Clinical trial NCT04641962
Conditions: Primary Mitochondrial Myopathy
Keywords: ASP0367 fatigue exercise intolerance muscle weakness Primary Mitochondrial Myopathy
Sponsor: Astellas Pharma Inc
Start date: 2021-05-24; Completion date: 2024-05-08
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the dose response of Bocidelpar on functional improvement relative to placebo, safety, and tolerability in participants with Primary Mitochondrial Myopathy.

Detailed description:
Efficacy (i.e., functional improvement) was assessed by a functional motor test, 6-minute walk test (6MWT). The study consisted of the following portions: screening (4 weeks); double-blind treatment period with 2 doses of Bocidelpar vs matching placebo (24 weeks) and follow up (4 weeks).

Participants were randomly placed into 1 of 3 arms (Bocidelpar 30 mgs, Bocidelpar 75 mgs or placebo).

Arms: arm 1: Participants received Bocidelpar 30 milligrams (mgs) orally once daily during the double blind treatment period. The Participants were followed up for another 4 weeks after the completion of treatment period. arm 2: Participants received Bocidelpar 75 mg orally once daily during the DB treatment period.. The Participants were followed up for another 4 weeks after the completion of treatment period. arm 3: Participants received Bocidelpar matching placebo orally once daily during the DB treatment period and received 30 mg ASP0367 in the OLE period. arm 4: Participants received Bocidelpar 30 mg or 75 mg orally once daily during the DB treatment period and received 30 mg Bocidelpar in the OLE period.
Interventions: intervention 1: Bocidelpar intervention 2: Placebo
Intervention descriptions: intervention 1: Oral intervention 2: Oral

Protocol documents:
Prot_000.pdf: 
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A Randomized, Double-blind, Placebo-controlled  
Phase 2 Study to Assess the Efficacy, Safety and Tolerability of 
ASP0367 in Participants  
with Primary Mitochondrial Myopathy 
 
MOUNTAINSIDE 
ISN/Protocol 0367-CL-1201 
Version 9.0 
Incorporating Substantial Amendment 8 
24 Jan 2024 
IND 146773 
 
Sponsor: 
Astellas Pharma Inc. 
2-5-1, Nihonbashi-Honcho, Chuo-Ku, 
Tokyo 103-8411, Japan 
 
Protocol History: 
Version 1.0 [05 May 2020] 
Version 1.1 Incorporating Nonsubstantial Amendment 1 [13 Jul 2020] 
Version 1.2 Incorporating Nonsubstantial Amendment 2 [30 Jul 2020] 
Version 2.0 Incorporating Substantial Amendment 1 [21 Sep 2020] 
Version 2.1 Incorporating Nonsubstantial Amendment 3 [28 Sep 2020] 
Version 2.2 Incorporating Nonsubstantial Amendment 4 [01 Oct 2020] 
Version 3.0 Incorporating Substantial Amendment 2 [02 Dec 2020] 
Version 3.1 Incorporating Nonsubstantial Amendment 5 [02 Mar 2021] 
Version 4.0 Incorporating Substantial Amendment 3 [07 May 2021] 
Version 5.0 Incorporating Substantial Amendment 4 [05 Nov 2021] 
Version 6.0 Incorporating Substantial Amendment 5 [17 Mar 2022] 
Version 7.0 Incorporating Substantial Amendment 6 [10 Nov 2022] 
Version 8.0 Incorporating Substantial Amendment 7 [24 Apr 2023] 
Version 8.1 Incorporating Nonsubstantial Amendment 6 [06 Jul 2023] 
The information contained in this document is supplied as a background for clinical investigations. This document contains 
confidential information, which is the intellectual property of Astellas. By accepting or reviewing this document, you agree 
to hold this information in confidence and not copy or disclose it to others or use it for unauthorized purposes except (1) as 
otherwise agreed to in writing; (2) where required by applicable law; (3) where disclosure is directly related to the care and 
safety of the research participant; and (4) where disclosure of such information is made to a member of the investigator’s 
team who agrees to hold this information in confidence.   


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Table of Contents 
SIGNATURES ································································································ 9 
CONTACT DETAILS OF SPONSOR’S KEY PERSONNEL ····································· 11 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ······································· 12 
1 
PROTOCOL SUMMARY ······································································· 26 
1.1 
Synopsis ························································································ 26 
1.2 
Study Schema ·················································································· 30 
1.3 
Schedule of Assessments ····································································· 31 
1.3.1 
Sample Collection Schedule ··························································· 34 
2 
INTRODUCTION ················································································· 35 
2.1 
Study Rationale ················································································ 35 
2.2 
Background ···················································································· 35 
2.2.1 
Mitochondria Diseases and Primary Mitochondrial Myopathy ···················· 35 
2.2.2 
Unmet Medical Need ··································································· 36 
2.2.3 
ASP0367 Development ································································· 36 
2.2.3.1 
Nonclinical ········································································· 36 
2.2.3.2 
Clinical ·············································································· 38 
2.3 
Risk/Benefit Assessment ····································································· 40 
2.3.1 
Risk Assessment ········································································· 40 
2.3.1.1 
Nonclinical ········································································· 40 
2.3.1.2 
Clinical ·············································································· 41 
2.3.1.3 
Cardiac and Skeletal Muscle ····················································· 43 
2.3.2 
Benefit Assessment ····································································· 44 
2.3.3 
Overall Risk-Benefit Conclusion ······················································ 44 
3 
OBJECTIVES, ENDPOINTS AND ESTIMANDS ········································· 44 
4 
STUDY DESIGN AND DOSE RATIONALE ················································ 46 
4.1 
Overall Study Design ········································································· 46 
4.2 
Scientific Rationale for Study Design ······················································ 47 
4.2.1 
Summary of Changes to Study Design ··············································· 47 
4.3 
Dose Rationale ················································································ 48 
4.4 
End of Study Definition ······································································ 49 
5 
STUDY POPULATION ·········································································· 49 
5.1 
Inclusion Criteria ·············································································· 49 


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5.2 
Exclusion Criteria ············································································· 50 
5.3 
Lifestyle Considerations ······································································ 52 
5.4 
Screen Failures ················································································ 52 
5.4.1 
Rescreening ·············································································· 53 
6 
INVESTIGATIONAL PRODUCT(S) ························································· 54 
6.1 
Investigational Product(s) Administered ··················································· 54 
6.2 
Preparation/Handling/Storage/Accountability ············································· 55 
6.2.1 
Packaging and Labeling ································································ 55 
6.2.2 
Handling, Storage and Accountability ················································ 55 
6.3 
Randomization and Blinding ································································ 56 
6.3.1 
Blinding Method ········································································· 56 
6.3.2 
Confirmation of the Indistinguishability of the Investigational Product ·········· 56 
6.3.3 
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking ·················································································· 56 
6.3.4 
Breaking the Treatment Code for Emergency ······································· 56 
6.3.5 
Breaking the Treatment Code by the Sponsor ······································· 57 
6.3.6 
Assignment and Allocation····························································· 57 
6.4 
Investigational Product Compliance ························································ 57 
6.5 
Dose Modification ············································································ 57 
6.6 
Continued Access to Investigational Product After the End of the Study ·············· 58 
6.7 
Treatment of Overdose ······································································· 58 
6.8 
Concomitant Therapy ········································································· 58 
6.8.1 
Previous and Concomitant Treatment ················································· 58 
6.8.2 
Prohibited Concomitant Treatment ···················································· 58 
6.8.3 
Restricted Concomitant Treatment ···················································· 59 
6.8.4 
Other Restrictions ······································································· 59 
7 
STUDY PROCEDURES AND ASSESSMENTS ············································ 59 
7.1 
Efficacy Assessments ········································································· 59 
7.1.1 
6-minute Walk Test ····································································· 59 
7.1.2 
5 Times Sit to Stand ····································································· 60 
7.1.3 
Quality of Life in Neurological Disorders ············································ 60 
7.1.4 
Modified Fatigue Impact Scale ························································ 60 
7.1.5 
Patient Global Impression of Change ················································· 61 
7.1.6 
The Patient Global Impression of Severity ··········································· 61 


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7.1.7 
5-level EQ-5D Version (EQ-5D-5L) ·················································· 61 
7.1.8 
Primary Mitochondrial Myopathy Video Assessments ····························· 61 
7.1.9 
Individualized Activity Assessments·················································· 61 
7.1.10 
Qualitative Interview ···································································· 62 
7.2 
Safety Assessments ··········································································· 62 
7.2.1 
Laboratory Assessments ································································ 62 
7.2.2 
Vital Signs ················································································ 63 
7.2.3 
Physical Examination ··································································· 63 
7.2.4 
Electrocardiogram ······································································· 63 
7.2.5 
Echocardiogram ········································································· 64 
7.2.6 
Body Weight ············································································· 64 
7.2.7 
Columbia-Suicide Severity Rating Scale ············································· 64 
7.2.8 
Order of Assessments ··································································· 64 
7.3 
Adverse Events and Other Safety Aspects ················································· 66 
7.3.1 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information····························································· 66 
7.3.2 
Method of Detecting Adverse Events and Serious Adverse Events ··············· 67 
7.3.3 
Follow-up of Adverse Events and Serious Adverse Events ························ 67 
7.3.4 
Regulatory Reporting Requirements for Serious Adverse Events ················· 67 
7.3.5 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events ·········································· 68 
7.3.6 
Adverse Events of Special Interest ···················································· 68 
7.3.7 
Special Situations ········································································ 68 
7.4 
Pharmacokinetics ·············································································· 69 
7.4.1 
Analysis of ASP0367 in Plasma ······················································· 69 
7.5 
Pharmacodynamics ··········································································· 69 
7.6 
Pharmacogenomics ··········································································· 69 
7.6.1 
Sample for Genotyping ································································· 69 
7.6.2 
Sample for Banked Pharmacogenomics ·············································· 70 
7.7 
Biomarkers ····················································································· 70 
7.7.1 
Urine Sample Analysis for TITIN ····················································· 70 
7.7.2 
Blood Sample for Serum Target Proteins ············································ 70 
7.8 
Immunogenicity Assessments ······························································· 70 
7.9 
Electronic Clinical Outcome Assessment ·················································· 70 
7.9.1 
Quality of Life in Neurological Disorders ············································ 71 


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7.9.2 
Modified Fatigue Impact Scale ························································ 71 
7.9.3 
Patient Global Impression of Change ················································· 71 
7.9.4 
Patient Global Impression of Severity ················································ 71 
7.9.5 
Columbia-Suicide Severity Rating Scale ············································· 71 
7.9.6 
European Quality of Life 5-Dimension, 5-Level Questionnaire ··················· 71 
7.9.7 
Primary Mitochondrial Myopathy Video Assessments ····························· 71 
7.9.8 
Individualized Activity Assessments·················································· 71 
7.9.9 
Qualitative Interview ···································································· 72 
7.10 
Other Assessments ············································································ 72 
7.10.1 
Exercise Status ··········································································· 72 
7.11 
Total Amount of Blood ······································································· 72 
8 
PARTICIPANT DISCONTINUATION ······················································ 73 
8.1 
Discontinuation of Individual Participant(s) from Study Treatment ···················· 73 
8.2 
Discontinuation of Individual Participant(s) from Study ································· 74 
8.3 
Lost to Follow-up ············································································· 74 
9 
STATISTICAL CONSIDERATIONS ························································· 75 
9.1 
Statistical Hypotheses ········································································ 75 
9.2 
Sample Size Determination ·································································· 75 
9.3 
Populations for Analyses ····································································· 76 
9.4 
Statistical Analyses ··········································································· 76 
9.4.1 
General Considerations ································································· 77 
9.4.2 
Analysis of Efficacy ····································································· 77 
9.4.2.1 
Analysis of Primary Endpoint ···················································· 77 
9.4.2.2 
Sensitivity Analysis/Supplementary Analysis ·································· 78 
9.4.2.3 
Analysis of Secondary Endpoints ················································ 78 
9.4.2.4 
Analysis of Exploratory Endpoints ·············································· 78 
9.4.3 
Analysis of Safety ······································································· 79 
9.4.3.1 
Adverse Events····································································· 79 
9.4.3.2 
Laboratory Assessments ·························································· 79 
9.4.3.3 
Vital Signs ·········································································· 79 
9.4.3.4 
Body Weight ······································································· 80 
9.4.3.5 
Electrocardiogram ································································· 80 
9.4.3.6 
Echocardiogram ···································································· 80 
9.4.3.7 
Columbia-Suicide Severity Rating Scale ······································· 80 


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9.4.4 
Analysis of Pharmacokinetics ·························································· 80 
9.4.5 
Analysis of Pharmacodynamics ······················································· 80 
9.4.5.1 
Analysis of Treatment-emergent Gene Expression ···························· 81 
9.4.5.2 
Estimation of Pharmacodynamic Parameters ··································· 81 
9.4.6 
Other Analyses ··········································································· 81 
9.4.6.1 
Analysis of Biomarkers ··························································· 81 
9.4.6.2 
Analysis of Genotyping ··························································· 81 
9.4.6.3 
Exposure-response Analysis ······················································ 81 
9.5 
Additional Conventions ······································································ 81 
9.6 
Interim Analysis ··············································································· 82 
9.6.1 
Interim Analysis of Efficacy ··························································· 82 
9.6.2 
Interim Analysis of Pharmacokinetics and Pharmacodynamics ··················· 82 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ············································································· 84 
10.1 
Appendix 1: Ethical, Regulatory and Study Oversight Considerations ················· 84 
10.1.1 
Regulatory and Ethical Considerations ··············································· 84 
10.1.2 
Financial Disclosure ···································································· 84 
10.1.3 
Informed Consent of Participants······················································ 84 
10.1.3.1 
Informed Consent Process ························································ 84 
10.1.3.2 
Supply of New and Important Information Influencing the 
Participant’s Consent and Revision of the Written Information ············· 85 
10.1.4 
Data Protection ·········································································· 85 
10.1.5 
Committee(s) Structure ································································· 86 
10.1.5.1 
Data Monitoring Committees ···················································· 86 
10.1.6 
Dissemination of Clinical Study Data················································· 87 
10.1.7 
Data Quality Assurance ································································· 87 
10.1.8 
Source Documents ······································································ 87 
10.1.9 
Study and Site Start and Closure ······················································ 88 
10.1.10 
Arrangement for Use of Information and Publication of the Study ··············· 89 
10.1.11 
Quality Assurance ······································································· 89 
10.2 
Appendix 2: Contraception Requirements ················································· 90 
10.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting ······················································ 92 
10.3.1 
Definition of Adverse Events ·························································· 92 
10.3.1.1 
Abnormal Laboratory Findings ·················································· 92 


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10.3.1.2 
Potential Cases of Drug-induced Liver Injury ·································· 93 
10.3.2 
Definition of Serious Adverse Events················································· 93 
10.3.3 
Assessment of Causality ································································ 94 
10.3.4 
Assessment of Severity ································································· 96 
10.3.5 
Recording and Follow-Up of AEs and/or SAEs ····································· 96 
10.3.6 
Reporting Procedures for Serious Adverse Events ·································· 97 
10.3.7 
Reporting Procedures for Special Situations ········································· 98 
10.3.7.1 
Contraceptive Guidance and Collection of Pregnancy Information ········· 98 
10.3.7.2 
Medication Error, Overdose and “Off-label Use” ····························· 99 
10.3.7.3 
Suspected Misuse/Abuse of Investigational Product ·························· 99 
10.3.7.4 
Occupational Exposure ··························································· 99 
10.3.7.5 
Suspected Drug-drug Interaction ·············································· 100 
10.3.8 
Supply of New Information Affecting the Conduct of the Study ················ 100 
10.3.9 
Urgent Safety Measures ······························································ 100 
10.3.10 
Reporting Urgent Safety Measures ·················································· 100 
10.4 
Appendix 4: Liver Safety Monitoring and Assessment ································· 101 
10.5 
Appendix 5: List of Excluded Concomitant Medications ······························ 104 
10.6 
Appendix 6: Clinical Laboratory Assessments ·········································· 105 
10.7 
Appendix 7: Pharmacogenomic Analysis with Banked Sample ······················· 107 
10.8 
Appendix 8 Clinical Study Continuity ···················································· 109 
10.9 
Appendix 9 List of Normal Ranges for Selected Laboratory Assessments ·········· 113 
10.10 
List of Abbreviations and Definition of Key Study Terms ····························· 114 
11 
REFERENCES ·················································································· 119 
12 
COORDINATING INVESTIGATOR’S SIGNATURE ·································· 121 
13 
SPONSOR SIGNATURES ···································································· 122 
 
List of In-text Tables 
Table 1 
Schedule of Assessments ····································································· 31 
Table 2 
Sample Collection Schedule ································································· 34 
Table 3 
Study Objectives and Endpoints ····························································· 44 
Table 4 
Investigational Product(s) ···································································· 54 
Table 5 
Treatment Groups and Duration ····························································· 55 
Table 6 
Order of Assessments under Protocol Version 9.0 (Substantial Amendment 8 
and Subsequent Versions) ···································································· 65 
Table 7 
Blood Volume ················································································· 72 
Table 8 
Grading Scale Defining the Severity of an Adverse Event ······························· 96 


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Table 9 
Moderate and Severe Liver Abnormalities ··············································· 101 
Table 10 
Clinical Laboratory Tests ·································································· 105 
Table 11 
Alternative Schedule of Assessments in Response to a Crisis ························· 110 
 
List of In-text Figures 
Figure 1 
Study Level Schema ·········································································· 30 
 


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SIGNATURES 
1.  SPONSOR’S SIGNATURES 
Required signatures (e.g., protocol authors and contributors, etc.) are located in [Section 13 
Sponsor’s Signatures].  
 


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2.  INVESTIGATOR’S SIGNATURE 
A Randomized, Double-blind, Placebo-controlled Phase 2 Study to Assess the Efficacy, 
Safety and Tolerability of ASP0367 in Participants with Primary Mitochondrial 
Myopathy 
ISN/Protocol 0367-CL-1201 
Version 9.0, Substantial Amendment 8 
24 Jan 2024 
I have read all pages of this protocol for which Astellas is the sponsor. I agree to conduct 
the study as outlined in the protocol and to comply with all the terms and conditions set out 
therein. I confirm that I will conduct the study in accordance with International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
Good Clinical Practice (GCP) guidelines and applicable local regulations. I will also 
ensure that subinvestigator(s) and other relevant members of my personnel have access to 
copies of this protocol and the ICH GCP guidelines to enable them to work in accordance 
with the provisions of these documents. 
Principal Investigator: 
Signature: 
 
 
 
 
Date (DD-MMM-YYYY) 
Printed Name:  
  
 
Address of 
trial site: 
 
 
 
 
 
 
 
 
 




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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Date 
Nonsubstantial Amendment 6 
06 Jul 2023 
Substantial Amendment 7 
24 Apr 2023 
Substantial Amendment 6 
10 Nov 2022 
Substantial Amendment 5 
17 Mar 2022 
Substantial Amendment 4 
05 Nov 2021 
Substantial Amendment 3 
07 May 2021 
Nonsubstantial Amendment 5 
02 Mar 2021 
Substantial Amendment 2 
02 Dec 2020 
Nonsubstantial Amendment 4 
01 Oct 2020 
Nonsubstantial Amendment 3 
28 Sep 2020 
Substantial Amendment 1 
21 Sep 2020 
Nonsubstantial Amendment 2 
30 Jul 2020 
Nonsubstantial Amendment 1 
13 Jul 2020 
Original Protocol 
05 May 2020 
Amendment 8 [Substantial] Date 24 Jan 2024 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and 
the Council of the European Union and EU Clinical Trial Regulation. 
Overall Rationale for the Amendment: 
The primary rationale for this amendment is to align with the guidance from the FDA to limit the dosing period to no longer than 6 months while the 
nonclinical carcinogenicity study results are under review by the FDA. The double-blind treatment period will be shortened from 52 weeks to 24 weeks 
and the open-label extension period has been removed. 
 




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Section Number 
Description of Change 
Brief Rationale 
2.2.3.1, 2.3.1.1 
Update ASP0367 nonclinical development and risk 
assessment with carcinogenicity study results. 
To add results from histopathological examination in a 2-year 
carcinogenicity study in rats.  
2.3.1.3 
Update the following sentences: 
“Only participants with a cTnI level below upper limit 
(or above upper limit and as assessed as clinically 
insignificant by the investigator) and a mean QT 
interval using Fridericia’s correction (QTcF) of ≤ 450 
msec for male participants and ≤ 480 msec for female 
participants will be allowed into the study.” 
“Participants who experience any signs or symptoms 
potentially reflecting cardiac involvement cardiac 
complaints will undergo ECG, echocardiogram 
(ECHO), and have a cTnI drawn for further evaluation 
prior to continuing study drug.” 
To be consistent with the change to Exclusion Criterion #4 to 
provide clear exclusion to subjects who have an elevation in cTnI 
that may indicate the possibility of cardiac injury. 
2.3.3 
Update the overall benefit-risk conclusion. 
To clarify that the sponsor considers the overall benefit-risk to 
participants with PMM taking part in Study 0367-CL-1201 to be 
favorable. 


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Section Number 
Description of Change 
Brief Rationale 
5.1 
• Update Inclusion Criterion #4a to the following: 
“a. Molecular genetic abnormality (i.e., nuclear or 
mitochondrial) known to be associated with causing 
mitochondrial dysfunction (such as, but not limited 
to, mtDNA single, variable deletions in CPEO and 
KSS; mtDNA m.3243 A > G common mutation in 
MELAS; pathogenic nuclear or mitochondrial 
genome variants demonstrated to cause primary 
mitochondrial disease), and…” 
• Update Inclusion Criterion #5 to the following: 
“Participant has been on stable dose regimen of 
coenzyme Q10 (CoQ10), carnitine, creatine or other 
mitochondrial disease-focused vitamins or 
supplemental therapies for the treatment of 
symptoms of the mitochondrial disease for at least 
3 months prior to randomization and intends to stay 
on a stable dose for duration of study period (for 
participants who take any above-mentioned 
medications or supplements).” 
To clarify terminology regarding molecular genetic abnormalities 
associated with mitochondrial dysfunction and to clarify that a 
participant must have been on stable dose regimens for the 
treatment of symptoms of mitochondrial disease to be included in 
the study. 


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5.2 
• Update Exclusion Criterion #1 to the following: 
“Participant has additional signs and/or symptoms 
due to non-myopathic process (e.g., cerebellar 
dysfunctions, movement disorder, peripheral 
neuropathy, stroke or other) or a gait problem not 
attributed to the myopathy that would interfere/may 
in addition to the myopathy affectwith the 
participant’s performance during 6MWT or 5 times 
sit to stand (5XSTS), in the opinion of the 
investigator.” 
• Update Exclusion Criterion #4 to the following: 
“Participant has cTnI > ULN at screening and is 
assessed as clinically significant by the investigator.” 
• Update Exclusion Criterion #5 to the following: 
“Participant has estimated glomerular filtration rate 
(eGFR) calculated by the Chronic Kidney Disease 
Epidemiology Collaboration equation 
< 60 mL/min/1.73 m2 at screening or a history of 
chronic kidney disease stage 3 or greater.*” 
• Update Exclusion Criterion #6 to the following: 
“Participant has at screening**: total bilirubin (TBL) 
> ULN or transaminase(s) (aspartate 
aminotransferase [AST] or alanine aminotransferase 
[ALT]) > ULN in the absence of elevations in CK. 
Participants who have a slightly elevated TBL and/or 
ALT and/or AST and are suitable candidates for the 
study, per investigator’s opinion, can may be 
enrolled after discussion of the case with the 
medical monitor and completion ofin the study as 
long as the investigator can rule out any underlying 
To clarify several criteria for excluding participants from 
participation in the study. 


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liver dysfunction by running additional tests** and 
after further evaluation as warranteddiscussing 
the case with the medical monitor.” 
• Update Exclusion Criterion #14 to the following: 
“ECG evidence of acute ischemia, atrial fibrillation 
or active conduction system abnormalities. The 
following conduction system abnormalities may 
be with the exception permitted per the 
investigator’s discretion, only after discussing the 
case with the medical monitorof any of the 
following: …” 
• Update Exclusion Criterion #15 to the following: 
“Participant requires any ventilatory support, 
inclusive of any respiratory device to support 
breathing such as home ventilators and any form 
of non-invasive positive pressure ventilation 
(including continuous positive airway pressure 
[CPAP], bilevel positive airway pressure [BiPAP], 
and average volume-assured pressure support 
[AVAPS]). Participants who require oxygen 
therapy (even by low-flow nasal cannula [LFNC]) 
are not candidates for this study.” 
• Update Exclusion Criterion #25 to the following: 
“Participant has initiated the use of CoQ10, 
carnitine, creatine or other mitochondrial disease-
focused supplements for the treatment of 
symptoms of the mitochondrial disease within 3 
months prior to study randomization.” 
• Update Exclusion Criterion #30 to the following: 
“Participant has signs or symptoms of bulbar 


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Section Number 
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Brief Rationale 
weakness, such as dysphagia, dysphonia, 
hoarseness or drooling/sialorrhea, due to either 
neuropathy or myopathy.” 
Also, added the following reference to footnote *: 
“https://www.kidney.org/atoz/content/stages-
chronic-kidney-disease-ckd” 
7.2.4, 7.2.5 
Update text specifying that ECG and echocardiogram 
will be performed within 24 hours of any of these 
events: an elevation of cTnI above the ULN (see 
Appendix 10.9 for reference range), or when there is an 
elevation of cTnT above the ULN (see Appendix 10.9 
for reference range) or above the participant’s baseline 
value if it was elevated, or when a participant has any 
signs or symptoms reflecting cardiac involvement, 
inclusive of new onset shortness of breath. If the ECG 
or echocardiogram is within normal limits, a repeat of 
the abnormal troponin value (cTnI or cTnT) should be 
obtained. For any of the situations above, it may be 
required to interrupt or discontinue further 
administration of IP. Participants with persistent cTnI 
or cTnT elevations, abnormal ECG or abnormal 
echocardiogram should undergo cardiology follow up. 
To 
 to implement additional 
safety monitoring for all participants who experience troponin 
elevations. 
CCI


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Section Number 
Description of Change 
Brief Rationale 
7.3.6 
Update the first 2 bullets describing (S)AEs of special 
interest: 
● 
“Cardiac tissue injury, indicated by cTnI above 
ULN (see Appendix 10.9 for reference range) or 
if the cTnT is above ULN (see Appendix 10.9 for 
reference range) or baseline if the participant’s 
baseline value of cTnT was above ULN” 
● 
“Cardiac tissue injury with any signs or symptoms 
reflecting cardiac involvement, inclusive of new 
onset shortness of breath cardiac complaints 
confirmed by ECG and/or 
ECHOechocardiogram” 
 
To clarify the AEs of Special Interest and 
 
 to implement additional safety monitoring for 
all participants who experience troponin elevations. 
CCI


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8.1 
Update the following bullets describing how an 
individual participant may be required to discontinue 
further administration of IP if any of the following 
occurs, which is considered to be clinically significant 
and related to IP: 
• “Participant who experiences a cTnI elevation (i.e., 
> ULN [see Appendix 10.9 for reference range] or 
> his/her baseline value if the baseline value is > 
ULN) or a cTnT elevation above the ULN (see 
Appendix 10.9 for reference range) or above the 
participant’s baseline value if it was elevated 
should interrupt IP and undergo ECG and 
ECHOechocardiogram within 24 hours. The 
investigator should determine whether it is 
appropriate to continue administration of IP to 
the participant while the evaluations are being 
completed. If the ECG and ECHOechocardiogram 
are within normal limits, a repeat of the abnormal 
value (cTnI or cTnT) should be obtained. 
Participants with persistent cTnI or cTnT 
elevations, abnormal ECG or 
ECHOechocardiogram should interrupt IP and 
undergo cardiology follow up.” 
● “Participant who develops any signs or symptoms 
potentially reflecting cardiac involvement, 
inclusive of complaints (which should include new 
onset shortness of breath,) should interrupt IP and 
undergo ECG, ECHOechocardiogram, and have a 
cTnI drawn to be evaluated prior to continuing IP.” 
To clarify several criteria for discontinuation of individual 
participants from further administration of IP. 


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Section Number 
Description of Change 
Brief Rationale 
● “Participant who newly develops signs or 
symptoms of bulbar weakness, such as dysphagia, 
dysphonia, hoarseness or drooling/sialorrhea, 
should discontinue IP after a discussion with the 
medical monitor.” 
● “Participant with a new requirement for oxygen 
therapy or for ventilatory support, inclusive of 
any respiratory device to support breathing, such 
as home ventilators and any form of non-invasive 
positive pressure ventilation (including CPAP, 
BiPAP, and AVAPS), ventilatory requirements 
should discontinue IP after a discussion with the 
medical monitor.” 
 
9, 9.1, 9.2, 9.3, 9.4, 
9.4.1, 9.4.2, 9.4.2.1, 
9.4.2.2, 9.4.2.3, 9.4.2.4  
Update the analysis of efficacy to clarify that a 24-week 
treatment analysis will be the primary focus. Available 
data collected after the 24-week double-blind period for 
participants who may have a treatment duration of up to 
76 weeks if enrolled in the study prior to 
implementation of Protocol Version 9.0 (Substantial 
Amendment 8) will be summarized and details 
provided in a separate statistical analysis plan. 
To best derive evidence of efficacy for ASP0367 to support a 
proof-of-concept declaration. 
 
 
 


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Nonsubstantial Changes 
Section Number 
Description of Change 
Brief Rationale 
1.1 
Update text to state that there will be up to 
approximately 25 sites in the United States. 
To clarify the planned location of the study sites. 
1.1, 4.1 
Update text to clarify that an independent Data and 
Safety Monitoring Board (DSMB) will review safety 
data as currently described in the protocol and a 
separate Data Monitoring Committee (DMC) for 
interim analysis, comprised of Astellas internal 
members, will assess the futility and efficacy of the 
study treatments and make recommendations about the 
ongoing conduct of the study. The previous detailed 
description of the DMC is removed, and reference links 
are provided in the text to details regarding the structure 
and role of each committee. An interim analysis of 
pharmacokinetic and pharmacodynamic data will also 
be reviewed by the DMC. 
To clarify that the study will utilize a DSMB to review safety 
data and a separate DMC for the interim analysis.  
1.3 (Table 1) 
Update the Schedule of Assessments. 
To align with the revised study design and assess relevant 
parameters for efficacy and safety monitoring. 
1.3 (Table 1), 7.2.4 
Remove the ECG performed at the participant’s home 
at week 4 and add ECGs at the study site visits at week 
4 and week 28 (follow-up period). 
To align with the revised study design and optimize the ECG 
schedule during the study. 
1.1, 1.3 (Table 1), 1.3.1 
(Table 2), 3 (Table 3), 
7.2.8 (Table 6), 7.11 
(Table 7) 
Update the pharmacokinetic (PK) sample collection 
schedule. 
To align with the revised study design and to optimize the PK 
sampling schedule. 


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Section Number 
Description of Change 
Brief Rationale 
1.1, 9, 9.1, 9.2, 9.6, 
9.6.1, 9.6.2 
Add text specifying that an interim analysis will occur 
after 24 weeks of double-blind treatment to evaluate 
futility and efficacy of the primary endpoint and update 
the interim analysis section by adding a subsection for 
“Interim Analysis of Efficacy” and a subsection for 
“Interim Analysis of Pharmacokinetics and 
Pharmacodynamics.” 
To specify the interim analyses that will be performed to decide 
if the study should continue based on efficacy data and the 
interim analysis of Pharmacokinetics and Pharmacodynamics 
data to help understand the results of the interim analysis for 
futility and efficacy. 
2.2.3.2, 2.3.1.2 
Update text with additional completed clinical studies. 
To add results from 3 completed clinical studies. 
4.3, 6.3.3 
Update text to clarify that an independent DSMB will 
be utilized to review safety and tolerability data.  
To clarify that the DSMB for safety will assess overall safety and 
tolerability. 
6.3.3 
Add text to clarify that the DMC will be provided with 
access to the treatment assignment for review of the 
interim analysis data, and that its operation will be 
documented in the DMC Charter. 
To clarify that the DMC will be provided with access to the 
treatment assignment for review of the interim analysis data. 
6.8.3 
Update text to be consistent with the revision to 
Exclusion Criterion #25.  
To clarify restricted concomitant treatments. 
7.1, 7.9 
Reorder the efficacy assessment and electronic clinical 
outcome assessment subheadings. 
To clarify the description of the efficacy and electronic clinical 
outcome assessments. 
7.11 (Table 7) 
Update with a revised number of samples and 
approximate total volume. 
To reflect changes in study design. 
9.4.2.3 
Text is updated to categorize participants with a PGIC 
score of 3 (Minimally Improved) as responders. 
To clarify that minimal improvement in PGIC score is also 
considered a response. 


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Brief Rationale 
9.4.3.1 
Remove the heading for “24-week Treatment Analysis” 
and replace with “Adverse Events” and update the 
definition of treatment-emergent adverse event (TEAE) 
to account for participants who consented for this study 
in Protocol Version 7.0 or former version and did not 
re-consent to Protocol Version 8.0 or later version by 
week 24, or who consented or re-consented to this study 
in Protocol Version 8.0 or later version by week 24. 
Also, remove the section describing the “76-week 
Treatment Analysis.” 
To clarify the TEAE definition and to align safety analysis text 
with the revised study design. 
9.4.4 
Revised text summarizing the analysis of 
pharmacokinetics and added text referencing the 
statistical analysis plans (SAPs) for details regarding 
the calculation of the pharmacokinetic parameters.  
To clarify the analysis of pharmacokinetics. 
9.4.5 
Added text describing that the analysis of 
pharmacodynamics data for participants enrolled prior 
to implementation of Protocol Version 9.0 (Substantial 
Amendment 8) will differ from analysis of data for 
participants enrolled starting with Protocol Version 9.0 
(Substantial Amendment 8). 
To clarify the analysis of pharmacodynamics. 
9.4.5.1 
Update the section heading to “Analysis of Treatment-
emergent Gene Expression” and replace Section 9.4.5.2 
with “Estimation of Pharmacodynamic Parameters.” 
To clarify the analysis of pharmacodynamics. 
9.4.6.1, 9.4.6.2, 9.4.6.3 
Update text to clarify that biomarker data and 
polymorphisms of genes may be summarized 
graphically and/or descriptively.  
Update text to clarify exposure-response analysis. 
To clarify analyses of biomarkers, genotyping and exposure-
response. 


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10.1.5.1, 10.1.5.1.1, 
10.1.5.1.2 
Add text specifying that an independent DSMB will be 
established to review safety data and a separate DMC 
for the interim analysis. Details regarding the structure 
and role of each committee are included in Sections 
10.1.5.1.1 and 10.1.5.1.2, respectively. 
To clarify that the study will utilize a DSMB to review safety 
data and a separate DMC for the interim analysis, and to provide 
details regarding the operation of each committee. 
10.8 (Table 11) 
Add Neuro-QoL Short Form Lower Extremity Function 
(Mobility), MFIS, PGIC, and PGIS to the list of critical 
assessments in the alternative schedule of assessments 
in response to a crisis. 
To include the continuation of assessment for these efficacy 
endpoints. 
10.9 
Added Appendix 9 List of Normal Ranges for Selected 
Laboratory Assessments. 
To 
 to implement additional 
safety monitoring for all participants who experience troponin 
elevations. 
Throughout 
Minor administrative-type changes (e.g., typos, format, 
abbreviations, numbering and consistency throughout 
the protocol) and updates to abbreviations in tables and 
list of abbreviations.  
To provide clarifications to the protocol and to ensure complete 
understanding of study procedures. 
 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Title of Study:   
A Randomized, Double-blind, Placebo-controlled Phase 2 Study to Assess the Efficacy, Safety and 
Tolerability of ASP0367 in Participants with Primary Mitochondrial Myopathy 
Planned Study Period:  
From approximately 2Q2021 to 2Q2026 
Study Objectives, Endpoints and Estimands:  
The study objectives and endpoints are outlined in the table below.  
Objectives 
Endpoints 
Primary 
● 
To assess the dose response of ASP0367 
on functional improvement relative to 
placebo 
● 
Change from baseline in distance walked 
on the 6MWT at week 24 
● 
To assess the safety and tolerability of 
ASP0367 relative to placebo 
● 
Safety and Tolerability through week 24 
and end of study: 
o Nature, frequency and severity of 
TEAEs 
o Vital signs 
o Weight 
o 12-lead ECG 
o Clinical laboratory tests (hematology, 
biochemistry [including serum 
cardiac troponin I] and urinalysis) 
o C-SSRS 
Secondary 
● 
To assess the dose response of ASP0367 
on functional improvement and fatigue 
relative to placebo 
● 
Change from baseline in Neuro-QoL 
Short Form Fatigue and Lower Extremity 
Function (Mobility) scores at week 24 
● 
Change from baseline in time spent on the 
5XSTS at week 24 
● 
Change from baseline in MFIS at week 24 
● 
To assess the effect of ASP0367 in 
overall participant functioning relative to 
placebo 
● 
PGIC scores at week 24 
● 
Change from baseline in PGIS scores at 
week 24 
Exploratory 
● 
To assess the pharmacokinetics of 
ASP0367 
● 
Plasma ASP0367: Ctrough at weeks 12 and 
24 and population pharmacokinetics 
● 
To assess the exposure-response 
relationship of ASP0367 
● 
Relationship between measured- and 
model-based pharmacokinetic exposure 
parameters (e.g., Ctrough, Cave, ss) of 
ASP0367 and endpoints of efficacy, 




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Estimands 
Primary estimand will be defined by the following 5 attributes: 
● 
Treatment: ASP0367 or placebo 
● 
Population: Participants with Primary Mitochondrial Myopathy (PMM), as defined by the 
inclusion/exclusion criteria of the study. 
● 
Endpoint: Change from baseline in distance walked on the 6-minute walk test (6MWT) at 
week 24. 
● 
Intercurrent events and their corresponding strategies (see table below). 
● 
Population level summary: Difference in change from baseline in distance walked on the 
6MWT at week 24 between ASP0367 group and placebo group. 
 
Intercurrent Events 
Strategies to Handle Intercurrent Events 
Treatment 
Discontinuation Due 
to Any Reason 
For those participants who discontinued treatment, all observations 
after treatment discontinuation (Date of Last Study Drug Taken + 7 
days) will be ignored. Analysis will be conducted assuming those 
participants remained assigned treatment and the condition that was 
observed before treatment discontinuation will continue, i.e., 
hypothetical strategy. 
Study 
Discontinuation 
For those participants who discontinued study, all observations after 
treatment discontinuation (Date of Last Study Drug Taken + 7 days) 
will be ignored. Analysis will be conducted assuming those participants 
remained assigned treatment and the condition that was observed before 
treatment discontinuation will continue, i.e., hypothetical strategy. 
Prohibited 
Concomitant 
Treatment Use 
For those participants who used the prohibited concomitant medication 
treatment, all observations will be included in the analysis, i.e., 
treatment policy strategy. 
Planned Total Number of Study Sites and Location(s): 
Up to approximately 25 sites in the United States. 
Study Population: 
Male and female participants (age 18 to < 65 years old) with PMM diagnosed by mitochondrial 
DNA (mtDNA) or nuclear DNA (nDNA) alterations, which are known to be associated with 
mitochondrial dysfunction, and by reported symptoms including muscle weakness, fatigue and 
exercise intolerance. 
Number of Participants: 
Approximately 66 randomized participants.  
Study Design Overview: 
This is a randomized, double-blind, placebo-controlled, oral dose, phase 2 study to evaluate the 
dose response of ASP0367 on functional improvement relative to placebo, safety and tolerability in 
participants with PMM.  Efficacy (i.e., functional improvement) will be assessed by a functional 
motor test, 6MWT. The study consists of the following portions: screening (4 weeks); double-blind 
treatment period with 2 doses of ASP0367 vs matching placebo (24 weeks); and follow-up 
(4 weeks).  
A 24-week treatment analysis of efficacy and safety will be the primary focus. Since participants 
enrolled in the study prior to implementation of Protocol Version 9.0 (Substantial Amendment 8), 
which removes the 52-week OLE period, may have a treatment duration of up to 76 weeks, a 






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1.3 
Schedule of Assessments 
Table 1 
Schedule of Assessments 
Assessments 
Screening 
Period 
Treatment Period 
Follow-up 
Period 
Double-blind Treatment (24 weeks) 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6
V7 
V8 
V9 
V10 
V11 
V12 
Week 
-4
0 
1 
2 
3 
4 
8 
12 
16 
20 
24 
28 
Day 
-28
-2 to 1c
8 
14 
22
29 
57 
85 
113 
141 
169/EOT_P
2d 
197/ 
EOSd
Visit window (days) 
-7 to +14
- 
± 3 
-2 to + 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
+ 7
Study site visita 
X 
X 
X 
X 
X 
X 
Follow-up phone callb 
X 
X 
X 
X 
X 
X 
Informed consent 
X 
Medical history 
X 
Demographics 
X 
On-site training for all endpoint 
assessments 
X 
Verify inclusion/ exclusion criteria 
X 
Xe 
Randomization 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
Height 
X 
Body weight 
X 
X 
X 
Vital signsf 
X 
Xe 
X 
X 
X 
X 
Hematology, biochemistry, 
urinalysisg
X 
X 
X 
X 
X 
X 
Abbreviated biochemistry and 
hematologyg 
X 
X 
X 
X 
X 
X 
Serology (hepatitis screening)
X 
Pregnancy test 
Xh 
Xe,i 
Xi 
Xi 
Xi 
Table continued on next page 
Footnotes


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Assessments 
Screening 
Period 
Treatment Period 
Follow-up 
Period 
Double-blind Treatment (24 weeks) 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6
V7 
V8 
V9 
V10 
V11 
V12 
Week 
-4
0 
1 
2 
3 
4 
8 
12 
16 
20 
24 
28 
Day 
-28
-2 to 1c
8 
14 
22
29 
57 
85 
113 
141 
169/EOT_P
2d 
197/ 
EOSd
Visit window (days) 
-7 to +14
- 
± 3 
-2 to + 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
+ 7
Study site visita 
X 
X 
X 
X 
X 
X 
Follow-up phone callb 
X 
X 
X 
X 
X 
X 
Urine drug and alcohol test 
X 
12-lead ECGj
X 
Xe 
X 
X 
X 
X 
X 
X 
C-SSRSk
X 
X 
X 
X 
X 
X 
6MWTl 
X 
X 
X 
X 
5XSTS 
X 
X 
X 
X 
Blood for plasma pharmaco-kineticsm
X 
X 
X 
Serum and urinary biomarkersn 
X 
X 
X 
Blood for pharmacodynamics (PPARδ 
target  
gene expression)o 
X 
X 
X 
Blood sample collection for 
genotyping  
X 
Blood sample collection for 
pharmaco-genomics (banking) 
X 
Patient reported outcomesp 
X 
X 
X 
X 
Dispense/ Collect IP 
X 
X 
X 
IP dosing 
X 
→
→
→
→
→
→
→
→
Previous and concomitant treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exercise statusq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
5XSTS: 5 time sit to stand; 6MWT: 6-minute walk test; ALDOA: aldolase A; CK: creatine kinase; C-SSRS: Columbia-Suicide Severity Rating Scale; CYC: cytochrome c; 
ECG: electrocardiogram; EOS: end of study; EOT_P2: end of treatment during double-blind treatment period; EQ-5D-5L: European Quality of Life 5-dimension, 5-level 
Footnotes


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questionnaire; FLNC: filamin-C; IP: investigational product; MB: isoenzymes found in heart muscle; MFIS: Modified Fatigue Impact Scale; MM: isoenzymes found in skeletal and 
heart muscle; Neuro-QoL: Quality of Life in Neurological Disorders; PGIC: Patient Global Impression of Change; PGIS: Patient Global Impression of Severity; PPARδ: peroxisome 
proliferator-activated receptor delta; QTcF: QT interval using Fridericia’s correction; WOCBP: women of childbearing potential 
a. 
All assessments at the study site visit may be performed over 2 to 3 days. Assessments scheduled for each study site visit should be completed within visit window. 
b. The site will perform follow-up phone call visits. Blood sample collection and ECG will be performed by qualified healthcare provider from the home healthcare vendor (ECG 
will be performed at weeks 2 and 8 only). In case the home healthcare visit is not feasible, the visit can be conducted at the study site. 
c. 
IP administration should be started after the completion of assessments at week 0, except for postdose blood sampling for pharmacokinetics. The day participants start taking the IP 
is considered as day 1. 
d. Participants who discontinue the study treatment will visit the site and perform EOT_P2 assessments. Participants will be encouraged to visit the study site for EOT_P2 
assessments as soon as the discontinuation of the study treatment. Participants who discontinue the study will be followed until the EOS visit. Participants who remain in the study 
for efficacy and safety evaluations will continue to follow the schedule of assessments without IP dosing. 
e. 
To be performed prior to randomization. 
f. 
Vital signs will be taken prior to blood draw. Blood pressure and pulse will be measured in the sitting or supine position after the participant has rested for at least 5 minutes. 
g. Safety laboratory will be done by a central laboratory from the screening to EOS. Blood collection for hematology and biochemistry; muscle biomarkers include CK, CK MM, 
CK-MB and cardiac troponins I and T. Urinary creatinine should be analyzed quantitatively like blood creatinine analysis that will be used for correcting urinary TITIN. 
Biochemistry and hematology samples will be taken prior to study assessment, except for ECG and vital signs. At follow-up phone call visits, abbreviated biochemistry (including 
cardiac troponin I) will be collected at the participant’s home (abbreviated hematology will only be collected at week 2) by a qualified healthcare provider from the home 
healthcare vendor. In case the home healthcare visit is not feasible, the visit can be conducted at the study site. 
h. Serum pregnancy tests will be performed for WOCBP. 
i. 
Urine pregnancy tests will be performed for WOCBP. 
j. 
ECGs should be performed prior to blood draw. ECGs will be recorded in triplicate (3 separate ECGs with 5-minute resting prior to first ECG and at least 1 minute apart per time 
point). In addition, ad hoc triplicate ECG may be required to follow up on an elevation of cTnI above the ULN (see Appendix 10.9 for reference range), or when there is an 
elevation of cTnT above the ULN (see Appendix 10.9 for reference range) or above the participant’s baseline value if it was elevated, or when a participant has any signs or 
symptoms reflecting cardiac involvement, inclusive of new onset shortness of breath. If the QTcF > 450 msec in male participants and > 480 msec in female participants at 
screening or randomization, one additional triplicate ECG can be performed on the same day in order to determine the participant’s eligibility. ECGs at weeks 2 and 8 will be 
performed at the participant’s home by a qualified healthcare provider from the home healthcare vendor. In case the home healthcare visit is not feasible, the visit can be conducted 
at the study site. 
k. At screening, the “Screening” version is to be used to determine eligibility. During all subsequent visits, the “Since Last Visit” version is used to monitor on-study suicidal ideation 
and behavior after the initial assessment. 
l. 
Following randomization, participants will be encouraged to perform all 6MWTs within a 2-hour window of the performance time recorded during visit 2. 
Footnotes continued on next page 


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m. A blood sample will be collected predose at week 12 (-90 minutes to 0 minutes before dosing) and predose at week 24. A blood sample will be collected postdose at week 0 
(Day 1) (0.5 to 4 hours after dosing) and postdose at week 12 (0.5 to 4 hours after dosing). For visits with postdose sample collections, site staff should document the type (high fat 
defined as ≥ 55 g fat, non-high fat defined as < 55 g fat or unknown) and completion time of the meal immediately prior to on-site dosing. Meal type and completion time are not 
collected at visits with only predose sample collection. A blood draw will be taken prior to study assessments, except for ECG and vital signs. The actual date and time of each 
blood sample collection and the actual date and time of IP administration on the site visit day and day before pharmacokinetics sampling visits will be collected. 
n. Serum biomarkers include FLNC, CYC and ALDOA. Urinary biomarker includes urinary TITIN. These samples will be taken prior to study assessment, except for ECG and vital 
signs. 
o. Blood samples for pharmacodynamics will be collected prior to dosing at weeks 0, 12 (-90 minutes to 0 minutes before dosing) and 24. A blood draw will be taken prior to study 
assessments, except for ECG and vital signs. Date and time of the last dose of IP before sampling (except for week 0) and the date and time of the dose of IP on day of sampling 
will be collected. 
p. Neuro-QoL measures of fatigue score and mobility score, MFIS score, PGIS and EQ-5D-5L will be assessed at weeks 0, 4, 12 and 24 at the study site. PGIC will be assessed at 
weeks 4, 12 and 24 at the study site. 
q. For the participants who are on exercise regimen, status of exercise regimen will be collected at each visit (on site or phone call). 
 
1.3.1 
Sample Collection Schedule 
Table 2 
Sample Collection Schedule 
Week 
Time Point 
Plasma pharmacokinetics 
Pharmacodynamics  
(PPARδ target gene expression) 
Genotyping 
PGx (banking) 
0 (Day 1) 
Predose  
 
X 
X 
X 
Postdose (0.5 to 4 h) 
X 
 
 
 
12 
Predose (-90 min to 0 min) 
X 
X 
 
 
Postdose (0.5 to 4 h) 
X 
 
 
 
24 
Predose  
X 
X 
 
 
h: hour; PGx: pharmacogenomics; PPARδ: peroxisome proliferator-activated receptor delta 
 


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2 
INTRODUCTION 
2.1 
Study Rationale 
Primary Mitochondrial Myopathies (PMMs) comprise a large heterogeneous group of 
disorders resulting from alterations in genes that affect mitochondrial function and lead to 
muscle disease. These diseases may be characterized by dysfunction in additional organ 
systems and extensive variability in clinical presentation. Currently, there is no approved 
treatment for mitochondrial myopathies.  
In skeletal and cardiac muscle, mitochondrial dysfunction contributes to poor energy 
production, increased lactate, decreased muscle repair, and increased inflammation. 
Peroxisome proliferator-activated receptor delta (PPARδ) is a nuclear receptor that, when 
activated, induces a transcriptional program that increases a cell’s capacity to transport and 
oxidize fatty acids, which can preserve glucose and decrease inflammation and fibrosis. 
 
Nonclinical data indicate that ASP0367: a) increases mitochondrial fatty acid oxidation 
(FAO) in normal and mitochondrial disease patient-derived fibroblasts; b) increases muscle 
function/distance run-in X-linked mutation of the murine dystrophin gene (mdx) mutant mice; 
c) improves locomotor activity impairment during the dark cycle in mouse model of mdx and 
diet-induced obesity; d) prevents cardiac function decline in aged mdx mice; and e) decreases 
running fatigue in aged, diet-induced obese (DIO) mice. ASP0367 was well-tolerated by 
healthy adult participants at doses up to 75 mg once daily for 14 days with an acceptable 
safety profile. Based on the nonclinical pharmacology data, as well as safety and tolerability 
profile observed in both nonclinical and phase 1 studies in humans, ASP0367 warrants 
further evaluation in PMM participants.  
2.2 
Background 
2.2.1 
Mitochondria Diseases and Primary Mitochondrial Myopathy 
Mitochondrial diseases are metabolic disorders mainly caused by pathogenic alterations in 
either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). The estimated prevalence of 
mitochondrial diseases is 1 in 4300 [Gorman et al, 2015]. Mitochondrial diseases affect 
multiple organ systems such as the nervous, muscular, cardiac and endocrine systems [Pfeffer 
& Chinnery, 2013]. Myopathy is not only one of the most prevalent manifestations but is also 
a very debilitating feature of these diseases because of weakness and exercise intolerance that 
impair mobility, as well as the capability of the patient to perform daily activities. In fact, a 
recent survey study performed on 2 independent cohorts of patients with PMM showed that 
among the symptoms experienced by patients, the principal symptoms motivating patients to 
participate in a clinical study were exercise intolerance, chronic fatigue and muscle weakness 
[Zolkipli-Cunningham et al, 2018]. 
Several primary mitochondrial syndromes such as chronic progressive external 
ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS), mitochondrial encephalomyopathy 
with lactic acidosis and stroke-like episodes (MELAS), and myoclonic epilepsy with 
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ragged-red fibers (MERRF) are well described and involve muscles and manifest with 
myopathy [de Barcelos et al, 2019]. Common clinical manifestations other than myopathy 
include diabetes, sensorineural hearing loss, optic atrophy, peripheral neuropathy, 
cardiomyopathy, nephropathy, hepatopathy, stroke-like episodes, seizures and dementia 
[Mancuso et al, 2017]. 
2.2.2 
Unmet Medical Need 
There are currently no approved disease-modifying therapies available for patients with 
PMM. Current treatment options aim at improving symptoms and typically include 
combinations of vitamin and supplements (typically referred to as mito-cocktail) and specific 
therapies that may have particular benefit for some genetic etiologies and/or shared 
phenotypes (e.g., arginine for metabolic strokes, creatine for metabolic myopathy); however, 
there is no clinical evidence for effectiveness of these treatments in patients with PMM 
[Montano et al, 2021; Barcelos et al, 2020; Ahmed et al, 2018; Mancuso et al, 2017]. 
2.2.3 
ASP0367 Development 
Refer to the Investigator’s Brochure for complete details of ASP0367 nonclinical and clinical 
studies conducted to date. 
Modulating PPARδ in patients with PMM is hypothesized to both benefit muscle metabolism 
and protect muscles from cell death. Through the targeting of FAO genes, ASP0367 is 
expected to increase the ability of patient muscle to utilize fatty acids thereby protecting it 
from exercise intolerance and fatigue. In addition, muscle myofiber loss may be reduced 
through improved mitochondrial function and turnover, improving the state of cellular stress 
that persists in PMM. Finally, ASP0367 is expected to reduce inflammation through various 
mechanisms such as release of the anti-inflammatory corepressor B-cell lymphoma 6, 
inhibition of nuclear factor kappa B, extracellular receptor kinase 1/2 and mitogen-activated 
protein kinase and induction of anti-inflammatory and antioxidant genes [Bishop-Bailey & 
Bystrom, 2009].  
2.2.3.1 Nonclinical 
In nonclinical studies, ASP0367 increased mRNA expression of PPARδ target genes in 
muscle cells and activated FAO in mouse myoblast C2C12 cells and in patient-derived 
fibroblasts with mitochondrial mutation including Leber hereditary optic neuropathy and 
Leigh syndrome, MELAS, KSS, and MERRF (additional details in the Investigator’s 
Brochure). 
ASP0367 was further tested in the DIO mouse model. Aged DIO mice were shown to present 
with reduced mitochondrial FAO and mitochondrial dysfunction in muscle and decreased 
exercise tolerance compared to wild type mice. DIO mice treated with ASP0367 had 
decreased exercise induced fatigue compared to vehicle-treated animals.  
Repeat-dose, Good Laboratory Practice (GLP), toxicity studies have been conducted up to 
11 weeks in juvenile rats, up to 26 weeks in adult Wistar Han rats (see 26-week adult rat 
study [doses up to 50 mg/kg per day] in the Investigator’s Brochure) and up to 52 weeks 


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(doses up to 500 mg/kg per day) in cynomolgus monkeys. In adult rats treated with ASP0367 
for 26 weeks, no tumors were observed. However, the incidence of hyperplasia of the 
limiting ridge of the non-glandular stomach and the incidence of hypertrophy/hyperplasia of 
the follicular cells in the thyroid gland were observed and the incidence increased in a 
dose-dependent manner. In the long-term toxicology study in monkeys treated with ASP0367 
for 52 weeks, no tumors or proliferative lesions were observed. Key toxicity findings with 
associated monitoring plans are summarized in [Section 2.3 Risk/Benefit Assessment].  
In the 2-year carcinogenicity study in rats, incidence of benign vaginal polyps and benign 
endometrial stromal polyps in the uterus were increased in females at 50 and ≥ 25 mg/kg per 
day, respectively. The incidence of benign vaginal polyps was not increased at 25 mg/kg per 
day. The increased incidence of benign endometrial stromal polyps at 25 mg/kg per day was 
significantly different compared with water control in 5 statistical tests but was not 
significantly different compared to vehicle control group in 4 of 5 statistical tests. The 
incidence of benign endometrial stromal polyps in the water control was below historical 
background control values. The incidence of benign endometrial stromal polyps at 25 mg/kg 
per day was within the range of historical background control values. Endometrial 
adenocarcinoma was observed in both control groups and all dose groups, however, there was 
no statistically significant difference between the controls and dose groups. Because the 
incidence of benign vaginal polyps at 25 mg/kg per day was not increased, and the incidence 
of benign endometrial stromal polyps at 25 mg/kg per day was within the range of historical 
background control values, the conclusion of this study is that this is the dose level at which 
no increased incidence of polyps occurred. The AUC24 at 25 mg/kg per day in rats was 16-
fold higher than the human AUC24 at 75 mg/day. For these reasons, the risk of human 
carcinogenicity is considered low at human doses up to 75 mg/day. 
ASP0367 showed no potential to induce genotoxicity or phototoxicity. 
With respect to cardiovascular function, ASP0367 caused a concentration-related inhibition 
of hERG channel-mediated potassium current in vitro in protein-free buffer, albeit with an 
IC50 of 44.4 µM (20400 ng/mL), which is 137 times the steady-state Cmax in human 
participants given ASP0367 at 75 mg/day in Study 0367-CL-0001. 
Daily oral administration of ASP0367 to rats did not affect fertility in either sex.  In addition, 
no findings were reported indicative of toxicity to male or female reproductive organs in 
repeat-dose toxicity studies in rats or monkeys. 
In studies in pregnant rats and rabbits dosed during the period of major organogenesis, 
ASP0367 was not teratogenic but did affect fetal growth and/or survival at higher dose levels.  
In a study of prenatal and postnatal development, including maternal function in rats, 
reduction in body weight gain/growth rate and lower survival were observed in F1 pups 
during the lactation period, which resolved after weaning. A few pups that died or were 
euthanized during the lactation period had bilateral lens opacity or a small caudate process in 
the liver. There were no detectable long-term effects, in particular on nervous or reproductive 


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system development, in F1 pups at any of the dose levels examined because ASP0367-related 
effects on F1 pups resolved when ASP0367 exposure ended at weaning. 
No human-specific ASP0367 metabolites were formed in vitro by hepatocytes.  Unchanged 
ASP0367 and 5 metabolites (including oxidative metabolites and acyl glucuronide conjugates 
of ASP0367) were detected in human plasma samples collected after repeated oral 
administration of ASP0367 to healthy adult participants.  The major metabolites of ASP0367 
in human clinical plasma samples are glucuronides.  Based on in vitro studies, multiple 
cytochrome P450 (CYP) and uridine diphosphate-glucuronosyltransferase (UGT) isoforms 
were suggested to be involved in the metabolism of ASP0367. CYP3A is the primary CYP-
mediated metabolism pathway. 
Based on results from in vitro studies, the risk of drug-drug interactions (DDI) with CYP1A2, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2D6 substrates is considered to be low. 
ASP0367 showed a time-dependent inhibition on CYP3A, but not on the other CYP 
isozymes examined. The anticipated concentrations with the ASP0367 doses in this study 
relative to the in vitro CYP3A inhibitory concentrations are low. Therefore, the risk of a DDI 
with concomitant administration of CYP3A substrates is considered to be low. 
In vitro, ASP0367 exhibited inhibitory effects on the transport of P-glycoprotein (P-gp), 
breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP)1B1, 
OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2 and 
multidrug and toxin extrusion (MATE)1 substrates; MATE2-K transport was not inhibited. 
Due to the anticipated concentrations in this study relative to the in vitro inhibitory 
concentrations, the likelihood of DDI with OAT1, OCT1, OCT2, MATE1 and MATE2-K is 
considered to be low. 
2.2.3.2 Clinical  
ASP0367 has been assessed in 4 completed phase 1 studies including first-in-human single 
ascending dose (SAD) and multiple ascending dose (MAD) (0367-CL-0001), absorption, 
metabolism and excretion (AME) (0367-CL-1103), hepatic impairment (0367-CL-1102) and 
renal impairment (0367-CL-1111) studies. Details and results from these studies are 
summarized in the Investigator’s Brochure. Overall, a total of 124 participants were exposed 
to ASP0367 in the completed phase 1 studies and ASP0367 was well-tolerated in all 
participants. No deaths or SAEs or TEAEs leading to withdrawal of treatment were reported 
across the completed phase 1 studies. 
ASP0367 has also been assessed in 1 completed phase 1b clinical study (0367-CL-0102) in 
late ambulatory and early non-ambulant participants with Duchenne Muscular Dystrophy 
(DMD). This phase 1b study included a 24-week double-blind (DB) part and a 12-week 
open-label extension (OLE) part. A total of 8 participants were exposed to ASP0367 in Study 
0367-CL-0102. No deaths, SAEs or TEAEs leading to withdrawal of treatment were 
reported. 
Relevant clinical findings with associated monitoring plans are summarized in [Section 2.3 
Risk/Benefit Assessment]. 


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ASP0367 showed roughly dose-proportional and time-invariant pharmacokinetics. After oral 
administration under fasted condition, ASP0367 was rapidly absorbed with median tmax 
reached by 2 hours postdose and eliminated with mean terminal elimination half-life of 
14.1 to 17.5 hours. Steady-state ASP0367 concentrations were achieved after approximately 
4 days of administration with negligible accumulation, following once-daily dosing. The 
exposure (AUCinf) of ASP0367 was not affected by high-fat meal. Cmax of ASP0367 was 
decreased by food consumption, as the Cmax geometric least squares mean fed/fasted ratio 
was 73.2%, with delayed tmax of approximately 1.7 hours compared to that observed when 
administered in the fasted state.  
In the AME study in healthy participants, the majority of the [14C]-radioactivity was 
recovered in feces (78.7%), with 13.8% recovered in urine. Only 0.0170% of the 
[14C]-radioactivity was excreted in urine as parent ASP0367, suggesting that the majority of 
urinary excretion was metabolites. ASP0367 and metabolites, AS3566736 (glucuronide 
metabolite) and AS3566737 (amidine metabolite), accounted for 64.4% of the total [14C]-
radioactivity in plasma. 
In participants with mild or moderate hepatic impairment, mild impairment increased Cmax 
and moderate impairment increased AUClast, AUCinf and Cmax of ASP0367 and its metabolite 
AS3566736, compared to the respective normal to match groups. 
In participants with severe renal impairment, severe impairment did not substantially affect 
the Cmax and AUCinf of ASP0367 or its metabolite AS3566736 (glucuronide metabolite); 
AS3566737 (amidine metabolite) AUCinf increased by approximately double in participants 
with severe renal impairment compared to matched healthy participants with normal renal 
function. 
Gene expression analysis in blood samples from healthy volunteers showed a similar pattern 
in PPARδ target gene upregulation as was observed in DIO mice and cells that harbor 
mutations in mtDNA. ASP0367, at doses of 10 mg or higher, showed consistent treatment- 
and dose-dependent up-regulation of the FAO-related PPARδ target genes (ABCA1, 
ACAA2, ACADVL, CPT1a, PDK4 and SLC25A20). The gene up-regulation was rapid after 
the administration of a single dose of ASP0367 and appeared to persist throughout the 24-
hour sampling period after the administration of multiple doses of ASP0367. Based on visual 
inspection of the results, the target gene up-regulation by ASP0367 on day 1 at doses of 10 
mg or higher showed consistent, treatment- and dose-dependent up-regulation and was 
suggestive of saturated dose-responses at higher dose levels and no major increments from 60 
mg or 75 mg to 120 mg. In addition, multiple doses of 10 mg ASP0367 or higher (40 mg and 
75 mg) appeared to have a dose-related effect on PPARδ target genes. 
The current study will be a randomized double-blind, placebo-controlled phase 2 study to 
evaluate the safety, tolerability, pharmacokinetics and efficacy of ASP0367 in participants 
with PMM 18 to < 65 years old. 


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2.3 
Risk/Benefit Assessment 
2.3.1 
Risk Assessment 
The safety profile of ASP0367 is based on the results of nonclinical studies and 2 clinical 
studies in healthy adult participants and participants with mild or moderate hepatic 
impairment. Please refer to the current Investigator’s Brochure for the most recent safety 
data. 
2.3.1.1 Nonclinical 
The toxicity profile of ASP0367 was similar in juvenile and adult rats, with effects targeting 
the heart; specifically, an increase in the incidence and/or the average grade of myocardial 
inflammation/necrosis in males, sometimes accompanied by an increased serum cardiac 
troponin I (cTnI) concentration. Myocardial inflammation/necrosis is a common, age-related 
background finding in male rats. The greater incidence and/or severity produced by 
administration of ASP0367 was not observed after dosing was stopped, suggesting the 
reversibility of these findings. 
In juvenile rats, there were no ASP0367-related effects on the development of organ systems 
that undergo postnatal development, such as the nervous, skeletal and reproductive systems. 
No microscopic kidney findings similar to those seen in the euthanized cynomolgus monkey 
(in the 13-week study) were observed in any animals (rats or monkeys) up to 13 weeks of 
daily dosing, and renal function safety markers were normal in all other animals.  
Nonclinical studies have identified the target organs of toxicity as the heart and skeletal 
muscle. In this phase 2 study in participants with PMM, cardiac (including cTnI, cardiac 
troponin T [cTnT] and creatine kinase [CK] isoenzymes found in heart muscle [CK-MB]) 
and skeletal muscle (including total CK and CK isoenzymes found in skeletal and heart 
muscle [CK-MM]) biomarkers indicative of damage will be measured frequently. 
The risk of carcinogenicity has not yet been fully evaluated. Histopathological examination 
from the carcinogenicity study in rats has been completed and another carcinogenicity study 
in mice is planned. During the longer-term toxicology studies in adult Wistar Han rats (up to 
26-weeks and doses up to 50 mg/kg per day) and in cynomolgus monkeys (up to 52-weeks 
and doses up to 500 mg/kg per day) no development of tumors was observed. However, in 
the 26-week rat study a dose-dependent increase in the incidence of hyperplasia of the 
limiting ridge of the non-glandular stomach and the incidence of hypertrophy/hyperplasia of 
the follicular cells in the thyroid gland were observed. In the monkey toxicology study, no 
proliferative lesions were observed during the course of this 52-week study. 
In the 2-year carcinogenicity study, Wistar Han (RccHan®: WIST) rats were treated with 
ASP0367 at dose levels of 0 (water), 0 (vehicle), 10, 25 and 50 mg/kg/day for 105 weeks. 
The histopathological data from this 2-year study comprised neoplastic observations, 
revealing statistically significant increases in benign vaginal polyps and benign endometrial 
stromal polyps, and statistically non-significant occurrences of endometrial adenocarcinoma. 


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● 
Benign vaginal polyps were observed in the water control and 50 mg/kg/day groups. The 
increased incidence of benign vaginal polyps in the 50 mg/kg/day group was statistically 
significant compared to the water and vehicle control groups.  
● 
Benign endometrial stromal polyps were observed at all dose levels, including the water 
and vehicle controls. The increased incidence of benign endometrial stromal polyps in 
the 25 and 50 mg/kg/day groups differed in statistical significance depending on the 
analysis. Of note, the overall rate of benign endometrial stromal polyps was within the 
range of historical control groups at the study sites for the 25 mg/kg/day group and 
slightly higher than historical control groups for the 50 mg/kg/day group. 
● 
Endometrial adenocarcinomas were observed at all dose levels, including water and 
vehicle controls. There were no statistically significant differences between ASP0367 
dose groups and the water or vehicle control groups. 
● 
No neoplastic findings were observed in the stomach or thyroid gland. 
There have been no reports of tumors in the female reproductive tract in the clinical study 
program to date. The safety margins for exposure at the dose levels administered to humans 
up to 75 mg/day compared to the exposure at the doses administered to rats are considered to 
be adequate in the ongoing Study 0367-CL-1201. Given the risk of carcinogenicity associated 
with the use of PPAR agonists and the neoplastic observations from the draft report for the 
2-year carcinogenicity rat study, administration of ASP0367 is currently limited to no longer 
than 6 months. 
In nonclinical safety pharmacology studies, ASP0367 revealed no effects on central nervous 
system or respiratory system function in rats at doses up to 300 mg/kg. Although ASP0367 
inhibited the hERG channel current in hERG transfected HEK293 cells, no QT prolongation 
or other effect on the cardiovascular system was discernable in cynomolgus monkeys at doses 
up to 1000 mg/kg. There was no evidence of genotoxic potential with ASP0367 based on the 
findings from a standard battery of genotoxicity assays. ASP0367 showed no phototoxic 
potential in an in vitro phototoxicity study in cultured Balb/c 3T3 cells. 
ASP0367 is considered unlikely to affect fertility in humans as daily oral administration of 
ASP0367 to rats did not affect fertility in either sex. Studies in pregnant rats and rabbits 
dosed during the period of major organogenesis suggest that ASP0367 is not teratogenic but 
may have the potential to affect fetal growth and/or survival in humans. Any potential 
embryofetal risks will be mitigated by enrolling participants under instruction of intensive 
control of pregnancy risk over the study duration. 
2.3.1.2 Clinical 
ASP0367 has been assessed in 4 completed phase 1 clinical studies (0367-CL-0001, 0367-
CL-1102, 0367-CL-1103 and 0367-CL-1111). ASP0367 was well tolerated in the healthy 
adult participants and participants with mild or moderate hepatic and severe renal 
impairment. There were no deaths and no serious adverse events (SAEs) reported. Also, there 
were no discontinuations due to treatment-emergent adverse events (TEAEs). All adverse 
events (AEs) were transient and mild or moderate in severity. No drug-related cardiac or 
skeletal muscle AEs were reported.  


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In the first-in-human Study 0367-CL-0001, one participant at the single dose of 60 mg had 
cTnI values above the upper limit of normal (ULN; 0.056 ng/ml and 0.047 ng/mL above the 
ULN of 0.045 ng/mL) at the end of study visit (8 days after a single dose) and repeat 
assessment poststudy on day 21, respectively, with no clinical signs associated and deemed 
not clinically relevant. There was no test article-related elevation in serum cTnT; CK-MB 
stayed within the normal range, and no participants were observed with ischemic changes or 
prolonged QT. Amylase and lipase elevations above the laboratory reference range were 
observed for a number of participants following administration of ASP0367 or placebo. 
There were no trends for treatment or dose, or day of onset-related trends in the frequency or 
magnitude of these elevations. The participants with amylase or lipase elevations remained 
asymptomatic and the elevations resolved without treatment. None of the amylase or lipase 
elevations were reported as TEAEs. There were no other clinically significant findings in 
laboratory tests (specifically in skeletal and other cardiac muscle markers [cTnT, CK-MB]), 
vital signs or electrocardiograms (ECGs; changes related to ischemia or QT interval 
changes).  
In Studies 0367-CL-1102 (mild and moderate hepatic impaired participants and healthy 
matched participants) and 0367-CL-1111 (severe renal impaired participants and healthy 
matched participants), the incidence of TEAEs reported during study conduct was low. In 
each study, 2 TEAEs were reported that were considered by the investigator to be mild and 
related to study intervention. In the hepatic impairment study, 1 participant with mild hepatic 
impairment experienced nausea and 1 participant with mild hepatic impairment experienced 
fatigue. In the renal impairment study, 1 participant with severe renal impairment had a 
TEAE of troponin I increased (single episode with onset on day 2; value of 0.09 ng/mL 
[normal range: not reported to 0.015 ng/mL]) and 1 participant with severe renal impairment 
had a TEAE of lipase increased (values above ULN of 92 U/L on day 5, 142 U/L at EOS visit 
and 85 U/L during a follow-up unscheduled visit [normal range: 11 to 82 U/L]). None of the 
participants in either study required concomitant medications for the treatment of these 
TEAEs. There were no other clinical laboratory (hematology, biochemistry and urinalysis) 
results, vital signs measurements or routine 12-lead ECG measurements reported as TEAEs 
during the conduct of these studies. None of the participants had potentially clinically 
significant values or increases in liver enzymes or TBL after study intervention 
administration.  
In the AME study 0367-CL-1103, 1 participant experienced a TEAE (diarrhea) that was 
considered by the investigator to be possibly related to study intervention. There were no 
clinical laboratory (hematology, biochemistry and urinalysis) results, vital sign measurements 
or routine 12-lead ECG measurements reported as TEAEs during the conduct of this study. 
No participant had potentially clinically significant increases in liver enzymes or TBL after 
study intervention administration. 
ASP0367 has also been assessed in 1 completed phase 1b clinical study (0367-CL-0102) in 
late ambulatory and early non-ambulant patients with DMD. No SAEs, drug-related TEAEs, 
TEAEs leading to death or TEAEs leading to withdrawal of treatment were observed in the 


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12-week DB or OLE parts of the study. Similar TEAE frequencies were reported across the 
ASP0367 and placebo treatment groups in the 12-week DB part. These events were 
consistent with the underlying disease of DMD. Overall, the mean changes in clinical 
laboratory values and vital signs were similar between treatment groups. No significant safety 
issues were observed in subjects who received ASP0367. 
2.3.1.3 Cardiac and Skeletal Muscle 
Based on the nonclinical findings observed with ASP0367, toxicity of the heart and skeletal 
muscle have been identified as important potential risks, although they have been observed 
only in rats but not in monkeys.  
Baseline cTnI values in patients with PMM are not well established. Since mitochondrial 
oxidative phosphorylation is the main source of energy in the heart, responsible over 95% of 
adenosine triphosphate synthesis [Zdończyk et al, 2020], cardiac involvement in 
mitochondrial diseases is common with an estimated prevalence of more than 20% in adult 
mitochondrial disease patients [Limongelli et al, 2010]. A single cTnI level at a fixed time 
point in patients with PMM is insufficient to determine clinical significance, particularly with 
biological variability (diurnal variation) and bioanalytic (assay variation) variability.  
In addition to routine standard monitoring of safety in the proposed study (0367-CL-1201), 
the sponsor proposes the following screening activities and repeated sequential monitoring to 
address the cardiac and skeletal muscle toxicity monitoring:  
All participants will undergo screening including cardiac biomarkers and ECG prior to 
enrollment in the study. This study appropriately excludes PMM patients with clinically 
significant and unstable cardiovascular disease as described in Exclusion Criteria #12 
through 14. As such, the investigator will clinically correlate the cTnI level to assess 
eligibility. Only participants with a cTnI level below upper limit and a mean QT interval 
using Fridericia’s correction (QTcF) of ≤ 450 msec for male participants and ≤ 480 msec for 
female participants will be allowed into the study.  
Sequential cardiac muscle monitoring will include assessment of serum cardiac enzymes, 
including cTnI, cTnT, CK-MB and ECGs at protocol-specified intervals. Participants who 
experience any signs or symptoms potentially reflecting cardiac involvement will undergo 
ECG, echocardiogram, and have a cTnI drawn for further evaluation prior to continuing study 
drug. Participants who develop an increase in cardiac enzymes levels (i.e., increased cTnI) 
will interrupt investigational product (IP) and will undergo more intensive assessments of 
cardiac function such as ECG and echocardiogram for further evaluation.  
Sequential monitoring for skeletal muscle injury will include assessment of CK, 
transaminases and lactate dehydrogenase at protocol-specific intervals. An individual 
participant may be required to discontinue treatment if they develop an elevation in CK 
levels ≥ 5 times the value of the ULN or the individual’s baseline value, whichever is higher 
and it is judged that this elevation is not related to an explainable increase including 
excessive movement, fall or disease state. 


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2.3.2 
Benefit Assessment 
At randomization, participants have a 2/3 chance of being randomized to active IP 
(ASP0367). Participants randomized to placebo are unlikely to benefit from the double-blind 
treatment period of the study. 
Additionally, enrollment in the study may be seen as an opportunity to contribute to the 
discovery of an effective drug for this highly unmet medical need. 
2.3.3 
Overall Risk-Benefit Conclusion 
ASP0367 has the potential to address fatigue, exercise intolerance and muscle weakness and 
improve quality of life in participants with PMM. With appropriate precautions (e.g., cardiac 
monitoring), the potential risks mentioned above do not preclude initiation of a clinical study 
in PMM patients. This phase 2 study in participants with PMM will continue to evaluate the 
safety profile of ASP0367 and apply careful risk characterization and minimization activities. 
The sponsor considers the overall benefit-risk to participants with PMM taking part in Study 
0367-CL-1201 to be favorable. 
3 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
The study objectives and endpoints are outlined in [Table 3].  
Table 3 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
● 
To assess the dose response of ASP0367 on 
functional improvement relative to placebo 
● 
Change from baseline in distance walked on the 
6MWT at week 24 
● 
To assess the safety and tolerability of 
ASP0367 relative to placebo 
● 
Safety and Tolerability through week 24 and end 
of study: 
o 
Nature, frequency and severity of TEAEs 
o 
Vital signs 
o 
Weight 
o 
12-lead ECG 
o 
Clinical laboratory tests (hematology, 
biochemistry [including serum cardiac 
troponin I] and urinalysis) 
o 
C-SSRS 
Secondary 
● 
To assess the dose response of ASP0367 on 
functional improvement and fatigue relative 
to placebo 
● 
Change from baseline in Neuro-QoL Short Form 
Fatigue and Lower Extremity Function (Mobility) 
scores at week 24 
● 
Change from baseline in time spent on the 5XSTS 
at week 24 
● 
Change from baseline in MFIS at week 24 
● 
To assess the effect of ASP0367 in overall 
participant functioning relative to placebo 
● 
PGIC scores at week 24 
● 
Change from baseline in PGIS scores at week 24 


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Objectives 
Endpoints 
Exploratory 
● 
To assess the pharmacokinetics of ASP0367 
● 
Plasma ASP0367: Ctrough at weeks 12 and 24 and 
population pharmacokinetics 
● 
To assess the exposure-response relationship 
of ASP0367 
● 
Relationship between measured- and model-based 
pharmacokinetic exposure parameters (e.g., 
Ctrough, Cave, ss) of ASP0367 and endpoints of 
efficacy, safety and pharmacodynamic 
biomarkers, as appropriate 
● 
To assess the effect of ASP0367 on lower 
extremity function relative to placebo 
● 
Change from baseline in distance walked on the 
6MWT at weeks 4 and 12 
● 
Change from baseline in minute-by-minute 
analyses (i.e., 6th vs 1st) of 6MWT at weeks 4, 12 
and 24 
● 
Change from baseline in time spent on 5XSTS at 
weeks 4 and 12 
● 
Change from baseline in Neuro-QoL Short Form 
Fatigue score at weeks 4 and 12  
● 
Change from baseline in Neuro-QoL Short Form 
Lower Extremity Function (Mobility) score at 
weeks 4 and 12 
● 
Change from baseline in MFIS score at weeks 4 
and 12 
● 
To assess the effects of ASP0367 on quality 
of movement and patient perception of 
change 
● 
PGIC scores at weeks 4 and 12 
● 
Change from baseline in PGIS scores at weeks 4 
and 12 
● 
Change from baseline in EQ-VAS and EQ-5D-5L 
index at weeks 4, 12 and 24 
● 
To assess the relationship between functional 
improvement and biochemical markers, as 
well as gene expression-based 
pharmacodynamic biomarkers 
● 
Change from baseline in the levels of serum and 
urinary biomarkers (serum FLNC, CYC, ALDOA 
and urinary TITIN) at weeks 12 and 24  
● 
Relative change from baseline of whole blood 
PPARδ target gene expression levels at weeks 12 
and 24† 
Note: Placebo comparison will be up to 24 weeks and will not include open-label extension. 
5XSTS: 5 Times Sit to Stand; 6MWT: 6-minute walk test; ALDOA: aldolase A; Cave, ss: average plasma 
concentration at steady state; C-SSRS: Columbia-Suicide Severity Rating Scale; Ctrough: concentration 
immediately prior to dosing at multiple dosing; CYC: cytochrome c; ECG: electrocardiogram; EQ-5D-5L: 
European Quality of Life 5-dimension, 5-level questionnaire; EQ-VAS: EuroQol visual analogue scale; FLNC: 
filamin-C; MFIS: Modified Fatigue Impact Scale; Neuro-QoL: Quality of Life in Neurological Disorders; 
PGIC: Patient Global Impression of Change; PGIS: Patient Global Impression of Severity; PPARδ: peroxisome 
proliferator-activated receptor delta; TEAE: treatment-emergent adverse event 
†Blood samples will be collected and stored appropriately over the course of the study and then analyzed. 


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Estimands 
Primary estimand will be defined by the following 5 attributes:  
● 
Treatment: ASP0367 or placebo 
● 
Population: Participants with PMM, as defined by the inclusion/exclusion criteria of the 
study. 
● 
Endpoint: Change from baseline in distance walked on the 6-minute walk test (6MWT) 
at week 24. 
● 
Intercurrent events and their corresponding strategies (see table below). 
● 
Population level summary: Difference in change from baseline in distance walked on the 
6MWT at week 24 between ASP0367 group and placebo group. 
Intercurrent Events 
Strategies to Handle Intercurrent Events 
Treatment 
Discontinuation Due to 
Any Reason 
For those participants who discontinued treatment, all observations after 
treatment discontinuation (Date of Last Study Drug Taken + 7 days) will 
be ignored. Analysis will be conducted assuming those participants 
remained assigned treatment and the condition that was observed before 
treatment discontinuation will continue, i.e., hypothetical strategy.  
Study Discontinuation 
For those participants who discontinued study, all observations after 
treatment discontinuation (Date of Last Study Drug Taken + 7 days) will 
be ignored. Analysis will be conducted assuming those participants 
remained assigned treatment and the condition that was observed before 
treatment discontinuation will continue, i.e., hypothetical strategy. 
Prohibited 
Concomitant Treatment 
Use 
For those participants who used the prohibited concomitant medication 
treatment, all observations will be included in the analysis, i.e., treatment 
policy strategy. 
4 
STUDY DESIGN AND DOSE RATIONALE 
4.1 
Overall Study Design 
This is a randomized, double-blind, placebo-controlled, oral dose, phase 2 study to evaluate 
the dose response of ASP0367 on functional improvement relative to placebo, safety and 
tolerability in participants with PMM. Efficacy (i.e., functional improvement) will be 
assessed by a functional motor test, 6MWT. The study consists of the following portions: 
screening (4 weeks); double-blind treatment period with 2 doses of ASP0367 vs matching 
placebo (24 weeks); and follow-up (4 weeks).  
A 24-week treatment analysis of efficacy and safety will be the primary focus. Since 
participants enrolled in the study prior to implementation of Protocol Version 9.0 (Substantial 
Amendment 8), which removes the 52-week OLE period, may have a treatment duration of 
up to 76 weeks, a separate treatment analysis will also be conducted at later timepoints up to 
76 weeks as per available data [Section 9]. An unblinded, independent Data and Safety 
CCI


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Monitoring Board (DSMB) will assess the overall safety and tolerability of ASP0367 
throughout the course of the study as summarized in [Section 10.1.5.1.1].  
Approximately 66 participants will be enrolled. At randomization, participants will be 
randomly placed into 1 of 3 arms (30 mg ASP0367, 75 mg ASP0367 or placebo; n = 22 for 
each arm) at a ratio of 1:1:1. Stratified randomization by site group (2 level: Mayo 
clinic_Minnesota; Non-Mayo clinic_Minnesota) will be applied.  
At week 24 while enrollment continues, data from the first approximately 30 evaluable 
participants will be reviewed in an interim analysis, as described in [Section 9.6], to 
determine if the futility or efficacy stopping criteria are met while the study is ongoing. An 
Astellas internal DMC for interim analysis will assess the futility and efficacy of the study 
treatments and make recommendations about the ongoing conduct of the study as 
summarized in [Section 10.1.5.1.2]. An interim analysis of pharmacokinetic and 
pharmacodynamic data will also be reviewed by the DMC.  
4.2 
Scientific Rationale for Study Design 
A randomized, placebo-controlled, parallel group design was chosen to detect changes in 
functional capacity and assess the safety/tolerability in PMM patients. Participants will be 
randomized to treatment to reduce selection bias, and further, both participants and the 
investigator will be blinded to treatment to reduce bias in the measurement of both safety and 
efficacy endpoints. Placebo was chosen as a comparator because there are no approved 
treatments for PMM. 
The double-blind treatment period of the study will assess the dose response of ASP0367 on 
functional improvement relative to placebo to confirm that the appropriate dose level within 
the biologically active dose window is being selected with the new ASP0367 tablet 
formulation [Section 4.3] and assess the safety and tolerability of ASP0367 relative to 
placebo. A 6MWT will be employed as the primary efficacy endpoint, since exercise 
intolerance was one of the most key symptoms motivating PMM patients to participate in a 
clinical trial [Zolkipli-Cunningham et al, 2018] and the 6MWT is a sub-maximal exercise test 
used to assess functional capacity by measuring distance walked in six minutes. With the 
support of available nonclinical toxicity studies up to 52 weeks, 24 weeks randomized study 
duration for 6MWT has been chosen in considering disease progress.  
As this current study is focusing on mitochondrial myopathies in which mitochondria are 
primarily involved, participants who demonstrate molecular genetic abnormality known to be 
associated with mitochondrial dysfunction will be enrolled in the study. Further, 
participant-reported symptoms (i.e., muscle weakness, fatigue and exercise intolerance) or 
physical examination findings of myopathy that are the predominant symptoms of the 
participant’s mitochondrial disorder are required for the enrollment.  
4.2.1 
Summary of Changes to Study Design 
The present study was originally designed as a randomized, double-blind, placebo-controlled, 
oral dose, adaptive phase 2/3 study with open-label extension (OLE) to evaluate the efficacy, 


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safety and tolerability of ASP0367 in participants with PMM. The original study design 
consisted of the following portions: screening (4 weeks); phase 2 dose selection portion with 
2 doses of ASP0367 vs matching placebo (2 weeks); phase 3 portion with selected, single 
dose treatment vs placebo (up to 52 weeks); OLE (24 weeks); and follow-up (4 weeks). 
Effective with implementation of Protocol Version 9.0 (Substantial Amendment 8), the 
original study design will be modified to become a phase 2 study (originally referred to as the 
“Phase 2 Portion”) with a double-blind treatment period (24 weeks) and no OLE period. An 
interim analysis of approximately 30 evaluable participants who have reached week 24 of the 
double-blind treatment period will be conducted to evaluate futility and efficacy. 
4.3 
Dose Rationale 
In Study 0367-CL-0001, ASP0367 in a capsule formulation was used. In the current study 
(0367-CL-1201), tablet formulation, which showed no appreciable difference of in vitro 
dissolution profile compared with the capsule formulation, will be used. 
ASP0367 was safe and well tolerated at a single dose of up to 120 mg and multiple doses of 
up to 75 mg for 14 days in healthy adults. No dose-liming toxicity was found, and maximum 
tolerated dose was not determined. ASP0367 showed treatment- and dose-dependent FAO-
related PPARδ target gene up-regulation in blood in healthy adults [Section 2.2.3.2 Clinical]. 
The safety profile of ASP0367 was further supported by the data from the GLP toxicity 
studies (13-week [both rats and monkey], 26-week [rat] and 52-week [monkey] repeated oral 
dose toxicity studies, and 11-week juvenile rat toxicity study), which showed higher no 
observed adverse effect levels (NOAELs) and associated systemic exposures than those seen 
in the 4-week repeated oral dose rat toxicity study [Section 2.2.3.1 Nonclinical]. Of note, in 
the GLP 26-week rat toxicity study, the NOAEL was considered to be 50 mg/kg per day, the 
highest dose level tested (equivalent to Cmax values of 15500 and 30400 ng/mL and AUC24 
values of 41200 and 111000 ng·h/mL for males and females, respectively, on day 182). In 
addition, in the GLP 52-week monkey toxicity study, the NOAEL was considered to be 
500 mg/kg per day, the highest dose level tested (equivalent to Cmax values of 1480 and 523 
ng/mL and AUC24 values of 8400 and 4090 ng·h/mL for males and females, respectively, on 
day 365). More details can be found in the Investigator’s Brochure. 
The planned doses of 30 and 75 mg once daily are expected to be safe and biologically active 
and chosen to support evaluation of a dose response.  These doses were therefore included in 
this study. The study design was modified (Protocol Version 9.0 Substantial Amendment 8) 
to assess the dose response after 24 weeks of treatment and to remove the OLE period. In 
addition, 2 clinical studies that recently completed clinical conduct assessed the 75 mg once 
daily dose for up to 20 weeks in patients with Duchenne Muscular Dystrophy (0367-CL-
0102) and up to 6 weeks in patients with reduced maximum oxygen uptake due to poor 
systemic oxygen extraction (0367-CL-1101). In the current study, overall safety and 
tolerability of ASP0367 will continue to be assessed by the independent DSMB for the 
duration of the study. 


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4.4 
End of Study Definition  
The end of the study is defined as the last visit or scheduled procedure shown in schedule of 
assessments [Table 1] for the last participant in the study. 
5 
STUDY POPULATION 
Male and female participants with PMM diagnosed by mtDNA or nDNA alterations, which 
are known to be associated with mitochondrial dysfunction, and by reported symptoms 
including muscle weakness, fatigue and exercise intolerance who are meeting following 
inclusion and exclusion criteria will be enrolled in the study.  
Molecular genetic abnormality, which is detected by either targeted gene sequencing for the 
commonly affected genes in both mtDNA or nDNA that cause the phenotype or by mtDNA, 
exome or genome sequencing in clinically relevant or affected tissue, will be confirmed in 
participant’s medical history.  
All screening assessments must be completed and reviewed to confirm the potential 
participant meets all eligibility criteria. Prospective approval of protocol deviations to 
eligibility criteria (also known as protocol waivers or exemptions) is not permitted.  
5.1 
Inclusion Criteria 
Participant is eligible for participation in the study if all of the following apply:  
1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
informed consent and privacy language as per national regulations (e.g., Health 
Insurance Portability and Accountability Act authorization for US study sites) must be 
obtained from the participant prior to any study-related procedures (including withdrawal 
of prohibited medication, if applicable). 
2. Participant agrees and is able to adhere to the study requirements for the length of the 
study, including performing 6MWT. 
3. Participant is ≥ 18 and < 65 years [Karaa et al, 2020] of age at the time of signing an 
informed consent form (ICF). 
4. Diagnosed with PMM in the opinion of the investigator, consisting of the following: 
a. 
Molecular genetic abnormality (i.e., nuclear or mitochondrial) known to be 
associated with mitochondrial dysfunction (such as, but not limited to, mtDNA 
single deletions in CPEO and KSS; mtDNA m.3243 A > G; pathogenic nuclear or 
mitochondrial genome variants demonstrated to cause primary mitochondrial 
disease), and 
b. Participant reported symptoms (i.e., muscle weakness, fatigue and exercise 
intolerance) or physical examination findings of myopathy that are the 
predominant symptoms of the participant’s mitochondrial disorder. 
5. Participant has been on stable dose regimen of coenzyme Q10 (CoQ10), carnitine, 
creatine or other mitochondrial disease-focused vitamins or supplemental therapies for 
the treatment of symptoms of the mitochondrial disease for at least 3 months prior to 
randomization and intends to stay on a stable dose for duration of study period. 


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6. Participant has been on stable exercise regimen within 4 weeks prior to randomization 
and intends to stay on a stable regimen for duration of study period (for participants who 
participate in a regular exercise regimen). 
7. Female participant is not pregnant (see Section 10.2, Appendix 2: Contraception 
Requirements) and at least one of the following conditions apply: 
a. 
Not a woman of childbearing potential (WOCBP) (see Section 10.2, Appendix 2: 
Contraception Requirements) 
b. WOCBP who agree to follow the contraceptive guidance (see Section 10.2, 
Appendix 2: Contraception Requirements) from the time of informed consent 
through at least 30 days after final study treatment administration. 
8. Female participant must agree not to breastfeed starting at screening and throughout the 
study period and for 30 days after final study treatment administration. 
9. Female participant must not donate ova starting at first dose of IP and throughout the 
study period and for 30 days after final study treatment administration. 
10. Male participant with female partner(s) of childbearing potential (including breastfeeding 
partner) must agree to use contraception (see Section 10.2, Appendix 2: Contraception 
Requirements) throughout the treatment period and for 30 days after final study 
treatment administration. 
11. Male participant must not donate sperm during the treatment period and for 30 days after 
final study treatment administration. 
12. Male participant with pregnant partner(s) must agree to remain abstinent or use a 
condom for the duration of the pregnancy throughout the study period and for 30 days 
after final study treatment administration. 
13. Participant agrees not to participate in another interventional study while participating in 
the present study. 
5.2 
Exclusion Criteria 
Participant will be excluded from participation in the study if any of the following apply:  
1. Participant has additional signs and/or symptoms due to non-myopathic process (e.g., 
cerebellar dysfunctions, movement disorder, peripheral neuropathy, stroke or other) or a 
gait problem not attributed to the myopathy that would interfere with the participant’s 
performance during 6MWT or 5 times sit to stand (5XSTS), in the opinion of the 
investigator. 
2. Participant has received any investigational therapy within 28 days or 5 half-lives, 
whichever is longer, prior to screening.  
3. Participant has any condition, which, in the investigator’s opinion, makes the participant 
unsuitable for study participation. 
4. Participant has cTnI > ULN at screening. 
5. Participant has estimated glomerular filtration rate (eGFR) calculated by the Chronic 
Kidney Disease Epidemiology Collaboration equation < 60 mL/min/1.73 m2 at screening 
or a history of chronic kidney disease stage 3 or greater.* 
6. Participant has at screening**: total bilirubin (TBL) > ULN or transaminase(s) (aspartate 
aminotransferase [AST] or alanine aminotransferase [ALT]) > ULN in the absence of 


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elevations in CK. Participants who have a slightly elevated TBL and/or ALT and/or AST 
and are suitable candidates for the study may be enrolled after discussion of the case 
with the medical monitor and completion of further evaluation as warranted. 
7. Participant has psychiatric conditions such as schizophrenia, bipolar disorder or major 
depressive disorder that has not been under control within 3 months prior to screening. 
8. Participant has a history of suicide attempt, suicidal behavior or has any suicidal ideation 
within 1 year prior to screening that meets criteria at a level of 4 or 5 by using the 
Columbia-Suicide Severity Rating Scale (C-SSRS) or who is at significant risk to 
commit suicide, as assessed by the investigator at screening. 
9. Participant has severe behavioral or cognitive problems that preclude participation in the 
study, in the opinion of the investigator. 
10. Participant has undergone an in-patient hospitalization that precludes participation in the 
study, in the opinion of the investigator, within the 30 days prior to the randomization. 
11. Participant has a planned hospitalization or a surgical procedure during the study, which 
may affect the study assessments in the opinion of the investigator. 
12. Participant has clinically significant and unstable respiratory disease and/or cardiac 
disease (medical history or current clinical findings) in the opinion of the investigator, or 
prior interventional cardiac procedure (e.g., cardiac catheterization, angioplasty/ 
percutaneous coronary intervention, balloon valvuloplasty, etc.) within 3 months prior to 
randomization. Participants with pacemakers are allowed in the study per investigator’s 
discretion and after discussion with the medical monitor, and as long as it is used for 
prevention and there is no underlying cardiac dysfunction. 
13. Participant has a corrected mean QTcF > 450 msec for male participants and > 480 msec 
for female participants at screening or randomization. If QTcF exceeds these limits, 
1 additional triplicate ECG can be repeated on the same day in order to determine the 
participant’s eligibility.  
14. ECG evidence of acute ischemia, atrial fibrillation or active conduction system 
abnormalities. The following conduction system abnormalities may be permitted per the 
investigator’s discretion, only after discussing the case with the medical monitor: 
a. 
First degree atrioventricular (AV)-block 
b. Second degree AV-block Type 1 (Mobitz Type 1/Wenckebach type) 
c. 
Right bundle branch block 
d. Left fascicular block 
e. 
Bi-fascicular block 
15. Participant requires any ventilatory support, inclusive of any respiratory device to 
support breathing such as home ventilators and any form of non-invasive positive 
pressure ventilation (including continuous positive airway pressure [CPAP], bilevel 
positive airway pressure [BiPAP], and average volume-assured pressure support 
[AVAPS]). Participants who require oxygen therapy (even by low-flow nasal cannula 
[LFNC]) are not candidates for this study. 
16. Participant has severe vision impairment that, in the opinion of the investigator, may 
interfere with their ability to complete all study requirements. 
17. Participant has an intractable seizure disorder that, in the opinion of the investigator, may 
interfere with their ability to complete all study requirements. 


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18. Active malignancy or any other cancer from which the participant has been disease-free 
for < 5 years, except for curative treated localized non-melanoma skin cancer (e.g., basal 
cell or squamous cell carcinoma). 
19. Participant has a solid organ transplant and/or is currently receiving treatment with 
therapy for immunosuppression. 
20. Participant has severe scoliosis or kyphoscoliosis that significantly impair respiratory 
capacity and pulmonary function tests or limit positioning due to pain who would be 
likely to require orthopedic surgical intervention within a year after study randomization. 
21. Participant has a positive test for human immunodeficiency virus (HIV), hepatitis B or 
hepatitis C infection at screening. 
22. Participant has previously received ASP0367. 
23. Participant has, in the opinion of the investigator, a history of active substance abuse 
within 1 year prior to randomization. 
24. Participant has used any peroxisome proliferator-activated receptor (PPAR) ligands such 
as fibrates and thiazolidinediones within 4 weeks prior to randomization.  
25. Participant has initiated the use of CoQ10, carnitine, creatine or other mitochondrial 
disease-focused supplements for the treatment of symptoms of the mitochondrial disease 
within 3 months prior to study randomization. 
26. Participant has a known or suspected hypersensitivity to ASP0367 or any components of 
the formulation used. 
27. Participant has walked longer than the distance that 85% of healthy people can walk in 
6MWT at the baseline visit (week 0) [see Section 7.1.1, 6-minute Walk Test].  
28. Participant has symptomatic COVID-19 infection within 3 months prior to study 
randomization that required treatment (Monoclonal antibodies, ventilator support, 
hospitalization) and/or led to long-term sequelae or lingering symptoms. 
29. Participant has body mass index (BMI) below 17 kg/m2 [Karaa et al, 2020] or above 
35 kg/m2 at screening. 
30. Participant has signs or symptoms of bulbar weakness, such as dysphagia, dysphonia, 
hoarseness or drooling/sialorrhea, due to either neuropathy or myopathy.  
*https://www.kidney.org/atoz/content/stages-chronic-kidney-disease-ckd 
**Note: Laboratory parameters of eGFR, TBL, AST and ALT may be repeated once within the screening 
window at the investigator’s discretion after consulting with the medical monitor. If increased AST and/or ALT 
values are observed, association with increased CK values will be evaluated by the investigator and medical 
monitor.  
5.3 
Lifestyle Considerations 
For the participants who are on exercise regimen, participants will be encouraged to keep a 
stable exercise regimen within 4 weeks prior to randomization and during the study. For 
participants enrolled in the study, participants will be asked to refrain from strenuous exercise 
on the day preceding and on the day of the on-site visit when 6MWT and 5XSTS will be 
performed (weeks 0, 4, 12 and 24). 
5.4 
Screen Failures 
A screen failure is defined as a potential participant who signed the ICF but did not meet 1 or 
more criteria required for participation in the study and was not randomized. 


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For screen failures, the demographic data, date of signing the ICF, inclusion and exclusion 
criteria, AEs up to the time of screen failure and reason for screen failure will be collected in 
the case report form (CRF). 
5.4.1 
Rescreening 
Rescreening after screen failure is allowed one time when there is a clinically relevant 
justification. If the participant meets exclusion criteria that cannot resolve during the 
screening period, the participant must be documented as a screen failure. In order to rescreen 
after prior screen failure, a new ICF must be signed and the participant entered into screening 
with a new participant identification number. Rescreening is only allowed once for an 
individual participant after consulting with the medical monitor if the participant was deemed 
ineligible due to a transient condition or if otherwise justified. 
During screening, laboratory parameters of eGFR, TBL, AST and ALT may be repeated once 
within the screening window at the investigator’s discretion after consulting with the medical 
monitor if ineligible due to a transient condition, which would not otherwise prevent the 
participant from taking part. ECG may be repeated once at the investigator’s discretion on the 
same day at screening or randomization. These can be repeated without the need to register 
the participant as a screen failure.   


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6 
INVESTIGATIONAL PRODUCT(S) 
6.1 
Investigational Product(s) Administered 
Table 4 
Investigational Product(s) 
Name 
ASP0367 
Placebo for ASP0367 
Use 
Test product 
Placebo 
Dosage Form 
Tablets 
Tablets 
Physical Description 
Round, light yellowish red film-coated 
tablet 
Matching placebo for ASP0367 
Unit Dose Strength 
10 and 25 mg  
Matching placebo for ASP0367 
Inactive Excipients 
Lactose monohydrate, croscarmellose 
sodium, hydroxypropyl cellulose, 
microcrystalline cellulose, magnesium 
stearate, hypromellose, polyethylene 
glycol, talc, titanium dioxide, yellow 
ferric oxide, red ferric oxide 
Mannitol, microcrystalline cellulose, 
croscarmellose sodium, magnesium 
stearate, hypromellose, polyethylene 
glycol, talc, titanium dioxide, yellow 
ferric oxide, red ferric oxide 
Storage 
20°C to 25°C (68°F to 77°F); 
excursions permitted between 15°C and 
30°C (59°F and 86°F) (as per USP 
Controlled Room Temperature). Protect 
from light. 
20°C to 25°C (68°F to 77°F); 
excursions permitted between 15°C 
and 30°C (59°F and 86°F) (as per 
USP Controlled Room Temperature). 
Protect from light. 
Packaging and 
Labeling 
HDPE bottles  
HDPE bottles 
Route of 
Administration 
Oral 
Oral 
Administration  
Once daily with or without food 
Participants should be instructed to take 
the IP in the morning at the same time 
each day as much as possible. Crushing 
of tablets is not allowed. 
Once daily with or without food 
Participants should be instructed to 
take the IP in the morning at the same 
time each day as much as possible. 
Crushing of tablets is not allowed. 
IMP or Non-IMP 
IMP 
IMP 
Sourcing 
Provided centrally by sponsor 
Provided centrally by sponsor 
HDPE: High-density polyethylene; IMP: Investigational Medicinal Product; IP: investigational product; 
USP: US Pharmacopeia 
The anticipated duration of the study for each participant, including screening and follow-up, 
is approximately 32 weeks. 
Participants should be instructed to take the IP in the morning at the same time each day as 
close as possible. Crushing of tablets is not allowed. IP will be administered orally with or 
without food.  
At study site visits, participants will visit the study site without taking the IP and take IP at 
the study site as instructed.  


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Table 5 
Treatment Groups and Duration 
Arm/IP Name 
ASP0367 
Placebo 
Use 
Test product 
Matching placebo for ASP0367 
Dose 
75 mg (3 × 25 mg tablet) 
30 mg (3 × 10 mg tablet) 
NA (3 × tablet) 
Frequency 
Once daily 
Once daily 
Route 
Oral 
Oral 
Duration 
24 weeks 
24 weeks 
IP: investigational product; NA: not applicable 
Refer to the pharmacy manual for detailed information regarding preparation, handling and 
storage of the IP.  
6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Packaging and Labeling 
All IP used in this study will be prepared, packaged and labeled under the responsibility of 
qualified personnel at Astellas Pharma Inc. (API) or sponsor’s designee in accordance with 
API or sponsor’s designee standard operating procedures (SOPs), current Good 
Manufacturing Practice (GMP) guidelines, International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice 
(GCP) guidelines and applicable local laws/regulations. 
Each bottle will bear a label conforming to regulatory guidelines, GMP and local laws and 
regulations that identifies the contents as investigational drug. 
Refer to the pharmacy manual for detailed information regarding packaging and labeling of 
the IP.  
6.2.2 
Handling, Storage and Accountability 
The handling, storage and accountability of the IP will be managed according to the 
following guidelines: 
● 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all IP received and any discrepancies are reported and 
resolved before use of the IP. 
● 
Only participants enrolled in the study may receive IP and only authorized study site 
personnel may supply or administer IP. Only IP with appropriate expiry/retest dating 
may be dispensed. 
● 
All IP must be stored in a secure, environmentally controlled and monitored (manual or 
automated) area in accordance with the labeled storage conditions and access must be 
limited to the investigator and authorized study site personnel. 
● 
The investigator, institution or the head of the medical institution (where applicable) is 
responsible for accountability, reconciliation and record maintenance (i.e., receipt, 
reconciliation and final disposition records).  


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● 
Further guidance and instruction on final disposition of used and unused IP is provided 
in the pharmacy manual. 
Refer to the pharmacy manual for detailed information regarding handling, storage and 
accountability of the IP. 
6.3 
Randomization and Blinding 
6.3.1 
Blinding Method  
This is a double-blinded study. Participants will be randomized to receive ASP0367 or 
placebo in a blinded manner such that neither the investigator, sponsor’s study management 
team, clinical personnel, caregiver, nor the participant will know which IP is being 
administered in the double-blind treatment period of the study. The randomization number 
will be assigned based on information obtained from the Interactive Response Technology 
(IRT) system.  
6.3.2 
Confirmation of the Indistinguishability of the Investigational Product 
The appearance of both the dosage form and packaging of ASP0367 are identical to those of 
the matching placebo. 
6.3.3 
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking  
The randomization list and treatment assignment blind will be maintained by the IRT system. 
The independent DSMB will be provided with access to the treatment assignment for 
periodic review of the overall safety and tolerability data. Its operation will be documented in 
the DSMB Charter.  
The DMC will be provided with access to the treatment assignment for review of the interim 
analysis data. Its operation will be documented in the DMC Charter. 
6.3.4 
Breaking the Treatment Code for Emergency  
The treatment code for each randomized participant will be obtained from the IRT system in 
the event of a medical emergency requiring knowledge of the treatment assigned to the 
participant. The IRT system will be programmed with blind-breaking instructions that can 
only be requested by the investigator or subinvestigators designated to have access to perform 
blind-breaking. In case of a medical emergency, the investigator (or his/her designated 
backup) has the sole responsibility for determining if unblinding of the participant’s 
treatment assignment is warranted. Participant safety must always be the first consideration in 
making such determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor prior to unblinding a 
participant’s treatment assignment unless this could delay emergency treatment for the 
participant.  


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Prior to the initial IP shipment, the investigator must have confirmed ability to access 
code-break through the IRT system and must have a designated backup (e.g., redundant 
processes) to support emergency unblinding requirements.  
Prior to randomization, participants should be provided with information that includes the 
study site emergency contact number and back-up contact number in case of a medical 
emergency. Any unblinding by the investigational personnel must be reported immediately to 
the sponsor and include an explanation of why the IP was unblinded. If unblinding is 
associated with a SAE, the investigator is to follow the instructions in [Section 10.3.6 
Reporting Procedures for Serious Adverse Events].  
Care will be taken to limit knowledge of the treatment assignment, in case this can affect the 
blinding of other participants or future study assessment for the participant.  
6.3.5 
Breaking the Treatment Code by the Sponsor  
The sponsor may break the treatment code for participants who experience a suspected 
unexpected serious adverse reaction (SUSAR), in order to determine if the individual case or 
a group of cases requires expedited regulatory reporting. Individual emergency codes will be 
provided to the limited personnel who are responsible to break the codes for all SUSAR cases 
for reporting purposes. 
6.3.6 
Assignment and Allocation 
Participants enrolled in this study will be randomized in a 1:1:1 ratio to the 30 mg ASP0367, 
75 mg ASP0367 or placebo arm.  
Randomization will be performed according to the schedule obtained via the IRT system and 
stratified by site group (2 level: Mayo clinic_Minnesota; Non-Mayo clinic_Minnesota). The 
study site personnel will dispense either ASP0367 or placebo according to the IRT system’s 
assignment. Specific procedures for randomization through the IRT system are contained in 
the study procedures manual.  
6.4 
Investigational Product Compliance 
Participants should be counseled on the need to meet 100% compliance with IP. Investigator 
or designee should ensure that participants meet this goal throughout the study. Participant 
compliance with IP will be assessed at each visit. Compliance will be assessed by counting 
returned tablets. Deviations from the prescribed dose regimen will be recorded. When IP is 
administered at the study site, it will be administered under the supervision of study 
personnel.  
6.5 
Dose Modification 
Dose modification for individual participants is not allowed.  
Dosing may be interrupted if further evaluation is required for ongoing AE(s), clinical 
laboratory abnormality or intercurrent illness. The investigator will assess the resolution of 
the event and determine, in consultation with the medical monitor, whether resuming dosing 
or continued participation in the clinical study is in the best interest of the participant.  


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6.6 
Continued Access to Investigational Product After the End of the 
Study 
Access to ASP0367 will not be available after the end of this study. The compound is still in 
an early phase of clinical development prior to the determination of the safety and efficacy 
data that would support continued development with the dose selected and the intent to 
pursue marketing approval. 
6.7 
Treatment of Overdose  
Any dose of IP greater than 75 mg/day will be considered an overdose. This overdose level 
may be adjusted based on emerging safety and tolerability data. 
Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator should: 
● 
Contact the medical monitor immediately. 
● 
Assess the participant and provide appropriate supportive care as needed. 
● 
Evaluate the participant along with safety information available to determine, in 
consultation with the medical monitor and the sponsor, whether study treatment should 
be discontinued. 
● 
Document the quantity of the excess dose as well as the duration of the overdose. 
Refer to [Section 10.3.7 Reporting Procedures for Special Situations] for reporting 
requirements for suspected overdose or other medication error.  
6.8 
Concomitant Therapy 
6.8.1 
Previous and Concomitant Treatment 
The investigator must record the use of all previous and concomitant treatment from 
3 months prior to randomization to follow-up visit in the CRF, both medication and 
nonmedication therapy. The investigator may record the use of previous treatment before 
3 months prior to randomization in the CRF as long as participants remember. Previous and 
concomitant treatment includes all vitamins, herbal remedies, over the counter and 
prescription medications, as well as exercise regimen and physical therapy.  
6.8.2 
Prohibited Concomitant Treatment 
● 
PPAR ligands listed in [Section 10.5 Appendix 5 List of Excluded Concomitant 
Medications] are not allowed within 4 weeks prior to randomization and during the 
study. 
● 
Substrates for P-gp, BCRP, OATP1B1, OATP1B3 and organic anion transporter (OAT)3 
are not allowed during the study. For participants using atorvastatin, rosuvastatin and 
simvastatin, switching to a less-interacting statin (pravastatin, pitavastatin and lovastatin) 
is allowed at investigator’s discretion.  
● 
Moderate and strong inhibitors of CYP3A are not allowed during the study. 
● 
Inhibitors for transporter BCRP are not allowed during the study. 
● 
Inhibitors of UGT1A3, UGT1A8 and UGT1A9 are not allowed during the study. 


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● 
Strong and moderate inducers of CYP3A and inducers for UGT1A3, UGT1A8, UGT1A9 
and transporters are not allowed during the study. 
● 
Triheptanoin, a synthetic medium chain triglyceride indicated in long-chain FAO 
disorders, is not allowed during the study. 
A list of prohibited medications is provided in [Section 10.5, Appendix 5: List of Excluded 
Concomitant Medications].  
6.8.3 
Restricted Concomitant Treatment 
CoQ10, carnitine, creatine or other mitochondrial disease-focused vitamins or supplemental 
therapies for the treatment of symptoms of the mitochondrial disease must be stable for 3 
months prior to randomization and for the duration of the study.   
6.8.4 
Other Restrictions 
See [Section 5.3 Lifestyle Considerations].  
7 
STUDY PROCEDURES AND ASSESSMENTS 
● 
Study procedures and their timing are summarized in the schedule of assessments 
[Table 1]. Adherence to the study design requirements, including those specified in the 
schedule of assessments, is essential and required for study conduct. Prospective protocol 
waivers or exemptions are not allowed.  
● 
Any change, divergence or departure from the study design or procedures identified in 
the protocol is considered a protocol deviation. All deviations from the protocol are to be 
recorded. 
● 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment. 
● 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
● 
Procedures conducted as part of the participant’s routine clinical management (e.g., 
imaging, blood count) and obtained before signing of the ICF may be utilized for 
screening or baseline purposes provided the procedures met the protocol-specified 
criteria and were performed within the time frame defined in the schedule of 
assessments. 
● 
Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded. 
7.1 
Efficacy Assessments 
7.1.1 
6-minute Walk Test 
The 6MWT will be performed indoors, along a long, flat, straight, enclosed corridor with a 
hard surface that is seldom traveled. The total distance walked by a participant, as well as 


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distance per minute will be calculated by rounding to the nearest meter and recorded. The 
6MWT will be video recorded for quality purposes unless restricted by policies of the study 
site.  
Participants will be asked to wear comfortable clothing and appropriate shoes for walking. A 
light meal is acceptable before early morning or early afternoon tests. Participants will be 
asked to refrain from strenuous exercise on the day preceding and on the day of the 6MWT. A 
“warm-up” period before the test will not be performed. Participants will sit at rest in a chair 
located near the starting position for at least 10 minutes before the test starts. The test will be 
performed as outlined in the schedule of assessments [Table 1]. 
The “1000 Norms Project Consortium” has established normative distance walked 6MWT 
data based on age, gender, weight, and height [McKay et al, 2017]. Study participants who 
walked longer than the distance that 85% of healthy people can walk based on “1000 Norms 
Project Consortium” at the baseline visit (week 0) can be considered as normal and will be 
excluded from the study. Each participant’s individual z-score will be calculated by entering 
age and gender, as well as distance walked in 6MWT at baseline (week 0) as indicated at 
“1000 Norms Project Consortium” website (https://clinicaloutcomemeasures.org/). The 
z-score > - 1.03 corresponds to the distance longer than 85% of healthy people can walk.  
7.1.2 
5 Times Sit to Stand 
For the 5XSTS, the participant will be instructed to sit with arms folded across their chest and 
with back against the chair and will be asked to stand up and sit down 5 times in a row, as 
quickly as he/she can. The instructor will make sure that the participant will stand up fully and 
try not to let his/her back touch the chair between each repetition. The duration from the time 
instructor indicates “Go” until the time participant’s body touches the chair following the fifth 
repetition will be recorded. If a participant is unable to complete the first sit to stand 
independently, without use of arms, the test will be terminated. The test will be performed as 
outlined in the schedule of assessments [Table 1]. 
7.1.3 
Quality of Life in Neurological Disorders 
The Quality of Life in Neurological Disorders (Neuro-QoL) is a measurement system that 
evaluates and monitors the physical, mental and social effects experienced by adults and 
children living with neurological conditions. Participants will report Neuro-QoL Item Bank 
v1.0 Fatigue Short Form and Lower Extremity Function (Mobility) Short Form, which 
consists of 8 items each. Neuro-QoL will be performed as outlined in the schedule of 
assessments [Table 1].  
7.1.4 
Modified Fatigue Impact Scale 
The Modified Fatigue Impact Scale (MFIS) is a modified form of the Fatigue Impact Scale. 
The questionnaire specifically measures how fatigue impacts the lives of those affected by 
fatigue-like symptoms.  


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There are 21 items in the scale measuring 3 domains of fatigue including physical, cognitive 
and psychosocial functioning. MFIS will be performed as outlined in the schedule of 
assessments [Table 1].  
7.1.5 
Patient Global Impression of Change 
The Patient Global Impression of Change (PGIC) scale evaluates the participant’s most 
bothersome symptom and assesses if there has been an improvement or decline in clinical 
status. The participant will rate his/her change on a 7-point scale. PGIC will be performed as 
outlined in the schedule of assessments [Table 1]. 
7.1.6 
The Patient Global Impression of Severity 
The Patient Global Impression of Severity (PGIS) is a questionnaire designed to assess 
patient’s impression of disease severity. The questionnaire asks the participant to best 
describe the severity of the participant’s most bothersome pre-defined symptom over the past 
week. PGIS will be performed as outlined in the schedule of assessments [Table 1].. 
7.1.7 
5-level EQ-5D Version (EQ-5D-5L) 
European Quality of Life (EuroQol) 5-Dimensions, 5-Level Questionnaire (EQ-5D-5L) is a 
brief, generic health-related quality of life assessment that can also be used to incorporate 
participant preferences into health economic evaluations. The EQ-5D-5L descriptive system 
comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort 
and anxiety/depression. Each dimension has 5 response levels: no problems, slight problems, 
moderate problems, severe problems and extreme problems/unable to perform the activity. In 
addition, it does record the patient’s self-rated health on a vertical visual analogue scale with 
response options ranging from 0 (worst imaginable health) to 100 (best imaginable health). 
The EQ-5D-5L will be performed as outlined in the schedule of assessments [Table 1].  
7.1.8 
Primary Mitochondrial Myopathy Video Assessments 
Effective with implementation of Protocol Version 8.0 (Substantial Amendment 7), PMMVA 
will no longer be collected. The Primary Mitochondrial Myopathy Video Assessments 
(PMMVA) tool provides a standardized way to document and assess patient quality of 
movement. A caregiver or a close observer will video record specific movement tasks at 
home using a secure mobile application. In addition to assigned movement tasks, the 
participant will complete one participant-choice activity. All participants will also have the 
option to submit a new ability video (if applicable). The participant-choice activity is an 
activity that the participant will select prior to baseline data capture that the participant is 
struggling with. The caregiver/observer will video record the same participant’s choice 
activity at each subsequent time point throughout the study. If the participant gains a new 
ability during the study, the caregiver/observer may video record the new ability at any time 
during the study in the study mobile application.  
7.1.9 
Individualized Activity Assessments 
Effective with implementation of Protocol Version 8.0 (Substantial Amendment 7), 
individualized activity assessments will no longer be collected. Participants will identify 3 


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activities during the screening period that are difficult due to their PMM and/or make them 
notice their PMM. They will rate the magnitude of interference of their PMM symptoms in 
the previous 2 weeks for each of their 3 identified activities and the change in ease/difficulty 
of performing that activity since baseline.  
7.1.10 Qualitative Interview 
Effective with the implementation of Protocol Version 8.0 (Substantial Amendment 7), 
qualitative interviews will no longer be conducted. Participants will complete qualitative 
audio interviews remotely to collect direct feedback about their experience in the study, 
particularly with respect to treatment and changes in disease burden. 
Trained interviewers will conduct the interviews using a semi-structured interview guide in a 
secure telemedicine platform.  
7.2 
Safety Assessments 
Study procedures and their timing are summarized in the schedule of assessments [Table 1]. 
Protocol waivers or exemptions are not allowed. Procedures conducted as part of a 
participant’s routine clinical management (i.e., standard of care) obtained before signing the 
ICF may be utilized for screening or baseline purposes, provided the procedures met the 
protocol-specified criteria and were performed within the timeframe, as defined in the 
schedule of assessments [Table 1].  
7.2.1 
Laboratory Assessments 
● 
See [Section 10.6, Appendix 6: Clinical Laboratory Assessments] for the list of clinical 
laboratory tests to be performed and refer to schedule of assessments [Table 1] for timing 
and frequency.  
● 
At follow-up phone call visits, a blood sample for abbreviated biochemistry will be 
collected at the participant’s home by a qualified healthcare provider from the home 
healthcare vendor. In addition, at week 2, a blood sample for abbreviated biochemistry 
and hematology will be collected. These samples should be collected at the participant’s 
home. In case the home healthcare visit is not feasible, the visit can be conducted at the 
study site. The detailed procedures will be described in the lab manual. 
● 
The investigator or subinvestigator must review the laboratory report, document this 
review and record any clinically significant changes occurring during the study as an AE. 
The laboratory reports must be filed with the source documents.  
● 
Clinical significance of out-of-range laboratory findings is to be determined and 
documented by the investigator or subinvestigator who is a qualified physician. 
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the investigator to be more severe than expected 
for the participant’s condition. 


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7.2.2 
Vital Signs 
● 
Body temperature, pulse and blood pressure will be assessed as outlined in the schedule 
of assessments [Table 1]. 
● 
Blood pressure (systolic blood pressure and diastolic blood pressure) and pulse 
measurements will be measured using a semiautomatic blood pressure recording device 
with an appropriate cuff size (same cuff size and same arm will be used for each time 
point). 
● 
When vital signs are scheduled for the same time as a blood sample, the vital signs will 
be taken before the blood sample. 
● 
Blood pressure and pulse will be measured in the sitting or supine position after the 
participant has rested for at least 5 minutes. 
7.2.3 
Physical Examination  
● 
Physical examinations will be conducted at study site visits as outlined in the schedule of 
assessments [Table 1]. Body systems to be evaluated include general appearance, skin, 
lymphatic, head and neck, ears, nose and throat, chest and lungs, cardio-vascular, 
abdomen, extremities, musculoskeletal and neuromuscular. Any clinically relevant 
abnormality at screening, including baseline symptoms for mitochondrial myopathy 
should be recorded as medical history. 
● 
Any clinically relevant change from baseline to the end of study will be recorded as an 
AE in the CRF.   
7.2.4 
Electrocardiogram  
● 
A standard 12-lead ECG will be conducted as outlined in the schedule of assessments 
[Table 1] using both a central ECG reading laboratory and local ECG reading. ECGs at 
weeks 2 and 8 will be performed at the participant’s home by a qualified healthcare 
provider from the home healthcare vendor. In case the home healthcare visit is not 
feasible, the visit can be conducted at the study site. 
● 
ECGs will be recorded in triplicate (3 separate ECGs, 5 minutes resting prior to first 
ECG and at least 1 minute apart per time point), prior to blood draw and transmitted 
electronically for central reading. The mean of the triplicate ECG from central and local 
read should be used for treatment decisions and AE reporting.  
● 
If the mean triplicate QTcF is > 500 msec at any time point, one follow-up triplicate 
ECG may be performed on the same day. If the follow-up mean QTcF is ≤ 500 msec, the 
participant may proceed with IP. If the follow-up mean QTcF > 500 msec is confirmed, 
then the participant must discontinue IP.  
● 
An ECG will also be performed within 24 hours of any of these events: an elevation of 
cTnI above the ULN (see Appendix 10.9 for reference range), or when there is an 
elevation of cTnT above the ULN (see Appendix 10.9 for reference range) or above the 
participant’s baseline value if it was elevated, or when a participant has any signs or 
symptoms reflecting cardiac involvement, inclusive of new onset shortness of breath. If 
the ECG is within normal limits, a repeat of the abnormal troponin value (cTnI or cTnT) 
should be obtained. For any of the situations above, it may be required to interrupt or 
discontinue further administration of IP as described in [Section 8.1 Discontinuation of 
Individual Participant(s) from Study Treatment]. Participants with persistent cTnI or 


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cTnT elevations, abnormal ECG or abnormal echocardiogram should undergo cardiology 
follow up. 
7.2.5 
Echocardiogram 
A local echocardiogram is to be performed within 24 hours of any of these events: an 
elevation of cTnI above the ULN (see Appendix 10.9 for reference range), or when there is 
an elevation of cTnT above the ULN (see Appendix 10.9 for reference range) or above the 
participant’s baseline value if it was elevated, or when a participant has any signs or 
symptoms reflecting cardiac involvement, inclusive of new onset shortness of breath. If the 
echocardiogram is within normal limits, a repeat of the abnormal troponin value (cTnI or 
cTnT) should be obtained. For any of the situations above, it may be required to interrupt or 
discontinue further administration of IP as described in [Section 8.1 Discontinuation of 
Individual Participant(s) from Study Treatment]. Participants with persistent cTnI or cTnT 
elevations, abnormal ECG or abnormal echocardiogram should undergo cardiology follow 
up.  
7.2.6 
Body Weight 
Body weight will be collected as outlined in the schedule of assessments [Table 1].  
7.2.7 
Columbia-Suicide Severity Rating Scale  
● 
The C-SSRS was developed as a screening tool to identify suicide risk. The interviewer 
asks participants detailed questions regarding suicidal ideation, behaviors, intensity of 
ideation and attempts. Response options and recall periods vary in accordance with the 
nature of the question. 
● 
The C-SSRS will be performed by trained site staff via interview as outlined in the 
schedule of assessments [Table 1]. At screening, the “Screening” version is to be used to 
determine eligibility. During all subsequent visits, the “Since Last Visit” version is used 
to monitor on study suicidal ideation and behavior after the initial assessment. If 
possible, continuity of raters should be maintained across visits for each participant. 
● 
Participant who has a history of suicide attempt, suicidal behavior or has any suicidal 
ideation within 1 year prior to screening that meets criteria at a level of 4 or 5 by using 
the C-SSRS or who is at significant risk to commit suicide, as assessed by the 
investigator at screening will be excluded. 
7.2.8 
Order of Assessments 
It is recommended that the participants follow the following order of assessments within each 
of the given visits [Table 6] to fulfill the requirements in the protocol.  
 


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Table 6 
Order of Assessments under Protocol Version 9.0 (Substantial Amendment 8 and Subsequent Versions) 
Week 0 
Week 4 
Week 12 
Week 24 
▪ Vital signs 
▪ 3 separate 12-lead ECG 
▪ Vital signs 
▪ 3 separate 12-lead ECG 
▪ Vital signs 
▪ 3 separate 12-lead ECG 
▪ Body Weight 
▪ Vital signs 
▪ 3 separate 12-lead ECG 
▪ 
Hematology, biochemistry, urinalysis 
▪ 
Serum and urinary biomarkers 
▪ 
Pregnancy test 
▪ 
Blood sample collection predose for 
genotyping  
▪ 
Blood sample collection predose for PGx 
(banking) 
▪ 
Blood sample collection predose for 
pharmacodynamics (PPARδ target gene 
expression) 
▪ Hematology, biochemistry, urinalysis 
▪ Pregnancy test 
▪ Hematology, biochemistry, urinalysis 
▪ Serum and urinary biomarkers 
▪ Pregnancy test 
▪ Blood for plasma pharmacokinetics at 
predose (-90 min to 0 min)* 
▪ Blood for pharmacodynamics (PPARδ target 
gene expression) at predose (-90 min to 
0 min)* 
▪ Hematology, biochemistry, urinalysis 
▪ Serum and urinary biomarkers 
▪ Pregnancy test 
▪ Blood for plasma pharmacokinetics at 
predose 
▪ Blood for pharmacodynamics (PPARδ 
target gene expression) at predose 
▪ 6MWT 
▪ Patient reported outcomes 
▪ C-SSRS 
▪ 5XSTS  
▪ Physical examination 
▪ 6MWT 
▪ Patient reported outcomes 
▪ C-SSRS 
▪ 5XSTS 
▪ Physical examination 
▪ 6MWT 
▪ Patient reported outcomes 
▪ C-SSRS 
▪ 5XSTS 
▪ Physical examination 
▪ 6MWT 
▪ Patient reported outcomes 
▪ C-SSRS 
▪ 5XSTS 
▪ Physical examination 
▪ Verify inclusion/ exclusion criteria 
▪ Dispense IP 
▪ Dispense IP 
 
▪ Randomization 
▪ IP dosing 
▪ IP dosing 
 
▪ Dispense IP 
 
▪ Blood for plasma pharmacokinetics at 
postdose (0.5-4 h) 
 
▪ IP dosing 
 
 
 
▪ Blood for plasma pharmacokinetics at 
postdose (0.5-4 h) 
 
 
 
5XSTS: 5 Times Sit to Stand; 6MWT: 6-minute walk test; C-SSRS: Columbia-Suicide Severity Rating Scale; ECG: electrocardiogram; IP: investigational product; PGx: 
pharmacogenomics; PPARδ: peroxisome proliferator-activated receptor delta 
Note: Assessments in the same box may be performed in any order.  
*Blood samples for pharmacokinetics and pharmacodynamics (PPARδ target gene expression) at week 12 will be collected within 90 minutes prior to IP dosing. When it is not feasible 
to complete 6MWT, Patient reported outcomes, C-SSRS, 5XSTS and physical examination in 90 minutes, collect blood samples for pharmacokinetics and pharmacodynamics after the 
assessments to comply with the sample collection window. 


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7.3 
Adverse Events and Other Safety Aspects 
The definitions of an AE or SAE can be found in [Sections 10.3.1 and 10.3.2], respectively. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate or the 
participant’s legally authorized representative).  
The investigator and any qualified designees are responsible for detecting, documenting and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study IP or that caused the 
participant to discontinue the IP and/or study [see Section 10.3, Appendix 3: Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-up and Reporting]. 
The method of recording, evaluating and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in [Section 10.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up and Reporting].  
7.3.1 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
All SAEs or AEs ([S]AEs) will be collected from the signing of the ICF until the follow-up 
visit or 28 days after the final IP administration, whichever is later, or when the participant is 
determined to be a screen failure, at the time points specified in the schedule of assessments 
[Table 1] and reported on the CRF. 
If the severity of an (S)AE changes, the event should be relisted on the CRF with the new 
severity and new onset date. 
If the severity decreases, the (S)AE should be relisted on the CRF with the new severity and 
new onset date. The exception is ongoing pre-dose events that continue post-dose and 
improve post-dose. Such events should not be re-listed. 
If the severity of an SAE reduces, the details of the AE should be provided on the SAE 
worksheet for the medical assessor to be able to assess the course of the event. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in [Section 10.3 Appendix 3: Adverse 
Events: Definitions and Procedures for Recording, Evaluating, Follow-up and Reporting]. 
The investigator will submit any updated SAE data to the sponsor within 24 hours of them 
being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study IP or study participation, the investigator must promptly 
notify the sponsor.  


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7.3.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
In previous versions of the protocol, if an AE had been reported or observed by the vendor 
during a qualitative interview or PMMVA, it would have been reported to the investigators 
and designated contract research organization (CRO). The investigator and any qualified 
designees are responsible for assessing, documenting, recording and reporting to the IRB/IEC 
any events that meet the definition of an AE or SAE.   
7.3.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and AEs of special interest (as defined in 
[Section 7.3.6 Adverse Events of Special Interest]) will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in [Section 8.3 Lost to Follow-up]). Further information on follow-up procedures is 
provided in [Section 10.3, Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting].  
If after the protocol-defined AE collection period [see Section 7.3.1 Time Period and 
Frequency for Collecting Adverse Event and Serious Adverse Event Information], an AE 
progresses to an SAE, or the investigator learns of any (S)AE including death, where he/she 
considers there is reasonable possibility it is related to the IP or study participation, the 
investigator must promptly notify the sponsor.  
7.3.4 
Regulatory Reporting Requirements for Serious Adverse Events 
● 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study IP under clinical investigation are met. 
● 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study IP under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC and investigators. 
● 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
● 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements.   


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7.3.5 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events 
Under this protocol, the following event(s) will not be considered as an (S)AE: 
● 
Pre-planned and elective hospital/clinical procedures/interventions or procedures for 
diagnostic, therapeutic or surgical procedures for a pre-existing condition that did not 
worsen during the course of the study. These procedures are collected per the completion 
guidelines on the CRF. 
7.3.6 
Adverse Events of Special Interest 
The following (S)AEs are considered of special interest:  
● 
Cardiac tissue injury, indicated by cTnI above ULN (see Appendix 10.9 for reference 
range) or if the cTnT is above ULN (see Appendix 10.9 for reference range) or baseline 
if the participant’s baseline value of cTnT was above ULN 
● 
Cardiac tissue injury with any signs or symptoms reflecting cardiac involvement, 
inclusive of new onset shortness of breath confirmed by ECG or echocardiogram 
● 
Skeletal muscle injury indicated by CK increase ≥ 5 times the value of the ULN or the 
individual’s baseline value, whichever is higher judged not related to an explainable 
increase, including excessive movement, fall or disease state 
● 
Suspected abuse of IP. ASP0367 has high-risk of doping potential and was assigned to 
category D (i.e., high-risk doping potential in sport). Hence, suspected abuse of IP will 
be analyzed for its muscle function improving characteristics per Astellas Doping 
Potential Guideline and will be closely followed up via compliance and participants, who 
will be expected to meet 100% compliance with IP. Compliance will be assessed by 
counting returned tablets. Deviations from the prescribed dose regimen will be recorded. 
When IP is administered at the study site, it will be administered under the supervision of 
study personnel [Section 6.4 Investigational Product Compliance]. Suspected abuse 
during study will be reported as special situations per [Section 7.3.7 Special Situations]. 
AEs (serious or nonserious) of special interest are to be collected in the CRF. If the AEs of 
special interest are classified as serious, they are to be collected via the SAE worksheet and 
reported within 24 hours as described in [Section 10.3.6 Reporting Procedures for Serious 
Adverse Events].   
7.3.7 
Special Situations  
Certain special situations observed in association with the IP, such as incorrect administration 
(e.g., wrong dose of IP or background therapy) are reported as protocol deviations and/or 
may require special reporting, as described below. These special situations are not considered 
AEs but do require to be communicated to Astellas as per the timelines defined below. 
If a special situation is associated with, or results in, an AE, the AE is to be assessed 
separately from the special situation and captured as an AE in the CRF. If the AE meets the 
definition of an SAE, the SAE is to be reported as described in [Section 10.3.6 Reporting 
Procedures for Serious Adverse Events] and the details of the associated special situation are 


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to be included in the clinical description on the special situation worksheet or pregnancy 
reporting form. 
The special situations are: 
● 
Pregnancy 
● 
Lactation 
● 
Medication error, overdose and use outside protocol 
● 
Suspected misuse/abuse of IP 
● 
Occupational exposure 
● 
Suspected drug-drug interaction 
Instructions and procedures for reporting special situations are provided in [Section 10.3.7 
Reporting Procedures for Special Situations].  
7.4 
Pharmacokinetics 
7.4.1 
Analysis of ASP0367 in Plasma 
Blood samples for the analysis of ASP0367 in plasma will be collected as described in the 
schedule of assessments [Table 1]. The actual date and time of each blood sample collection 
and the actual date and time of IP administration on the site visit day and day before 
pharmacokinetic sampling visits will be collected in the source documents. Site staff should 
document the type (high fat defined as ≥ 55 g fat, non-high fat defined as < 55 g fat or 
unknown and completion time of the meal immediately prior to on-site dosing. Meal type and 
completion time are not collected at visits with only predose sample collection. Plasma will 
be prepared according to procedures further specified in the laboratory manual. Standard 
high-quality screw-cap sample tubes will be used. Samples will be shipped on dry ice to the 
designated CRO and analyzed using a validated method.  
The plasma samples remaining after the pharmacokinetic analysis may be used for 
exploratory metabolic profiling. The plasma samples will be sent to Astellas Pharma Inc. 
(API, Tsukuba, Japan) or designated CRO. Observed Ctrough data will be summarized in the 
clinical study report (CSR), along with exploratory/graphical Ctrough vs response for key 
endpoints, as appropriate. Modeled pharmacokinetic and exposure response analyses will be 
summarized in a separate report. 
7.5 
Pharmacodynamics 
Blood samples for PPARδ target gene expression assay will be collected at time points as 
detailed in the schedule of assessments [Table 1]. Blood sample collection, processing, 
handling and storage will be described in the laboratory manual. 
7.6 
Pharmacogenomics 
7.6.1 
Sample for Genotyping 
Knowledge of polymorphisms of genes PPARδ and peroxisome proliferator-activated 
receptor gamma coactivator 1 alpha (PPARGC1A) may help understand/explain observed 
differences in efficacy of ASP0367. A 2 mL whole blood sample for the analysis of these 


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genes (pharmacogenomics [PGx]) will be collected as indicated in the schedule of 
assessments [Table 1]. For detailed sample collection, sample labeling and sample shipment 
procedures, refer to the laboratory manual. All samples will be transferred to the central 
laboratory and then shipped to the analytical laboratory where they will be analyzed using 
appropriate validated methods. 
7.6.2 
Sample for Banked Pharmacogenomics 
PGx research may be conducted in the future to analyze or determine genes of relevance to 
clinical response, pharmacokinetics and toxicity/safety. A 4-mL sample of whole blood for 
possible banked PGx analysis will be collected as indicated in the schedule of assessments 
[Table 1]. Samples will be shipped to a sponsor-designated banking CRO. Details on sample 
collection, labeling, storage and shipment procedures will be provided in a separate 
laboratory manual. See [Section 10.7, Appendix 7: Pharmacogenomic Analysis with Banked 
Sample] for further details on the banking procedures. 
7.7 
Biomarkers 
7.7.1 
Urine Sample Analysis for TITIN 
Urine samples for TITIN of ASP0367 will be collected according to the schedule of 
assessments [Table 1]. 
Details on sampling, processing, storage and shipment procedures will be provided in the 
laboratory manual.  
7.7.2 
Blood Sample for Serum Target Proteins 
A blood sample for serum target proteins (aldolase A [ALDOA], cytochrome c [CYC] and 
filamin-C [FLNC]) will be done in blood collection tubes at the time points indicated in the 
schedule of assessments [Table 1].  
For detailed sampling, processing of samples, storage and shipment procedures refer to the 
laboratory manual. 
7.8 
Immunogenicity Assessments 
Not applicable 
7.9 
Electronic Clinical Outcome Assessment 
The following clinical outcome assessments will be captured on an electronic device.  
The collected electronic source data will be hosted by the vendor. The investigator or site 
designee will review the questionnaire data throughout the study to ensure completion and 
protocol compliance. 
The questionnaire data will be transferred electronically to sponsor or designee at predefined 
intervals during the study. The vendor will provide the investigator with a complete and clean 
copy of their site’s data and will provide the sponsor or designee with a complete and clean 
copy of the study data. The ownership of this data is with the investigator and subsequently 


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any changes requested by the investigator or designee to these participant- or clinician-
reported data will be made following the vendor’s process. The requested change must be 
supported by documented evidence at the site.  
7.9.1 
Quality of Life in Neurological Disorders 
Neuro-QoL will be performed at the study site during study site visits. The assessments will 
be answered by the participant and collected on an electronic device.  
7.9.2 
Modified Fatigue Impact Scale 
MFIS will be performed at the study site during study site visits. The assessments will be 
completed by the participant on an electronic device.  
7.9.3 
Patient Global Impression of Change 
PGIC will be performed at the study site during study site visits. The assessments will be 
completed by the participant on an electronic device. 
7.9.4 
Patient Global Impression of Severity 
PGIS will be performed at the study site during study site visits. The assessments will be 
completed by the participant on an electronic device. 
7.9.5 
Columbia-Suicide Severity Rating Scale 
The C-SSRS will be performed at the study site during study site visits. The assessments will 
be completed by trained site staff via interview on an electronic device. 
7.9.6 
European Quality of Life 5-Dimension, 5-Level Questionnaire 
The EQ-5D-5L will be performed at the study site during site visits. The assessments will be 
completed by the participant on an electronic device.  
7.9.7 
Primary Mitochondrial Myopathy Video Assessments 
Effective with implementation of Protocol Version 8.0 (Substantial Amendment 7), PMMVA 
will no longer be collected. In previous versions of the protocol, PMMVA was performed at 
participant’s home setting by participants using a secure mobile application. Participants 
registered for the study mobile application and downloaded the mobile application on an 
Apple (IOS 10+) or Android (5.1+) smartphone. Participants were provided with training 
materials in the study mobile application and in the study kit to learn how to video record the 
assigned movement activities. Participants provided an electronic signature within the study 
mobile application to document training completion. The specific movement activities were 
detailed in the Training Manual.  
7.9.8 
Individualized Activity Assessments 
Effective with implementation of Protocol Version 8.0 (Substantial Amendment 7), 
individualized activity assessments will no longer be collected. In previous versions of the 
protocol, the assessments for individualized activities were rated at participant’s home using 
a secure mobile application.  


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7.9.9 
Qualitative Interview 
Effective with implementation of Protocol Version 8.0 (Substantial Amendment 7), 
qualitative interviews will no longer be conducted. In previous versions of the protocol, 
Qualitative audio interviews were conducted remotely by trained interviewers using a 
semi-structured interview guide in a secure telemedicine platform in participant’s home 
setting.  
7.10 
Other Assessments 
7.10.1 Exercise Status 
For the participants who are on an exercise regimen, changes to the status of the exercise 
regimen will be collected at each visit (on site or phone call). 
7.11 
Total Amount of Blood 
The total amount of blood for each participant will vary depending on the course of their 
disease, duration on treatment and local laboratory requirements. At any time during the 
study, if any laboratory abnormalities are found for a participant, additional blood may be 
drawn for safety monitoring [Table 7].  
Table 7 
Blood Volume 
Sample Type 
Number 
of 
Samples 
Approximate 
Sample 
Volume (mL) 
Approximate 
Total Volume 
(mL) 
Hematology, biochemistry, serology and serum pregnancy 
test (if applicable) at screening 
1 
22 
22 
Biochemistry and hematology at weeks 0, 4, 12, 24 and 28 
5 
16 
80 
Abbreviated biochemistry and abbreviated hematology at 
week 2  
1 
11.5 
11.5 
Abbreviated biochemistry at phone call visits 
5 
10.5 
52.5 
Pharmacokinetics of ASP0367 
4 
2 
8 
Serum biomarkers 
3 
4 
12 
Genotyping 
1 
2 
2 
Pharmacogenomics (banking)* 
1 
4 
4 
Pharmacodynamics of PPARδ target gene expression 
3 
5 
15 
Total 
207 
PPARδ: peroxisome proliferator-activated receptor delta 
*Pharmacogenomics (banking) will be performed for the participants who were given the consent. 
 


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8 
PARTICIPANT DISCONTINUATION 
Refer to [Section 10.1.9 Study and Site Start and Closure] regarding discontinuation of study 
sites or of the study as a whole. An interim analysis will be performed to determine if 
efficacy or futility stopping criteria are met while the study is ongoing. Refer to [Section 9.6] 
for details regarding the interim analysis and stopping criteria.   
8.1 
Discontinuation of Individual Participant(s) from Study Treatment  
A discontinuation from treatment is defined as a participant who enrolled in the study and for 
whom study treatment is permanently discontinued for any reason.  
The participant is free to withdraw from the study treatment and/or study for any reason and 
at any time without giving reason for doing so and without penalty or prejudice. The 
investigator is also free to discontinue the participant from study treatment or to terminate a 
participant’s involvement in the study at any time if the participant’s clinical condition 
warrants it. 
The reason for discontinuation from study treatment must be documented in the participant’s 
medical records. 
A participant must discontinue study treatment for any of the following reasons: 
● 
Participant requests to stop treatment.  
● 
Any clinical AE, laboratory abnormality or intercurrent illness, in the opinion of the 
investigator, indicates continued treatment is not in the best interest of the participant. 
● 
Participant remains non-compliant with the protocol based on investigator’s or sponsor’s 
assessment. 
● 
Female participant becomes pregnant. 
An individual participant may be required to discontinue further administration of IP if any of 
the following occurs, which is considered to be clinically significant and to be considered 
related to IP:  
● 
SUSAR 
● 
Participant has a mean QTcF > 500 msec measured by a triplicate ECG. If the mean 
QTcF exceeds 500 msec, a follow-up triplicate ECG may be performed on the same day. 
If the follow-up mean QTcF is still > 500 msec, the participant must discontinue IP. 
● 
Participant who experiences a cTnI elevation (i.e., > ULN [see Appendix 10.9 for 
reference range]) or a cTnT elevation above the ULN (see Appendix 10.9 for reference 
range) or above the participant’s baseline value if it was elevated should undergo ECG 
and echocardiogram within 24 hours. The investigator should determine whether it is 
appropriate to continue administration of IP to the participant while the evaluations are 
being completed. If the ECG and echocardiogram are within normal limits, a repeat of 
the abnormal value (cTnI or cTnT) should be obtained. Participants with persistent cTnI 
or cTnT elevations, abnormal ECG or echocardiogram should interrupt IP and undergo 
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● 
Participant who develops any signs or symptoms potentially reflecting cardiac 
involvement, inclusive of  new onset shortness of breath, should interrupt IP and undergo 
ECG, echocardiogram, and have a cTnI drawn to be evaluated prior to continuing IP. 
● 
Participant who develops an elevation in CK levels ≥ 5 times the value of the ULN or the 
individual’s baseline value, whichever is higher and it has been judged that this elevation 
is not related to an explainable cause such as excessive activity or disease state. 
● 
Participant who develops elevated levels of ALT or AST > 3 × ULN, or TBL > 2 × ULN 
persisting after 72 hours in the absence of elevated CK levels must discontinue IP. 
Generally, liver chemistry will be followed by repeated measurements until they return 
to baseline or stable values. 
● 
Participant who presents evidence of suicidality during the C-SSRS assessments by 
meeting the criteria at a level of 4 or 5 since last visit must discontinue IP and upon 
immediate evaluation, the investigator will decide an appropriate referral. 
● 
Participant who develops symptomatic viral infection should be evaluated by the 
Investigator and assessed for the need to stop IP until clinically improved. 
● 
Participant who newly develops signs or symptoms of bulbar weakness, such as 
dysphagia, dysphonia, hoarseness or drooling/sialorrhea, should discontinue IP. 
● 
Participant with a new requirement for oxygen therapy or for ventilatory support, 
inclusive of any respiratory device to support breathing, such as home ventilators and 
any form of non-invasive positive pressure ventilation (including CPAP, BiPAP, and 
AVAPS), should discontinue IP. 
8.2 
Discontinuation of Individual Participant(s) from Study 
All participants who discontinue study treatment will remain in the study and must continue 
to be followed for protocol-specific follow-up procedures as outlined in the schedule of 
assessments [Table 1]. The only exception to this is when the participant specifically 
withdraws consent for any further contact with him/her or persons previously authorized by 
the participant to provide this information.  
To encourage participants who discontinue assigned treatment to remain in the study for 
efficacy and safety evaluations, the ICF will highlight continued collection of data in 
participants that do not adhere to treatment but remain in the study and distinguish the 
difference between withdrawing from the treatment and withdrawing from the study. 
In addition, to minimize the amount of missing data, the sponsor will keep track of the 
amount of missing data of 6MWTs and the reasons for withdrawal from the treatment or 
study. If any issue is identified, a root cause analysis will be conducted and it will address the 
issue appropriately.  
8.3 
Lost to Follow-up 
Every reasonable effort is to be made to contact any participant lost to follow-up during the 
course of the study to complete study-related assessments, record outstanding data and 
retrieve IP. These contact attempts should be documented in the participant’s medical record. 


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9 
STATISTICAL CONSIDERATIONS 
Given the design, a 24-week treatment analysis, which is of the primary focus, will be 
provided to assess efficacy and safety during the 24-week double-blind treatment period. This 
will occur after all participants have completed 24 weeks of treatment. Unblinding will be 
performed after database lock for 24-week data. Once the entire study is completed and the 
database is locked, additional efficacy and safety data will be summarized and a separate 
treatment analysis will be conducted at later timepoints up to 76 weeks as per available data. 
This section includes the principal feature of the analysis for the 24-week double-blind 
treatment period and interim analysis. Available data collected after the 24-week double-
blind treatment period will be summarized, and details will be provided in a separate 
statistical analysis plan (SAP). An interim analysis will be performed when approximately 30 
participants complete the 6MWT assessment at week 24. 
9.1 
Statistical Hypotheses 
The hypothesis for the primary endpoint is given as follows: 
H0: The change from baseline in distance walked on the 6MWT at week 24 for each dose of 
ASP0367 and placebo are the same. 
H1: The change from baseline in distance walked on the 6MWT at week 24 for each dose of 
ASP0367 and placebo are not the same. 
To control the family-wise type I error rate (i.e., the probability of incorrectly rejecting at 
least one true null hypothesis) under the nominal significance level of 0.10 2-sided, a two-
stage group sequential design with Lan-DeMets alpha-spending function determined by 
means of the O'Brien-Fleming approach will be used for the interim analysis. Additionally, 
the hierarchical testing procedure in the following order will be applied for the primary 
analysis in the 24-week treatment analysis: 
1. Comparison between ASP0367 75 mg and placebo 
2. Comparison between ASP0367 30 mg and placebo 
9.2 
Sample Size Determination 
The sample size of this study was determined from feasibility and statistical perspectives. 
From the statistical perspective, 57 participants (19 participants in each group) will provide 
> 80% power to detect a difference of 45 meters in 6MWT between ASP0367 and placebo at 
a 2-sided significance level of 0.10 assuming a common standard deviation of 55.0 meters.  
The 45-meter difference in 6MWT under the 24-week treatment is assumed based on 
preliminary results that were observed in cohort 1 of the MMPOWER-2 phase 2 randomized 
controlled crossover study of elamipretide [Cohen et al, 2018].  
Considering the interim analysis, 60 participants will be required to maintain > 80% power in 
the efficacy analysis, and assuming an approximately 10% study discontinuation (drop out) 
rate during the double-blind treatment period, 66 participants are required to be randomized. 
This sample size supports an evaluation of proof of concept. 


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9.3 
Populations for Analyses 
The following populations are defined for the 24-week treatment analysis:  
Population 
Description 
Full Analysis Set (FAS) 
All participants who receive at least 1 dose of ASP0367 or placebo for 
the double-blind treatment period and have at least 1 post baseline 
efficacy measurement. 
The FAS will be used for all summaries of efficacy data. 
Safety Analysis Set 
(SAF) 
All participants who receive at least 1 dose of ASP0367 or placebo for 
the double-blind treatment period. 
The SAF will be used for all summaries of the safety data. 
Pharmacokinetic 
analysis set (PKAS) 
All participants who receive at least 1 dose of IP for which 
concentration data are available for at least 1 time point. Inclusion of 
participants in the PKAS with missing data or major protocol deviations 
will be considered by the pharmacokineticist on a case-by-case basis. 
The PKAS will be used for all summaries and analyses of the 
pharmacokinetic data. 
Extended 
pharmacokinetic 
analysis set (EPKAS) 
All participants who receive at least 1 dose of IP for which at least 1 
pharmacokinetic parameter is available at week 0 and/or week 2. 
Inclusion of participants in the EPKAS with missing data or major 
protocol deviations will be considered by the pharmacokineticist on a 
case-by-case basis. The EPKAS will be used for noncompartmental 
analyses of the pharmacokinetic data and concentration and 
pharmacokinetic parameter summaries at weeks 0 and 2.  
Biomarker analysis set 
(BMAS) 
All participants who receive at least 1 dose of ASP0367 or placebo and 
have data from at least 1 post baseline biomarker test or 
pharmacodynamic test available. 
The BMAS will be used for all summaries and analyses of the 
biomarker as well as pharmacodynamic data. 
9.4 
Statistical Analyses 
A SAP will be written to provide details of the analysis, along with specifications for tables, 
listings and figures to be produced. SAPs will be prepared for analyses at the end of 24 weeks 
of double-blind treatment for objectives and endpoints of this protocol and additional 
objectives and endpoints specific to the endpoints in the 0367-CL-1201 [MAYO] Protocol. 
Other SAPs will be prepared for analysis at the end of 76 weeks of treatment for objectives 
and endpoints of this protocol and additional objectives and endpoints specific to the 0367-
CL-1201 [MAYO] Protocol. The SAPs for the 24-week double-blind treatment analysis and 
76-week treatment analysis will be finalized before unblinding for 24-week data and before 
database lock for 76-week data, respectively. Changes from the planned analyses in the final 
SAP that impact the statistical analyses will be justified in the CSR. Additionally, the interim 
analysis plans will be prepared to provide the details of the interim analysis. The interim 
analysis plans will be finalized prior to the interim analyses. 


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9.4.1 
General Considerations 
In general, continuous data will be summarized with descriptive statistics (number of 
participants, mean, SD, minimum, median and maximum), frequency and percentage for 
categorical data. Percentage by categories will be based on the number of participants with no 
missing data (i.e., will add up to 100%).  
Baseline will be defined as the last non-missing observation prior to first administration of 
IP, unless otherwise specified. 
Demographics and baseline characteristics (age, sex, race and ethnicity, body weight, height 
and BMI) and genetic abnormality for PMM will be summarized by treatment group and 
overall for the Safety Analysis Set (SAF). 
The number and percentage of participants who complete and discontinue 24 weeks of 
treatment and reasons for treatment discontinuation will be presented for all randomized 
participants by treatment group and overall. All disposition details and dates of first and last 
evaluations for each participant will be listed. 
All previous and concomitant treatment and medical history will be listed. Medical history 
will be coded using MedDRA and will be summarized by system organ class (SOC) and 
preferred term (PT) by treatment group and overall for the SAF. All IP exposure data will be 
listed.  
9.4.2 
Analysis of Efficacy  
Efficacy analysis will be conducted on the Full Analysis Set and statistical testing will be 
performed to compare each dose group of ASP0367 and placebo group at the 2-sided 0.10 
significance level. Details will be provided in the SAP. 
9.4.2.1 Analysis of Primary Endpoint 
For primary efficacy endpoint, change from baseline in distance walked on the 6MWT at 
week 24, a mixed model for repeated measures (MMRM) with treatment groups (3 level: 
ASP0367 75 mg, ASP0367 30 mg, and placebo group), week (weeks 4, 12 and 24) and site 
group (2 level: Mayo clinic_Minnesota; Non-Mayo clinic_Minnesota) as factors, with 
baseline measurement as a covariate, as well as an interaction of treatment by week and an 
interaction of baseline measurement by week. If the number of participants from either site 
group is small, the site group will be removed from the model. It will be determined before 
the unblinding and pre-defined in the SAP. 
The 6MWT evaluated below will be included in the analysis. 
• For participants who consented for this study in Protocol Version 7.0 or former 
version and did not re-consent to Protocol Version 8.0 or later by week 24: the 
6MWT evaluated until 7 days after the last dose of IP for the double-blind treatment 
period of the study or moving to the OLE or day 182, whichever comes first.  


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• For participants who consented or re-consented this study in Protocol Version 8.0 or 
later version by week 24: the 6MWT evaluated until 7 days after the last dose of IP 
for the double-blind treatment period of the study. 
9.4.2.2 Sensitivity Analysis/Supplementary Analysis 
Sensitivity analysis and supplementary analysis will be performed for the primary endpoint 
using the MMRM based on the Full Analysis Set to assess the robustness of the primary 
efficacy results. The following analyses are planned:  
● 
MMRM with additional covariate(s).  
● 
MMRM including the data after treatment discontinuation. 
9.4.2.3 Analysis of Secondary Endpoints  
The change from baseline to week 24 in 5XSTS and MFIS will be analyzed using the same 
MMRM as with the primary endpoint. 
For Neuro-QoL Short Form Fatigue and Lower Extremity Function (Mobility) scores, a 
transformed T-score will be used, which rescale raw scores into standardized scores with a 
mean of 50 and a standard deviation of 10. Change of T-scores from baseline to week 24 will 
be analyzed using the same MMRM as with the primary endpoint. 
For PGIC score at week 24, generalized estimating equation model will be used with 
treatment group (3 level: ASP0367 75 mg, ASP0367 30 mg, and  placebo group), week 
(weeks 4, 12 and 24) and site group (2 level: Mayo clinic_Minnesota; Non-Mayo 
clinic_Minnesota) as factors, as well as an interaction of treatment by week. In addition, 
responder analysis will be used. Participants with scores of 1 (Very Much Improved), 2 
(Much Improved) and 3 (Minimally Improved) will be considered as responders, whereas 
participants with scores of 4 (No Change), 5 (Minimally Worse), 6 (Much Worse) and 7 
(Very Much Worse) will be treated as nonresponders. 
For PGIS score, change from baseline to week 24 will be analyzed using generalized 
estimating equation model with treatment group (3 level: ASP0367 75 mg, ASP0367 30 mg, 
and placebo group), week (weeks 4, 12 and 24) and site group (2 level: Mayo 
clinic_Minnesota; Non-Mayo clinic_Minnesota) as factors, baseline value as a covariate, as 
well as an interaction of treatment by week and an interaction of baseline value by week. 
For the secondary endpoints, the multiplicity of statistical comparison will not be adjusted. 
9.4.2.4 Analysis of Exploratory Endpoints  
For 6MWT, 5XSTS, Neuro-QoL Short Form Fatigue and Lower Extremity Function 
(Mobility) scores, change from baseline to week 4 and 12 will be summarized by treatment 
group and time point. The change from baseline in minute-by-minute analyses (i.e., 6th vs 1st) 
of 6MWT at weeks 4, 12 and 24 will be summarized by treatment group.   
For MFIS score and PGIS scores, change from baseline to weeks 4 and 12 will be 
summarized by treatment group and time point. Moreover, PGIC scores at weeks 4 and 12 
will also be displayed in the same way.  


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For the EQ-5D-5L descriptive systems, the number and percentage of participants will be 
summarized by scored level (1 to 5) of each dimension and treatment group, as well as time 
point. Change from baseline in EQ-VAS and EQ-5D-5L index values at weeks 4, 12 and 24 
will be summarized by treatment group and time point. 
9.4.3 
Analysis of Safety 
Safety analyses will be conducted on the SAF. Summary tables and listings of safety 
information will be provided in the SAPs. 
9.4.3.1 Adverse Events  
AEs will be coded using MedDRA.  
A TEAE is defined as below: 
• For participants who consented for this study in Protocol Version 7.0 or former 
version and did not re-consent to Protocol Version 8.0 or later version by week 24: an 
AE observed after starting administration of the IP to 28 days after the last dose of IP 
for the double-blind treatment period of the study or moving to the OLE or day 182, 
whichever comes first.  
• For participants who consented or re-consented to this study in Protocol Version 8.0 
or later version by week 24: an AE observed after starting administration of the IP to 
28 days after the last dose of IP for the double-blind treatment period of the study or 
moving to the OLE, whichever comes first. 
The number and percentage of participants with TEAEs, SAEs, AEs leading to withdrawal of 
treatment and AEs related to IP will be summarized by SOC, PT and treatment group. The 
number and percentage of AEs by severity will also be summarized. The worst severity will 
be summarized if the same AE is recorded more than once for a participant. 
An IP-related TEAE is defined as any TEAE with a causal relationship of “yes” by the 
investigator. 
AE data will be listed. 
9.4.3.2 Laboratory Assessments  
For quantitative clinical laboratory measurements (hematology, biochemistry and urinalysis), 
descriptive statistics will be used to summarize results and change from baseline by treatment 
group and time point.  
Laboratory data will be listed. 
9.4.3.3 Vital Signs  
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
by treatment group and time point.  
Vital signs data will be listed. 


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9.4.3.4 Body Weight 
Body weight data will be displayed in listings. 
9.4.3.5 Electrocardiogram 
9.4.3.5.1 
Routine 12-lead Electrocardiogram 
The routine 12-lead ECG results will be summarized by treatment group and time point. 
All ECG interpretations will be displayed in listings. 
9.4.3.5.2 
Continuous 12-lead Electrocardiogram  
For all analyses, replicates at each time point will be averaged for each continuous 12-lead 
ECG parameter. 
Descriptive statistics will be used to summarize the continuous 12-lead ECG parameter 
results and changes from baseline by treatment group and time point.  
The number and percentage of participants with absolute QTcF interval ≤ 450 msec,  
> 450 msec, > 480 msec, > 500 msec will be provided by treatment group at each time point 
and overall by visit. Similar summary information will be provided for QTcF interval 
increases from baseline of ≤ 30 msec, > 30 msec and > 60 msec. 
Continuous 12-lead ECG data (individual replicates and the averages) will be listed. 
9.4.3.6 Echocardiogram 
Echocardiogram results will be displayed in listings. 
9.4.3.7 Columbia-Suicide Severity Rating Scale 
C-SSRS data will be summarized by treatment group and time point. 
9.4.4 
Analysis of Pharmacokinetics 
Descriptive statistics will include n, mean, SD, minimum, median, maximum, coefficient of 
variation (CV), geometric mean and geometric CV, where applicable. Noncompartmental 
analysis will be performed on the dense pharmacokinetic samples from participants who have 
already provided these and will be reported in the CSR. Further details on the calculation of 
the pharmacokinetic parameters will be provided in the SAPs. No noncompartmental analysis 
will be conducted on samples from new participants. Only Ctrough will be reported for new 
participants in the CSR, and pharmacokinetic profiles will be analyzed via population 
pharmacokinetics. 
9.4.5 
Analysis of Pharmacodynamics 
Analysis of pharmacodynamics data for participants enrolled prior to implementation of 
Protocol Version 9.0 (Substantial Amendment 8) will differ from analysis of data for 
participants enrolled starting with Protocol Version 9.0 (Substantial Amendment 8). 


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9.4.5.1 Analysis of Treatment-emergent Gene Expression 
Summaries of absolute values and relative changes from baseline for each gene by scheduled 
sample time point and treatment group will be provided. Baseline for gene expression is 
predose measurements on day 1. Absolute values and relative changes from baseline for gene 
expression will be listed. If deemed appropriate, gene expression data may be log-
transformed and/or graphically summarized. 
9.4.5.2 Estimation of Pharmacodynamic Parameters 
Further details on the calculation of the pharmacodynamic parameters will be provided in the 
SAP. 
9.4.6 
Other Analyses 
9.4.6.1 Analysis of Biomarkers 
Descriptive statistics (e.g., n, mean, SD, median, minimum CV, geometric mean and 
geometric CV where applicable) will be used to summarize the effects of ASP0367 (result 
and relative change from baseline) for serum FLNC, CYC and ALDOA, and urinary TITIN. 
The summaries will be presented by treatment group and by scheduled sampling time point. 
For 24-week treatment analysis, a summary will be provided by treatment group. 
Descriptive statistics will be used to summarize results and relative change of biomarker 
measurements from baseline by time point. 
All biomarker data (results and relative change from baseline) will be listed. In addition, 
biomarker data may be summarized graphically and/or descriptively as they relate to clinical 
measures, as applicable. Additional exploratory biomarker analyses may be performed and 
defined in a biomarker SAP. 
9.4.6.2 Analysis of Genotyping 
Polymorphisms of genes PPARδ and PPARGC1A will be tabulated. In addition, 
polymorphisms of genes may be summarized graphically and/or descriptively as they relate 
to clinical measures, as applicable. All analyses described in this section are based on 
availability of the data. 
9.4.6.3 Exposure-response Analysis 
The relationship between PK parameters (e.g., Ctrough) of ASP0367 and efficacy, safety and 
pharmacodynamics will be investigated. The details of this analysis will be described in the 
SAP. Other exposure metrics such as Cave,ss may be investigated using pharmacokinetic 
parameters estimated in population pharmacokinetic analysis and reported separately from 
the CSR, as calculable pending the population PK model. 
9.5 
Additional Conventions 
If the start and stop dates of AEs and concomitant medications are incomplete, imputed dates 
will be used to determine whether an AE is/is not treatment emergent or to allocate a 
concomitant medication to the study period it was taken.  


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Refer to the SAPs for details of the definition for analysis windows to be used for analyses by 
visit. 
9.6 
Interim Analysis 
9.6.1 
Interim Analysis of Efficacy 
The analysis of futility and of efficacy will be performed when approximately 30 participants 
complete the 6MWT assessment at week 24 for the evaluation of whether a change may be 
observed in the primary endpoint. If no appreciable change is noted, the study may be 
stopped due to futility. If efficacy is observed, the study may continue or may be brought to a 
completion in order to proceed to a final full analysis of the study.  
The change from baseline in distance walked on the 6MWT at week 24 will be analyzed 
using the same MMRM as with the primary endpoint excluding the site group from the 
model to decide whether the study will continue.  
Analysis of Futility 
For the futility stop, the study may be stopped if the conditional probability of achieving the 
criteria below at the final analysis is less than 10%. 
Criteria: Lower limit of the 90% CI for the difference is greater than 0 m AND the point 
estimate of the difference between the ASP0367 75 mg group and the placebo group is 
greater than 30 m. 
In addition to 6MWT at week 24, outputs for participant disposition, demographics and the 
secondary endpoints 5XSTS, Neuro-QoL Short Form Fatigue score, Neuro-QoL Short Form 
Lower Extremity Function (Mobility) score, MFIS, PGIC, and PGIS at week 24 may be 
analyzed at the interim analysis.  
The interim analysis outputs will be prepared by an external statistician and presented to the 
DMC for interim analysis who will make recommendations about the ongoing conduct of the 
study. 
Details of the analysis will be defined in the interim analysis plan. 
Analysis of Efficacy 
For the efficacy stop, a two-stage group sequential design with Lan-DeMets alpha-spending 
function determined by means of the O'Brien-Fleming approach will be used to preserve the 
overall two-sided type I error rate of 0.10 between this single interim analysis and the final 
analysis. If the p-value of the comparison between ASP0367 75 mg and placebo groups at 
interim analysis is lower than the boundary determined by O'Brien-Fleming approach, 
efficacy would be considered to be achieved at week 24. 
9.6.2 
Interim Analysis of Pharmacokinetics and Pharmacodynamics 
An interim analysis of pharmacokinetic and pharmacodynamic data may be conducted with 
data from approximately 30 participants. These analysis results will help in understanding the 
results of the interim analysis for futility and efficacy. The interim analysis will be detailed in 


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a separate interim pharmacokinetic and pharmacodynamic analysis plan. Personnel external 
to the study team will be specified in the interim analysis plan and will analyze the 
pharmacokinetic and pharmacodynamic data and prepare a report to be shared with the DMC 
and others. Only mean values and figures with variability will be shared with the study team 
and DMC to maintain the study team blind before database lock. 


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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Appendix 1: Ethical, Regulatory and Study Oversight 
Considerations 
10.1.1 Regulatory and Ethical Considerations 
● 
This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
o Applicable ICH GCP Guidelines 
o Applicable laws and regulations 
● 
The protocol, protocol amendments, ICF, Investigator’s Brochure and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
● 
Any amendments to the protocol will require IRB/IEC approval before implementation 
of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
● 
The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable) and all 
other applicable local regulations 
10.1.2 Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.  
10.1.3 Informed Consent of Participants 
10.1.3.1 Informed Consent Process 
● 
The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 
● 
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of  


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21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act requirements, where applicable, and the IRB/IEC or study center. 
● 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
● 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
● 
A copy of the signed ICF must be provided to the participant. 
10.1.3.2 Supply of New and Important Information Influencing the Participant’s 
Consent and Revision of the Written Information 
● 
The investigator or his/her representative will immediately inform the participant 
verbally whenever new information becomes available that may be relevant to the 
participant’s consent or may influence the participant’s willingness to continue 
participating in the study (e.g., report of serious adverse drug reaction). The 
communication must be documented in the participant’s medical records and whether the 
participant is willing to remain in the study or not must be confirmed and documented.  
● 
The investigator must update the participant’s ICF and submit it for approval to the 
IRB/IEC. The investigator or his/her representative must obtain written informed consent 
from the participant on all updated ICFs throughout their participation in the study. The 
investigator or his/her designee must reconsent participants with the updated ICF even if 
relevant information was provided verbally. The investigator or his/her representative 
who obtained the written informed consent and the participant should sign and date the 
ICF. A copy of the signed ICF will be given to the participant and the original will be 
placed in the participant’s medical record. An entry must be made in the participant’s 
records documenting the reconsent process. 
10.1.4 Data Protection 
Individual participant medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited unless the participant provides 
written consent or approval. Additional medical information may be given only after 
approval of the participant to the investigator or to other appropriate medical personnel 
responsible for the participant’s well-being. 
The sponsor shall not disclose any confidential information on participants obtained during 
the performance of their duties in the study without justifiable reasons.  
Even though any individuals involved in the study, including the study monitors and auditors, 
may get to know matters related to a participant’s privacy due to direct access to source 
documents, or from other sources, they may not disclose the content to third parties.  
The sponsor affirms the participant’s right to protection against invasion of privacy. Only a 
participant identification number will identify participant data retrieved by the sponsor. 
However, the sponsor requires the investigator to permit the sponsor, sponsor’s 


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representative(s), the IRB/IEC and when necessary, representatives of the regulatory health 
authorities to review and/or to copy any medical records relevant to the study. 
The sponsor agrees to comply and process personal data in accordance with all applicable 
privacy laws and regulations, including, without limitation, the Personal Information 
Protection Law in Japan and privacy laws in the US. If the services will involve the collection 
or processing of personal data (as defined by applicable data protection legislation) within the 
European Economic Area (EEA), then the sponsor shall serve as the controller of such data, 
as defined by the EU Data Protection Directive (DPD), and investigator and/or third party 
shall act only under the instructions of the sponsor in regard to personal data. If the sponsor is 
not based in the EEA, the sponsor must appoint a third party to act as its local data protection 
representative or arrange for a co-controller established in the EU for data protection 
purposes in order to comply with the DPD. 
10.1.5 Committee(s) Structure 
10.1.5.1 Data Monitoring Committees 
This study will utilize an independent DSMB and a separate DMC for the interim analysis 
and their operation will be defined in detail in the charter documents.  
10.1.5.1.1 Data and Safety Monitoring Board 
The DSMB will be an independent and external multidisciplinary group consisting of at least 
2 physicians and a biostatistician. One of the physicians will be named DSMB Chair and at 
least 1 of these physicians must be an expert in mitochondrial disorders. The third member of 
the DSMB will be a biostatistician with relevant experience in drug development. All DSMB 
members will be familiar with the general guidelines for data and safety monitoring set forth 
by FDA and other relevant regulatory authorities. The DSMB meeting(s) will be conducted 
periodically (i.e., every 3 months) following the first meeting to be held after the first 30 
participants complete week 2 assessments during the double-blind treatment period in person 
or via teleconference with both an open and closed session according to the DSMB charter.  
The DSMB will assess the overall safety and tolerability of ASP0367 throughout the course 
of the study. Safety data including AEs, vital signs, routine 12-lead ECGs, safety laboratory 
tests and cumulative AE data will be reviewed in an unblinded fashion. The DSMB may 
provide recommendations to continue or terminate the study if deemed in the best interest of 
the participants.  
10.1.5.1.2 Data Monitoring Committee for Interim Analysis 
The DMC for interim analysis will be an Astellas internal multidisciplinary group. 
The DMC for interim analysis will assess the efficacy of the study treatments and make 
recommendations about the ongoing conduct of the study. The DMC for interim analysis will 
be responsible for examining the data reported by treatment assignment, including the 6MWT 
assessment at week 24, using statistical boundaries specified in the interim analysis plan. The 
DMC could recommend the discontinuation of the study due to efficacy or futility. The 


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interim analysis will be detailed in an interim analysis plan and presented to the DMC who 
will make recommendations about the ongoing conduct of the study. 
10.1.6 Dissemination of Clinical Study Data 
ICH E3 guidelines recommend, and EU Directive 2001/83/EC requires, that a final CSR that 
forms part of a marketing authorization application, be signed by the representative for the 
coordinating investigator(s) or the principal investigator(s). The representative for the 
coordinating investigator(s) or the principal investigator(s) will have the responsibility to 
review the final study results to confirm to the best of his/her knowledge it accurately 
describes the conduct and results of the study. The representative for the coordinating 
investigator(s) or the principal investigator(s) will be selected from the participating 
investigators by the sponsor prior to database lock.  
10.1.7 Data Quality Assurance 
● 
All participant data relating to the study will be recorded on the CRF unless transmitted 
to the sponsor or designee electronically in an external data file (e.g., central laboratory 
data). The investigator is responsible for verifying that data entries on the CRF are 
accurate and correct by physically or electronically signing the CRF. 
● 
Guidance on completion of CRFs will be provided in a separate CRF Completion 
Guideline. 
● 
The investigator must permit study-related monitoring, audits, IRB/IEC review and 
regulatory agency inspections and provide direct access to source data documents. 
● 
Quality tolerance limits (QTLs) will be predefined in the applicable plan(s) to identify 
systematic issues that can impact participant safety and/or reliability of study results. 
These predefined parameters will be monitored during the study, and important 
deviations from the QTLs and remedial actions taken will be summarized in the CSR. 
● 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan. 
● 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
● 
The sponsor assumes accountability for actions delegated to other individuals (e.g., 
CROs). 
● 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator according to ICH or applicable local regulatory 
requirements, whichever is longer, after study completion. No records may be destroyed 
during the retention period without the written approval of the sponsor. No records may 
be transferred to another location or party without written notification to the sponsor. 
10.1.8 Source Documents 
1. Source data must be available at the study site to document the existence of the 
participants and to substantiate the integrity of study data collected. Source data must 


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include the original documents relating to the study, as well as the medical treatment and 
medical history of the participant.  
2. The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
3. The investigator is responsible for ensuring the source data are attributable, legible, 
contemporaneous, original, accurate and complete whether the data are handwritten on 
paper or entered electronically. If source data are created (first entered), modified, 
maintained, archived, retrieved or transmitted electronically via computerized systems 
(and/or other kind of electronic devices) as part of regulated study activities, such 
systems must be compliant with all applicable laws and regulations governing use of 
electronic records and/or electronic signatures. Such systems may include, but are not 
limited to, electronic medical/health records, protocol-related assessments, AE tracking, 
electronic clinical outcome assessment and/or drug accountability.  
4. Paper records from electronic systems used in place of electronic format must be 
certified copies. A certified copy must be an exact copy and must have all the same 
attributes and information as the original. Certified copies must include signature and 
date of the individual completing the certification. Certified copies must be a complete 
and chronological set of study records (including notes, attachments and audit trail 
information, if applicable). All printed records must be kept in the participant’s file and 
be available for archiving.  
5. Study monitors will perform ongoing source data review to confirm that the safety and 
rights of participants are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, ICH 
GCP and all applicable regulatory requirements. 
10.1.9 Study and Site Start and Closure 
The study start date is the date the first participant signs the ICF for the study. 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.  
Reasons for the early closure of a study site by the sponsor or investigator may include but 
are not limited to: 
For study termination: 
● 
Discontinuation of further study test product development 
For site termination: 
● 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines 


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● 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
● 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the sponsor or designee shall promptly 
inform the Investigators, the IECs/IRBs, the regulatory authorities and any CRO(s) used in 
the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should 
assure appropriate participant therapy and/or follow-up. 
10.1.10 Arrangement for Use of Information and Publication of the Study 
Information concerning the test product, patent applications, processes, unpublished scientific 
data, the Investigator’s Brochure and other pertinent information is confidential and remains 
the property of the sponsor. Details should be disclosed only to the persons involved in the 
approval or conduct of the study. The investigator may use this information for the purpose 
of the study only. It is understood by the investigator that the sponsor will use the 
information obtained during the study in connection with the development of the product and 
therefore may disclose it as required to other clinical investigators or to regulatory agencies. 
In order to allow for the use of the information derived from this study, the investigator 
understands that he/she has an obligation to provide the sponsor with all data obtained during 
the study.  
Publication of the study results is discussed in the study agreement. 
10.1.11 Quality Assurance 
The sponsor is implementing and maintaining quality assurance (QA) and quality control 
(QC) systems with written SOPs to ensure that studies are conducted and data are generated, 
documented, recorded and reported in compliance with the protocol, GCP and applicable 
regulatory requirement(s). Where applicable, the QA and QC systems and written SOPs of 
the CRO will be applied. 
The sponsor or sponsor’s designee may arrange to audit the study at any or all study sites and 
facilities. The audit may include on-site review of regulatory documents, CRFs and source 
documents. Direct access to these documents will be required by the auditors. 


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10.2 
Appendix 2: Contraception Requirements 
WOCBP who are eligible for participation in the study, including those who choose complete 
abstinence, must have pregnancy tests as specified in the schedule of assessments. Pregnancy 
test results must confirm that the participant is not pregnant. 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND METHODS OF 
CONTRACEPTION DEFINITIONS 
A female is considered fertile (i.e., WOCBP) following menarche and until becoming 
postmenopausal unless permanently sterile.  
Females in the following categories are not considered WOCBP 
● 
Premenarchal 
● 
Premenopausal with one of the following (i.e., permanently sterile): 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
● 
Postmenopausal 
A postmenopausal state is defined as at least 12 months after last menstrual bleeding without 
an alternative medical cause.  
In case the last menstrual bleeding cannot be clearly determined, confirmation with more 
than one follicle-stimulating hormone (FSH) measurement of at least > 40 IU/L (or higher 
per local institutional guidelines) is required.  
Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt 
will be required to use one of the nonestrogen hormonal highly effective contraception 
methods if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status by repeated FSH 
measurements before study enrollment. 
Documentation of any of these categories can come from the study site personnel’s review of 
the female participant’s medical records, medical examination or medical history interview. 
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF 
CHILDBEARING POTENTIAL 
Female participants of childbearing potential are eligible for participation in the study if they 
agree to use one of the highly effective methods of contraception listed below from the time 
of signing the ICF and until the end of relevant systemic exposure, defined as 30 days after 
the final IP administration.a 
Highly effective methods of contraception (failure rate of < 1% per year when used 
consistently and correctly):b 


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● 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation 
o Oral 
o Intravaginal 
o Transdermal 
● 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
o Oral 
o Injectable 
o Implantable 
● 
Other combined (estrogen- and progesterone-containing) methods 
o Vaginal ring 
o Injectable 
o Implantable 
o Intrauterine hormone-releasing system or intrauterine device 
o Bilateral tubal occlusion 
● 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
● 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the test 
product. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant. It is not 
necessary to use any other method of contraception when complete abstinence is elected. 
aLocal laws and regulations may require use of alternative and/or additional contraception methods. 
bTypical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants participating 
in clinical studies. 
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) 
OF CHILDBEARING POTENTIAL 
Male participants with female partners of childbearing potential are eligible for participation 
in the study if they agree to the following during treatment and until the end of relevant 
systemic exposure defined as 30 days after final drug administration.a 
● 
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator 
● 
Use a condom 
● 
Female partners of male participants who have not undergone a vasectomy with the 
absence of sperm confirmed or a bilateral orchiectomy should consider use of effective 
methods of contraception 
aLocal laws and regulations may require use of alternative and/or additional contraception methods. 


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10.3 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting 
10.3.1 Definition of Adverse Events 
AE Definition: 
An AE is any untoward medical occurrence in a patient or clinical study participant, temporally 
associated with the use of study IP, whether or not considered related to the study IP. 
“Adverse event” means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of study IP. This includes events related to the comparator and events related to the 
(study) procedures.  
Events Meeting the AE Definition 
● 
Any abnormal laboratory test results (hematology, clinical chemistry or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease). 
● 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
● 
New conditions detected or diagnosed after study IP administration even though it may 
have been present before the start of the study. 
Events NOT Meeting the AE Definition 
● 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
● 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
● 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads 
to the procedure is the AE. 
● 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
● 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.1.1 Abnormal Laboratory Findings 
Any abnormal laboratory test result (e.g., hematology, biochemistry or urinalysis) or other 
safety assessment (e.g., vital signs, physical examination or ECGs), including those that 


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worsen from baseline, that is considered to be clinically significant in the medical and 
scientific judgment of the investigator and not related to underlying disease, is to be reported 
as an (S)AE. 
Any clinically significant abnormal laboratory finding or other abnormal safety assessment, 
which is associated with the underlying disease, does not require reporting as an (S)AE, 
unless judged by the investigator to be more severe than expected for the participant’s 
condition. 
Repeating an abnormal laboratory test or other safety assessment, in the absence of any of the 
above criteria, does not constitute an AE. Any abnormal test result that is determined to be an 
error does not require reporting as an AE. 
10.3.1.2 Potential Cases of Drug-induced Liver Injury 
Refer to [Section 10.4, Appendix 4: Liver Safety Monitoring and Assessment] for detailed 
instructions on drug induced liver injury. Abnormal values in AST and/or ALT concurrent or 
with abnormal elevations in TBL that meet the criteria outlined in [Section 10.4, Appendix 4: 
Liver Safety Monitoring and Assessment], in the absence of other causes of liver injury, are 
considered potential cases of drug-induced liver injury (potential Hy’s Law cases) and are 
always to be considered important medical events and reported per [Section 10.3.6 Reporting 
Procedures for Serious Adverse Events].  
10.3.2 Definition of Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that, at any dose: 
● 
Results in death 
● 
Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
● 
Requires inpatient hospitalization or prolongation of existing hospitalization 
o 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
o 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
● 
Results in persistent or significant disability/incapacity 
o 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 


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o 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza 
and accidental trauma (e.g., sprained ankle), which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
● 
Is a congenital anomaly/birth defect 
● 
Other situations: 
o 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious. 
o 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
If an event is not an AE per definition in [Section 10.3.1 Definition of Adverse Events], then 
it cannot be an SAE even if serious conditions are met (e.g., hospitalization for 
signs/symptoms of the disease under study, death due to progression of disease). 
10.3.3 Assessment of Causality 
● 
The investigator is obligated to assess the relationship between study IP and each 
occurrence of each AE/SAE. 
● 
A “reasonable possibility” of a relationship conveys that there are facts, evidence and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
● 
The investigator will use clinical judgment to determine the relationship. 
● 
Alternative causes, such as underlying disease(s), concomitant therapy and other risk 
factors, as well as the temporal relationship of the event to study IP administration will 
be considered and investigated. 
● 
The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
● 
For each (S)AE, the investigator must document in the medical notes that he/she has 
reviewed the (S)AE and has provided an assessment of causality. 
● 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the sponsor. 
● 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
● 
The causality assessment is one of the criteria used when determining regulatory 
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Following a review of the relevant data, the causal relationship between the IP and each 
(S)AE will be assessed by answering “yes” or “no” to the question “Do you consider that 
there is a reasonable possibility that the event may have been caused by the IP?” 
When making an assessment of causality, the following factors are to be considered when 
deciding if there is evidence and/or arguments to suggest there is a “reasonable possibility” 
that an (S)AE may have been caused by the IP (rather than a relationship cannot be ruled out) 
or if there is evidence to reasonably deny a causal relationship:  
● 
Has the participant been administered IP?  
● 
Plausibility (i.e., could the event have been caused by the suspect IP? Consider biologic 
and/or pharmacologic mechanism, half-life, literature evidence, drug class, preclinical 
and study data, etc.) 
● 
Dechallenge/dose reduction/rechallenge:  
o Dechallenge: Did the (S)AE resolve or improve after only stopping the dose of the 
suspect drug without any treatment? 
o Dose reduction: Did the (S)AE resolve or improve after reducing the dose of the 
suspect drug? 
o Rechallenge: Did the (S)AE reoccur if the suspected drug was reintroduced after 
having been stopped?  
● 
Laboratory or other test results: a specific lab investigation supports the assessment of 
the relationship between the (S)AE and the IP (e.g., based on values pre-, during and 
post-treatment) 
● 
Available alternative explanations independent of IP exposure; such as other 
concomitant drugs, past medical history, concurrent or underlying disease, risk factors 
including medical and family history, season, location, etc., and strength of the 
alternative explanation  
● 
Temporal relationship between exposure to the IP and (S)AE onset and/or resolution. 
Did the (S)AE occur in a reasonable temporal relationship to the administration of the 
IP?  
● 
Finally, judging which are more likely based on all the above contents, factors of 
reasonable possibility or confounding factors, comprehensive judgment of plausible will 
be provided.  
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor. While it is very important that the 
investigator always assesses causality for every event before the initial transmission of the 
SAE data to the sponsor, the initial report should be submitted without delay (i.e., within 
24 hours of awareness). With limited or insufficient information about the event to make an 
informed medical judgment and in absence of any indication or evidence to establish a causal 
relationship, a causality assessment of “no” is to be considered. In such instance, the 
investigator is expected to obtain additional information regarding the event as soon as 
possible and to re-evaluate the causality upon receipt of additional information. The 
medically qualified investigator may revise his/her assessment of causality in light of new 


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information regarding the SAE and shall send an SAE follow-up report and update the CRF 
with the new information and updated causality assessment.  
10.3.4 Assessment of Severity  
AEs, including abnormal clinical laboratory values, will be graded using the National Cancer 
Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) guidelines 
(version 5.0). The items that are not stipulated in the NCI-CTCAE version 5.0 will be 
assessed according to the criteria below and entered into the CRF: 
Table 8 
Grading Scale Defining the Severity of an Adverse Event 
Grade 
Assessment Standard 
1 – Mild 
Asymptomatic or mild symptoms, clinical or diagnostic observations only; 
intervention not indicated 
2 – Moderate 
Minimal local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL† 
3 – Severe 
Medically significant but not immediately life threatening, hospitalization or 
prolonged hospitalization indicated; disabling; limiting self-care ADL‡ 
4 – Life-threatening 
Life threatening consequences, urgent intervention indicated 
5 – Death 
Death related to AE 
ADL: activities of daily living; AE: adverse event 
†Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
‡Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications and 
not bedridden. 
10.3.5 Recording and Follow-Up of AEs and/or SAEs 
AE and SAE Recording 
● 
When an (S)AE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports and diagnostics reports) 
related to the event. 
● 
The investigator will then record all relevant (S)AE information in the CRF. 
● 
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor in lieu of completion of the CRF. 
● 
There may be instances when copies of medical records for certain cases are requested 
by the sponsor. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the sponsor. 
● 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the (S)AE. 
Follow-up of AEs and SAEs 
● 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor 
to elucidate the nature and/or causality of the (S)AE as fully as possible. This may 


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include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
● 
If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the sponsor with a copy of any post mortem findings 
including histopathology. 
● 
New or updated information will be recorded in the originally completed CRF. 
● 
The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information. 
10.3.6 Reporting Procedures for Serious Adverse Events 
The investigator must complete and submit an SAE worksheet containing all information that 
is required by local and/or regional regulations to the sponsor by fax or email immediately 
(within 24 hours of awareness).  
The SAE worksheet must be signed by a medically qualified investigator (as identified on 
delegation of authority log). Signature confirms accuracy and completeness of the SAE data, 
as well as the investigator causality assessment including the explanation for the causality 
assessment. 
If the SAE is associated with emergency unblinding by the investigator as outlined in 
[Section 6.3.4 Breaking the Treatment Code for Emergency], this is to be recorded on the 
SAE worksheet. On the SAE worksheet, the investigator is to include when unblinding took 
place in association with the SAE.  
For contact details, see [Contact Details of Sponsor’s Key Personnel]. Fax or email the 
SAE/special situations/product defect worksheet to: 
Astellas Pharma Global Development Inc. 
Pharmacovigilance  
North America fax number: +1-888-396-3750 
North America alternate fax number: +1-847-317-1241 
International Fax: +44-800-471-5263 
Email: safety-us@astellas.com 
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
sponsor’s medical monitor/study physician or their designee [Contact Details of Sponsor’s 
Key Personnel].  
Follow-up information for the event should be sent promptly (as soon as available, but no 
longer than within 7 days of the initial notification). 
Full details of the SAE should be recorded on the medical records, SAE/special situation 
worksheet and on the CRF. 
The following minimum information is required: 
● 
International study number/study number  
● 
Participant number, sex and age 


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● 
Date of report 
● 
Description of the SAE (event and seriousness criteria)  
● 
Causal relationship to the IP (including reason) 
● 
Drug provided (if any) 
The sponsor or sponsor’s designee will medically evaluate the SAE and determine if the 
report meets the requirements for expedited reporting based on seriousness, causality and 
expectedness of the events (e.g., SUSAR reporting) according to current local/regional 
regulatory requirements. The sponsor or sponsor’s designee will submit expedited safety 
reports to competent authorities and concerned ethics committee per current local regulations, 
and will inform the investigators of such regulatory reports as required. Investigators must 
submit safety reports as required by their IRB/IEC within timelines set by regional 
regulations (e.g., EMA, FDA) where required. Documentation of the submission to and 
receipt by the IRB/IEC of expedited safety reports should be retained by the study site. In the 
US, FDA expedited IND reporting guidelines will be followed. 
The sponsor will notify all investigators responsible for ongoing clinical studies with the test 
product of all SUSARs, which require submission per local requirements. 
The investigators should provide written documentation of IRB/IEC notification for each 
report to the sponsor. 
The investigator may contact the sponsor’s medical monitor/study physician for any other 
problem related to the rights, safety or well-being of the participant.  
10.3.7 Reporting Procedures for Special Situations 
10.3.7.1 Contraceptive Guidance and Collection of Pregnancy Information 
If a female participant becomes pregnant during the study dosing period or within 30 days 
from the discontinuation of dosing, the investigator is to report the information to the sponsor 
according to the timelines in [Section 10.3.6 Reporting Procedures for Serious Adverse 
Events] using the SAE worksheet as a special situation and in the CRF.  
The investigator will attempt to collect pregnancy information on any female partner of a 
male participant who becomes pregnant during the study dosing period or within 30 days 
from the discontinuation of dosing and report the information to the sponsor according to the 
timelines in [Section 10.3.6 Reporting Procedures for Serious Adverse Events] using the 
special situation worksheet or pregnancy form.  
The expected date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated conception date, pregnancy result and neonatal data, etc., should be included in this 
information. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
termination (including elective termination) of a pregnancy is to be reported for a female 
participant as an AE in the CRF or SAE per [Section 10.3.6 Reporting Procedures for Serious 
Adverse Events]. Participant pregnancy outcomes listed below are to be reported as SAEs: 


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● 
Spontaneous abortion/miscarriage, abortion and missed abortion 
● 
Death of a newborn or infant within 1 month after birth is to be reported as an SAE 
regardless of its relationship with the IP. 
● 
If an infant dies more than 1 month after the birth, it is to be reported if a relationship 
between the death and intrauterine exposure to the IP is judged as “possible” by the 
investigator. 
● 
Congenital anomaly (including anomaly in miscarried fetus) 
● 
Benign hydatidiform mole 
● 
Blighted ovum 
Unless a congenital anomaly is identified prior to spontaneous abortion or miscarriage, the 
embryo or fetus should be assessed for congenital defects by visual examination or other 
means as appropriate. (S)AEs experienced by the newborn/infant should be reported via the 
pregnancy reporting form. Generally, follow up will be no longer than 6 to 8 weeks following 
the estimated delivery date.  
10.3.7.2 Medication Error, Overdose and “Off-label Use” 
If a medication error (defined as an unintended failure in the treatment process that leads to, 
or has the potential to lead to, harm to the participant), overdose or “off-label use” (i.e., use 
outside of the target disease defined in the protocol) is suspected, refer to [Section 6.7 
Treatment of Overdose]. Any associated (S)AEs are to be reported in the CRF. If the AE 
meets the definition of an SAE, the SAE is also to be reported as described in [Section 10.3.6 
Reporting Procedures for Serious Adverse Events] together with the details of the medication 
error, overdose and/or “off-label use.”  
10.3.7.3 Suspected Misuse/Abuse of Investigational Product 
Definition of misuse: Situations where the IP is/are intentionally and inappropriately used not 
in accordance with the intended use as defined in the protocol. 
Definition of abuse: Persistent or sporadic, intentional excessive use of medicinal products 
which is accompanied by harmful physical or psychological effects. 
If misuse or abuse of the IP is suspected, the investigator must forward the special situation 
worksheet to the sponsor by fax or email immediately (within 24 hours of awareness). Any 
associated (S)AEs are to be reported in the CRF. If the AE meets the definition of an SAE, 
the SAE is also to be reported as described in [Section 10.3.6 Reporting Procedures for 
Serious Adverse Events] together with details of the misuse or abuse of the IP. 
10.3.7.4 Occupational Exposure 
If occupational exposure (e.g., inadvertent exposure to the IP of study site personnel while 
preparing it for administration to the participant) to the IP occurs, the investigator must 
forward the special situation worksheet to the sponsor by fax or email immediately (within 
24 hours of awareness). Any associated (S)AEs occurring to the individual associated with or 
resulting from the special situation are to be reported on the special situations worksheet. 


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10.3.7.5 Suspected Drug-drug Interaction 
If a drug-drug interaction associated with the IP is suspected, the investigator must forward 
the special situation worksheet to the sponsor by fax or email immediately (within 24 hours 
of awareness). Any associated (S)AEs are to be reported in the CRF. If the AE meets the 
definition of an SAE, the SAE is also to be reported as described in [Section 10.3.6 Reporting 
Procedures for Serious Adverse Events] together with details of the suspected drug-drug 
interaction.  
10.3.8 Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that is necessary for conducting the study properly, 
the sponsor will inform all investigators involved in the study, as well as the appropriate 
regulatory authorities. Investigators should inform the IRB/IEC of such information when 
needed.  
The investigator will also inform the participants who will be required to sign an updated ICF 
in order to continue in the study. 
10.3.9 Urgent Safety Measures  
An urgent safety measure (USM) is an intervention that is not defined by the protocol and 
can be put in place with immediate effect without needing to gain prior approval by the 
sponsor, relevant competent authorities, IRB/IEC, where applicable, in order to protect 
participants from any immediate hazard to their health and/or safety. Either the investigator 
or the sponsor can initiate a USM. The cause of a USM can be safety-, product- or 
procedure-related.  
10.3.10 Reporting Urgent Safety Measures 
In the event of a potential USM, the investigator must contact the study physician (within 
24 hours of awareness). Full details of the potential USM are to be recorded in the 
participant’s medical records. The sponsor may request additional information related to the 
event to support their evaluation.  
If the event is confirmed to be a USM, the sponsor will take appropriate action to ensure the 
safety and welfare of the participants. These actions may include but are not limited to a 
change in study procedures or study treatment, halting further enrollment in the study, or 
stopping the study in its entirety. The sponsor or sponsor’s designee will notify the relevant 
competent authorities and concerned ethics committee within the timelines required per 
current local regulations, and will inform the investigators, as required. When required, 
investigators must notify their IRB/IEC within timelines set by regional regulations. 


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10.4 
Appendix 4: Liver Safety Monitoring and Assessment 
The purpose of this appendix is to provide guidance for the monitoring of drug-induced liver 
injury during the course of the study. It should be noted that this section does not specify the 
end-of-study analyses of liver enzymes. The end-of-study liver enzymes analyses will be 
described in the SAP. Any participant enrolled in the study with active drug therapy and 
reveals an increase of serum aminotransferases (AT) to > 3 × ULN or TBL > 2 × ULN should 
undergo detailed testing for liver enzymes (including at least gamma-glutamyltransferase 
[GGT], ALT, AST, alkaline phosphatase [ALP], TBL and glutamate dehydrogenase). 
Participants whose baseline ALT or AST values were > 3 × ULN (with elevated creatine 
kinase [CK]) and who have a clinically significant rise as assessed by the investigator should 
also undergo detailed testing for liver enzymes. Testing should be repeated within 72 hours of 
notification of the test results. For studies for which a central laboratory is used, alerts will be 
generated by the central laboratory regarding moderate and severe liver abnormality to 
inform the investigator and study team. Participants should be asked if they have any 
symptoms suggestive of hepatobiliary dysfunction.   
In addition, free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating 
hormone (TSH) should be measured to monitor the thyroid function in case of hepatobiliary 
dysfunction. If FT3, FT4 or TSH show any abnormalities and/or clinically significant 
symptoms, the investigator should determine if further follow up of liver chemistry tests 
and/or thyroid function tests are required. 
For cases with concurrent CK elevation, participants should undergo detailed testing for liver 
enzymes (including at least GGT, ALT, AST, ALP, TBL and glutamate dehydrogenase). 
Once the investigator can confirm absence of hepatobiliary injury based on the detailed liver 
enzyme testing, the investigator will determine if further follow up of liver chemistry tests are 
required. If concurrent hepatobiliary injury cannot be ruled out, the guidance should be 
followed as described in Follow-up Procedures in this appendix. 
Definition of Liver Abnormalities 
Confirmed abnormalities will be characterized as moderate and severe where ULN is as 
shown below.  
Table 9 
Moderate and Severe Liver Abnormalities 
 
ALT or AST 
 
TBL 
Moderate 
> 3 × ULN  
or 
> 2 × ULN 
Severe 
> 3 × ULN  
and† 
> 2 × ULN 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; TBL: total bilirubin; ULN: upper limit of 
normal 
†Samples taken simultaneously or within maximum 24 hours. 
In addition, the participant should be considered to have severe hepatic abnormalities for any 
of the following: 
● 
ALT or AST > 8 × ULN 
● 
ALT or AST > 5 × ULN for more than 2 weeks 


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● 
ALT or AST > 3 × ULN and† international normalized ratio (INR) > 1.5 (If INR testing 
is applicable/evaluated) 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%)  
†Samples taken simultaneously or within a maximum of 24 hours. 
The investigator may determine that abnormal liver chemistry results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring 
and follow-up.  
Follow-up Procedures 
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination and clinical laboratory tests. The study site personnel are to complete 
the liver abnormality case report form (LA-CRF). Participants with confirmed abnormal liver 
function testing should be followed as described below. 
Confirmed moderately abnormal liver function tests should be repeated 2 to 3 times weekly, 
and then weekly or less if abnormalities stabilize or the IP has been discontinued and the 
participant is asymptomatic.  
Severe hepatic liver function abnormalities as defined above, in the absence of another 
etiology, may be considered an important medical event and may be reported as a SAE. The 
sponsor should be contacted and informed of all participants for whom severe hepatic liver 
function abnormalities possibly attributable to IP are observed.  
To further assess abnormal hepatic laboratory findings, the investigator is expected to: 
● 
Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms 
and new-onset diseases are to be recorded as “AEs” within the CRF. Illnesses and 
conditions such as hypotensive events and decompensated cardiac disease that may lead 
to secondary liver abnormalities should be noted. Nonalcoholic steatohepatitis is seen in 
obese hyperlipoproteinemic and/or diabetic participants and may be associated with 
fluctuating AT levels. The investigator should ensure that the medical history form 
captures any illness that predates study enrollment that may be relevant in assessing 
hepatic function.  
● 
Obtain a history of concomitant drug use (including nonprescription medication, 
complementary and alternative medications), alcohol use, recreational drug use and 
special diets. Medications are to be entered in the CRF. Information on alcohol, other 
substance use and diet should be entered on the LA-CRF or an appropriate document. 
● 
Obtain a history of exposure to environmental chemical agents. 
● 
Based on the participant’s history, other testing may be appropriate including:  
o Acute viral hepatitis (A, B, C, D, E or other infectious agents) 
o Ultrasound or other imaging to assess biliary tract disease 
o Other clinical laboratory tests, including INR and direct bilirubin 
● 
Consider gastroenterology or hepatology consultations. 
● 
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document. 


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Study Treatment Discontinuation 
In the absence of an explanation for increased liver chemistry tests, such as viral hepatitis, 
preexisting or acute liver disease, or exposure to other agents associated with liver injury, the 
participant may be discontinued from study treatment. The investigator may determine that it 
is not in the participant’s best interest to continue study treatment. Discontinuation of study 
treatment should be considered if the participant has severe hepatic abnormalities.  
In addition, if close monitoring for a participant with moderate or severe hepatic laboratory 
tests is not possible, study treatment should be discontinued. 
Hy’s Law definition: Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10% to 50% 
mortality (or transplant).   
The 2 “requirements” for Hy’s Law are:  
1. Evidence that a drug can cause hepatocellular-type injury, generally shown by an increase 
in AT elevations > 3 × ULN (“2 × ULN elevations are too common in treated and 
untreated participants to be discriminating”).  
2. Cases of increased TBL (at least 2 × ULN) with concurrent AT elevations at least 
3 × ULN and no evidence of intra- or extra-hepatic bilirubin obstruction (elevated ALP) 
or Gilbert’s syndrome [Temple, 2006]. 
FDA Guidance for Industry titled, “Drug-induced Liver Injury: Premarketing Clinical 
Evaluation” issued by the FDA on July 2009: 
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations > ULN of ALT or AST than the (nonhepatotoxic) control drug or 
placebo. 
2. Among participants showing such AT elevations, often with ATs much greater than 
3 × ULN, one or more also show elevation of serum TBL to > 2 × ULN, without initial 
findings of cholestasis (elevated serum ALP). 
3. No other reason can be found to explain the combination of increased AT and TBL, such 
as viral hepatitis A, B or C; preexisting or acute liver disease; or another drug capable of 
causing the observed injury. 


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10.5 
Appendix 5: List of Excluded Concomitant Medications 
Type of Prohibited Medication 
Name of Medication 
PPAR ligands 
clinofibrate, clofibrate, fenofibrate, gemfibrozil, 
fibrates, thiazolidinediones 
P-gp substrates 
dabigatran, digoxin, fexofenadine 
BCRP substrates 
rosuvastatin, sulfasalazine 
OATP1B1 and OATP1B3 substrates 
asunaprevir, atorvastatin, bosentan, danoprevir, 
docetaxel, fexofenadine, nateglinide, paclitaxel, 
repaglinide, rosuvastatin, simvastatin 
OAT3 substrates 
cefaclor, ceftizoxime, famotidine, furosemide, 
methotrexate, oseltamivir carboxylate, penicillin G 
Strong and Moderate Inhibitors of CYP3A 
boceprevir, cobicistat, danoprevir/ritonavir, 
elvitegravir/ritonavir, grapefruit juice, 
indinavir/ritonavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, paritaprevir/ritonavir/(ombitasvir 
and/or dasabuvir), posaconazole, ritonavir, 
saquinavir/ritonavir, telaprevir, tipranavir/ritonavir, 
telithromycin, troleandomycin, voriconazole, 
clarithromycin, idelalisib, nefazodone, nelfinavir, 
aprepitant, ciprofloxacin, conivaptan, crizotinib, 
cyclosporine, diltiazem, dronedarone, erythromycin, 
fluconazole, fluvoxamine, imatinib, tofisopam, 
verapamil 
BCRP inhibitors 
curcumin, cyclosporine A, eltrombopag 
Strong and moderate inducers of CYP3A 
and inducers for UGT1A3, UGT1A8, 
UGT1A9 and transporters 
apalutamide, carbamazepine, enzalutamide, 
mitotane, phenytoin, rifampin, St. John’s Wort, 
bosentan, efavirenz, etravirine, phenobarbital, 
primidone, ritonavir, telmisartan 
Inhibitors of UGT1A3, UGT1A8 and 
UGT1A9  
probenecid, mefenamic acid, tipranavir, 
tipranavir/ritonavir, atazanavir, atazanavir/ritonavir 
Triheptanoin, a synthetic medium chain 
triglyceride 
Triheptanoin 
BCRP: breast cancer resistance protein; CYP: cytochrome P450; OAT: organic anion transporter; OATP: 
organic anion transporting polypeptide; P-gp: P-glycoprotein; PPAR: peroxisome proliferator-activated 
receptor; UGT: uridine diphosphate-glucuronosyltransferase 
 


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10.6 
Appendix 6: Clinical Laboratory Assessments 
Laboratory tests will be performed according to the schedule of assessments.  
Table 10 
Clinical Laboratory Tests 
Panel/Assessments 
Parameters to be Analyzed 
Hematology 
Hematocrit (Hct) 
Hemoglobin (Hgb) 
Mean corpuscular hemoglobin concentrations (MCHC) 
Mean corpuscular volume 
Platelet count 
Red blood cell count (RBC) 
White blood cell count (WBC) 
White blood cell differential 
Biochemistry 
Alanine aminotransferase (ALT) 
Albumin (Alb) 
Alkaline phosphatase (ALP) 
Amylase 
Aspartate aminotransferase (AST) 
Blood urea nitrogen (BUN) 
Calcium (Ca) 
Cardiac troponin I (cTnI) 
Cardiac troponin T (cTnT) 
Chloride (Cl) 
C-reacting protein (CRP) 
Creatinine 
Creatine kinase (CK) 
Creatine kinase isoenzymes: 
• 
Heart muscle (CK-MB)¶ 
• 
Skeletal and heart muscle (CK-MM)¶ 
Cystatin C 
Gamma glutamyl transferase (GGT) 
Glucose (Gluc) 
Glutamate dehydrogenase (GLDH) 
HbA1c 
High-density lipoproteins (HDL) 
Inorganic phosphorus (P) 
Lactate dehydrogenase (LDH) 
Lipase  
Low-density lipoproteins (LDL) 
Magnesium (Mg) 
Plasma lactate 
Potassium (K) 
Sodium (Na) 
Total bilirubin (TBL) 
Total cholesterol (TC) 
Total protein (TP) 
Triglycerides (TG) 
Uric acid (UA) 
Table continued on next page 


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Panel/Assessments 
Parameters to be Analyzed 
Abbreviated hematology 
Hemoglobin (Hgb) 
Platelet count 
Red blood cell count (RBC) 
White blood cell count (WBC) 
White blood cell differential 
Abbreviated biochemistry 
Alanine transaminase (ALT) 
Alkaline phosphatase (ALP) 
Amylase 
Aspartate transaminase (AST) 
Blood urea nitrogen (BUN) 
Calcium (Ca) 
Cardiac troponin I (cTnI) 
Cardiac troponin T (cTnT) 
Chloride (Cl) 
Creatinine 
Creatine kinase (CK) 
Creatine kinase isoenzymes: 
• 
Heart muscle (CK-MB)¶ 
• 
Skeletal and heart muscle (CK-MM)¶ 
Cystatin C 
Gamma glutamyl transferase (GGT) 
HbA1c 
Lipase 
Potassium (K) 
Sodium (Na) 
Total bilirubin (TBL) 
Serology 
Hepatitis A virus antibodies 
(immunoglobulin M) 
Hepatitis B surface antigen 
Hepatitis C virus antibodies 
Human immunodeficiency virus 1+2 antibodies 
Urinalysis 
Blood 
Creatinine (Cr) 
Glucose 
pH 
Protein 
Urine specific gravity 
Pregnancy test (serum) 
Human chorionic gonadotropin 
Pregnancy test (urine) 
Human chorionic gonadotropin 
Urine drug test 
Amphetamines 
Barbiturates 
Benzodiazepines 
Cannabinoids 
Cocaine 
MDMA 
Methadone 
Methamphetamines 
Opiates 
Oxycodone 
Urine alcohol test 
Alcohol 
Note: FT3, FT4 and TSH should be measured to monitor thyroid function in case of hepatobiliary dysfunction. 
¶Creatine kinase isoenzymes (CK-MB and CK-MM) are measured in reflex test based on CK result. 
 


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10.7 
Appendix 7: Pharmacogenomic Analysis with Banked Sample 
INTRODUCTION 
PGx research aims to provide information regarding how naturally occurring differences in a 
participant’s gene and/or expression of genes based on genetic variation may impact what 
treatment options are best suited for the participant. Through investigation of PGx by 
technologies such as genotyping, gene sequencing, statistical genetics and Genome-Wide 
Association studies, the relationship between gene profiles and a drug’s kinetics, efficacy, 
toxicity or disease may be better understood. As many diseases may be influenced by one or 
more genetic variations, PGx research may identify which genes are involved in determining 
the way a participant may or may not respond to a drug. 
OBJECTIVES 
The PGx research that may be conducted in the future with acquired blood samples is 
exploratory. The objective of this research will be to analyze or determine genes of relevance 
to clinical response, pharmacokinetics and/or toxicity/safety and/or disease. 
By analyzing genetic variations, it may be possible to predict an individual participant’s 
response to treatment in terms of efficacy and/or toxicity and/or disease. 
PARTICIPANT PARTICIPATION 
Participants who have consented to participate in this study may participate in the PGx 
substudy. Participants must provide written consent prior to providing any blood samples that 
may be used at a later time for PGx analysis. 
SAMPLE COLLECTION AND STORAGE 
Participants who consent to participate in this substudy will provide 4 mL sample of whole 
blood per Astellas’ instructions. Each sample will be identified by the unique participant 
number. Samples will be shipped to a designated banking CRO as directed by Astellas. 
PGx ANALYSIS 
Details on the potential PGx analysis cannot be established yet. Astellas may initiate the PGx 
analysis if evidence suggests that genetic variants may be influencing the drug’s 
pharmacokinetics, efficacy and/or safety and/or disease.  
DISPOSAL OF PGx SAMPLES/DATA 
All PGx samples collected will be stored for a period of up to 15 years following study 
database lock. If there is no requirement for analysis, the whole blood sample will be 
destroyed after the planned storage period. The participant has the right to withdraw consent 
at any time. When a participant’s withdraw notification is received, the PGx sample will be 
destroyed. The results of any PGx analysis conducted on a sample prior to its withdrawal will 
be retained at Astellas indefinitely unless otherwise specified by local regulation.  


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INFORMATION DISCLOSURE TO THE PARTICIPANTS 
Exploratory PGx analysis may be conducted following the conclusion of the study, if 
applicable. The results of the PGx analysis will not be provided to any investigators or 
participants, nor can the results be requested at a later date. Any information that is obtained 
from the PGx analysis will be the property of Astellas.  


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10.8 
Appendix 8 
Clinical Study Continuity 
INTRODUCTION 
The purpose of this appendix is to provide acceptable alternate methods to assess safety and 
efficacy parameters, as appropriate, in the event the clinical study is interrupted at the 
country, state, site or participant level during any crisis (e.g., natural disaster, pandemic).  
BENEFIT-RISK RATIONALE 
Maintaining the safety of clinical study participants and delivering continuity of care in the 
clinical study setting is paramount during any crisis. The site is expected to follow the 
protocol and associated schedule of assessments [Table 1] unless the site principal 
investigator discusses the need with the Astellas medical monitor to implement the alternate 
measures.  
The approach outlined within this appendix defines which assessments are required to 
maintain a favorable benefit/risk to the participant, to maintain overall study integrity and to 
provide acceptable alternate methods to complete the study-required assessments and 
procedures if study activities are unable to be performed as described in [Section 7] due to a 
crisis. 
INFORMED CONSENT 
Participants who need to follow any or all of the alternate measures outlined in this Appendix 
will be required to provide informed consent, which explicitly informs them of the nature of 
and rationale for these changes and gain their agreement to continue participation in the study 
prior to the implementation of any of these changes. In the event the urgency of 
implementing the alternate measures does not allow for the participant to provide written 
consent prior to implementation, the principal investigator or designee will obtain oral 
agreement from the participant followed by written documentation as soon as is feasible. A 
separate addendum to the study ICF will be provided to document the participant’s consent to 
the changes.  
PARTICIPANT PROCEDURES ASSESSMENT 
Sites with participants who are currently enrolled into this clinical study may consider 
implementing the alternate methods outlined below if 1 or more of the following conditions 
are met due to the crisis: 
● 
Regional or local travel has been restricted, inclusive of mandatory shelter in place 
measures, which makes participant travel to/from the study site nearly impossible. 
● 
Site facilities have been closed for clinical study conduct.  
● 
Site has been restricted to treating patients with conditions outside of the scope of the 
study. 
● 
Site personnel have temporarily relocated the conduct of the study to a location that 
place a burden on the participant with respect to time and travel. 
● 
Participant(s) have temporarily relocated from the current study site to an alternate study 
site to avoid placing a burden on the participant with respect to travel. 


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● 
Participant(s) have temporarily relocated from their home location and the new distances 
from the site would cause undue burden with respect to time and travel. 
● 
Participant has risk factors for which traveling to the site poses an additional risk to the 
participant’s health and safety. 
Adherence to the original protocol as reflected in the schedule of assessments [Table 1] is 
expected, where plausible, in the case of a crisis. The alternate measures as noted in 
[Table 11] below are only permissible in the event of a crisis, and after discussing the need 
with the Astellas medical monitor to implement the alternate measures. This is to allow for 
continuity of receiving study intervention and maintaining critical safety and efficacy 
assessments for participants in the study at a time of crisis. 
If 1 or more of the alternate measures noted below is implemented for a participant, the site 
should document in the participant’s source document the justification for implementing the 
alternate measure and the actual alternate measures that were implemented, along with the 
corresponding timepoint(s). 
Table 11 
Alternative Schedule of Assessments in Response to a Crisis 
Critical Assessments 
Alternate Approach(es) 
Timepoints 
Physical examination 
Recommended to be performed onsite but 
missed assessments are acceptable when 
the duration of the site visit should be 
minimized. 
Refer to protocol 
schedule of 
assessments. 
Body weight 
Recommended to be performed onsite but 
missed assessments are acceptable when 
the duration of the site visit should be 
minimized. 
Vital signs 
Recommended to be performed onsite but 
missed assessments are acceptable when 
the duration of the site visit should be 
minimized. 
Hematology, biochemistry 
Home visits with follow-up phone call are 
allowed. At home visits, the assessments 
can be replaced with abbreviated 
biochemistry and abbreviated hematology. 
Urinalysis 
Recommended to be performed onsite but 
missed assessments are acceptable when 
the duration of the site visit should be 
minimized. 
Abbreviated biochemistry, 
abbreviated hematology 
Home visits with follow-up phone call are 
allowed. 
Pregnancy test (urine) 
Recommended to be performed onsite but 
missed assessments are acceptable when 
the duration of the site visit should be 
minimized. 
12-lead ECG 
Recommended to be performed onsite but 
missed assessments are acceptable when 
the duration of the site visit should be 
minimized. 
C-SSRS 
Interview via phone by trained site staff is 
acceptable. 
Table continued on next page 


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Critical Assessments 
Alternate Approach(es) 
Timepoints 
6MWT 
V2 (week 0) and V11 (week 24) are 
required but missed other timepoints are 
acceptable when the duration of the site 
visit should be minimized. 
Refer to protocol 
schedule of 
assessments. 
5XSTS 
Recommended to be performed onsite but 
missed assessments are acceptable when 
the duration of the site visit should be 
minimized. 
Blood for plasma pharmacokinetics 
Expected to be performed onsite but 
missed assessments can be acceptable 
where unfeasible. 
Serum and urinary biomarkers 
Missed assessments are acceptable when 
the duration of the site visit should be 
minimized. 
Blood for pharmacodynamics 
(PPARδ target gene expression) 
Expected to be performed onsite but 
missed assessments can be acceptable 
where unfeasible. 
Neuro-QoL Short Form Fatigue, 
Neuro-QoL Short Form Lower 
Extremity Function (Mobility), 
MFIS, PGIC, and PGIS 
Recommended to be performed onsite but 
missed assessments are acceptable when 
the duration of the site visit should be 
minimized. 
Dispense/Collect IP 
Direct-to-patient shipment is allowed. 
Previous and concomitant treatment 
Home visits with follow-up phone call are 
allowed. 
Exercise status 
Home visits with follow-up phone call are 
allowed. 
Adverse event assessment 
Home visits with follow-up phone call are 
allowed. 
 


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STUDY INTERVENTION SUPPLY 
If any of the conditions outlined above in the Participants Procedures Assessment are met, the 
following mitigating strategy will be employed, as needed, to ensure continuity of study 
intervention supply to the participants: 
● 
Direct-to-Participant (DTP) shipments of study intervention from the site to the 
participant’s home. 
DATA COLLECTION REQUIREMENTS 
Additional data may be collected in order to indicate how participation in the study may have 
been affected by a crisis and to accommodate data collection resulting from alternate 
measures implemented to manage the conduct of the study and participant safety.  
● 
Critical assessments for safety and efficacy based on study endpoints to be identified as 
missing or altered (performed virtually, at alternative locations, out of window or other 
modifications) due to the crisis.  
 
 


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10.9 
Appendix 9 
List of Normal Ranges for Selected Laboratory 
Assessments 
Analyte 
Sex 
Age 
Reference Range 
Troponin T (cTnT) 
Both 
≥ 18 years 
≤ 14.0 pg/mL 
Troponin I (cTnI) 
Both 
≥ 0 years 
≤ 0.06 ng/mL 
Source: Laboratory Specifications Document v11 (06 Nov 2023) 
 


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10.10 List of Abbreviations and Definition of Key Study Terms 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
5XSTS 
5 Times Sit to Stand 
6MWT 
6-minute walk test 
AE 
adverse event 
ALDOA 
aldolase A 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AME 
absorption, metabolism and excretion 
API 
Astellas Pharma Inc. 
AST 
aspartate aminotransferase 
AT 
aminotransferases 
AUC24 
area under the concentration-time curve from the time of dosing to 24 hours 
AUCinf 
area under the concentration-time curve from zero to infinity 
AUClast 
area under the concentration-time curve from the time of dosing to the last 
measurable concentration 
AV 
atrioventricular 
AVAPS 
average volume-assured pressure support 
BCRP 
breast cancer resistance protein 
BiPAP 
bilevel positive airway pressure 
BMAS 
biomarker analysis set  
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CK 
creatine kinase 
CK-MB 
creatine kinase isoenzymes found in heart muscle 
CK-MM 
creatine kinase isoenzymes found in skeletal and heart muscle 
Cmax 
maximum concentration 
CoQ10 
coenzyme Q10 
CPAP 
continuous positive airway pressure  
CPEO 
chronic progressive external ophthalmoplegia 
CRF 
case report form 
CRO 
contract research organization 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
Ctrough 
concentration immediately prior to dosing at multiple dosing 
cTnI 
cardiac troponin I 
cTnT 
cardiac troponin T 
CV 
coefficient of variation 
CYC 
cytochrome c 
CYP 
cytochrome P450 
DB 
double-blind 


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Abbreviations 
Description of abbreviations 
DIO 
diet-induced obese 
DMC 
Data Monitoring Committee 
DMD 
Duchenne Muscular Dystrophy 
DPD 
Data Protection Directive 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
EEA 
European Economic Area 
EU 
European Union 
eGFR 
estimated glomerular filtration rate 
EPKAS 
extended pharmacokinetic analysis set 
EQ-5D 
European Quality of Life 5-dimension questionnaire 
EQ-5D-5L 
European Quality of Life 5-dimension, 5-level questionnaire 
EuroQol 
European Quality of Life 
FAO 
fatty acid oxidation 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FLNC 
filamin-C 
FSH 
follicle-stimulating hormone 
FT3 
free triiodothyronine  
FT4 
free thyroxine 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HEK293 
human embryonic kidney 293 
hERG 
human ether-à-go-go-related gene 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH  
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISN 
international study number 
KSS 
Kearns-Sayre syndrome 
LA-CRF 
liver abnormality case report form 
LOCF 
last observation carried forward 
MAD 
multiple ascending dose 
MATE 
multidrug and toxin extrusion 
mdx 
X-linked mutation of the murine dystrophin gene 


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Abbreviations 
Description of abbreviations 
MELAS 
mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes 
MERRF 
myoclonic epilepsy with ragged-red fibers 
MFIS 
Modified Fatigue Impact Scale 
MMRM 
mixed model for repeated measures 
mRNA 
messenger RNA 
mtDNA 
mitochondrial DNA 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Event 
nDNA 
nuclear DNA 
Neuro-QoL 
Quality of Life in Neurological Disorders 
NOAEL 
no observed adverse effect level 
OAT 
organic anion transporter 
OATP 
organic anion transporting polypeptide 
OCT 
organic cation transporter 
OLE 
open-label extension 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
P-gp 
P-glycoprotein 
PGx 
pharmacogenomics 
PKAS 
pharmacokinetic analysis set  
PMM 
Primary Mitochondrial Myopathy 
PMMVA 
Primary Mitochondrial Myopathy Video Assessment 
PPAR 
peroxisome proliferator-activated receptor 
PPARδ 
peroxisome proliferator-activated receptor delta 
PPARGC1A 
peroxisome proliferator-activated receptor gamma coactivator 1 alpha 
PT 
preferred term 
QA 
quality assurance 
QC 
quality control 
QTcF 
QT interval using Fridericia’s correction 
QTL 
quality tolerance limits 
SAD 
single ascending dose 
(S)AE 
serious adverse event or adverse event 
SAE 
serious adverse event 
SAF 
Safety Analysis Set 
SAP 
statistical analysis plan 
SOC 
system organ class 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reactions 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid stimulating hormone 
tmax 
time of maximum concentration  
UGT 
uridine diphosphate-glucuronosyltransferase 


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Abbreviations 
Description of abbreviations 
ULN 
upper limit of normal 
USM 
urgent safety measure 
WOCBP 
woman/women of childbearing potential 


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Definition of Key Study Terms 
Terms 
Definition of Terms 
Baseline  
Assessments of participants as they enter a study before they receive any 
treatment.  
Endpoint  
Variable that pertains to the efficacy or safety evaluations of a study. 
Enroll 
To register or enter a participant into a study. Note: Once a participant has 
received the investigational product or placebo, the protocol applies to the 
participant.  
Randomization 
The process of assigning participants to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias. 
Screening 
A process of active consideration of potential participants for enrollment in a 
study. 
Screen failure 
Potential participant who signed the informed consent form but did not meet 
one or more criteria required for participation in the study and was not 
enrolled. 
Screening period 
Period of time before entering the study period, usually from the time when 
a participant signs the consent form until just before the test product or 
comparative drug (sometimes without randomization) is given to a 
participant.  
Study period 
Period of time from the first study site initiation date to the last study site 
completing the study. 
Variable 
Any entity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values. 


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11 
REFERENCES 
Ahmed ST, Craven L, Russell OM, Turnbull DM, Vincent AE. Diagnosis and treatment of 
mitochondrial myopathies. Neurotherapeutics. 2018;15:943-53. 
Barcelos I, Shadiack E, Ganetzky RD, Falk MJ. Mitochondrial medicine therapies: rationale, 
evidence, and dosing guidelines. Curr Opin Pediatr. 2020;32:707-18. 
Bishop-Bailey D, Bystrom J. Emerging roles of peroxisome proliferator-activated receptor-beta/delta 
in inflammation. Pharmacol Ther. 2009;124(2):141-50. 
Cohen B, Karaa A, Haas R, Goldstein A, Vockley G. Effects of elamipretide in adults with primary 
mitochondrial myopathy: a Phase 2 double-blind, randomized, placebo-controlled crossover 
trial (MMPOWER-2). Neurology. 2018;90(15 Supplement):S5.003. 
de Barcelos I, Emmanuele V, Hirano M. Advances in primary mitochondrial myopathies. Curr Opin 
Neurol. 2019;32:715-21. 
Gorman GS, Schaefer AM, Ng Y, Gomex N, Blakely EL, Alston CL, et al. Prevalence of nuclear and 
mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol. 
2015;77(5):753-59. 
Karaa A, Haas R, Goldstein A, Vockley J, Cohen BH. A randomized crossover trial of elamipretide in 
adults with primary mitochondrial myopathy. J Cachexia Sarcopenia Muscle. 2020;11(4):909-
18. 
Limongelli G, Tome-Esteban M, Dejthevaporn C, Rahman S, Hanna MG, Elliot PM. Prevalence and 
natural history of heart disease in adults with primary mitochondrial respiratory chain disease. 
Eur J Heart Fail. 2010;12(2):114-21. 
Mancuso M, McFarland R, Klopstock T, Hirano M. 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):1126-37. 
McKay MJ, Baldwin JN, Ferreira P, Simic M, Vanicek N, Burns J. Reference values for developing 
responsive functional outcome measures across the lifespan. Neurology. 2017;18; 88(16):1512-
19. 
Montano V, Gruosso F, Simoncini C, Siciliano G, Mancuso M. Clinical features of mtDNA-related 
syndromes in adulthood. Arch Biochem Biophys. 2021;697:108689. 
Pfeffer G, Chinnery PF. Diagnosis and treatment of mitochondrial myopathies. Ann Med. 
2013;45:4-16. 
Temple R. Hy’s Law: Predicting Serious Hepatotoxicity. Pharmacoepidemiol Drug Saf. 
2006;15(4):241-43. 
Zdończyk O, Kierdaszuk B, Kurnicka K, Pruszczyk P. Mitochondrial diseases: what the cardiologist 
should know? Folia Cardiologica. 2020;15(2):122-29. 


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Zolkipli-Cunningham Z, Xiao R, Stoddart A, McCormick EM, Holberts A, Burrill N, et al. 
Mitochondrial disease patient motivations and barriers to participate in clinical trials. PLoS 
ONE. 2018;13(5):e0197513. 


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12 
COORDINATING INVESTIGATOR’S SIGNATURE 
A Randomized, Double-blind, Placebo-controlled Phase 2 Study to Assess the Efficacy, 
Safety and Tolerability of ASP0367 in Participants with Primary Mitochondrial 
Myopathy 
ISN/Protocol 0367-CL-1201  
Version 9.0, Incorporating Substantial Amendment 8 
24 Jan 2024 
I have read all pages of this protocol for which Astellas is the sponsor. I agree that it 
contains all the information required to conduct this study. 
Coordinating Investigator: 
Signature: 
 
 
 
 
Date (DD-MMM-YYYY) 
Printed Name:  
  
 
Address: 
 
 
 
 
 
 
 
 
 
 
 


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13 
SPONSOR SIGNATURES 
Required sponsor signatures as required by ICH GCP 4.5.1 are located in the first attachment 
Attachment 1 
Electronic Sponsor Signatures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Global Protocol Format V9.0  

SAP_001.pdf: 
Sponsor: Astellas Pharma Inc. 
SAP Final Version 
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09-Jul-2024 
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Page 1 of 33 
 
 
 
STATISTICAL ANALYSIS PLAN 
(Double Blind Part) 
 
Final Version 3.0 dated 09-Jul 2024 
 
A Randomized, Double-blind, Placebo-controlled Phase 2 Study to Assess the Efficacy, 
Safety and Tolerability of ASP0367 in Participants with Primary Mitochondrial Myopathy 
 
 
 
 
ISN: 0367-CL-1201 
 
IND number: 146773 
 
 
 
Astellas Pharma Inc. (API) 
 
 
 
This document contains confidential information which is the intellectual property of Astellas. By accepting or reviewing 
this document, you agree to hold this information in confidence and not copy or disclose it to others or use it for 
unauthorized purposes except (1) as otherwise agreed to in writing; (2) where required by applicable law; (3) where 
disclosure is directly related to the care and safety of the research participant; and (4) where disclosure of such information 
is made to a member of the investigator’s team who agrees to hold this information in confidence. 


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Table of Contents 
I. 
LIST OF ABBREVIATIONS AND KEY TERMS ··········································· 4 
1 
INTRODUCTION ·················································································· 7 
2 
STUDY OBJECTIVES AND DESIGN ························································· 7 
2.1 
Study Objectives, Endpoints and Estimands ················································ 7 
2.2 
Study Design ···················································································· 9 
2.3 
Randomization ················································································· 10 
3 
SAMPLE SIZE····················································································· 10 
4 
ANALYSIS SETS ················································································· 10 
5 
EFFICACY AND SAFETY ENDPOINTS ··················································· 11 
5.1 
Primary Efficacy Endpoint (6-minute Walk Test) ········································ 11 
5.2 
Secondary Efficacy Endpoints ······························································· 11 
5.2.1 
5 Times Sit To Stand (5XSTS) ························································ 11 
5.2.2 
Quality of Life in Neurological Disorders (Neuro-QoL) ··························· 11 
5.2.3 
Modified Fatigue Impact Scale (MFIS) ··············································· 11 
5.2.4 
Patient Global Impression of Change (PGIC) ········································ 11 
5.2.5 
Patient Global Impression of Severity (PGIS) ······································· 12 
5.3 
Exploratory Endpoints ········································································ 12 
5.3.1 
European Quality of Life 5-dimension, 5-level questionnaire (EQ-5D-5L) ······ 12 
5.4 
Primary Safety Endpoints ···································································· 12 
5.4.1 
Treatment Emergent Adverse Events (TEAEs) ······································ 12 
5.4.2 
Vital signs ················································································ 12 
5.4.3 
12-lead Electrocardiogram (ECG) ····················································· 12 
5.4.4 
Echocardiogram (ECHO) ······························································· 13 
5.4.5 
Body Weight ············································································· 13 
5.4.6 
Laboratory test (hematology, biochemistry and urinalysis) ························ 13 
5.4.7 
Columbia-Suicide Severity Rating Scale (C-SSRS) ································ 13 
5.5 
Other Endpoints ··············································································· 14 
5.5.1 
Pharmacokinetics Endpoints ··························································· 14 
5.5.2 
Pharmacodynamics Endpoints ························································· 14 
5.5.3 
Biomarkers ··············································································· 14 
6 
STATISTICAL METHODOLOGY ··························································· 14 
6.1 
General Considerations ······································································· 14 


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6.2 
Study Population ·············································································· 15 
6.2.1 
Disposition of Participants ····························································· 15 
6.2.2 
Protocol Deviations ····································································· 16 
6.2.3 
Demographic and Other Baseline Characteristics ··································· 17 
6.3 
Study Drugs Exposure and Compliance ···················································· 19 
6.4 
Analysis of Efficacy ·········································································· 19 
6.4.1 
Analysis of Primary Efficacy Endpoint(s) ············································ 19 
6.4.2 
Analysis of Secondary Efficacy Endpoints ··········································· 20 
6.5 
Analysis of Safety ············································································· 21 
6.5.1 
Adverse Events ·········································································· 21 
6.5.2 
Clinical Laboratory Evaluation ························································ 23 
6.5.3 
Vital Signs ················································································ 23 
6.5.4 
Electrocardiograms ······································································ 24 
6.5.5 
Other Safety-Related Assessment ····················································· 24 
6.6 
Other Analyses ················································································ 25 
6.7 
Interim Analysis ··············································································· 25 
6.7.1 
Interim Analysis of Efficacy ··························································· 25 
6.8 
Additional Conventions ······································································ 25 
6.8.1 
Analysis Windows ······································································ 25 
6.8.2 
Imputation Rules for Incomplete Dates ··············································· 26 
6.8.3 
Outliers ··················································································· 27 
7 
REVISION AND RATIONALE ································································ 28 
8 
REFERENCES ···················································································· 28 
9 
APPENDICES ····················································································· 29 
9.1 
Appendix 1: Neuro-QoL ····································································· 29 
9.1.1 
Neuro-QoL Item Bank v1.0 Fatigue Short Form and Lower Extremity 
Function (Mobility) Short Form ······················································· 29 
9.1.2 
Scoring Transformation Table for Neuro-QoL Item Bank v1.0 Fatigue 
Short Form ··············································································· 30 
9.1.3 
Scoring Transformation Table for Neuro-QoL Lower Extremity Function 
(Mobility) Short Form ·································································· 30 
9.2 
Appendix 2: MFIS ············································································ 31 
9.3 
Appendix 3: Author and Approver Signatures ············································ 33 
 


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I. 
LIST OF ABBREVIATIONS AND KEY TERMS 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
5XSTS 
5 times sit to stand  
6MWT 
6-minute walk test 
AE 
adverse event 
AESI 
adverse events of special interest 
AIDMC 
Astellas Internal Data Monitoring Committee 
ALDOA 
aldolase A 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase  
BMI 
body mass index 
Cave, ss 
average plasma concentration at steady state 
CI 
confidence interval 
CK 
creatine kinase 
CPEO 
Chronic Progressive Externa Ophthalmoplegia 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
cTnI 
cardiac troponin I 
cTnT 
cardiac troponin T 
Ctrough 
concentration immediately prior to dosing at multiple dosing 
CYC 
cytochrome c 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
EQ-5D 
European Quality of Life 5-dimension questionnaire 
EQ-5D-5L 
European Quality of Life 5-dimension, 5-level questionnaire 
EQ-VAS 
EuroQol visual analogue scale 
FAS 
full analysis set 
FLNC 
filamin-C 
ICF 
informed consent form 
ICH  
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IND 
investigational new drug 
IP 
investigational product 
IRT 
interactive response technology 
ISN 
international study number 
KSS 
Kearns Sayre Syndrome 
LS 
least-squares 
MedDRA 
medical dictionary for regulatory activities 
MEGDEL 
3-methylglutaconic aciduria, Deafness, Encephalopathy, and Leigh-like 
disease 
MELAS 
Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes 
MERRF 
Myoclonic Epilepsy with Ragged Red Fibers 
MFIS 
modified fatigue impact scale 
MIDD 
Maternally Inherited Diabetes Deafness 
MMRM 
mixed model for repeated measures 
Neuro-QoL 
Quality of Life in Neurological Disorders 
OLE 
open-label extension 


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Abbreviations 
Description of abbreviations 
PD 
protocol deviation 
PGIC 
patient global impression of change 
PGIS 
patient global impression of severity 
PMM 
primary mitochondrial myopathy  
POLG 
polymerase-gamma 
PPARδ 
peroxisome proliferator-activated receptor delta 
QTcF 
QT interval using Fridericia’s correction 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard errors 
TEAE 
treatment emergent adverse event 
TLF 
tables, listings and figures 
ULN 
upper limit of normal 
 


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List of Key Terms 
Terms 
Definition of terms 
Baseline  
Assessments of participants as they enter a study before they receive any 
treatment.  
Endpoint  
Variable that pertains to the efficacy or safety evaluations of a study. 
Enroll 
To register or enter a participant into a study. Note: Once a participant has 
received the investigational product or placebo, the protocol applies to the 
participant.  
Randomization 
The process of assigning participants to treatment or control groups using 
an element of chance to determine assignments in order to reduce bias. 
Screening 
A process of active consideration of potential participants for enrollment 
in a study. 
Screen failure 
Potential participant who signed the informed consent form but did not 
meet one or more criteria required for participation in the study and was 
not enrolled. 
Variable 
Any entity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values. 


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1 
INTRODUCTION 
This SAP contains technical and detailed elaboration of the principal features of the analysis 
described in the protocol and includes procedures for executing the statistical analysis to 
fulfil the objectives of the study. 
The study was designed to be, and executed as, a double-blinded with an OLE. The OLE was 
removed from protocol version 9.0 and so, the use of the present tense is no longer accurate. 
In addition to the objectives and endpoints defined in Study 0367-CL-1201 protocol (core 
protocol), some additional objectives and endpoints specific to the Mayo Clinic (Minnesota) 
had been defined in Study 0367-CL-1201 [MAYO] Protocol. However, as there have been no 
participants recruited to the protocol from the Mayo sites, therefore there will be no SAP 
created. Until protocol version 7.0, the double-blinded period was 52 weeks and open label 
extension period was 24 weeks. However, from protocol version 8.0 onwards, the double-
blinded period was revised to 24 weeks and in protocol version 9.0 the OLE period was 
removed. Since no participants have been evaluated under protocol version 8.0 or later, two 
SAPs will be prepared: one for analyses up to 52 weeks of treatment (the double-blind part of 
the study), and the other one for analyses at the end of 76 weeks of treatment (the double-
blind part and the OLE part of the study). In analysis for the double-blind part and the OLE 
part of the study, participants assigned ASP0367 in the double-blinded period will be 
analyzed for through the double-blinded part and the OLE part of the study including follow-
up visit, while participants switched from Placebo to ASP0367 in the OLE part will be 
analyzed in the OLE part only including follow-up visit. 
This document is an analysis plan for 52 weeks (double-blinded part) including follow-up 
visit which correspond to protocol v7.0. However, inferential analyses for efficacy endpoints 
will be conducted at week 24 aligned with protocol v9.0. 
Analyses for pharmacokinetic and pharmacodynamic (target gene expression and 
biochemical markers) endpoints, including exposure-response assessment, will be described 
in the separate analysis plan and this SAP only focus on efficacy and safety endpoints. 
This document will be finalized prior to the database lock at the end of study. If there are any 
changes from the planned analyses in the final version of the SAP that impact the statistical 
analyses, then it will be documented in the CSR.  
2 
STUDY OBJECTIVES AND DESIGN 
2.1 
Study Objectives, Endpoints and Estimands 
Objectives 
Endpoints 
Primary 
● 
To assess the dose response of ASP0367 on 
functional improvement relative to placebo 
● 
Change from baseline in distance walked on the 
6MWT at week 24 
● 
To assess the safety and tolerability of 
ASP0367 relative to placebo 
● 
Safety and Tolerability through week 24 and end 
of study: 
o 
Nature, frequency and severity of TEAEs 
o 
Vital signs 


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Note: Placebo comparison will be up to 24 weeks and will not include open-label extension. 
5XSTS: 5 times sit to stand; 6MWT: 6-minute walk test; ALDOA: aldolase A; Cave, ss: average plasma 
concentration at steady state; C-SSRS: Columbia-Suicide Severity Rating Scale; Ctrough: concentration 
immediately prior to dosing at multiple dosing; CYC: cytochrome c; ECG: electrocardiogram; EQ-5D-5L: 
o 
Weight 
o 
12-lead ECG 
o 
Clinical laboratory tests (hematology, 
biochemistry [including serum cardiac 
troponin I] and urinalysis) 
o 
C-SSRS 
Secondary 
● 
To assess the dose response of ASP0367 on 
functional improvement and fatigue relative 
to placebo 
● 
Change from baseline in Neuro-QoL Short Form 
Fatigue and Lower Extremity Function (Mobility) 
scores at week 24 
● 
Change from baseline in time spent on the 5XSTS 
at week 24 
● 
Change from baseline in MFIS at week 24 
● 
To assess the effect of ASP0367 in overall 
participant functioning relative to placebo 
● 
PGIC scores at week 24 
● 
Change from baseline in PGIS scores at week 24 
Exploratory 
● 
To assess the pharmacokinetics of ASP0367 
● 
Plasma ASP0367: Ctrough at weeks 12 and 24 and 
population pharmacokinetics 
● 
To assess the exposure-response relationship 
of ASP0367 
● 
Relationship between measured- and model-based 
pharmacokinetic exposure parameters (e.g., 
Ctrough, Cave, ss) of ASP0367 and endpoints of 
efficacy, safety and pharmacodynamic 
biomarkers, as appropriate 
● 
To assess the effect of ASP0367 on lower 
extremity function relative to placebo 
● 
Change from baseline in distance walked on the 
6MWT at weeks 4 and 12 
● 
Change from baseline in minute-by-minute 
analyses (i.e., 6th vs 1st) of 6MWT at weeks 4, 12 
and 24 
● 
Change from baseline in time spent on 5XSTS at 
weeks 4 and 12 
● 
Change from baseline in Neuro-QoL Short Form 
Fatigue score at weeks 4 and 12  
● 
Change from baseline in Neuro-QoL Short Form 
Lower Extremity Function (Mobility) score at 
weeks 4 and 12 
● 
Change from baseline in MFIS score at weeks 4 
and 12 
● 
To assess the effects of ASP0367 on quality 
of movement and patient perception of 
change 
● 
PGIC scores at weeks 4 and 12 
● 
Change from baseline in PGIS scores at weeks 4 
and 12 
● 
Change from baseline in EQ-VAS and EQ-5D-5L 
index at weeks 4, 12 and 24 
● 
To assess the relationship between functional 
improvement and biochemical markers, as 
well as gene expression-based 
pharmacodynamic biomarkers 
● 
Change from baseline in the levels of serum and 
urinary biomarkers (serum FLNC, CYC, ALDOA 
and urinary TITIN) at weeks 12 and 24  
● 
Relative change from baseline of whole blood 
PPARδ target gene expression levels at weeks 12 
and 24† 


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European Quality of Life 5-dimension, 5-level questionnaire; EQ-VAS: EuroQol visual analogue scale; FLNC: 
filamin-C; MFIS: modified fatigue impact scale; Neuro-QoL: Quality of Life in Neurological Disorders; PGIC: 
patient global impression of change; PGIS: patient global impression of severity; PPARδ: peroxisome 
proliferator-activated receptor delta; TEAE: treatment emergent adverse event. 
†Blood samples will be collected and stored appropriately over the course of the study and then analyzed. 
Estimands 
Primary estimand will be defined by the following 5 attributes:  
● 
Treatment: ASP0367 or placebo 
● 
Population: Participants with PMM, as defined by the inclusion/exclusion criteria of the 
study. 
● 
Endpoint: Change from baseline in distance walked on the 6MWT at week 24. 
● 
Intercurrent events and their corresponding strategies (see table below). 
● 
Population level summary: Difference in change from baseline in distance walked on the 
6MWT at week 24 between ASP0367 group and placebo group. 
Intercurrent Events 
Strategies to Handle Intercurrent Events 
Treatment 
Discontinuation Due to 
Any Reason 
For those participants who discontinued treatment, all observations after 
treatment discontinuation (Date of Last Study Drug Taken + 7 days) will 
be ignored. Analysis will be conducted assuming those participants 
remained assigned treatment and the condition that was observed before 
treatment discontinuation will continue, i.e., hypothetical strategy.  
Study Discontinuation 
For those participants who discontinued study, all observations after 
treatment discontinuation (Date of Last Study Drug Taken + 7 days) will 
be ignored. Analysis will be conducted assuming those participants 
remained assigned treatment and the condition that was observed before 
treatment discontinuation will continue, i.e., hypothetical strategy. 
Prohibited 
Concomitant Treatment 
Use 
For those participants who used the prohibited concomitant medication 
treatment, all observations will be included in the analysis, i.e., treatment 
policy strategy. 
2.2 
Study Design 
This is a randomized, double-blind, placebo-controlled, oral dose, phase 2 study to evaluate 
the dose response of ASP0367 on functional improvement relative to placebo, safety and 
tolerability in participants with PMM. Efficacy (i.e., functional improvement) will be 
assessed by a functional motor test, 6MWT. The study consists of the following portions: 
screening (4 weeks); double-blind treatment period with 2 doses of ASP0367 vs matching 
placebo (24 weeks); and follow-up (4 weeks).  
A 24-week treatment analysis of efficacy and safety will be the primary focus of this study. 
Since participants enrolled and participated in the study prior to implementation of protocol 
version 9.0, which removes the 52-week OLE period, they may have a treatment duration of 
up to 76 weeks, a separate analysis will be conducted up to 76 weeks and follow-up as per 
available data. 


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2.3 
Randomization 
Approximately 66 participants will be enrolled. At randomization, participants will be 
randomly placed into 1 of 3 arms (30 mg ASP0367, 75 mg ASP0367 or placebo; n = 22 for 
each arm) at a ratio of 1:1:1. Stratified randomization by site group (2 level: Mayo 
clinic_Minnesota; Non-Mayo clinic_Minnesota) will be applied if there are any participants 
available from the Mayo site group.  
3 
SAMPLE SIZE 
The sample size of this study was determined from feasibility and statistical perspectives. 
From the statistical perspective, 57 participants (19 participants in each group) will provide 
> 80% power to detect a difference of 45 meters in 6MWT between ASP0367 and placebo at 
a 2-sided significance level of 0.10 assuming a common standard deviation of 55.0 meters.  
The 45-meter difference in 6MWT under the 24-week treatment is assumed based on 
preliminary results that were observed in cohort 1 of the MMPOWER-2 phase 2 randomized 
controlled crossover study of elamipretide [Cohen et al, 2018].  
Considering the interim analysis, 60 participants will be required to maintain > 80% power in 
the efficacy analysis, and assuming an approximately 10% study discontinuation (drop out) 
rate during the double-blind treatment period, 66 participants are required to be randomized. 
This sample size supports an evaluation of proof of concept. 
4 
ANALYSIS SETS 
In accordance with ICH recommendations in guidelines E3 and E9, the following analysis 
sets will be used for the analyses. 
The determination of whether participants are included or excluded from the safety and 
efficacy analysis sets will be made prior to database lock for the primary study report and 
prior to unblinding. 
The following populations are defined for the 52-week treatment analysis: 
Population 
Description 
FAS 
All participants who receive at least 1 dose of ASP0367 or placebo for the 
double-blind treatment period and have at least 1 post baseline efficacy 
measurement. The randomized treatment for each participant will be used for 
summaries by treatment group based on the FAS, even if a participant 
erroneously received a different treatment. 
The FAS will be used for all summaries of efficacy data. 
SAF 
All participants who receive at least 1 dose of ASP0367 or placebo for the 
double-blind treatment period. If a participant erroneously received the wrong 
treatment during the double-blind treatment period, then the actual treatment 
received (i.e. the treatment received for longest time in the double-blind 
treatment period) will be used for summaries based on the SAF. 
The SAF will be used for all summaries of the safety data. 
FAS: full analysis set; SAF: safety analysis set. 


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5 
EFFICACY AND SAFETY ENDPOINTS  
5.1 
Primary Efficacy Endpoint (6-minute Walk Test) 
The 6MWT will be performed indoors, along a long, flat, straight, enclosed corridor with a 
hard surface that is seldom traveled. The total distance walked by a participant, as well as 
distance per minute will be calculated by rounding to the nearest meter and recorded. The 
6MWT will be video recorded for quality purposes. 
Participants will be asked to wear comfortable clothing and appropriate shoes for walking. A 
light meal is acceptable before early morning or early afternoon tests. Participants will be 
recommended not to have exercised within 2 hours prior to beginning of the test. A “warm 
up” period before the test will not be performed. Participants will sit at rest in a chair located 
near the starting position for at least 10 minutes before the test starts. The test will be 
performed at weeks 0, 4, 12, 24, 36 and 52. 
5.2 
Secondary Efficacy Endpoints 
5.2.1 
5 Times Sit To Stand (5XSTS)    
For the 5XSTS, the participant will be instructed to sit with arms folded across their chest 
and with back against the chair and will be asked to stand up and sit down 5 times in a row, 
as quickly as he/she can. The instructor will make sure that the participant will stand up fully 
and try not to let his/her back touch the chair between each repetition. The duration from the 
time instructor indicates “Go” until the time participant’s body touches the chair following 
the fifth repetition will be recorded. If participant is unable to complete the first sit to stand 
independently, without use of arms, the test will be terminated. The test will be performed at 
weeks 0, 4, 12, 24, 36 and 52.  
5.2.2 
Quality of Life in Neurological Disorders (Neuro-QoL)  
The Neuro-QoL is a measurement system that evaluates and monitors the physical, mental 
and social effects experienced by adults and children living with neurological conditions. 
Participants will report Neuro-QoL Item Bank v1.0 Fatigue Short Form and Lower Extremity 
Function (Mobility) Short Form, which consists of 8 items each. Neuro-QoL will be 
performed at weeks 0, 4, 12, 24, 36 and 52. 
5.2.3 
Modified Fatigue Impact Scale (MFIS)   
The MFIS is a modified form of the Fatigue Impact Scale. The questionnaire specifically 
measures how fatigue impacts the lives of those affected by fatigue-like symptoms.  
There are 21 items in the scale measuring 3 domains of fatigue including physical, cognitive 
and psychosocial functioning. MFIS will be performed at weeks 0, 4, 12, 24, 36 and 52. 
5.2.4 
Patient Global Impression of Change (PGIC)   
The PGIC scale evaluates the participant’s most bothersome symptom and assesses if there 
has been an improvement or decline in clinical status. The participant will rate his/her change 
on a 7-point scale. The PGIC score will be evaluated at weeks 4, 12, 24, 36 and 52. 


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5.2.5 
Patient Global Impression of Severity (PGIS) 
The PGIS is a questionnaire designed to assess patient’s impression of disease severity. The 
questionnaire asks the participant to best describe the severity of the participant’s most 
bothersome pre-defined symptom over the past week. The PGIS score will be assessed at 
weeks 0, 4, 12, 24, 36 and 52. 
5.3 
Exploratory Endpoints 
5.3.1 
European Quality of Life 5-dimension, 5-level questionnaire (EQ-5D-5L) 
The EQ-5D-5L is a brief, generic health-related quality of life assessment that can also be 
used to incorporate participant preferences into health economic evaluations. The EQ-5D-5L 
descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 response levels: no problems, 
slight problems, moderate problems, severe problems and extreme problems/unable to 
perform the activity.  In addition, it does record the patient’s self-rated health on a vertical 
visual analogue scale with response options ranging from 0 (worst imaginable health) to 100 
(best imaginable health). The EQ-5D-5L will be assessed at weeks 0, 4, 12, 24, 36 and 52. 
5.4 
Primary Safety Endpoints 
5.4.1 
Treatment Emergent Adverse Events (TEAEs) 
AE collection begins after the ICF has been signed and continues until the follow up visit or 
28 days after the final IP administration or when the participant is determined to be a screen 
failure. A TEAE is defined as an AE observed after starting administration of the IP to 28 
days after the last dose of IP for double-blind treatment period of the study or moving to the 
OLE part, whichever comes first.   
An IP-related TEAE is defined as any TEAE with a causal relationship of “yes” by the 
investigator.  
5.4.2 
Vital signs 
Vital signs including blood pressure, pulse rate and body temperature will be assessed at each 
visit scheduled in the protocol. 
5.4.3 
12-lead Electrocardiogram (ECG) 
● 
A standard 12-lead ECG will be conducted using both a central ECG reading laboratory 
and local ECG reading. ECGs at weeks 2 and 8 will be performed at the participant’s 
home by a qualified healthcare provider from the home healthcare vendor. In case the 
home healthcare visit is not feasible, the visit can be conducted at the study site. 
● 
ECGs will be recorded in triplicate (3 separate ECGs, 5 minutes resting prior to first 
ECG and at least 1 minute apart per time point), prior to blood draw and transmitted 
electronically for central reading. The mean of the triplicate ECG from central and local 
read should be used for treatment decisions and AE reporting.  
● 
If the mean triplicate QTcF is > 500 msec at any time point, one follow-up triplicate 
ECG may be performed on the same day. If the follow-up mean QTcF is ≤ 500 msec, the 


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participant may proceed with IP. If the follow-up mean QTcF > 500 msec is confirmed, 
then the participant must discontinue IP.  
● 
An ECG will also be performed within 24 hours of any of these events: an elevation of 
cTnI above the ULN (see Appendix 10.9 in the protocol for reference range), or when 
there is an elevation of cTnT above the ULN (see Appendix 10.9 in the protocol for 
reference range) or above the participant’s baseline value if it was elevated, or when a 
participant has any signs or symptoms reflecting cardiac involvement, inclusive of new 
onset shortness of breath. If the ECG is within normal limits, a repeat of the abnormal 
troponin value (cTnI or cTnT) should be obtained. For any of the situations above, it 
may be required to interrupt or discontinue further administration of IP. Participants with 
persistent cTnI or cTnT elevations, abnormal ECG or abnormal echocardiogram should 
undergo cardiology follow up. 
The requirement to perform an ECG after elevations observed in Troponin T was not added 
to the protocol until version 9.0. Therefore, this ECG requirement related to cTnT elevation 
was not implemented as all participants enrolled under and participated in the protocol 
version 7.0 or earlier. 
5.4.4 
Echocardiogram (ECHO) 
A local echocardiogram is to be performed within 24 hours of any of these events: an 
elevation of cTnI above the ULN (see Appendix 10.9 in the protocol for reference range), or 
when there is an elevation of cTnT above the ULN (see Appendix 10.9 in the protocol for 
reference range) or above the participant’s baseline value if it was elevated, or when a 
participant has any signs or symptoms reflecting cardiac involvement, inclusive of new onset 
shortness of breath. If the echocardiogram is within normal limits, a repeat of the abnormal 
troponin value (cTnI or cTnT) should be obtained. For any of the situations above, it may be 
required to interrupt or discontinue further administration of IP. Participants with persistent 
cTnI or cTnT elevations, abnormal ECG or abnormal echocardiogram should undergo 
cardiology follow up.  
The requirement to perform an ECHO after elevations observed in Troponin T was not added 
to the protocol until version 9.0. Therefore, this ECHO requirement related to cTnT elevation 
was not implemented as all participants enrolled under and participated in the protocol 
version 7.0 or earlier. 
5.4.5 
Body Weight 
Body weight is planned to be collected at each visit scheduled in the protocol. 
5.4.6 
Laboratory test (hematology, biochemistry and urinalysis) 
Safety laboratory tests will be done by a central laboratory from the screening to the end of 
the study. The scheduled visit and the list of clinical laboratory tests are described in the 
protocol.  
5.4.7 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS will be performed by trained site staff via interview at screening, 
randomization, and all subsequent study visits. At screening, the “Screening” version is to be 


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used to determine eligibility.  During all subsequent visits, the “Since Last Visit” version is 
used to monitor on study suicidal ideation and behavior after the initial assessment. If 
possible, continuity of raters should be maintained across visits for each patient. The 
following five questions regarding suicidal ideation, six questions regarding suicidal behavior 
and question for non-suicidal self-injurious behavior will be used for analysis. 
● 
Suicidal Ideation ('Yes' to any one of the below 5 questions for suicidal ideation) 
o Wish to be Dead (No/Yes) 
o Non-Specific Active Suicidal Thoughts (No/Yes) 
o Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
(No/Yes) 
o Active Suicidal Ideation with Some Intent to Act, without Specific Plan (No/Yes) 
o Active Suicidal Ideation with Specific Plan and Intent (No/Yes) 
● 
Suicidal Behavior ('Yes' to any one of the below 5 questions for suicidal behavior) 
● 
Preparatory Acts or Behavior (No/Yes) 
o Aborted Attempt (No/Yes) 
o Interrupted Attempt (No/Yes) 
o Actual Attempt (No/Yes) 
o Completed Suicide (No/Yes) 
● 
Suicidal Ideation or Behavior ('Yes' to any one of the above 10 questions for suicidal 
ideation and behavior) 
● 
Self-injurious Behavior Without Suicidal Intent (No/Yes) 
5.5 
Other Endpoints 
5.5.1 
Pharmacokinetics Endpoints 
Plasma ASP0367: Ctrough at week 12 and 24. 
Relationship between measured- and model-based pharmacokinetic exposure parameters 
(e.g., Ctrough, Cave, ss) of ASP0367 and endpoints of efficacy, safety and pharmacodynamic 
biomarkers, as appropriate. 
5.5.2 
Pharmacodynamics Endpoints 
Blood samples for PPARδ target gene expression assay 
5.5.3 
Biomarkers 
Urine samples for TITIN 
Blood samples for serum target proteins (ALDOA, CYC and FLNC) 
6 
STATISTICAL METHODOLOGY 
6.1 
General Considerations 
Continuous data will be summarized descriptively including the number of participants (n), 
mean, standard deviation (SD), median, minimum and maximum.  Categorical data will be 
summarized by frequencies and percentages. Percentages by categories will be based on the 


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number of participants with no missing data, i.e. the percentages for the non-missing 
categories will add up to 100%. 
There are 4 different groups defined based in the randomization group in double-blind 
treatment period of the study: 
● 
ASP0367 30 mg: Participants randomly assigned to 30 mg of ASP0367 during double-
blind treatment period. 
● 
ASP0367 75 mg: Participants randomly assigned to 75 mg of ASP0367 during double-
blind treatment period. 
● 
ASP0367 any dose: Participants randomly assigned to 30mg or 75 mg of ASP0367 
during double-blind treatment period. 
● 
Placebo group: Participants randomly assigned to placebo during double-blind treatment 
period. 
Summaries based on FAS (e.g. efficacy data) will be presented by analysis group (ASP0367 
30 mg group, ASP0367 75 mg group or placebo group), unless specifically stated otherwise. 
Statistical model and inference based on FAS will be performed and obtained by analysis 
group. To control the family-wise type I error under the nominal significance level of 10% 2-
sided, the hierarchical testing procedure in the following order (Comparison between 
ASP0367 75 mg and placebo; Comparison between ASP0367 30 mg and placebo) will be 
applied in the primary analysis. 
Safety analysis and other summaries based on SAF will be presented by analysis group 
(ASP0367 30 mg group, ASP0367 75 mg group or placebo group), unless specifically stated 
otherwise.  
All data summarization and analyses will be performed using SAS® Version 9.4 or higher on 
Linux. Specifications for table, figures, and data listing formats can be found in the TLF 
specifications. 
For continuous variables that are recorded as “<X”, “<=X”, “>X”, or “>=X”, the value of 
“X” will be used in the calculation of summary statistics if otherwise noted. This approach 
may result in a summary that reflects the presence of an analyte (such as troponin) when in 
fact the analyte was not detected but report as less than the lower limit of detection by the 
assay. 
6.2 
Study Population 
6.2.1 
Disposition of Participants 
The following participant data will be presented. Unique participants are defined as 
rescreened participants for whom the data from the last enrollment are used, unless stated 
otherwise. 
Analysis population: All participants with informed consent, Analysis group: Total 


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● 
Number of participants with informed consent and who were discontinued before 
randomization. For any participant who was screened multiple times, the participant will 
be counted for each screening attempt,  
● 
Number of unique participants with informed consent and who were discontinued before 
randomization. For any participant who was screened multiple times, the participant will 
be only counted once, 
● 
Number of participants with re-screening. For any participant who was re-screened 
multiple times, the participant will be counted for each re-screening attempt, 
● 
Number of participants who were randomized, 
● 
Number and percentage of participants who discontinued before randomization, by 
primary reason for study discontinuation. 
Analysis population: All randomized participants, Analysis group: 30, 75 mg, any dose of 
ASP0367, placebo group and Total 
● 
Number and percentage of participants who were randomized in each analysis set, 
administered at least one dose of study drug, 
● 
Number and percentage of participants who completed and those who discontinued the 
treatment during double-blind treatment period, by primary reason for treatment 
discontinuation, 
● 
Number and percentage of participants who completed and those who discontinued the 
study during double-blind treatment period, by primary reason for study discontinuation. 
6.2.2 
Protocol Deviations 
Analysis population: All randomized participants, Analysis group: 30, 75 mg, any dose of 
ASP0367, placebo group and Total 
The number and percentage of participants with the following deviation criteria (defined as 
an important protocol deviation) will be summarized for each criterion and overall, by 
treatment group and total as well as by investigative site. Participants deviating from a 
criterion more than once will be counted only once for the corresponding criterion. 
The unique identifiers will be as follows: 
PD1 - Inclusion/Exclusion,  
PD2 - Withdrawal Criteria, 
PD3 - Study Intervention, 
PD4 - Excluded Concomitant Medications, 
PD5 - Informed Consent, 
PD6 - Safety Reporting, and 
PD7 - Procedures/Tests 


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6.2.3 
Demographic and Other Baseline Characteristics 
Analysis population: All randomized participants, SAF and FAS, Analysis group: 30, 75 mg, 
any dose of ASP0367, placebo group and Total 
● 
Demographic and other baseline characteristics (age, sex, race and ethnicity, body 
weight, height and BMI), as well as genetic abnormality for PMM will be summarized 
by descriptive statistics and frequency tabulations [Table 1].  


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Table 1 
Demographic and baseline characteristics 
Item 
Classification 
Sex 
1: Male 
2: Female 
Age (Years) [Informed Consent] 
Measurement value 
Age 
1: >=18 to <65 
2: >=65 to <=80 
Ethnicity 
1: Not Hispanic or Latino 
2: Hispanic or Latino 
Race 
1: White 
2: Black or African American 
3: Asian 
4: American Indian or Alaska Native 
5: Native Hawaiian or Other Pacific Islander 
6: Other 
Height (cm) [Screening] 
Measurement value 
Weight (kg) [Screening] 
Measurement value 
BMI (kg/m^2) [Screening] 
Measurement value 
BMI 
1: < 25 
2: >=25 
Site Group 
1: Mayo clinic_Minnesota  
2: Non-Mayo clinic Minnesota 
Walking aid use [Week 0] 
0: No 
1: Yes 
Duration of disease† (Years) 
Measurement value 
Treated with medication [Screening] 
0: No 
1: Yes 
Syndrome 
1: Kearns Sayre Syndrome (KSS) 
2: Mitochondrial Encephalomyopathy, Lactic Acidosis and 
Stroke-like episodes (MELAS) 
3: Maternally Inherited Diabetes Deafness (MIDD) 
4: Myoclonic Epilepsy with Ragged Red Fibers (MERRF) 
5: Chronic Progressive Externa Ophthalmoplegia (CPEO) 
6: 3-methylglutaconic aciduria, Deafness, Encephalopathy, 
and Leigh-like disease (MEGDEL) 
7: Leigh Syndrome 
8: Multisystem mitochondrial disorder 
9: Mitochondrial Myopathy 
10: POLG-related disorders 
11: Others 
Genetic abnormality 
1: Mitochondrial DNA 
2: Nuclear DNA 
Mitochondrial DNA mutant heteroplasmy 
information is available 
0: No 
1: Yes 
Level of heteroplasmy (%) 
Measurement value 
BMI: body mass index; CPEO: Chronic Progressive Externa Ophthalmoplegia; KSS: Kearns Sayre Syndrome; 
MEGDEL: 3-methylglutaconic aciduria, Deafness, Encephalopathy, and Leigh-like disease; MELAS: 
Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes; MERRF: Myoclonic Epilepsy 
with Ragged Red Fibers; MIDD: Maternally Inherited Diabetes Deafness; POLG: polymerase-gamma. 
†: Duration of disease will be calculated as follows: 
(“Date of First Study Drug Taken”-“Date of Diagnosis” + 1)/365.25. 
If Date of Diagnosis is missing or incomplete, then impute the date following the rule stated in [Section 6.8.2]. 


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6.3 
Study Drugs Exposure and Compliance 
Analysis population: SAF, Analysis group: ASP0367 30 mg group, ASP0367 75 mg group, 
ASP0367 any dose group or placebo group 
● 
The duration of study drug exposure for each participant in double blind part will be 
summarized by descriptive statistics and frequency tabulations. The following categories 
of the duration of exposure (days) will be defined: 
o < 29 (4 weeks) 
o >= 29 (4 weeks) to < 85 (12 weeks) 
o >= 85 (12 weeks) to < 169 (24 weeks) 
o >= 169 (24 weeks) to < 253 (36 weeks) 
o >= 253 (36 weeks) to < 365 (52 weeks) 
o >= 365 (52 weeks) 
The duration of study drug exposure in double blind part will be calculated as follows: 
{“Date of Last Study Drug Taken in double blind part” – “Date of First Study Drug 
Taken”} + 1. 
Date of Last Study Drug Taken in double blind part is defined as the latest date of [“Date 
of Last Study Drug Taken (Phase 2 Treatment Period)” or “Date of Last Study Drug 
Taken (Dose selection Period)” or “Date of Last Study Drug Taken (Phase 3 Treatment 
Period)”]. 
● 
The compliance of study drug exposure for each participant in double blind part will be 
summarized by descriptive statistics and frequency tabulations. The following categories 
of the study drug compliance (%) will be defined: 
o < 50 
o >= 50 to < 75 
o >= 75 to < 90 
o >= 90 
o Unknown 
The compliance of study drug exposure in double blind part will be calculated as 
follows: 
Total number of dispensed tablets - Total number of returned tablets in double blind part
The number of tablets to be taken in double blind part
×100 
The number of tablets to be taken in double blind part is defined as follows: 
[{“Date of Last Study Drug Taken in double blind part” – “Date of First Study Drug 
Taken”} + 1] x 3. 
6.4 
Analysis of Efficacy  
6.4.1 
Analysis of Primary Efficacy Endpoint(s) 
The primary efficacy endpoint is change from baseline to week 24 in distance walked on the 
6MWT. 


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6.4.1.1 Primary Analysis for Primary Efficacy Endpoint 
Analysis population: FAS, Analysis group: ASP0367 30 mg group, ASP0367 75 mg group or 
placebo group 
The primary efficacy endpoint will be analyzed on FAS for primary analysis. In order to 
compare the change from baseline in distance walked on the 6MWT between ASP0367 and 
placebo group, the null and alternative hypothesis will be constructed: 
H0: The change from baseline in distance walked on the 6MWT at week 24 for each dose of 
ASP0367 and placebo are the same. 
H1: The change from baseline in distance walked on the 6MWT at week 24 for each dose of 
ASP0367 and placebo are not the same. 
To control the family-wise type I error rate (i.e., the probability of incorrectly rejecting at 
least one true null hypothesis), the hierarchical testing procedure in the following order will 
be applied: 
Comparison between ASP0367 75 mg and placebo 
Comparison between ASP0367 30 mg and placebo 
Comparison to placebo will be conducted using a MMRM with treatment group (3 level: 
ASP0367 75 mg, ASP0367 30 mg, and placebo group), week (weeks 4, 12 and 24) as factors, 
with baseline measurement as a covariate, as well as an interaction of treatment by week and 
an interaction of baseline measurement by week. An unstructured covariance structure will 
be used to model the within-participant correlation. If the unstructured covariance structure 
fails to converge, then compound symmetry will be used. The Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom and adjust standard errors.  
Contrasts will be constructed to compare each dose group of ASP0367 to the placebo group 
at week 24. The LS mean change from baseline in distance walked on the 6MWT with 
associated SE will be displayed for each treatment group. Estimated treatment differences 
between each dose group of ASP0367 and placebo group along with corresponding 2-sided 
90% CI and p-values will also be presented. 
6.4.2 
Analysis of Secondary Efficacy Endpoints  
Analysis population: FAS, Analysis group: ASP0367 30 mg group, ASP0367 75 mg group or 
placebo group 
The change from baseline to week 24 in 5XSTS and MFIS will be analyzed using the same 
MMRM model as with the primary analysis for primary endpoint. 
The change from baseline to week 24 in T-scores for Neuro-QoL Short Form Fatigue and 
Lower Extremity Function (Mobility) scores will be analyzed using the same MMRM model 
as with the primary analysis for primary endpoint. 
For PGIC score at week 24, responder analysis will be used. Participants with scores of 1 
(Very Much Improved), 2 (Much Improved) and 3 (Minimally Improved) will be considered 


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as responders, whereas participants with scores of 4 (No Change), 5 (Minimally Worse), 6 
(Much Worse) and 7 (Very Much Worse) will be treated as nonresponders. 
For PGIS score, responder analysis will be used for post baseline visits. Participants who 
have a lower severity score than baseline will be considered as responders, otherwise will be 
treated as non-responders. The participants who have 0 (None) as baseline score will be 
excluded from this responder analysis. 
For the secondary endpoints, the multiplicity of statistical comparison will not be adjusted. 
The change from baseline in 6MWT, 5XSTS, MFIS and Neuro-QoL Short Form Fatigue and 
Lower Extremity Function (Mobility) scores will be summarized by treatment group and time 
point (other than week 24). 
PGIC score and PGIS score will also be summarized by treatment group and time point 
(other than week 24). 
6.5 
Analysis of Safety 
Analysis population: SAF, Analysis group: 30, 75 mg of ASP0367, ASP0367 any dose group 
or placebo group 
6.5.1 
Adverse Events 
AEs will be coded using the MedDRA.   
An overview table will include the following: 
● 
Number of TEAEs, 
● 
Number and percentage of participants with TEAEs, 
● 
Number of drug related TEAEs, 
● 
Number and percentage of participants with drug related TEAEs, 
● 
Number of serious TEAEs, 
● 
Number and percentage of participants with serious TEAEs, 
● 
Number of serious drug related TEAEs, 
● 
Number and percentage of participants with serious drug related TEAEs, 
● 
Number of TEAEs leading to death, 
● 
Number and percentage of participants with TEAEs leading to death, 
● 
Number of drug related TEAEs leading to death, 
● 
Number and percentage of participants with drug related TEAEs leading to death, 
● 
Number of TEAEs leading to withdrawal of study drug, 
● 
Number and percentage of participants with TEAEs leading to withdrawal of study drug, 
● 
Number of drug related TEAEs leading to withdrawal of study drug, 
● 
Number and percentage of participants with drug related TEAEs leading to withdrawal 
of study drug, and 
● 
Number of deaths. 


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Number of deaths is counted all reported deaths after starting administration of the IP. For 
participants who move to the OLE, all reported deaths after starting administration of the IP 
to moving to the OLE. 
The number and percentage of participants with TEAEs, as classified by SOC, and PT will be 
summarized by analysis group. Summaries will be provided for the following: 
● 
TEAEs, 
● 
drug related TEAEs,  
● 
serious TEAEs,  
● 
drug related serious TEAEs,  
● 
TEAEs leading to withdrawal of study drug,  
● 
drug related TEAEs leading to withdrawal of study drug,  
● 
TEAEs excluding Serious AEs that equal to or exceed a threshold of 5.0% in any 
analysis group. 
The number of TEAEs and the number and percentage of participants with TEAEs, as 
classified by SOC and PT will be summarized by severity and by relationship to study drug. 
In the participant count, if a participant has multiple TEAEs with the same SOC or PT, but 
with differing severity or relationship, then the participant will be counted once with the 
worst severity and highest degree of relationship. If severity or relationship is missing for all 
episodes of the event, the participant will be counted under missing severity or relationship.  
The following AESIs are defined: 
● 
Cardiac tissue injury defined by cTnI above ULN or if the cTnT is above ULN or 
baseline if the participant’s baseline value was above ULN and a TEAE as pre-defined 
by a MedDRA search strategy for elevated troponin. 
● 
Cardiac tissue injury with any signs or symptoms defined by an echocardiogram or 
electrocardiogram interpretation is reported as abnormal, clinically significant and a 
TEAE as pre-defined by a MedDRA search strategy for cardiac complaints. 
● 
Skeletal muscle injury defined by CK increase >= 5 times the value of the ULN or the 
individual’s baseline value, whichever is higher and a TEAE as pre-defined by a 
MedDRA search strategy for skeletal muscle injury. 
AESIs prior to version 9.0 of the protocol did not include elevations in cTnT in the definition 
of an AESI but instead only included elevations of cTnI. All participants participated in 
protocol version 7.0 or earlier; therefore participants for whom elevations in cTnT were 
observed may not have been identified as having experienced an AESIs during study conduct 
and for this reason may not have had additional ECG and echocardiographic evaluations 
performed. 
The number and percentage of participants who report AESIs will be summarized by analysis 
group. In addition, any (serious) AEs that are considered abuse of the study drug will also be 
collected and followed. The number and percentage of AEs of special interest related to 
abuse, as classified by SOC and PT will be summarized by analysis group. 


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6.5.2 
Clinical Laboratory Evaluation 
Quantitative values including hematology, biochemistry, and urinalysis will be summarized 
using mean, standard deviation, minimum, maximum and median by analysis group at each 
analysis visit. Additionally, a within-participant change will be calculated as the post-
baseline measurement minus the baseline measurement and summarized in the same way. 
Frequency tabulations of qualitative clinical laboratory variables (urinalysis) will be 
presented for each analysis group at each visit. 
Additionally, amylase, lipase and troponin elevations above the ULN and 2xULN will be 
summarized by analysis group. The denominator for each criterion will be the number of 
participants who have at least one value after the day of first IP taken to 28 days after the last 
dose of IP for the double-blind treatment period of the study or moving to the OLE, 
whichever comes first.  
The number and percentage of participants meeting the criteria during the defined period 
above will be summarized by analysis group. 
6.5.2.1 Liver Safety Assessment  
The liver safety assessments will be summarized by the categories below based on the 
measurements from ALP, ALT, total bilirubin, AST and their combination. These parameters 
will be based on measurements from a local laboratory. If the baseline value is above ULN 
then use the baseline value instead of ULN. 
● 
ALT > ULN, > 2xULN, > 3xULN, > 5xULN, > 10xULN, > 20xULN 
● 
AST > ULN, > 2xULN, > 3xULN, > 5xULN, > 10xULN, > 20xULN 
● 
ALT or AST > ULN, > 2xULN, > 3xULN, > 5xULN, > 10xULN, > 20xULN 
● 
ALP > 1.5xULN, 2xULN, 2.5xULN 
● 
Total Bilirubin > 2xULN 
● 
(ALT or AST > 3xULN) and Total Bilirubin > 2xULN 
● 
(ALT or AST > 3xULN) and ALP < 2xULN and Total Bilirubin > 2xULN 
The last 2 criteria where 2 or more parameters are evaluated will be with the measurements 
on the same day or up to 1 day apart. 
The denominator for each criterion will be the number of participants who have at least one 
value after the day of first dose taken to 28 days after the last dose of IP for the 52 weeks or 
moving to the OLE, whichever comes first. The number and percentage of participants 
meeting the criteria by 28 days after the last dose of IP for the 52 weeks or moving to the 
OLE will be summarized by analysis group. 
6.5.3 
Vital Signs 
Vital signs (systolic blood pressure, diastolic blood pressure, and pulse rate) will be 
summarized using mean, standard deviation, minimum, maximum and median by analysis 
group and visit. Additionally, a within-participant change will be calculated per visit as the 


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post-baseline measurement minus the baseline measurement and summarized by analysis 
group and visit. 
6.5.4 
Electrocardiograms  
6.5.4.1 Routine 12-lead Electrocardiograms 
The number and percent of participants with normal, not clinically significant abnormal, and 
clinically significant abnormal results as assessed by site principal investigator for the 12 lead 
ECG will be tabulated by analysis group and time point. Continuous 12-lead 
Electrocardiogram 
For all analyses, replicates at each visit will be averaged for each continuous ECG parameter.  
ECG parameters [Heart Rate (bpm), PR Interval (ms), QRS Interval (ms) and QTcF (ms)] 
read by the central laboratory will be summarized using mean, standard deviation, minimum, 
maximum and median for each analysis group at each visit, including changes from baseline. 
The QTcF interval will be summarized using frequency tables for each visit for values of 
clinical importance using the range criteria below. 
 
QTcF Interval Criteria Value (msec)  
Normal 
Borderline 
Prolonged 
Clinically significant 
≤ 450 
> 450  
> 480  
> 500 
QTcF: QT interval using Fridericia’s correction. 
The QTcF interval will also be summarized by the frequencies of participants with an 
increase from baseline of clinical importance using the criteria identified below. These 
summaries will be provided for each visit. 
QTcF: QT interval using Fridericia’s correction. 
6.5.5 
Other Safety-Related Assessment 
6.5.5.1 Body Weight 
Body weight will be summarized using mean, standard deviation, minimum, maximum and 
median by analysis group and visit. Additionally, a within-subject change will be calculated 
per visit as the post-baseline measurement minus the baseline measurement (screening visit) 
and summarized by analysis group. 
6.5.5.2 C-SSRS 
The results of five questions regarding suicidal ideation, six questions regarding suicidal 
behavior, suicidal ideation or behavior and self-injurious behavior without suicidal intent will 
be summarized using number and percent of participants by analysis group at each visit. For 
Variable 
Change from Baseline  
QTcF Interval (msec) 
≤ 30 
> 30 
> 60  


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all analysis visits, the data “by the last dose + 7 days” and the data before the first dose date 
of open label extension part will be included. 
6.6 
Other Analyses 
Not applicable in this study. 
6.7 
Interim Analysis  
6.7.1 
Interim Analysis of Efficacy 
The analysis of futility and of efficacy was performed when the first 33 participants 
completed the efficacy evaluation at week 24 or discontinued as of date the last participant 
had the week 24 visit, 20-Nov-2023. The change from baseline in distance walked on the 
6MWT at week 24 was analyzed using the same MMRM as with the primary endpoint 
excluding the site group from the model to decide whether the study will continue. 
Analysis of Futility 
For the futility stop, the study may be stopped if the conditional probability of achieving the 
criteria below at the final analysis is less than 10%. 
Criteria: Lower limit of the 90% CI for the difference is greater than 0 m AND the point 
estimate of the difference between the ASP0367 75 mg group and the placebo group is 
greater than 30 m. 
In addition to 6MWT at week 24, outputs for participant disposition, demographics and the 
secondary endpoints 5XSTS, Neuro-QoL Short Form Fatigue score, Neuro-QoL Short Form 
Lower Extremity Function (Mobility) score, MFIS, PGIC, and PGIS at week 24 were 
analyzed at the interim analysis.  
Analysis of Efficacy 
For the efficacy stop, a two-stage group sequential design with Lan-DeMets alpha-spending 
function determined by means of the O'Brien-Fleming approach was used to preserve the 
overall two-sided type I error rate of 0.10 between this single interim analysis and the final 
analysis. If the p-value of the comparison between ASP0367 75 mg and placebo groups at 
interim analysis is lower than the boundary determined by O'Brien-Fleming approach, 
efficacy would be considered to be achieved at week 24. 
The interim analysis outputs were prepared by an external statistician and presented to the 
AIDMC who made recommendations about the ongoing conduct of the study. After the 
AIDMC reviewed the interim analysis results, the AIDMC recommended the study to be 
stopped because the study met results of the interim analysis the criteria for futility. Details of 
the analysis were defined in the interim analysis plan. 
6.8 
Additional Conventions 
6.8.1 
Analysis Windows 
Day 1 and Day -1 are defined as the day of start taking the IP and its prior day, respectively. 


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The following analysis window will be used. 
The data summary by visits will be done following the analysis windows specified in the 
table below: 
Analysis Visits 
Scheduled Day in 
Protocol 
Analysis Windows (day) 
Screening 
Day -28 
-35 to -14 
Week 0 (Baseline) 
Day -2 to 1  
-2 to 1 
Week 1 
Day 8 
5 to 13 
Week 2 
Day 14 
14 to 18 
Week 3 
Day 22 
19 to 25 
Week 4 
Day 29 
26 to 42 
Week 8 
Day 57 
43 to 70 
Week 12 
Day 85 
71 to 98 
Week 16 
Day 113 
99 to 126 
Week 20 
Day 141 
127 to 154 
Week 24 
Day 169 
155 to 182 
Week 28 
Day 197 
183 to 210 
Week 32 
Day 225 
211 to 238 
Week 36 
Day 253 
239 to 266 
Week 40 
Day 281 
267 to 294 
Week 44 
Day 309 
295 to 322 
Week 48 
Day 337 
323 to 350 
Week 52 
Day 365 
351 to 378 
End of Double Blind Part 
Day 365 
2 to 378 
Follow-up 
The last dose + 28 
days 
The last dose + 28 days to the last dose + 
35 days 
For the analyses of safety and efficacy, for all analysis visits excluding follow-up visit, the 
data “by the last dose + 7 days” and the data before the first dose date of open label extension 
part will be included. 
If more than one observation exists within the analysis window, the observation closest to the 
scheduled visit day will be selected for that visit. If there are two observations that have the 
same distance from the scheduled day, the value that is after the scheduled day will be 
selected in the analysis. If more than one observation is made on the same day, an average 
value if continuous or the worst value if categorical will be included in the analysis. 
6.8.2 
Imputation Rules for Incomplete Dates 
For AEs, a missing or incomplete onset date will be imputed according to the following 
conventions. 
If an onset date is missing, the imputed onset date will be the date of first dose of study drug. 
If only the year is known for the AE onset date, the imputed onset date will be the latest of 
the following non-missing dates: 
● 
Date of first dose of study drug  
● 
January 1 of the year of AE onset date  


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If only the month and year is known for the onset date, set the surrogate onset date to the first 
day of that month and then apply the following rules. 
● 
If the month and year of the onset date is prior to the month and year of the first dose of 
study drug, then the surrogate onset date will be the imputed onset date. 
● 
If the month and year of the onset date is on or after the month and year of the first dose 
of study drug, then the imputed onset date will be the latest of the following non-missing 
dates: 
● 
Date of first dose of study drug 
● 
Surrogate onset date 
● 
If the imputed onset date is after the AE end date, the imputed onset date will be the 
same as the AE end date. 
For duration of disease of primary diagnosis, a missing or incomplete diagnosis date will be 
imputed according to the following conventions. 
If a diagnosis date is missing, the diagnosis date will not be imputed. The duration of disease 
in baseline analysis will be treated as missing data. 
If only the year is known for the diagnosis date, the imputed diagnosis date will be January 1 
of the year of the diagnosis date. 
If only the month and year is known for the diagnosis date, set the imputed diagnosis date 
will be the first day of that month. 
6.8.3 
Outliers 
All values will be included in the analyses. 


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7 
REVISION AND RATIONALE 
Version Date 
Changes 
Comment/rationale for 
change 
1.0 
16-
Jul-
2020 
 
Document finalized 
2.0  
5-
Aug-
2020 
Section 2.3: 
● 
Removed description of stratified 
randomization by site group. 
Section 6.4.1.1, 6.4.2: 
● 
Removed site group factor from analysis 
model. 
Section 6.4.1.4: 
● 
Removed site from grouping variables. 
Updated due to Protocol 
amendment 2 
3.0  
9-Jul-
2024 
● 
Revised study design and statistical 
methodology related sections based on 
substantial protocol amendments 7 and 8. 
● 
Removed several statistical analyses due 
to the futility stop. 
● 
Updated the description of analysis sets 
● 
Updated due to change in the duration of 
the study periods for the DB and OLE and 
the addition of an interim analysis in 
substantial protocol amendment 7 and the 
removal of the OLE period and the 
addition of an AESI of elevated cardiac 
troponin T in substantial protocol 
amendment 8. 
 
Updated due to changes in 
study design and some 
protocol details added in 
substantial protocol 
amendments 7 and 8. 
Adjusted some descriptions to 
align the data and/or TOC 
Clarified the detail definition 
of analysis sets 
8 
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Mitochondrial Myopathy: a Phase 2 Double-Blind, Randomized, Placebo-Controlled Crossover 
Trial (MMPOWER-2). Neurology. 2018;90(Suppl 15):S5.003. 
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics) 
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics) 


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9 
APPENDICES 
9.1 
Appendix 1: Neuro-QoL  
9.1.1 
Neuro-QoL Item Bank v1.0 Fatigue Short Form and Lower Extremity 
Function (Mobility) Short Form 
● 
Missing Items: A score can be approximated if a participant skips a question. If items are 
missing, first check how many items were answered. For short forms with 8 items, 
confirm that 4 items have been answered. After confirming that enough responses were 
provided, sum the response scores from the items that were answered. Multiply this sum 
by the total number of items in the short form. Finally, divide by the number of items 
that were answered. If the result is a fraction, round up to the nearest whole number. 
● 
The total raw score equals sum of the values of the response to each question. For fatigue 
short forms with 8 items, the total raw score ranges from 8 to 40. 
● 
T-score distributions rescale raw scores into standardized scores with a mean of 50 and a 
SD of 10. 
● 
Neuro-QoL Item Bank v1.0 Fatigue Short Form consists of the following eight items: 
● 
In the past 7 days. 
o Q1 
I felt exhausted. 
o Q2 
I felt that I had no energy. 
o Q3 
I felt fatigued. 
o Q4 
I was too tired to do my household chores. 
o Q5 
I was too tired to leave the house. 
o Q6 
I was frustrated by being too tired to do the things I wanted to do. 
o Q7 
I felt tired. 
o Q8 
I had to limit my social activity because I was tired. 
● 
Neuro-QoL Item Bank v1.0 Fatigue Short Form items employ five response options: 
Never (1); Rarely (2); Sometimes (3); Often (4); Always (5). 
● 
Neuro-QoL Lower Extremity Function (Mobility) Short Form consists of the following 
eight items: 
o Q1 
Are you able to get on and off the toilet? 
o Q2 
Are you able to step up and down curbs? 
o Q3 
Are you able to get in and out of a car? 
o Q4 
Are you able to get out of bed into a chair? 
o Q5 
Are you able to push open a heavy door? 
o Q6 
Are you able to run errands and shop? 
o Q7 
Are you able to get up off the floor from lying on your back without help? 
o Q8 
Are you able to go for a walk of at least 15 minutes? 
Neuro-QoL Lower Extremity Function (Mobility) Short Form items employ five response 
options: Unable to do (1); With much difficulty (2); With some difficulty (3); With a little 
difficulty (4); Without any difficulty (5). 


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9.1.2 
Scoring Transformation Table for Neuro-QoL Item Bank v1.0 Fatigue Short 
Form 
Neuro-QoL Item Bank 1.0 Fatigue Short Form (Adult) 
Raw Score 
T-Score 
SE 
Raw Score 
T-score 
SE 
Raw Score 
T-score 
SE 
8 
29.5 
4.4 
19 
46.5 
1.7 
30 
57.6 
1.8 
9 
34.1 
2.7 
20 
47.4 
1.7 
31 
58.8 
1.8 
10 
36.5 
2.2 
21 
48.4 
1.7 
32 
59.9 
1.8 
11 
38.2 
2.0 
22 
49.3 
1.7 
33 
61.1 
1.8 
12 
39.5 
1.9 
23 
50.3 
1.7 
34 
62.3 
1.8 
13 
40.7 
1.8 
24 
51.3 
1.8 
35 
63.5 
1.8 
14 
41.8 
1.7 
25 
52.3 
1.7 
36 
64.8 
1.9 
15 
42.8 
1.7 
26 
53.3 
1.7 
37 
66.2 
2.0 
16 
43.8 
1.7 
27 
54.4 
1.7 
38 
67.9 
2.2 
17 
44.7 
1.7 
28 
55.4 
1.7 
39 
70.1 
2.7 
18 
45.6 
1.7 
29 
56.5 
1.8 
40 
74.1 
4.0 
Neuro-QoL: Quality of Life in Neurological Disorders; SE: standard errors. 
The scoring transformation table is only accurate when all questions on the short form have 
been answered. Approximations can be estimated by prorating the raw sum score based upon 
those questions that are answered, however this diminishes the advantages of IRT scoring. 
9.1.3 
Scoring Transformation Table for Neuro-QoL Lower Extremity Function 
(Mobility) Short Form 
Neuro-QoL Lower Extremity Function (Mobility) Short Form (Adult) 
Raw Score 
T-Score 
SE 
Raw Score 
T-score 
SE 
Raw Score 
T-score 
SE 
8 
16.5 
3.0 
19 
30.7 
2.1 
30 
39.1 
2.2 
9 
19.2 
2.8 
20 
31.5 
2.1 
31 
39.9 
2.2 
10 
21.1 
2.6 
21 
32.2 
2.1 
32 
40.8 
2.3 
11 
22.6 
2.4 
22 
33.0 
2.1 
33 
41.7 
2.4 
12 
23.9 
2.3 
23 
33.7 
2.0 
34 
42.8 
2.5 
13 
25.1 
2.3 
24 
34.5 
2.1 
35 
43.9 
2.6 
14 
26.2 
2.2 
25 
35.2 
2.1 
36 
45.2 
2.9 
15 
27.2 
2.2 
26 
36.0 
2.1 
37 
46.7 
3.1 
16 
28.1 
2.1 
27 
36.7 
2.1 
38 
48.6 
3.3 
17 
29.0 
2.1 
28 
37.5 
2.1 
39 
51.2 
3.8 
18 
29.9 
2.1 
29 
38.3 
2.1 
40 
58.6 
6.4 
Neuro-QoL: Quality of Life in Neurological Disorders; SE: standard error. 
The scoring transformation table is only accurate when all questions on the short form have 
been answered. Approximations can be estimated by prorating the raw sum score based upon 
those questions that are answered, however this diminishes the advantages of IRT scoring. 


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9.2 
Appendix 2: MFIS 
Fatigue is a feeling of physical tiredness and lack of energy that many people experience 
from time to time. But people who have medical conditions like multiple sclerosis experience 
stronger feelings of fatigue more often and with greater impact than others. 
Following is a list of statements that describe the effects of fatigue. Please read each 
statement carefully, the circle the one number that best indicates how often fatigue has 
affected you in this way during the past 4 weeks. (If you need help in marking your 
responses, tell the interviewer the number of the best response.) Please answer every 
question. If you are not sure which answer to select choose the one answer that comes closest 
to describing you. Ask the interviewer to explain any words or phrases that you do not 
understand. 
Because of my fatigue during the past 4 weeks 
 
 
 
 
1. 
I have been less alert. 
0 
1 
2 
3 
4 
2. 
I have had difficulty paying attention for long periods 
of time. 
0 
1 
2 
3 
4 
3. 
I have been unable to think clearly. 
0 
1 
2 
3 
4 
4. 
I have been clumsy and uncoordinated. 
0 
1 
2 
3 
4 
5. 
I have been forgetful. 
0 
1 
2 
3 
4 
6. 
I have had to pace myself in my physical activities. 
0 
1 
2 
3 
4 
7. 
I have been less motivated to do anything that requires 
physical effort. 
0 
1 
2 
3 
4 
8. 
I have been less motivated to participate in social 
activities. 
0 
1 
2 
3 
4 
9. 
I have been limited in my ability to do things away 
from home. 
0 
1 
2 
3 
4 
10. 
I have trouble maintaining physical effort for 
long periods. 
0 
1 
2 
3 
4 
11. 
I have had difficulty making decisions. 
0 
1 
2 
3 
4 
12. 
I have been less motivated to do anything that requires 
thinking. 
0 
1 
2 
3 
4 
13. 
My muscles have felt weak. 
0 
1 
2 
3 
4 
14. 
I have been physically uncomfortable. 
0 
1 
2 
3 
4 
15. 
I have had trouble finishing tasks that require thinking. 
0 
1 
2 
3 
4 
16. 
I have had difficulty organizing my thoughts when 
doing things at home or at work. 
0 
1 
2 
3 
4 
17. 
I have been less able to complete tasks that require 
physical effort. 
0 
1 
2 
3 
4 
18. 
My thinking has been slowed down. 
0 
1 
2 
3 
4 
Never 
Rarely 
Sometimes 
Often 
Almost 
Always 


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19. 
I have had trouble concentrating. 
0 
1 
2 
3 
4 
20. 
I have limited my physical activities. 
0 
1 
2 
3 
4 
21. 
I have needed to rest more often or for longer periods. 
0 
1 
2 
3 
4 
 
Instructions for Scoring the MFIS 
Items on the MFIS can be aggregated into three subscales (physical, cognitive, and 
psychosocial), as well as into a total MFIS score. All items are scaled so that higher scores 
indicate a greater impact of fatigue on a person’s activities. If there is the assessment with the 
missing data, then the score for that assessment will not be calculated and will be excluded 
from the analysis. 
 
Physical Subscale 
This scale can range from 0 to 36. It is computed by adding raw scores on the following 
items: 4+6+7+10+13+14+17+20+21. 
 
 
Cognitive Subscale 
This scale can range from 0 to 40. It is computed by adding raw scores on the following 
items: 1+2+3+5+11+12+15+16+18+19. 
 
Psychosocial Subscale 
This scale can range from 0 to 8. It is computed by adding raw scores on the following items: 
8+9. 
 
Total MFIS Score 
The total MFIS score can range from 0 to 84. It is computed by adding scores on the 
physical, cognitive, and psychosocial subscales. 




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STATISTICAL ANALYSIS PLAN 
(Double Blind Part And Open-Label Extension Part) 
  
Final Version 1.0 dated 09-Jul 2024 
 
A Randomized, Double-blind, Placebo-controlled Phase 2 Study to Assess the Efficacy, 
Safety and Tolerability of ASP0367 in Participants with Primary Mitochondrial Myopathy 
 
 
 
 
ISN: 0367-CL-1201 
 
IND number: 146773 
 
 
 
Astellas Pharma Inc. (API) 
 
 
 
 
This document contains confidential information which is the intellectual property of Astellas. By accepting or reviewing 
this document, you agree to hold this information in confidence and not copy or disclose it to others or use it for 
unauthorized purposes except (1) as otherwise agreed to in writing; (2) where required by applicable law; (3) where 
disclosure is directly related to the care and safety of the research participant; and (4) where disclosure of such information 
is made to a member of the investigator’s team who agrees to hold this information in confidence. 


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Table of Contents 
I. 
LIST OF ABBREVIATIONS AND KEY TERMS ··········································· 4 
1 
INTRODUCTION ·················································································· 7 
2 
STUDY OBJECTIVES AND DESIGN ························································· 7 
2.1 
Study Objectives, Endpoints and Estimands ················································ 7 
2.2 
Study Design ···················································································· 9 
2.3 
Randomization ················································································· 10 
3 
SAMPLE SIZE····················································································· 10 
4 
ANALYSIS SETS ················································································· 10 
4.1 
Safety Analysis Set ··········································································· 10 
5 
EFFICACY AND SAFETY ENDPOINTS ··················································· 10 
5.1 
Exploratory Endpoints ········································································ 10 
5.1.1 
6-minute Walk Test ····································································· 10 
5.1.2 
5 Times Sit To Stand (5XSTS) ························································ 11 
5.1.3 
Quality of Life in Neurological Disorders (Neuro-QoL) ··························· 11 
5.1.4 
Modified Fatigue Impact Scale (MFIS) ··············································· 11 
5.1.5 
Patient Global Impression of Change (PGIC) ········································ 11 
5.1.6 
The Patient Global Impression of Severity (PGIS) ·································· 11 
5.1.7 
European Quality of Life 5-dimension, 5-level questionnaire (EQ-5D-5L) ······ 12 
5.2 
Safety Endpoints ·············································································· 12 
5.2.1 
Treatment Emergent Adverse Events (TEAEs) ······································ 12 
5.2.2 
Vital signs ················································································ 12 
5.2.3 
12-lead Electrocardiogram (ECG) ····················································· 12 
5.2.4 
Echocardiogram (ECHO) ······························································· 13 
5.2.5 
Body Weight ············································································· 13 
5.2.6 
Laboratory test (hematology, biochemistry and urinalysis) ························ 13 
5.2.7 
Columbia-Suicide Severity Rating Scale (C-SSRS) ································ 13 
5.3 
Other Endpoints ··············································································· 14 
5.3.1 
Pharmacokinetics Endpoints ··························································· 14 
5.3.2 
Pharmacodynamics Endpoints ························································· 14 
5.3.3 
Biomarkers ··············································································· 14 
6 
STATISTICAL METHODOLOGY ··························································· 14 
6.1 
General Considerations ······································································· 14 


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6.2 
Study Population ·············································································· 15 
6.2.1 
Disposition of Participants ····························································· 15 
6.2.2 
Protocol Deviations ····································································· 15 
6.2.3 
Demographic and Other Baseline Characteristics ··································· 16 
6.3 
Study Drugs Exposure and Compliance ···················································· 17 
6.4 
Analysis of Efficacy ·········································································· 18 
6.5 
Analysis of Safety ············································································· 18 
6.5.1 
Adverse Events ·········································································· 18 
6.5.2 
Clinical Laboratory Evaluation ························································ 20 
6.5.3 
Vital Signs ················································································ 20 
6.5.4 
Electrocardiograms ······································································ 21 
6.5.5 
Other Safety-Related Assessment ····················································· 21 
6.6 
Other Analyses ················································································ 22 
6.7 
Interim Analysis ··············································································· 22 
6.7.1 
Interim Analysis of Efficacy ··························································· 22 
6.8 
Additional Conventions ······································································ 23 
6.8.1 
Analysis Windows ······································································ 23 
6.8.2 
Imputation Rules for Incomplete Dates ··············································· 24 
6.8.3 
Outliers ··················································································· 24 
7 
REVISION AND RATIONALE ································································ 25 
8 
REFERENCES ···················································································· 25 
9 
APPENDICES ····················································································· 26 
9.1 
Appendix 1: Author and Approver Signatures ············································ 26 
 


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I. 
LIST OF ABBREVIATIONS AND KEY TERMS 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
5XSTS 
5 times sit to stand  
6MWT 
6-minute walk test 
AE 
adverse event 
AESI 
adverse events of special interest 
AIDMC 
Astellas Internal Data Monitoring Committee 
ALDOA 
Aldolase A 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase  
BMI 
body mass index 
Cave, ss 
average plasma concentration at steady state 
CI 
confidence interval 
CK 
creatine kinase 
CK-MB 
creatine kinase isoenzymes found in heart muscle 
CK-MM 
creatine kinase isoenzymes found in skeletal and heart muscle 
CPEO 
Chronic Progressive Externa Ophthalmoplegia 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
cTnI 
cardiac troponin I 
cTnT 
cardiac troponin T 
Ctrough 
concentration immediately prior to dosing at multiple dosing 
CYC 
Cytochrome c 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
EQ-5D 
European Quality of Life 5-dimension questionnaire 
EQ-5D-5L 
European Quality of Life 5-dimension, 5-level questionnaire 
EQ-VAS 
EuroQol visual analogue scale 
FLNC 
Filamin-C 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IP 
investigational product 
ISN 
international study number 
KSS 
Kearns Sayre Syndrome 
MedDRA 
medical dictionary for regulatory activities 
MEGDEL 
3-methylglutaconic aciduria, Deafness, Encephalopathy, and Leigh-
like disease 
MELAS 
Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like 
episodes 
MERRF 
Myoclonic Epilepsy with Ragged Red Fibers 
MIDD 
Maternally Inherited Diabetes Deafness 
MMRM 
mixed effect models for repeated measures 
Neuro-QoL 
Quality of Life in Neurological Disorders 
OLE 
open-label extension 
PD 
protocol deviation 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 


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Abbreviations 
Description of abbreviations 
PMM 
primary mitochondrial myopathy  
POLG 
polymerase-gamma 
PPARδ 
peroxisome proliferator-activated receptor delta 
QTcF 
QT interval using Fridericia’s correction 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SD 
standard deviation 
TEAE 
treatment emergent adverse event 
TLF 
tables, listings and figures 
ULN 
upper limit of normal 
 


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List of Key Terms 
Terms 
Definition of terms 
Baseline 
Assessments of participants as they enter a study before they receive 
ASP0367.  
Endpoint 
Variable that pertains to the efficacy or safety evaluations of a study. 
Enroll 
To register or enter a participant into a study. Note: Once a participant has 
received the investigational product or placebo, the protocol applies to the 
participant.  
Randomization 
The process of assigning participants to treatment or control groups using 
an element of chance to determine assignments in order to reduce bias. 
Screening 
A process of active consideration of potential participants for enrollment 
in a study. 
Screen failure 
Potential participant who signed the informed consent form but did not 
meet one or more criteria required for participation in the study and was 
not enrolled. 
Variable 
Any entity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values. 
 


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1 
INTRODUCTION 
This SAP contains technical and detailed elaboration of the principal features of the analysis 
described in the protocol and includes procedures for executing the statistical analysis to 
fulfil the objectives of the study. 
The study was designed to be, and executed as, a double-blinded with an OLE. The OLE was 
removed from protocol version 9.0 and so the use of the present tense is no longer accurate. 
In addition to the objectives and endpoints defined in Study 0367-CL-1201 protocol (core 
protocol), some additional objectives and endpoints specific to the Mayo Clinic (Minnesota) 
had been defined in Study 0367-CL-1201 [MAYO] Protocol. However, as there have been no 
participants recruited to the protocol from the Mayo sites, therefore there will be no SAP 
created. Until protocol version 7.0, the double-blinded period was 52 weeks and open label 
extension period was 24 weeks. However, from protocol version 8.0 onwards, the double-
blinded period was revised to 24 weeks and in protocol version 9.0 the OLE period was 
removed. Since no participants have been evaluated under protocol version 8.0 or later, two 
SAPs will be prepared: one for analyses up to 52 weeks of treatment (the double-blind part of 
the study), and the other one for analyses at the end of 76 weeks of treatment (the double-
blind part and the OLE part of the study). In this analysis, participants assigned ASP0367 in 
the double-blinded period will be analyzed for through the double-blinded part and the OLE 
part of the study including follow-up visit, while participants switched from Placebo to 
ASP0367 in the OLE part will be analyzed in the OLE part only including follow-up visit. 
This document is an analysis plan for the up to 76 weeks (double-blinded part and OLE part 
of the study) including follow-up visit.  
Analyses for pharmacokinetic and pharmacodynamic (target gene expression and 
biochemical markers) endpoints, including exposure-response assessment, will be described 
in the separate analysis plan and this SAP only focus on safety endpoints. 
This document will be finalized prior to the database lock at the end of study. If there are any 
changes from the planned analyses in the final version of the SAP that impact the statistical 
analyses, then it will be documented in the CSR. 
2 
STUDY OBJECTIVES AND DESIGN 
2.1 
Study Objectives, Endpoints and Estimands 
Objectives 
Endpoints 
Primary 
● 
To assess the dose response of ASP0367 on 
functional improvement relative to placebo 
● 
Change from baseline in distance walked on the 
6MWT at week 24 
● 
To assess the safety and tolerability of 
ASP0367 relative to placebo 
● 
Safety and Tolerability through week 24 and end 
of study: 
o 
Nature, frequency and severity of TEAEs 
o 
Vital signs 
o 
Weight 
o 
12-lead ECG 


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Note: Placebo comparison will be up to 24 weeks and will not include open-label extension. 
5XSTS: 5 Times Sit to Stand; 6MWT: 6-minute walk test; ALDOA: aldolase A; Cave, ss: average plasma 
concentration at steady state; C-SSRS: Columbia-Suicide Severity Rating Scale; Ctrough: concentration 
immediately prior to dosing at multiple dosing; CYC: cytochrome c; ECG: electrocardiogram; EQ-5D-5L: 
European Quality of Life 5-dimension, 5-level questionnaire; EQ-VAS: EuroQol visual analogue scale; FLNC: 
o 
Clinical laboratory tests (hematology, 
biochemistry [including serum cardiac 
troponin I] and urinalysis) 
o 
C-SSRS 
Secondary 
● 
To assess the dose response of ASP0367 on 
functional improvement and fatigue relative 
to placebo 
● 
Change from baseline in Neuro-QoL Short Form 
Fatigue and Lower Extremity Function (Mobility) 
scores at week 24 
● 
Change from baseline in time spent on the 5XSTS 
at week 24 
● 
Change from baseline in MFIS at week 24 
● 
To assess the effect of ASP0367 in overall 
participant functioning relative to placebo 
● 
PGIC scores at week 24 
● 
Change from baseline in PGIS scores at week 24 
Exploratory 
● 
To assess the pharmacokinetics of ASP0367 
● 
Plasma ASP0367: Ctrough at weeks 12 and 24 and 
population pharmacokinetics 
● 
To assess the exposure-response relationship 
of ASP0367 
● 
Relationship between measured- and model-based 
pharmacokinetic exposure parameters (e.g., 
Ctrough, Cave, ss) of ASP0367 and endpoints of 
efficacy, safety and pharmacodynamic 
biomarkers, as appropriate 
● 
To assess the effect of ASP0367 on lower 
extremity function relative to placebo 
● 
Change from baseline in distance walked on the 
6MWT at weeks 4 and 12 
● 
Change from baseline in minute-by-minute 
analyses (i.e., 6th vs 1st) of 6MWT at weeks 4, 12 
and 24 
● 
Change from baseline in time spent on 5XSTS at 
weeks 4 and 12 
● 
Change from baseline in Neuro-QoL Short Form 
Fatigue score at weeks 4 and 12  
● 
Change from baseline in Neuro-QoL Short Form 
Lower Extremity Function (Mobility) score at 
weeks 4 and 12 
● 
Change from baseline in MFIS score at weeks 4 
and 12 
● 
To assess the effects of ASP0367 on quality 
of movement and patient perception of 
change 
● 
PGIC scores at weeks 4 and 12 
● 
Change from baseline in PGIS scores at weeks 4 
and 12 
● 
Change from baseline in EQ-VAS and EQ-5D-5L 
index at weeks 4, 12 and 24 
● 
To assess the relationship between functional 
improvement and biochemical markers, as 
well as gene expression-based 
pharmacodynamic biomarkers 
● 
Change from baseline in the levels of serum and 
urinary biomarkers (serum FLNC, CYC, ALDOA 
and urinary TITIN) at weeks 12 and 24  
● 
Relative change from baseline of whole blood 
PPARδ target gene expression levels at weeks 12 
and 24† 


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filamin-C; MFIS: Modified Fatigue Impact Scale; Neuro-QoL: Quality of Life in Neurological Disorders; 
PGIC: Patient Global Impression of Change; PGIS: Patient Global Impression of Severity; PPARδ: peroxisome 
proliferator-activated receptor delta; TEAE: treatment emergent adverse event. 
†Blood samples will be collected and stored appropriately over the course of the study and then analyzed. 
Estimands 
Primary estimand will be defined by the following 5 attributes:  
● 
Treatment: ASP0367 or placebo 
● 
Population: Participants with PMM, as defined by the inclusion/exclusion criteria of the 
study. 
● 
Endpoint: Change from baseline in distance walked on the 6MWT at week 24. 
● 
Intercurrent events and their corresponding strategies (see table below). 
● 
Population level summary: Difference in change from baseline in distance walked on the 
6MWT at week 24 between ASP0367 group and placebo group. 
 
Intercurrent Events 
Strategies to Handle Intercurrent Events 
Treatment 
Discontinuation Due to 
Any Reason 
For those participants who discontinued treatment, all observations after 
treatment discontinuation (Date of Last Study Drug Taken + 7 days) will 
be ignored. Analysis will be conducted assuming those participants 
remained assigned treatment and the condition that was observed before 
treatment discontinuation will continue, i.e., hypothetical strategy.  
Study Discontinuation 
For those participants who discontinued study, all observations after 
treatment discontinuation (Date of Last Study Drug Taken + 7 days) will 
be ignored. Analysis will be conducted assuming those participants 
remained assigned treatment and the condition that was observed before 
treatment discontinuation will continue, i.e., hypothetical strategy. 
Prohibited 
Concomitant Treatment 
Use 
For those participants who used the prohibited concomitant medication 
treatment, all observations will be included in the analysis, i.e., treatment 
policy strategy. 
 
2.2 
Study Design 
This is a randomized, double-blind, placebo-controlled, oral dose, phase 2 study to evaluate 
the dose response of ASP0367 on functional improvement relative to placebo, safety and 
tolerability in participants with PMM. Efficacy (i.e., functional improvement) will be 
assessed by a functional motor test, 6MWT. The study consists of the following portions: 
screening (4 weeks); double-blind treatment period with 2 doses of ASP0367 vs matching 
placebo (24 weeks); and follow-up (4 weeks).  
A 24-week treatment analysis of efficacy and safety will be the primary focus of this study. 
Since participants enrolled and participated in the study prior to implementation of protocol 
version 9.0, which removes the 52-week OLE period, they may have a treatment duration of 
up to 76 weeks, a separate analysis will be conducted up to 76 weeks and follow-up as per 
available data. 


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2.3 
Randomization 
Approximately 66 participants will be enrolled. At randomization, participants will be 
randomly placed into 1 of 3 arms (30 mg ASP0367, 75 mg ASP0367 or placebo; n = 22 for 
each arm) at a ratio of 1:1:1. Stratified randomization by site group (2 level: Mayo 
clinic_Minnesota; Non-Mayo clinic_Minnesota) will be applied, if there are any participants 
from in the Mayo site group. 
3 
SAMPLE SIZE 
The sample size of this study was determined from feasibility and statistical perspectives. 
From the statistical perspective, 57 participants (19 participants in each group) will provide 
> 80% power to detect a difference of 45 meters in 6MWT between ASP0367 and placebo at 
a 2-sided significance level of 0.10 assuming a common standard deviation of 55.0 meters.  
The 45-meter difference in 6MWT under the 24-week treatment is assumed based on the 
results of the MMPOWER-2 study of elamipretide [Cohen et al, 2018]. 
Considering the interim analysis, 60 participants will be required to maintain > 80% power in 
the efficacy analysis, and assuming an approximately 10% study discontinuation (drop out) 
rate during the double-blind treatment period, 66 participants are required to be randomized. 
This sample size supports an evaluation of proof of concept. 
4 
ANALYSIS SETS 
In accordance with ICH recommendations in guidelines E3 and E9, the following analysis 
sets will be used for the analyses. 
4.1 
Safety Analysis Set 
The SAF consists of all participants who receive at least 1 dose of ASP0367. The SAF only 
includes participants who were randomly assigned to ASP0367 in DB part or participants 
who were randomly assigned to placebo in the DB part and continued into the OLE part. 
Participants who were randomly assigned to placebo and discontinued the study in the DB 
part are not included in the SAF, even if they erroneously received ASP0367 during the DB 
part. 
The SAF will be used for all summaries of the safety data. 
5 
EFFICACY AND SAFETY ENDPOINTS  
5.1 
Exploratory Endpoints 
5.1.1 
6-minute Walk Test 
The 6MWT will be performed indoors, along a long, flat, straight, enclosed corridor with a 
hard surface that is seldom traveled. The total distance walked by a participant, as well as 
distance per minute will be calculated by rounding to the nearest meter and recorded. The 
6MWT will be video recorded for quality purposes. 


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Participants will be asked to wear comfortable clothing and appropriate shoes for walking. A 
light meal is acceptable before early morning or early afternoon tests. Participants will be 
recommended not to have exercised within 2 hours prior to beginning of the test. A “warm 
up” period before the test will not be performed. Participants will sit at rest in a chair located 
near the starting position for at least 10 minutes before the test starts. The test will be 
performed at weeks 0, 4, 12, 24, 36, 52, 64 and 76. 
5.1.2 
5 Times Sit To Stand (5XSTS)    
For the 5XSTS, the participant will be instructed to sit with arms folded across their chest 
and with back against the chair and will be asked to stand up and sit down 5 times in a row, 
as quickly as he/she can. The instructor will make sure that the participant will stand up fully 
and try not to let his/her back touch the chair between each repetition. The duration from the 
time instructor indicates “Go” until the time participant’s body touches the chair following 
the fifth repetition will be recorded. If participant is unable to complete the first sit to stand 
independently, without use of arms, the test will be terminated. The test will be performed at 
weeks 0, 4, 12, 24, 36, 52, 64 and 76. 
5.1.3 
Quality of Life in Neurological Disorders (Neuro-QoL)  
The Neuro-QoL is a measurement system that evaluates and monitors the physical, mental 
and social effects experienced by adults and children living with neurological conditions. 
Participants will report Neuro-QoL Item Bank v1.0 Fatigue Short Form and Lower Extremity 
Function (Mobility) Short Form, which consists of 8 items each. Neuro-QoL will be 
performed at weeks 0, 4, 12, 24, 36, 52, 64 and 76. 
5.1.4 
Modified Fatigue Impact Scale (MFIS)   
The Modified Fatigue Impact Scale (MFIS) is a modified form of the Fatigue Impact Scale. 
The questionnaire specifically measures how fatigue impacts the lives of those affected by 
fatigue-like symptoms.  
There are 21 items in the scale measuring 3 domains of fatigue including physical, cognitive 
and psychosocial functioning. MFIS will be performed at weeks 0, 4, 12, 24, 36, 52, 64 and 
76. 
5.1.5 
Patient Global Impression of Change (PGIC)   
The Patient Global Impression of Change (PGIC) scale evaluates the participant’s most 
bothersome symptom and assesses if there has been an improvement or decline in clinical 
status. The participant will rate his/her change on a 7-point scale. The PGIC score will be 
evaluated at weeks 4, 12, 24, 36, 52, 64 and 76. 
5.1.6 
The Patient Global Impression of Severity (PGIS) 
The Patient Global Impression of Severity (PGIS) is a questionnaire designed to assess 
patient’s impression of disease severity. The questionnaire asks the participant to best 
describe the severity of the participant’s most bothersome pre-defined symptom over the past 
week. The PGIS score will be assessed at weeks 0, 4, 12, 24, 36, 52, 64 and 76. 


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5.1.7 
European Quality of Life 5-dimension, 5-level questionnaire (EQ-5D-5L) 
The EQ-5D-5L is a brief, generic health-related quality of life assessment that can also be 
used to incorporate participant preferences into health economic evaluations. The EQ-5D-5L 
descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 response levels: no problems, 
slight problems, moderate problems, severe problems and extreme problems/unable to 
perform the activity.  In addition, it does record the patient’s self-rated health on a vertical 
visual analogue scale with response options ranging from 0 (worst imaginable health) to 100 
(best imaginable health). The EQ-5D-5L will be assessed at weeks 0, 4, 12, 24, 36, 52, 64 
and 76. 
5.2 
Safety Endpoints 
5.2.1 
Treatment Emergent Adverse Events (TEAEs) 
AE collection begins after the ICF has been signed and continues until the follow up visit or 
28 days after the final IP administration or when the participant is determined to be a screen 
failure. A TEAE is defined as an AE observed after starting administration of the ASP0367 to 
28 days after the last dose of ASP0367.   
An IP-related TEAE is defined as any TEAE with a causal relationship of “yes” by the 
investigator.  
5.2.2 
Vital signs 
Vital signs including blood pressure, pulse rate and body temperature will be assessed at each 
visit scheduled in the protocol. 
5.2.3 
12-lead Electrocardiogram (ECG) 
● 
A standard 12-lead ECG will be conducted using both a central ECG reading laboratory 
and local ECG reading. ECGs at weeks 2 and 8 will be performed at the participant’s 
home by a qualified healthcare provider from the home healthcare vendor. In case the 
home healthcare visit is not feasible, the visit can be conducted at the study site. 
● 
ECGs will be recorded in triplicate (3 separate ECGs, 5 minutes resting prior to first 
ECG and at least 1 minute apart per time point), prior to blood draw and transmitted 
electronically for central reading. The mean of the triplicate ECG from central and local 
read should be used for treatment decisions and AE reporting.  
● 
If the mean triplicate QTcF is > 500 msec at any time point, one follow-up triplicate 
ECG may be performed on the same day. If the follow-up mean QTcF is ≤ 500 msec, the 
participant may proceed with IP. If the follow-up mean QTcF > 500 msec is confirmed, 
then the participant must discontinue IP.  
● 
An ECG will also be performed within 24 hours of any of these events: an elevation of 
cTnI above the ULN (see Appendix 10.9 in the protocol for reference range), or when 
there is an elevation of cTnT above the ULN (see Appendix 10.9 in the protocol for 
reference range) or above the participant’s baseline value if it was elevated, or when a 
participant has any signs or symptoms reflecting cardiac involvement, inclusive of new 
onset shortness of breath. If the ECG is within normal limits, a repeat of the abnormal 
troponin value (cTnI or cTnT) should be obtained. For any of the situations above, it 


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may be required to interrupt or discontinue further administration of IP. Participants with 
persistent cTnI or cTnT elevations, abnormal ECG or abnormal echocardiogram should 
undergo cardiology follow up. 
The requirement to perform an ECG after elevations observed in Troponin T was not added 
to the protocol until version 9.0. Therefore, this ECG requirement related to cTnT elevation 
was not implemented as all participants enrolled under and participated in the protocol 
version 7.0 or earlier. 
5.2.4 
Echocardiogram (ECHO) 
A local echocardiogram is to be performed within 24 hours of any of these events: an 
elevation of cTnI above the ULN (see Appendix 10.9 in the protocol for reference range), or 
when there is an elevation of cTnT above the ULN (see Appendix 10.9 in the protocol for 
reference range) or above the participant’s baseline value if it was elevated, or when a 
participant has any signs or symptoms reflecting cardiac involvement, inclusive of new onset 
shortness of breath. If the echocardiogram is within normal limits, a repeat of the abnormal 
troponin value (cTnI or cTnT) should be obtained. For any of the situations above, it may be 
required to interrupt or discontinue further administration of IP. Participants with persistent 
cTnI or cTnT elevations, abnormal ECG or abnormal echocardiogram should undergo 
cardiology follow up.  
The requirement to perform an ECHO after elevations observed in Troponin T was not added 
to the protocol until version 9.0. Therefore, this ECHO requirement related to cTnT elevation 
was not implemented as all participants enrolled under and participated in the protocol 
version 7.0 or earlier.  
5.2.5 
Body Weight 
Body weight is planned to be collected at each visit scheduled in the protocol. 
5.2.6 
Laboratory test (hematology, biochemistry and urinalysis) 
Safety laboratory tests will be done by a central laboratory from the screening to the end of 
the study. The scheduled visit and the list of clinical laboratory tests are described in the 
protocol.  
5.2.7 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS will be performed by trained site staff via interview at screening, 
randomization, and all subsequent study visits. At screening, the “Screening” version is to be 
used to determine eligibility.  During all subsequent visits, the “Since Last Visit” version is 
used to monitor on study suicidal ideation and behavior after the initial assessment. If 
possible, continuity of raters should be maintained across visits for each patient. The 
following five questions regarding suicidal ideation, six questions regarding suicidal behavior 
and question for non-suicidal self-injurious behavior will be used for analysis. 
● 
Suicidal Ideation ('Yes' to any one of the below 5 questions for suicidal ideation) 
o Wish to be Dead (No/Yes) 
o Non-Specific Active Suicidal Thoughts (No/Yes) 


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o Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
(No/Yes) 
o Active Suicidal Ideation with Some Intent to Act, without Specific Plan (No/Yes) 
o Active Suicidal Ideation with Specific Plan and Intent (No/Yes) 
● 
Suicidal Behavior ('Yes' to any one of the below 5 questions for suicidal behavior) 
● 
Preparatory Acts or Behavior (No/Yes) 
o Aborted Attempt (No/Yes) 
o Interrupted Attempt (No/Yes) 
o Actual Attempt (No/Yes) 
o Completed Suicide (No/Yes) 
● 
Suicidal Ideation or Behavior ('Yes' to any one of the above 10 questions for suicidal 
ideation and behavior) 
● 
Self-injurious Behavior Without Suicidal Intent (No/Yes) 
5.3 
Other Endpoints 
5.3.1 
Pharmacokinetics Endpoints 
Relationship between measured- and model-based pharmacokinetic exposure parameters 
(e.g., Ctrough, Cave, ss) of ASP0367 and endpoints of efficacy, safety and pharmacodynamic 
biomarkers, as appropriate. 
5.3.2 
Pharmacodynamics Endpoints 
Blood samples for PPARδ target gene expression assay 
5.3.3 
Biomarkers 
Urine samples for TITIN 
Blood samples for serum target proteins (ALDOA, CYC and FLNC) 
6 
STATISTICAL METHODOLOGY 
6.1 
General Considerations 
Continuous data will be summarized descriptively including the number of participants (n), 
mean, standard deviation (SD), median, minimum and maximum.  Categorical data will be 
summarized by frequencies and percentages. Percentages by categories will be based on the 
number of participants with no missing data, i.e. the percentages for the non-missing 
categories will add up to 100%. 
There are 2 different groups defined based in the randomization group: 
● 
ASP0367 any dose group: Participants randomly assigned to ASP0367. 
● 
Placebo to ASP0367 group: Participants randomly assigned to placebo and who continue 
into the OLE and receive ASP0367. 
Safety analysis and other summaries based on SAF will be presented by analysis group 
(ASP0367 any dose group or Placebo to ASP0367 group), unless specifically stated 
otherwise.  


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All data summarization and analyses will be performed using SAS® Version 9.4 or higher on 
Linux. Specifications for table, figures, and data listing formats can be found in the TLF 
specifications. 
For continuous variables that are recorded as “<X”, “<=X”, “>X”, or “>=X”, the value of 
“X” will be used in the calculation of summary statistics if otherwise noted. This approach 
may result in a summary that reflects the presence of an analyte (such as troponin) when in 
fact the analyte was not detected but reported as less than the lower limit of detection by the 
assay. 
6.2 
Study Population 
6.2.1 
Disposition of Participants 
The following participant data will be presented: 
Analysis population: All participants who complete double blind part, Analysis group: 
ASP0367 any dose group, Placebo to ASP0367 group and Total 
● 
Number and percentage of participants who were administered at least one dose of study 
drug during the OLE part, 
● 
Number and percentage of participants who completed and those who discontinued the 
treatment during the OLE part, by primary reason for treatment discontinuation, 
● 
Number and percentage of participants who completed and those who discontinued the 
follow-up period, by primary reason for follow-up discontinuation. 
6.2.2 
 Protocol Deviations 
Analysis population: All randomized participants who took ASP0367, Analysis group: 
ASP0367 any dose group, Placebo to ASP0367 group and Total 
The number and percentage of participants with the following protocol deviation criteria 
(defined as an important protocol deviation) will be summarized for each criterion and 
overall, by treatment group and total as well as by investigative site. Participants deviating 
from a criterion more than once will be counted only once for the corresponding criterion. 
The unique identifiers will be as follows: 
PD1 - Inclusion/Exclusion,  
PD2 - Withdrawal Criteria, 
PD3 - Study Intervention, 
PD4 - Excluded Concomitant Medications, 
PD5 - Informed Consent, 
PD6 - Safety Reporting, and 
PD7 - Procedures/Tests 


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6.2.3 
Demographic and Other Baseline Characteristics 
Analysis population: SAF, Analysis group: ASP0367 any dose group, Placebo to ASP0367 
group and Total 
● 
Demographic and other baseline characteristics (age, sex, race and ethnicity, body 
weight, height and BMI) will be summarized by descriptive statistics and frequency 
tabulations [Table 1].  
Table 1 
Demographic and baseline characteristics 
Item 
Classification 
Sex 
1: Male 
2: Female 
Age (Years) [Informed Consent] 
Measurement value 
Age 
1: >=18 to <65 
2: >=65 to <=80 
Ethnicity 
1: Not Hispanic or Latino 
2: Hispanic or Latino 
Race 
1: White 
2: Black or African American 
3: Asian 
4: American Indian or Alaska Native 
5: Native Hawaiian or Other Pacific Islander 
6: Other 
Height (cm) [Screening] 
Measurement value 
Weight (kg) [Screening] 
Measurement value 
BMI (kg/m^2) [Screening] 
Measurement value 
BMI 
1: < 25 
2: >=25 
Site Group 
1: Mayo clinic_Minnesota  
2: Non-Mayo clinic Minnesota 
Walking aid use [Baseline†] 
0: No 
1: Yes 
Duration of disease (Years)‡ 
Measurement value 
Treated with medication [Screening] 
0: No 
1: Yes 
Syndrome 
1: Kearns Sayre Syndrome (KSS) 
2: Mitochondrial Encephalomyopathy, Lactic Acidosis and 
Stroke-like episodes (MELAS) 
3: Maternally Inherited Diabetes Deafness (MIDD) 
4: Myoclonic Epilepsy with Ragged Red Fibers (MERRF) 
5: Chronic Progressive Externa Ophthalmoplegia (CPEO) 
6: 3-methylglutaconic aciduria, Deafness, Encephalopathy, 
and Leigh-like disease (MEGDEL) 
7: Leigh Syndrome 
8: Multisystem mitochondrial disorder 
9: Mitochondrial Myopathy 
10: POLG-related disorders 
11: Others 
Genetic abnormality 
1: Mitochondrial DNA 
2: Nuclear DNA 
Mitochondrial DNA mutant heteroplasmy 
information is available 
0: No 
1: Yes 
Level of heteroplasmy (%) 
Measurement value 
BMI: body mass index; CPEO: Chronic Progressive Externa Ophthalmoplegia; KSS: Kearns Sayre Syndrome; 


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MEGDEL: 3-methylglutaconic aciduria, Deafness, Encephalopathy, and Leigh-like disease; MELAS: 
Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes; MERRF: Myoclonic Epilepsy 
with Ragged Red Fibers; MIDD: Maternally Inherited Diabetes Deafness; POLG: polymerase-gamma. 
†: For participants received ASP0367 on double blind part, the measurement at week 0 will be used as baseline, 
and for participants received placebo on double blind part, the measurement at week 52 will be used as baseline. 
‡: Duration of disease will be calculated as follows: 
[(“Date of First Study Drug Taken” – “Date of Diagnosis”) + 1] / 365.25. 
If Date of Diagnosis is missing or incomplete, then impute the date following the rule stated in [Section 6.8.2]. 
6.3 
Study Drugs Exposure and Compliance 
Analysis population: SAF, Analysis group: ASP0367 any dose group or Placebo to ASP0367 
group 
● 
The duration of ASP0367 exposure for each participant will be summarized by 
descriptive statistics and frequency tabulations. The following categories of the duration 
of exposure (days) will be defined: 
o < 29 (4 weeks) 
o >= 29 (4 weeks) to < 85 (12 weeks) 
o >= 85 (12 weeks) to < 169 (24 weeks) 
o >= 169 (24 weeks) to < 253 (36 weeks) 
o >= 253 (36 weeks) to < 365 (52 weeks) 
o >= 365 (52 weeks) to < 449 (64 weeks) 
o >=449 (64 weeks) to  <533 (76 weeks) 
o >=533 (76 weeks) 
The duration of ASP0367 exposure will be calculated as follows: {“Date of Last Study Drug 
Taken” – “Date of First ASP0367 Taken*”} + 1. 
Date of Last Study Drug Taken is defined as the latest date of [“Date of Last Study Drug 
Taken (Phase 2 Treatment Period)”, “Date of Last Study Drug Taken (Dose selection 
Period)”, or “Date of Last Study Drug Taken (Open-Label Extension Part)”]. 
*: For participants received ASP0367 on double blind part, “Date of First Study Drug Taken” 
will be used. For participants received placebo on double blind part, “Date of First Study 
Drug Taken (Open-Label Extension Part)” will be used. 
● 
The compliance of ASP0367 exposure for each participant will be summarized by 
descriptive statistics and frequency tabulations. The following categories of the study 
drug compliance (%) will be defined: 
o < 50 
o >= 50 to < 75 
o >= 75 to < 90 
o >= 90 
o Unknown 
The compliance of study drug exposure for ASP0367 any dose group will be calculated as 
follows: 


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Total number of dispensed tablets of ASP0367 - Total number of returned tablets of ASP0367
The number of tablets of ASP0367 to be taken
×100 
The number of tablets to be taken is defined as follows; 
[{“Date of Last Study Drug Taken” – “Date of First Study Drug Taken”} + 1] x the 
number of tablets per day. 
The compliance of study drug exposure for Placebo to ASP0367 arm will be calculated as 
follows: 
Total number of dispensed tablets in OLE part - Total number of returned tablets in OLE part
The number of tablets to be taken in OLE part
×100 
The number of tablets to be taken in OLE part is defined as follows; 
[“Date of Last Study Drug Taken (Open-Label Extension Part)” – “Date of First Study Drug 
Taken (Open-Label Extension Part)” + 1] x the number of tablets per day. 
6.4 
Analysis of Efficacy  
No efficacy analyses will be conducted in this OLE SAP. 
6.5 
 Analysis of Safety 
Analysis population: SAF, Analysis group: ASP0367 any dose group or Placebo to ASP0367 
group 
6.5.1 
 Adverse Events 
AEs will be coded using the MedDRA.   
An overview table will include the following: 
● 
Number of TEAEs, 
● 
Number and percentage of participants with TEAEs, 
● 
Number of drug related TEAEs, 
● 
Number and percentage of participants with drug related TEAEs, 
● 
Number of serious TEAEs, 
● 
Number and percentage of participants with serious TEAEs, 
● 
Number of serious drug related TEAEs, 
● 
Number and percentage of participants with serious drug related TEAEs, 
● 
Number of TEAEs leading to death, 
● 
Number and percentage of participants with TEAEs leading to death, 
● 
Number of drug related TEAEs leading to death, 
● 
Number and percentage of participants with drug related TEAEs leading to death, 
● 
Number of TEAEs leading to withdrawal of study drug, 
● 
Number and percentage of participants with TEAEs leading to withdrawal of study drug, 
● 
Number of drug related TEAEs leading to withdrawal of study drug, 
● 
Number and percentage of participants with drug related TEAEs leading to withdrawal 
of study drug, and 


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● 
Number of deaths. 
The number and percentage of participants with TEAEs, as classified by SOC, and PT will be 
summarized by analysis group. Summaries will be provided for the following: 
● 
TEAEs, 
● 
drug related TEAEs,  
● 
serious TEAEs,  
● 
drug related serious TEAEs,  
● 
TEAEs leading to withdrawal of study drug,  
● 
drug related TEAEs leading to withdrawal of study drug,  
● 
TEAEs excluding Serious AEs that equal to or exceed a threshold of 5.0% in any 
analysis group. 
The number of TEAEs and the number and percentage of participants with TEAEs, as 
classified by SOC and PT will be summarized by severity and by relationship to study drug. 
In the participant count, if a participant has multiple TEAEs with the same SOC or PT, but 
with differing severity or relationship, then the participant will be counted once with the 
worst severity and highest degree of relationship. If severity or relationship is missing for all 
episodes of the event, the participant will be counted under missing severity or relationship.  
The following AESIs are defined: 
● 
Cardiac tissue injury defined by cTnI above ULN or if the cTnT is above ULN or 
baseline if the participant’s baseline value was above ULN and a TEAE as pre-defined 
by a MedDRA search strategy for elevated troponin. 
● 
Cardiac tissue injury with any signs or symptoms defined by an echocardiogram or 
electrocardiogram interpretation is reported as abnormal, clinically significant and a 
TEAE as pre-defined by a MedDRA search strategy for cardiac complaints. 
● 
Skeletal muscle injury defined by CK increase >= 5 times the value of the ULN or the 
individual’s baseline value, whichever is higher and a TEAE as pre-defined by a 
MedDRA search strategy for skeletal muscle injury. 
AESIs prior to version 9.0 of the protocol did not include elevations in cTnT in the definition 
of an AESI but instead only included elevations of cTnI. All participants participated in 
protocol version 7.0 or earlier; therefore participants for whom elevations in cTnT were 
observed may not have been identified as having experienced an AESIs during study conduct 
and for this reason may not have had additional ECG and echocardiographic evaluations 
performed. 
The number and percentage of participants who report AESIs will be summarized by analysis 
group. In addition, any (serious) AEs that are considered abuse of the study drug will also be 
collected and followed. The number and percentage of AEs of special interest related to 
abuse, as classified by SOC and PT will be summarized by analysis group. 


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6.5.2 
Clinical Laboratory Evaluation 
Quantitative values including hematology, biochemistry, and urinalysis will be summarized 
using mean, standard deviation, minimum, maximum and median by analysis group at each 
analysis visit. Additionally, a within-participant change will be calculated as the post-
baseline measurement minus the baseline measurement and summarized in the same way. 
Each laboratory result will be classified as low (L), normal (N), or high (H) at each visit 
according to the site supplied reference ranges. For the Placebo and ASP0367 groups, 
baseline values for CK-MM and CK-MB will be defined as the last non-missing observation 
prior to the first administration of ASP0367. 
Frequency tabulations of qualitative clinical laboratory variables (urinalysis) will be 
presented for each analysis group at each visit. 
Additionally, amylase, lipase and troponin elevations above the ULN and 2xULN will be 
summarized by analysis group. The denominator for each criterion will be the number of 
participants who have at least one value after the day of first ASP0367 taken to 28 days after 
the last dose of ASP0367. The number and percentage of participants meeting the criteria by 
28 days after the last dose of ASP0367 will be summarized by analysis group. 
6.5.2.1 Liver Safety Assessment  
The liver safety assessments will be summarized by the categories below based on the 
measurements from ALP, ALT, total bilirubin, AST and their combination. These parameters 
will be based on measurements from a local laboratory. If the baseline value is above ULN 
then use the baseline value instead of ULN. 
● 
ALT > ULN, > 2xULN, > 3xULN, > 5xULN, > 10xULN, > 20xULN 
● 
AST > ULN, > 2xULN, > 3xULN, > 5xULN, > 10xULN, > 20xULN 
● 
ALT or AST > ULN, > 2xULN, > 3xULN, > 5xULN, > 10xULN, > 20xULN 
● 
ALP > 1.5xULN, 2xULN, 2.5xULN 
● 
Total Bilirubin > 2xULN 
● 
(ALT or AST > 3xULN) and Total Bilirubin > 2xULN 
● 
(ALT or AST > 3xULN) and ALP < 2xULN and Total Bilirubin > 2xULN 
The last 2 criteria where 2 or more parameters are evaluated will be with the measurements 
on the same day or up to 1 day apart. 
The denominator for each criterion will be the number of participants who have at least one 
value after the day of first ASP0367 taken to 28 days after the last dose of ASP0367. The 
number and percentage of participants meeting the criteria by 28 days after the last dose of 
ASP0367 will be summarized by analysis group. 
6.5.3 
Vital Signs 
Vital signs (systolic blood pressure, diastolic blood pressure, and pulse rate) will be 
summarized using mean, standard deviation, minimum, maximum and median by analysis 
group and visit. Additionally, a within- participant change will be calculated per visit as the 


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post-baseline measurement minus the baseline measurement and summarized by analysis 
group and visit. 
6.5.4 
Electrocardiograms  
6.5.4.1 Routine 12-lead Electrocardiograms 
The number and percent of participants with normal, not clinically significant abnormal, and 
clinically significant abnormal results as assessed by site principal investigator for the 12 lead 
ECG will be tabulated by analysis group and time point. Continuous 12-lead 
Electrocardiogram. 
For all analyses, replicates at each visit will be averaged for each continuous ECG parameter.  
ECG parameters [Heart Rate (bpm), PR Interval (ms), QRS Interval (ms) and QTcF (ms)] 
read by the central laboratory will be summarized using mean, standard deviation, minimum, 
maximum and median for each analysis group at each visit, including changes from baseline. 
The QTcF interval will be summarized using frequency tables for each visit for values of 
clinical importance using the range criteria below. 
 
QTcF Interval Criteria Value (msec)  
Normal 
Borderline 
Prolonged 
Clinically significant 
≤ 450 
> 450  
> 480  
> 500 
QTcF: QT interval using Fridericia’s correction. 
The QTcF interval will also be summarized by the frequencies of participants with an 
increase from baseline of clinical importance using the criteria identified below. These 
summaries will be provided for each visit. 
Variable 
Change from Baseline  
QTcF Interval (msec) 
≤ 30 
> 30 
> 60  
QTcF: QT interval using Fridericia’s correction. 
6.5.5 
Other Safety-Related Assessment 
6.5.5.1 Body Weight 
Body weight will be summarized using mean, standard deviation, minimum, maximum and 
median by analysis group and visit. Additionally, a within-subject change will be calculated 
per visit as the post-baseline measurement minus the baseline measurement and summarized 
by analysis group. For Placebo to ASP0367 group, the measurement at week 52 is used as 
baseline, and for ASP0367 Any Dose, the measurement at Screening is used as baseline. 


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6.5.5.2 C-SSRS 
The results of five questions regarding suicidal ideation, six questions regarding suicidal 
behavior, suicidal ideation or behavior and self-injurious behavior without suicidal intent will 
be summarized using number and percent of participants by analysis group at each visit.  
6.6 
Other Analyses 
No analyses will be conducted. 
6.7 
Interim Analysis  
6.7.1 
Interim Analysis of Efficacy 
The analysis of futility and of efficacy was performed when the first 33 participants 
completed the efficacy evaluation at week 24 or discontinued as of date the last participant 
had the week 24 visit, 20-Nov-2023. The change from baseline in distance walked on the 
6MWT at week 24 was analyzed using the same MMRM as with the primary endpoint 
excluding the site group from the model to decide whether the study will continue.  
Analysis of Futility 
For the futility stop, the study may be stopped if the conditional probability of achieving the 
criteria below at the final analysis is less than 10%. 
Criteria: Lower limit of the 90% CI for the difference is greater than 0 m AND the point 
estimate of the difference between the ASP0367 75 mg group and the placebo group is 
greater than 30 m. 
In addition to 6MWT at week 24, outputs for participant disposition, demographics and the 
secondary endpoints 5XSTS, Neuro-QoL Short Form Fatigue score, Neuro-QoL Short Form 
Lower Extremity Function (Mobility) score, MFIS, PGIC, and PGIS at week 24 were 
analyzed at the interim analysis.  
Analysis of Efficacy 
For the efficacy stop, a two-stage group sequential design with Lan-DeMets alpha-spending 
function determined by means of the O'Brien-Fleming approach was used to preserve the 
overall two-sided type I error rate of 0.10 between this single interim analysis and the final 
analysis. If the p-value of the comparison between ASP0367 75 mg and placebo groups at 
interim analysis is lower than the boundary determined by O'Brien-Fleming approach, 
efficacy would be considered to be achieved at week 24. 
The interim analysis outputs were prepared by an external statistician and presented to the 
AIDMC who made recommendations about the ongoing conduct of the study. After the 
AIDMC reviewed the interim analysis results, the AIDMC recommended the study to be 
stopped because the results of the interim analysis met the criteria for futility. Details of the 
analysis were defined in the interim analysis plan. 


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6.8 
Additional Conventions 
6.8.1 
Analysis Windows 
Day 1 and Day -1 are defined as the day of start taking the IP and its prior day, respectively. 
The following analysis window will be used. The data summary by visits will be done 
following the analysis windows specified in the table below: 
Analysis Visits 
Scheduled Day in 
Protocol 
Analysis Windows (day) 
Screening 
Day -28 
-35 to -14 
Week 0 
Day -2 to 1  
-2 to 1 
Week 1 
Day 8 
5 to 13 
Week 2 
Day 14 
14 to 18 
Week 3 
Day 22 
19 to 25 
Week 4 
Day 29 
26 to 42 
Week 8 
Day 57 
43 to 70 
Week 12 
Day 85 
71 to 98 
Week 16 
Day 113 
99 to 126 
Week 20 
Day 141 
127 to 154 
Week 24 
Day 169 
155 to 182 
Week 28 
Day 197 
183 to 210 
Week 32 
Day 225 
211 to 238 
Week 36 
Day 253 
239 to 266 
Week 40 
Day 281 
267 to 294 
Week 44 
Day 309 
295 to 322 
Week 48 
Day 337 
323 to 350 
Week 52 
Day 365 
351 to 378 
Week 56 
Day 393 
379 to 406 
Week 60 
Day 421 
407 to 434 
Week 64 
Day 449 
435 to 462 
Week 68 
Day 477 
463 to 490 
Week 72 
Day 505 
491 to 518 
Week 76 
Day 533 
519 to 560 
End of Treatment 
Day 533 
2 to 560 
Follow-up 
The last dose + 28 
days 
The last dose + 28 days to the last dose + 
35 days 
For all analysis visits excluding follow-up visit, the data “by the last dose + 7 days” will be 
included. 
For participants who received ASP0367 on the double blind part, all analysis visits will be 
used. For participants received placebo on the double blind part, baseline and analysis visit at 
and after the first ASP0367 taken will be used.  
If more than one observation exists within the analysis window, the observation closest to the 
scheduled visit day will be selected for that visit. If there are two observations that have the 
same distance from the scheduled day, the value that is after the scheduled day will be 
selected in the analysis. If more than one observation is made on the same day, an average 
value if continuous or the worst value if categorical will be included in the analysis. 


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For Placebo to ASP0367 group, the measurement at week 52 is used as baseline, and for 
ASP0367 groups, the measurement at week 0 is used as baseline, unless otherwise specified. 
6.8.2 
Imputation Rules for Incomplete Dates 
For AEs, a missing or incomplete onset date will be imputed according to the following 
conventions. 
If an onset date is missing, the imputed onset date will be the date of first dose of study drug. 
If only the year is known for the AE onset date, the imputed onset date will be the latest of 
the following non-missing dates: 
● 
Date of first dose of study drug  
● 
January 1 of the year of AE onset date  
If only the month and year is known for the onset date, set the surrogate onset date to the first 
day of that month and then apply the following rules. 
● 
If the month and year of the onset date is prior to the month and year of the first dose of 
study drug, then the surrogate onset date will be the imputed onset date. 
● 
If the month and year of the onset date is on or after the month and year of the first dose 
of study drug, then the imputed onset date will be the latest of the following non-missing 
dates: 
● 
Date of first dose of study drug 
● 
Surrogate onset date 
● 
If the imputed onset date is after the AE end date, the imputed onset date will be the 
same as the AE end date. 
For duration of disease of primary diagnosis, a missing or incomplete diagnosis date will be 
imputed according to the following conventions. 
If a diagnosis date is missing, the diagnosis date will not be imputed. The duration of disease 
in baseline analysis will be treated as missing data.  
If only the year is known for the diagnosis date, the imputed diagnosis date will be January 1 
of the year of the diagnosis date. 
If only the month and year is known for the diagnosis date, set the imputed diagnosis date 
will be the first day of that month. 
6.8.3 
Outliers 
All values will be included in the analyses. 
 
 


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7 
REVISION AND RATIONALE 
Version 
Date 
Changes 
Comment/rationale for change 
1.0 
09-JUL-2024 
NA 
Document finalized 
 
8 
REFERENCES 
Cohen B, Karaa A, Haas R, Goldstein A, Vockley G. Effects of Elamipretide in Adults with Primary 
Mitochondrial Myopathy: a Phase 2 Double-Blind, Randomized, Placebo-Controlled Crossover 
Trial (MMPOWER-2). Neurology. 2018;90(Suppl 15):S5.003. 
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics) 
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics)