month 3. 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 for mtDNA-
PMM subjects as well as identifying nDNA-PMM subjects. 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 
Month 3. The plots will be repeated for subjects who have completed the 24 h profile. The 
nominal sampling time will be used on the x-axis. The number of subjects contributing to 
each time point will be included on the plots. Lines will be included for all subjects and by 
mutational genotype. 
A listing of all REN001-202 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. 
Month 3 PK parameters will be summarized for subjects recruited under protocol version 
1.0 using descriptive statistics. Ctrough, Cmax, and AUC  will include the additional summary 
statistics of geometric mean, geometric CV% and CV%; and for Tmax only the summary 
statistics median, minimum and maximum will be presented. PK parameters will be listed. 
 


Mavodelpar (REN001)  
 
Reneo Pharma Ltd. 
REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
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12. 
ANALYSIS OF SAFETY DATA 
All safety evaluations will be performed using each safety analysis set unless specified 
otherwise. 
As the nDNA-PMM subjects will only be recruited from a subset of the REN001-202 sites, 
summaries may also be presented only including mtDNA-PMM subjects from the same 
sites. Two separate sets of subjects may be used: the subjects who received mavodelpar in 
REN001-201 with their data from the start of REN001-201, and the subjects who received 
placebo in REN001-201 from the start of REN001-202. Consideration will be given to the 
duration of exposure for nDNA-PMM subjects when summarising the data from the 
mtDNA-PMM subjects (e.g., if the duration of exposure of nDNA-PMM subjects is up to 6 
months, only the first 6 months of data for the mtDNA-PMM subjects will be used). 
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 administration 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.  
Any AEs reported prior to dosing in either REN001-201 or REN001-202 (for subjects 
enrolling at REN001-201 Exit, from REN001-101 or nDNA-PMM subjects) will be 
reported as pre-treatment AEs in the databases and will therefore not be reported as TE 
(checks will be made of the AE start date against the start of dosing). Subjects who receive 
placebo in REN001-201 will have their TE events reported in REN001-201 assigned to 
placebo. Any events that are ongoing at the start of REN001-202 will only be assigned to 
mavodelpar if they worsen in severity on or after the start of dosing in REN001-202.  
Note, any ongoing AEs at the end of REN001-201 for subjects enrolling at REN001-201 
W24 or REN001-201 FU will be recorded on the pre-treatment AE eCRF page for 
REN001-202; if the event resolves during REN001-202 the record will be updated. These 
events will be considered TE to the REN001-201 treatment. 
If an adverse event has a missing start date where the 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 
the stop date is before the start date of dosing, the date will be imputed as the day of 
informed consent and 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 based on the database that the AE was 
recorded in: 


Mavodelpar (REN001)  
 
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REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
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 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 
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. Summaries will be presented overall and split by time period looking at AEs 
reported (based on AE start date) in the first month (up to and including Day 28), 2-6 
months (Day 29 to Day 168 inclusive), 6-12 months (Day 169 to Day 336 inclusive) and 
>12 months (after Day 336). Summaries will be repeated for the subgroups  age (<65 
 
An overall summary 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 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.  
SOC and PT summaries of TEAEs by maximum severity (mild, moderate or severe) will 
be presented.   


Mavodelpar (REN001)  
 
Reneo Pharma Ltd. 
REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
Page 66 of 77 
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 REN001 treatment group (i.e., from start of REN001-201 and from start of 
REN001 treatment this will be the REN001 100 mg group, and from start of REN001-202 
this will be the mtDNA PMM Overall REN001 100 mg 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 last 
contact 
The listing will 
identify treatment emergent AEs, AESI and SAEs. The associated study (REN001-201 and 
REN001-202) of AE onset and the assigned treatment emergence period (pre-treatment, 
REN001-201 or REN001-202) will also be listed.  
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 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 using 
descriptive statistics. The summary will also be split by sex and baseline 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 
-
than a count of zero.  
Box plots of changes from baseline by visit and group will be presented for the clinical 
laboratory parameters hemoglobin, HbA1c, high density lipoprotein (HDL), low density 


Mavodelpar (REN001)  
 
Reneo Pharma Ltd. 
REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
Page 67 of 77 
lipoprotein (LDL), lymphocytes, leukocytes, platelets, neutrophils, vitamin D, calcium, 
CK, ALT, AST, BSAP and urine N-terminal telopeptide (NTx) values. The whiskers will 
display the 5th and 95th percentiles. For the reporting group from the start of REN001-202 
the box plot will be repeated for the overall mt-DNA-PMM versus nDNA-PMM groups 
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 by sex and baseline 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 
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) 
 
level 
Aldolase 
Normal baseline value and post > ULN 
Troponin I 
> ULN 
AST, total bilirubin and 
alkaline phosphatase) 
ALT or AST > 3 x ULN and 
Total bilirubin > 2 x ULN and 
 
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. 
i.e., ALT = 3 x ULN and 
total bilirubin = 2 x ULN, will be added. The plot will identify 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) 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. 
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 group and mutation type will be identified. 


Mavodelpar (REN001)  
 
Reneo Pharma Ltd. 
REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
Page 68 of 77 
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. 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. 
12.3. 
DUAL ENERGY X-RAY ABSORPTIOMETRY (DXA) SCAN 
Summaries of DXA data will only be presented from the start of REN001-202 and from 
the start of REN001 treatment. 
Observed, change from baseline and percent change from baseline values for the DXA 
endpoints will be summarized for the DXA set. The summary will be presented overall 
within the 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 set. 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 visits alongside one another for each group. The plot will be 
repeated by sex and menopausal status. 
For the DXA set, the study day of the follow-up DXA scans (Months 6, 30 and 54 relative 
to the start of REN001-201) will be summarized using descriptive statistics. 
12.4. 
VITAL SIGNS 
Observed and change from baseline values will be summarized by visit using descriptive 
statistics.  
Box plots of change from baseline by visit and group will be presented for 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 
systolic blood pressure of <10 mmHg, 
 mmHg or 
 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, 
 
 
<20 
 
 mmHg. 


Mavodelpar (REN001)  
 
Reneo Pharma Ltd. 
REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
Page 69 of 77 
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.  
12.5. 
ECG 
Observed and change from baseline values will be summarized by visit using descriptive 
statistics.   
A shift table from baseline to 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 
 
 
 
QTcF increase from baseline 
< 30 msec 
 
 
* Values of PCI. 
 
Observed and change from baseline values will be listed. The listing will identify 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 the 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.  


Mavodelpar (REN001)  
 
Reneo Pharma Ltd. 
REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
Page 70 of 77 
Eye examination data will be listed. Eye examination data will be listed separately - 
refraction, BCVA, pinhole visual acuity, slit lamp examination, cataract grading, 
tonometry and irido-corneal drainage angle assessment. 
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 (0, 1, 2, 3, >4) received at each visit 
 Documented COVID-19 prior to first dose and during the study 
All data will be listed. 


Mavodelpar (REN001)  
 
Reneo Pharma Ltd. 
REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
Page 71 of 77 
13. 
INTERIM ANALYSES 
An interim synoptic CSR will be prepared for this study to be included in the regulatory 
submission package. The data cut will be the date of the last subject last visit in REN001-
201 and the data will be extracted from the database after REN001-201 database has been 
locked. This CSR will include all REN001-202 data up to the data cut date and best efforts 
will be made to clean data up to this data cut date.  
There will be a reduced set of safety outputs generated after submission for the 120-day 
safety update which is required as part of the submission package. The final CSR will 
occur after all subjects have had the ability to complete REN001-202, the data has been 
cleaned and the database locked.  
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 is detailed in the REN001-202 SRC charter. The SRC review of safety data will 
be limited to data from REN001-202 and will not be combined with REN001-201 data. 
 


Mavodelpar (REN001)  
 
Reneo Pharma Ltd. 
REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
Page 72 of 77 
14. 
CHANGES FROM PLANNED ANALYSES SPECIFIED 
IN THE PROTOCOL 
None. 
 
 


Mavodelpar (REN001)  
 
Reneo Pharma Ltd. 
REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
Page 73 of 77 
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.  
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. 
Patient-Reported Outcomes Measurement Information System. Published February 28, 
2019. 
https://staging.healthmeasures.net/images/PROMIS/manuals/PROMIS_Fatigue_Scoring_
Manual.pdf 
 
 


Mavodelpar (REN001)  
 
Reneo Pharma Ltd. 
REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
Page 74 of 77 
APPENDIX 1  COUNTRY SPECIFIC PROTOCOL AMENDMENTS 
The following country specific protocol amendments have been approved for REN001-
202: 
Country 
Amendment, Version (Date) 
France 
Amendment 1, Version 1.0 (22nd December 2021) 
Germany 
Amendment 1, Version 1.0 (7th December 2021) 
Netherlands 
Amendment 1, Version 1.0 (12 July 2022) 
Germany 
Amendment 2, Version 2.0 (8 February 2023) 
Netherlands 
Amendment 2, Version 2.0 (1 February 2023) 
Germany 
Amendment 3, Version 3.0 (18 October 2023) 
The following country specific protocol amendments have been approved for REN001-
201: 
Country 
Amendment, Version (Date) 
Canada 
Amendment 3, Version 4.0 (21st March 2021)  
France 
Amendment 3, Version 4.0 (1st April 2021) 
Germany 
Amendment 3, Version 4.0 (20th May 2021) 
Canada 
Amendment 4, Version 5.0 (29th June 2022)  
France 
Amendment 4, Version 5.0 (29th June 2022) 
Germany 
Amendment 4, Version 5.0 (29th June 2022) 
 
 
 
 


Mavodelpar (REN001)  
 
Reneo Pharma Ltd. 
REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
Page 75 of 77 
APPENDIX 2  REN001-201 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 
 


Mavodelpar (REN001)  
 
Reneo Pharma Ltd. 
REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
Page 76 of 77 
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) 
Urine NTX 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
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 
 
 
 
 
 
 
 
 
 
 
 
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. 
 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.  


Mavodelpar (REN001)  
 
Reneo Pharma Ltd. 
REN001-201 & REN001-202 
Statistical Analysis Plan  
Version 2.0 
 
Page 77 of 77 
5. 
uestionnaires, 
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. 
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.