Clinical trial NCT03214588
Conditions: Friedreich Ataxia
Keywords: Drug Therapy
Sponsor: Neurocrine Biosciences
Start date: 2017-11-08; Completion date: 2018-12-27
Enrollment: 67 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy of TAK-831 versus placebo on upper extremity (arm and hands) motor function and manual dexterity. This study will also evaluate the efficacy of TAK-831 versus placebo on activities of daily living (ADL) and other secondary assessments.

Detailed description:
The drug being tested in this study is called TAK-831. TAK-831 is being tested to treat people who have Friedreich ataxia. This study will look at upper extremity (arms and hands) motor function and manual dexterity of people who take TAK-831. Efficacy evaluations also include other neurological, functional, and patient performance assessments.

The study will enroll approximately 65 participants. Participants will be randomly assigned in a 2:1:2 ratio to one of the three treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* TAK-831 High dose
* TAK-831 Low dose
* Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient

All participants will be asked to take three tablets of high dose, low dose, or placebo twice a day for 12 weeks.

This multi-center trial will be conducted in the United States. The overall time to participate in this study is approximately 13 weeks. Participants will make 5 visits to the clinic, and will be contacted by telephone for an exit interview no later than 7 days after their final visit or termination. Participants will also receive a safety follow-up phone call 7 to 17 days after receiving their last dose of TAK-831.

Arms: arm 1: TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks. arm 2: TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks. arm 3: TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Interventions: intervention 1: TAK-831 intervention 2: TAK-831 Placebo
Intervention descriptions: intervention 1: TAK-831 tablets intervention 2: TAK-831 placebo matching tablets

Protocol documents:
Prot_000.pdf: 



Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Arm Study to Evaluate 
Efficacy, Tolerability, and Pharmacokinetics of Multiple Doses of Oral TAK-831 in Adult Subjects 
With Friedreich Ataxia
NCT Number: NCT03214588
Protocol Approve Date: 06 October 2017
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Arm Study to Evaluate 
Efficacy, Tolerability, and Pharmacokinetics of Multiple Doses of Oral TAK-831 in Adult 
Subjects With Friedreich Ataxia
Short Title: TAK-831 in Friedreich Ataxia
Sponsor:
Takeda Development Center Americas, Inc.
One Takeda Parkway
Deerfield, IL 60015 
Study Number:
TAK-831-1501
IND Number:
132,633
EudraCT Number:
Not Applicable
Compound:
TAK-831
Date:
06 October 2017
Version Number:
Amendment No. 
01
Amendment History: 
Date
Amendment Number
Amendment Type 
Region
12 April 2017
Initial Protocol
Not applicable
Global
06 October 2017
Amendment 01
Substantial
Global
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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts 
A separate contact information list will be provided to each site.
Takeda Development Center Americas, Inc. (TDC Americas) sponsored investigators per United 
States (US) requirements will be provided with emergency medical contact information cards to be 
carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
Contact
Serious adverse event and pregnancy 
reporting
Medical Monitor
(medical advice on protocol and study drug)
Responsible Medical Officer 
(carries overall responsibility for the conduct
of the study)
Property of Takeda: For non-commer
du
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o the applicable Terms of Use
er Unite
er Uni
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n cards
or assign
assig
evant gui
nt gu
actct
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1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this study protocol and also in accordance with the following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The electronic signatures of the responsible Takeda medical officer (and other signatories, as listed 
below) are provided on the last page of this document.
Property of Takeda: For non-com
bject to the applicable Terms of Use
dance
dance
olidated
lidate
ta privac
priva
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
2.0
STUDY SUMMARY ....................................................................................................11
2.1
Protocol Amendment No. 01 Summary of Changes .................................................16
3.0
STUDY REFERENCE INFORMATION ......................................................................17
3.1
Study-Related Responsibilities.................................................................................17
3.2
Coordinating Investigator.........................................................................................17
3.3
List of Abbreviations ...............................................................................................18
3.4
Corporate Identification...........................................................................................19
4.0
INTRODUCTION.........................................................................................................20
4.1
Background .............................................................................................................20
4.1.1
Study Drug.........................................................................................................20
4.1.2
Friedreich Ataxia ...............................................................................................20
4.1.3
Nonclinical Background.....................................................................................21
4.1.4
Clinical Background ..........................................................................................21
4.2
Rationale for the Proposed Study.............................................................................23
4.3
Benefit/Risk Profile .................................................................................................24
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................26
5.1
Objectives................................................................................................................26
5.1.1
Primary Objective ..............................................................................................26
5.1.2
Secondary Objectives.........................................................................................26
5.1.3
Exploratory Objectives.......................................................................................27
5.2
Endpoints.................................................................................................................27
5.2.1
Primary Endpoint...............................................................................................27
5.2.2
Secondary Endpoints..........................................................................................27
5.2.3
Safety Endpoints................................................................................................28
5.2.4
Exploratory Endpoints .......................................................................................29
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................30
6.1
Study Design ...........................................................................................................30
6.2
Justification for Study Design, Dose, and Endpoints ................................................31
6.2.1
Justification of Study Design and Subject Population.........................................31
6.2.2
Justification of Dose...........................................................................................32
6.2.3
Justification of Measurements............................................................................33
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6.2.3.1
Primary Outcome Measure: 9-HPT..........................................................33
6.2.3.2
Secondary Outcome Measure: .................................................................33
6.2.3.3
Exploratory Outcome Measures...............................................................35
6.3
Premature Termination or Suspension of Study or Study Site...................................36
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................36
6.3.2
Criteria for Premature Termination or Suspension of Study Sites .......................37
6.3.3
Procedures for Premature Termination or Suspension of the Study or the
Participation of Study Site(s)..............................................................................37
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............38
7.1
Inclusion Criteria .....................................................................................................38
7.2
Exclusion Criteria ....................................................................................................39
7.3
Excluded Medications, Supplements, and Dietary Products .....................................40
7.4
Diet, Fluid, Activity Control ....................................................................................41
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................42
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................43
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................44
8.1
Study Drug and Materials ........................................................................................44
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................44
8.1.1.1
Study Drug ..............................................................................................44
8.1.1.2
Sponsor-supplied Drug ............................................................................44
8.1.2
Storage...............................................................................................................44
8.1.3
Dose and Regimen .............................................................................................44
8.1.4
Overdose............................................................................................................45
8.2
Study Drug Assignment and Dispensing Procedures ................................................45
8.3
Randomization Code Creation and Storage..............................................................45
8.4
Study Drug Blind Maintenance................................................................................45
8.5
Unblinding Procedure..............................................................................................45
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................46
9.0
STUDY PLAN ..............................................................................................................48
9.1
Study Procedures.....................................................................................................48
9.1.1
Informed Consent Procedure..............................................................................48
9.1.1.1
9.1.2
Demographics, Medical History, and Medication History Procedure..................48
9.1.3
Physical Examination Procedure ........................................................................48
9.1.4
Weight, Height, and BMI...................................................................................49
9.1.5
Vital Sign Procedure..........................................................................................49
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9.1.6
Other Safety Measurements ...............................................................................50
9.1.7
Primary and Secondary Efficacy Measurements.................................................50
9.1.8
Documentation of Concomitant Medications......................................................51
9.1.9
Documentation of Concurrent Medical Conditions.............................................51
9.1.10 Procedures for Clinical Laboratory Samples.......................................................51
9.1.11 Contraception and Pregnancy Avoidance Procedure...........................................53
9.1.11.1
Male Subjects and Their Female Partners ................................................53
9.1.11.2
Female Subjects and Their Male Partners ................................................53
9.1.11.3
Definitions and Procedures for Contraception and Pregnancy Avoidance.53
9.1.12 Pregnancy ..........................................................................................................55
9.1.13 ECG Procedure..................................................................................................56
9.1.14 Pharmacogenomic Sample Collection ................................................................56
9.1.15 PK Sample Collection and Analysis ...................................................................57
9.1.15.1
Bioanalytical Methods.............................................................................57
9.1.16 PD Sample Collection and Analysis ...................................................................57
9.1.16.1
Bioanalytical Methods.............................................................................57
9.1.17 PD Parameters of D- and L-Serine .....................................................................58
9.1.18 Documentation of Screen Failure .......................................................................58
9.1.19 Documentation of Randomization......................................................................58
9.2
Monitoring Subject Treatment Compliance..............................................................58
9.3
Schedule of Observations and Procedures................................................................59
9.3.1
Screening...........................................................................................................59
9.3.2
Study Entrance/Randomization ..........................................................................59
9.3.3
Treatment Phase.................................................................................................59
9.3.4
Interim Phone Calls............................................................................................59
9.3.5
Safety Follow-up Phone Call or Early Termination ............................................59
9.3.6
Exit Interview Phone Call ..................................................................................59
9.3.7
Post Study Care..................................................................................................59
9.4
Biological Sample Retention and Destruction ..........................................................59
9.5
Blood Volume .........................................................................................................60
10.0
PRETREATMENT EVENTS AND AES ......................................................................62
10.1
Definitions...............................................................................................................62
10.1.1 PTEs..................................................................................................................62
10.1.2 AEs....................................................................................................................62
10.1.3 Additional Points to Consider for PTEs and AEs................................................62
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10.1.4 SAEs..................................................................................................................64
10.1.5 Intensity of PTEs and AEs .................................................................................65
10.1.6 Causality of AEs ................................................................................................65
10.1.7 Relationship to Study Procedures.......................................................................65
10.1.8 Start Date...........................................................................................................66
10.1.9 Stop Date...........................................................................................................66
10.1.10
Frequency ....................................................................................................66
10.1.11
Action Concerning Study Drug ....................................................................66
10.1.12
Outcome.......................................................................................................66
10.2
Procedures...............................................................................................................67
10.2.1 Collection and Reporting of AEs........................................................................67
10.2.1.1
PTE and AE Collection Period.................................................................67
10.2.1.2
PTE and AE Reporting ............................................................................67
10.2.2 Collection and Reporting of SAEs......................................................................68
10.2.3 Reporting of Abnormal Liver Function Tests .....................................................68
10.3
Follow-up of SAEs ..................................................................................................69
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities..................69
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................70
12.0
DATA HANDLING AND RECORDKEEPING............................................................71
12.1
CRFs (Electronic)....................................................................................................71
12.2
Record Retention .....................................................................................................71
13.0
STATISTICAL METHODS..........................................................................................73
13.1
Statistical and Analytical Plans ................................................................................73
13.1.1 Analysis Sets......................................................................................................73
13.1.1.1
Full Analysis Set......................................................................................73
13.1.1.2
Safety Analysis Set..................................................................................73
13.1.1.3
PD Analysis Set.......................................................................................73
13.1.1.4
Per-Protocol Set.......................................................................................73
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................73
13.1.3 Efficacy Analysis...............................................................................................74
13.1.3.1
Primary Efficacy Analysis .......................................................................74
13.1.3.2
Secondary Efficacy Analysis ...................................................................74
13.1.4 PK and PD Modeling Analysis...........................................................................74
13.1.5 PD Analysis .......................................................................................................75
13.1.6 Safety Analysis ..................................................................................................75
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13.1.6.1
Analysis of AEs.......................................................................................75
13.1.6.2
Analysis of Other Safety Assessments .....................................................75
13.1.7 Responder Analysis............................................................................................76
13.2
Interim Analysis and Criteria for Early Termination ................................................76
13.3
Determination of Sample Size..................................................................................76
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................77
14.1
Study-Site Monitoring Visits ...................................................................................77
14.2
Protocol Deviations..................................................................................................77
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................77
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................78
15.1
IRB..........................................................................................................................78
15.2
Subject Information, Informed Consent, and Subject Authorization .........................78
15.3
Subject Confidentiality ............................................................................................80
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................80
15.4.1 Publication and Disclosure.................................................................................80
15.4.2 Clinical Trial Registration..................................................................................80
15.4.3 Clinical Trial Results Disclosure ........................................................................81
15.5
Insurance and Compensation for Injury....................................................................81
16.0
REFERENCES..............................................................................................................82
LIST OF IN-TEXT TABLES
Table 6.a
Schematic of Study Design ................................................................................30
Table 7.a
Excluded/Allowed Medications and Treatments.................................................41
Table 8.a
Dose and Regimen .............................................................................................44
Table 9.a
Clinical Laboratory Tests...................................................................................52
Table 9.b
Approximate Blood Volume ..............................................................................60
Table 10.a
Takeda Medically Significant AE List................................................................65
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................31
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LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................85
Appendix B
Responsibilities of the Investigator.....................................................................90
Appendix C
Elements of the Subject Informed Consent.........................................................92
Appendix D
Investigator Consent to Use of Personal Information..........................................95
Appendix E
Detailed Description of Amendments to Text.....................................................96
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2.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc.
Compound:
TAK-831
Title of Protocol: A Phase 2, Randomized, Double-Blind, 
Placebo-Controlled, Parallel-Arm Study to Evaluate Efficacy, Tolerability, 
and Pharmacokinetics of Multiple Doses of Oral TAK-831 in Adult 
Subjects with Friedreich Ataxia 
IND No.:
132,633
EudraCT No.:
Not Applicable
Study Number: TAK-831-1501
Phase: 2
Study Design:
TAK-831-1501 is a phase 2, randomized, double-blind, placebo-controlled, parallel-arm study designed to evaluate 
the efficacy, safety, pharmacodynamic (PD) effects, and pharmacokinetics (PK) of 2 dose levels of oral TAK-831 in 
adult subjects with Friedreich ataxia (FRDA). 
The study will include a Screening Period (Days -28 to -2), a Training Period (Day -1), Treatment (Days 1 to 84), a 
Phone Exit Interview (within 7 days from the last dose of study medication of the Double-Blind Treatment Period or 
within 7 days of notification of termination for the Early Termination Visit), and a Safety Follow-up Phone Call (7 to 
17 days after last dose of study drug).
Approximately 65 subjects that meet the study entry criteria during Screening will be invited on Day -1 to attend 
training to minimize practice effect on efficacy assessment. On Day 1, subjects who continue to meet inclusion and 
none of the exclusion criteria will be randomized in a 2:1:2 ratio to TAK-831 high dose, TAK-831 low dose, or 
placebo, respectively. Randomization will be stratified by ambulation status (ambulatory vs nonambulatory).
Subjects will receive study drug or placebo dosing twice daily (BID) from Day 1 through Day 84. Clinic visits include 
Day 1 and end of Weeks 2, 7, and 12. Clinical assessments, blood collections, and laboratory tests will be conducted at 
specific time points per the schedule of study procedures. A semistructured Exit Interview will be conducted by phone 
to provide an in-depth, qualitative evaluation of the subject experience and subject-perceived change due to treatment, 
and a Safety Follow-up Phone Call will be conducted. 
Table 1. Schematic of Study Design
Screening
Efficacy 
Assessment 
Training
Treatment (TAK-831 high dose, 
TAK-831 low dose, or placebo)
Phone Exit 
Interview
Safety Follow-up 
Phone Call (a)
Randomization, 
Baseline, and 
Dosing
Efficacy, PK, PD, and 
Safety Assessments
Days
-28 to -2
Day -1
Day 1
Day 14 (±3 days),
Day 49 (±3 days), 
Day 84 (±2 days)
≤7 days after 
Final Visit or 
termination
7 to 17 days after 
last dose
(a) The Follow-up phone call will occur 7 to 17 days after the last dose of study drug by telephone unless subject report 
concerning AEs. In these cases, subjects will be brought back into the clinic for re-evaluation at the investigator’s 
discretion.
Primary Objective:

To evaluate the efficacy of TAK-831 versus placebo on upper extremity (arm and hands) motor function and 
manual dexterity, as measured by the 9-hole peg test (9-HPT).
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Secondary Objectives:
!
To evaluate the efficacy of TAK-831 versus placebo on Activities of Daily Living (ADL), as measured by the 
ADL component of the Friedreich Ataxia Rating Scale (FARS), and those items that are related to upper limb 
function.
!
To evaluate the efficacy of TAK-831 versus placebo on neurological function, as measured by the modified 
Friedreich Ataxia Rating Scale neurological examination (mFARS-neuro) Total Score. 
!
To evaluate the efficacy of TAK-831 versus placebo on lower extremity motor function, as measured by the 
Timed 25-Foot Walk (T25FW).
!
To evaluate the efficacy of TAK-831 versus placebo on limb ataxia, as measured by the composite of the T25FW 
and 9-HPT.
!
To evaluate the efficacy of TAK-831 versus placebo on visual acuity, as measured by the low-contrast letter 
acuity (LCLA) testing with Sloan charts.
!
To evaluate the efficacy of TAK-831 versus placebo on global improvement, as measured by the Clinical Global 
Impression-Improvement (CGI-I).
!
To evaluate the efficacy of TAK-831 versus placebo on global improvement, as measured by the Patient Global 
Impression-Improvement (PGI-I).
!
To evaluate the efficacy of TAK-831 versus placebo on upper extremity functional improvement, as measured by 
the CGI-I.
!
To evaluate the efficacy of TAK-831 versus placebo on upper extremity functional improvement, as measured by 
the PGI-I.
!
To evaluate the efficacy of TAK-831 versus placebo on global severity, as measured by the Clinical Global 
Impression-Severity (CGI-S).
!
To evaluate the efficacy of TAK-831 versus placebo on global severity, as measured by the Patient Global 
Impression-Severity (PGI-S).
!
To evaluate the efficacy of TAK-831 versus placebo on upper extremity functional severity, as measured by the 
CGI-S.
!
To evaluate the efficacy of TAK-831 versus placebo on upper extremity functional severity, as measured by the 
PGI-S.
!
To evaluate the safety and tolerability of TAK-831. 
Exploratory Objectives:
!
To evaluate the efficacy of TAK-831 versus placebo on speech, as measured by digital assessments.
!
To evaluate the efficacy of TAK-831 versus placebo on motor function such as gait, balance, and upper limb 
coordination, as measured by digital sensors.
!
To evaluate the PK and PD (plasma D-serine and L-serine levels and D-serine:Total serine ratios), and explore the 
relationships between TAK-831 exposures and D- and L-serine levels or selected measures of efficacy.
!
To correlate plasma D-serine and L-serine levels, and D-serine:Total serine ratios with clinical parameters of 
disease status.
!
To quantify subject-perceived meaningful change in upper limb motor function, as evaluated by the Exit 
Interview.
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Subject Population: Male and female subjects aged 18 to 55 years, inclusive, with genetically-confirmed FRDA 
disease of stages 2 to 5, as determined by the Functional Staging for Ataxia, and able to complete the 9-HPT in 
≤150 seconds. 
Number of Subjects:
2:1:2 ratio for placebo, low, and high dose, 
respectively 
Estimated total: 65 subjects randomized
Number of Sites: 
Approximately 6 or more specialized academic 
neurological clinical centers in the United States
Dose Levels:
Placebo BID 
TAK-831 75 mg BID
TAK-831 300 mg BID
Route of Administration:
Oral
Duration of Treatment:
12 weeks
Period of Evaluation:
12 weeks of treatment + 7 to 17 days after the last 
administration of study drug
Main Criteria for Inclusion:
!
The subject is an adult male or female aged 18 to 55 years, inclusive, with genetically-confirmed diagnosis 
(homozygous for guanine-adenine-adenine repeat expansions in the frataxin (FXN) gene in the affected range of 
FRDA or a compound heterozygous expansion with a point mutation or deletion), with an established disease 
stage of 2 to 5, inclusive, as determined by the Functional Staging for Ataxia, at Screening.
!
The subject is able to complete the 9-HPT test in ≤150 seconds at Screening.
!
Male subjects who are nonsterilized and sexually active with a female partner of childbearing potential must agree 
to use adequate contraception from signing of informed consent throughout the duration of the study and for 
95 days after last dose.
!
Female subjects of childbearing potential must have a negative serum pregnancy test at Screening and must agree 
to use adequate contraception from signing of informed consent throughout the duration of the study and for 
35 days after last dose.
!
The subject is able to swallow study drug in tablet form. 
!
If a subject requires a caregiver to accompany him/her during the study for clinic visits, a caregiver and backup 
caregivers should be available.
Main Criteria for Exclusion:
!
The subject has a diagnosis of ataxic syndromes other than FRDA.
!
The subject has, based on medical history and investigator clinical judgment, uncontrolled, clinically significant 
neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, endocrine disease (including 
uncontrolled diabetes), or other abnormality (other than the disease being studied), which may impact the ability 
of the subject to participate or potentially confound the efficacy and safety evaluation. The subject has medical 
history or conditions that, in the opinion of the investigator, may interfere with study conduct or clinical 
assessments.
!
The subject has received treatment with other experimental therapies within the last 30 days or 5 half-lives, 
whichever is longer, prior to the first dose of study drug.
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
The subject has a known hypersensitivity to any component of the formulation of TAK-831.

The subject has taken any excluded medication, or has had insufficient washout of medications as listed in the 
Excluded/Allowed Medications, Procedures, and Treatments table listed in Section 7.3 or is unable or unwilling 
to discontinue medications as required by the protocol.

The subject is considered by the investigator to be at imminent risk of suicide or injury to self, others, or property 
or subjects who within the past year prior to Screening have attempted suicide or have positive answers on item 
4 or 5 on the Columbia Suicide Severity Rating Scale ([C-SSRS], life-time version) at Screening or Day 1.

The subject has clinically significant cardiac abnormalities at Screening that, in the opinion of the investigator, 
would make the subject unsuitable for enrollment, including but not limited to heart failure meeting criteria for 
class IV insufficiency by the New York Heart Association or documented ejection fraction <40%. 

The subject has a QT interval with Fridericia correction method (QTcF) >450 ms (males) or>470 ms (females), 
confirmed with 1 repeat testing, at Screening or Day 1.

If female, the subject is of childbearing potential and lactating, pregnant (positive prerandomization serum 
pregnancy test), or plans to become pregnant before participating in the study, during the study, or within 35 days 
after last dose of the study drug.
Main Criteria for Evaluation and Analyses:
Primary Endpoint
The primary endpoint for this study is the change from Baseline to Week 12 in the inverse of the time to complete the 
9-HPT (9-HPT-1) after treatment with TAK-831, compared with placebo. 
Secondary endpoints

The change from Baseline to Weeks 2, 7, and 12 on the ADL component of the FARS, after treatment with 
TAK-831, compared with placebo. 

The change from Baseline to Weeks 2, 7, and 12 on the ADL component upper limb function items (ADL items 
3-5) of the FARS, after treatment with TAK-831, compared with placebo. 

The change from Baseline to Weeks 2 and 7 on the 9-HPT after treatment with TAK-831, compared with placebo.

The change from Baseline to Weeks 2 and 7 on the ADL individual items after treatment with TAK-831, 
compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on the mFARs-neuro total score after treatment with TAK-831, 
compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on the mFARS-neuro subscales and individual items after 
treatment with TAK-831, compared with placebo. 

The change from Baseline to Weeks 2, 7, and 12 on the T25FW after treatment with TAK-831, compared with 
placebo.

The change from Baseline to Weeks 2, 7, and 12 on the 9-HPT and T25FW composite score after treatment with 
TAK-831, compared with placebo.

Percentage of subjects whose 9-HPT completion time is reduced by at least 15% and at least 20% from Baseline.

The change from Baseline to Weeks 2, 7, and 12 on LCLA test score after treatment, compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on CGI-I (global change) after treatment with TAK-831, 
compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on PGI-I (global change) after treatment with TAK-831, 
compared with placebo. 
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
The change from Baseline to Weeks 2, 7, and 12 on CGI-I (upper extremity functional change) after treatment 
with TAK-831, compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on PGI- I (upper extremity functional change) after treatment 
with TAK-831, compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on CGI-S (global severity) after treatment with TAK-831, 
compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on PGI-S (global severity) after treatment with TAK-831, 
compared with placebo. 

The change from Baseline to Weeks 2, 7, and 12 on CGI-S (upper extremity functional severity) after treatment 
with TAK-831, compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on PGI-S (upper extremity functional severity) after treatment 
with TAK-831, compared with placebo. 
Safety endpoints

Adverse events and clinical laboratory and electrocardiogram measures after treatment with TAK-831, compared 
with placebo.

Assessment of suicidal ideation and behavior as measured by the C-SSRS at Screening, Baseline, and all other 
timepoints.
Exploratory endpoints

The change from Baseline to Weeks 2, 7 and 12 on the digital speech assessment after treatment with TAK-831, 
compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on the digital motor sensors measurements such as gait, stability 
and upper limb coordination after treatment with TAK-831, compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on TAK-831 plasma D-serine and L-serine levels and 
D-serine:Total serine ratios after treatment with TAK-831, compared with placebo.

Percent of subjects reporting a meaningful change in upper limb function from Baseline to Week 12 after 
treatment with TAK-831, compared with placebo, as evaluated by the Exit Interview. 

Correlation of change in 9-HPT with that of patient reported improvement of change in upper limb function, such 
as ADL items 3 to 5 and PGI. 

TAK-831 plasma concentration.
Statistical Considerations:
The primary endpoint for this study is the change from Baseline to Week 12 in the inverse of the time to complete the 
9-HPT (9-HPT-1) after treatment with TAK-831, compared with placebo. The 2 TAK-831 doses will be compared 
with placebo, controlling multiplicity using Holm’s method. The dose with the smaller p-value will be tested at the 
1-sided 0.05 level, then the dose with the larger p-value will be tested at the 1-sided 0.10 level only if the smaller 
p-value is significant. This procedure will control the overall type I error rate at the 1-sided 0.10 level.
Sample Size Justification:
Approximately 65 subjects will be randomized in a 2:1:2 ratio to the high dose, low dose, or placebo, respectively. It is 
assumed that approximately 60 subjects (92%) will complete 12 weeks and be evaluable on the primary endpoint. If 
the rate of early withdrawal is substantially greater than predicted, then an increase to the number of randomized 
subjects may be considered. Assuming an effect size of 0.6 for each dose, this approach gives 77% power for at least 
1 dose to be deemed superior to placebo and 54% power for both doses. The effect size was chosen based on expert 
advice that a treatment effect equivalent to preventing or reversing 2 years of decline due to Friedreich ataxia (FDRA)
would be clinically meaningful. The target effect size should be approximately 0.6 for each endpoint. 
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2.1
Protocol Amendment No. 01 Summary of Changes 
Rationale for Amendment No. 01
This document describes the changes in reference to the protocol incorporating Amendment 
No. 01. The primary reasons for this amendment are to amend the dose, clarify/recategorize study 
objectives and endpoints, modify study procedures to reduce the number of visits and blood draws 
and update randomization scheme, clarify study entrance criteria and excluded medications, 
update the clinical data summary, and add an internal Data Monitoring Committee (DMC). 
Personnel changes, inconsistencies, and minor grammatical, editorial, and formatting changes are 
included for clarification purposes only.
For specific description of text changes and where the changes are located, see Appendix E. 
Changes in Amendment No. 01
1. Revision of study procedures (reduce the number of visits and blood draws, and update the 
randomization scheme).
2. Revision of TAK-831 dose.
3. Recatagorizing of objectives and endpoints related to Activities of Daily Living.
4. Clarification of endpoints related to the 9-hole peg test.
5. Revision and clarification of study entry criteria.
6. Clarification of excluded medications and products.
7. Revision of statistical analysis.
8. Inclusion of the summary of clinical data from Studies TAK-831-1004 and TAK-831-1005.
9. Engagement of an internal DMC to review unblinded safety data. 
10. Personnel change
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Coordinating Investigator 
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study drug, their expertise in the therapeutic area and the conduct of clinical research 
as well as study participation. The Signatory Coordinating Investigator will be required to review 
and sign the clinical study report and by doing so agrees that it accurately describes the results of 
the study.
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3.3
List of Abbreviations 
Term
Definition
9-HPT
9-hole peg test
ADL
Activities of Daily Living
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC∞
area under the concentration-time curve from time 0 to infinity
BID
twice daily
BMI
body mass index
CFR
Code of Federal Regulations
CGI
Clinical Global Impression Scale
CGI-I
Clinical Global Impression-Improvement 
CGI-S
Clinical Global Impression-Severity 
Cmax
maximum observed concentration
CNS
central nervous system
CSF
cerebrospinal fluid
C-SSRS
Columbia-Suicide Severity Rating Scale
DAO
D-amino acid oxidase
ECG
electrocardiogram, electrocardiographic
eCRF
electronic case report form 
EIIBs
eosinophilic intranuclear inclusion bodies
FACOMS
Friedreich Ataxia Clinical Outcome Measures Study
FARS
Friedreich Ataxia Rating Scale
FAS
full analysis set
FDA
Food and Drug Administration
FRDA
Friedreich ataxia
FSH
follicle-stimulating hormone
FXN
frataxin gene
GAA
guanine-adenine-adenine
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HPLC
high-performance liquid chromatography
HRQoL
health-related quality of life
ICH
The International Council for Harmonisation 
ID
identification
IEC
independent ethics committee
INR
international normalized ratio
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Term
Definition
IRB
institutional review board
IRT
interactive response technology
LCLA
low-contrast letter acuity
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
mFARS
modified Friedreich Ataxia Rating Scale 
mFARS-neuro
modified Friedreich Ataxia Rating Scale neurological examination
MMRM
mixed model for repeated measures
MRD
multiple-rising dose
NMDA
N-methyl-D-aspartate
PD
pharmacodynamic(s)
PET
positron emission tomography
PGI-I
Patient Global Impression-Improvement
PGI-S
Patient Global Impression-Severity
PGx
pharmacogenomics
PTE
pretreatment event
QTcF
QT interval with Fridericia correction method 
SAE
serious adverse event
SAP
statistical analysis plan
SRD
single-rising dose
SUSAR
suspected unexpected serious adverse reaction
T25FW
Timed 25-Foot Walk
UGT
uridine 5'-diphosphate glucuronosyltransferase
ULN
upper limit of normal
3.4
Corporate Identification
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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4.0
INTRODUCTION
4.1
Background
4.1.1
Study Drug
TAK-831 is a highly selective and potent small molecule inhibitor of D-amino acid oxidase 
(DAO) being developed by Takeda. DAO is the major enzyme responsible for the 
catabolism/degradation of small neutral amino acids like D-serine and is highly expressed in the 
cerebellum [1]. Inhibiting DAO leads to a measurable increase in D-serine levels in plasma, 
cerebrospinal fluid (CSF), and cerebellum in rodents (Study TAK-831-10031). D-serine is a 
potent N-methyl-D-aspartate (NMDA)-type glutamate receptor coagonist and an agonist for the 
2 glutamate receptor, which has been implicated in synaptic plasticity and long-term depression 
[2,3]. As a DAO inhibitor that increases D-serine in the cerebellum, TAK-831 has the potential to 
increase NMDA-dependent glutamatergic signaling. The literature suggests that D-serine is a 
critical mediator of glutamate receptor–dependent functions of the cerebellum, which coordinates 
muscular activity [2,3]. Therefore, inhibition of DAO and a subsequent increase in D-serine in the 
cerebellum may lead to an improvement in cerebellar output.
4.1.2
Friedreich Ataxia
Ataxia manifests as impaired coordination of muscle movements. It is a nonspecific clinical 
manifestation indicative of dysfunction in the parts of the central nervous system (CNS) that 
coordinate movement. Patients with ataxia have trouble regulating the force, range, direction, 
velocity, and rhythm of muscle contractions, resulting in a characteristic type of irregular, 
uncoordinated movement that can manifest itself in many possible ways, such as asthenia, 
asynergy, delayed reaction time, and dyschronometria [4]. Patients also display instability of gait, 
difficulty with eye movements, dysarthria, dysphagia, hypotonia, dysmetria, and 
dysdiadochokinesia (impaired ability to perform rapid, alternating movements). These difficulties 
can affect employability, lead to disability, increase caregiver burden, and significantly reduce a 
person’s health-related quality of life (HRQoL) [5]. 
There are numerous types of ataxias, many genetically mediated and others idiopathic. Friedreich 
ataxia (FRDA) is the most common of the hereditary ataxias and occurs in approximately 50% of 
overall cases of hereditary ataxia in Europe and North America (prevalence of 1:50,000 
Caucasians) [6,7]. The number of individuals affected with FRDA at any given time in the United 
States is approximately 5,000 [8]. In people with FRDA, a guanine-adenine-adenine (GAA) 
trinucleotide repeat expansion mutation in intron 1 of the frataxin gene (FXN) results in drastically 
reduced levels of the frataxin protein [9,10], which in turn leads to mitochondrial dysfunction, 
neurodegeneration, cardiomyopathy, diabetes mellitus, and skeletal deformities [7,11,12]. A small 
number of cases are caused by a compound heterozygous expansion with a point mutation or 
deletion [12]. This disorder has a sensory ataxia component secondary to involvement of the dorsal 
root ganglia and spinocerebellar tracts, with loss of proprioceptive function and sensory 
neuropathy, as well as gradual decreases in sensory function that lead to visual and hearing 
impairments [13]. There is also progressive destruction of the cerebellar dentate nucleus and the 
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corticospinal tract [13]. FRDA is a debilitating, life-shortening, and degenerative multiple system 
disorder. Onset of symptoms can vary from 5 years old to adulthood, with the childhood onset 
tending to be associated with a more rapid progression. A progressive loss of coordination and 
muscle strength leads to motor incapacitation and often the full-time use of a wheelchair. Most 
young people diagnosed with FRDA require mobility aids such as a cane, walker, or wheelchair by 
their teens or early twenties. As a rare disease with no currently approved treatments, FRDA 
represents an area of significant unmet medical need.
Various compounds are under investigation [14]. However, there is currently no cure or approved 
effective treatment for FRDA [15]. Thus, there is a great need to identify and develop effective 
therapies for FRDA.
4.1.3
Nonclinical Background
In nonclinical studies, TAK-831 increased D-serine levels in rat cerebellum and plasma. In the 
YG8sR transgenic mouse model, a model relevant for FRDA, TAK-831 at an oral daily dose of 
3 mg/kg significantly improved motor coordination deficits of the mutant mice in the beam-walk 
test. Five hours after administration of the first dose, TAK-831–treated mutant mice crossed the 
beam approximately 30% faster than vehicle-treated animals, and TAK-831 treatment completely 
reversed the motor coordination deficit in these mice back to Baseline observed in healthy mice on 
Day 15. Therefore, TAK-831 holds the potential to treat patients with FRDA.
In vivo enzyme occupancy studies with a tracer molecule in mice demonstrated that TAK-831 
binds to DAO in the kidney, cerebellum, and brain stem in a dose-dependent manner. Increasing 
enzyme occupancy by TAK-831 in the cerebellum correlated with plasma concentrations of drug, 
with maximal enzyme occupancy achieved at a dose of 10 mg/kg in mice.
Cerebellar enzyme activity was examined ex vivo. TAK-831 potently inhibited DAO activity in 
mouse cerebellum in a dose-dependent manner with a 50% inhibitory dose for DAO activity at 
10 mg/kg. Similarly, TAK-831 increased rat cerebellar D-serine levels in a dose- and 
time-dependent manner with a maximal effect observed at an oral dose of 10 mg/kg at 10 hours 
postdose. These findings indicate that TAK-831 can increase D-serine levels via inhibition of 
DAO in vivo.
The development of TAK-831 included an extensive nonclinical safety pharmacology program 
that contributed to its overall safety assessment. Summaries of these studies and results can be 
found in the Investigator’s Brochure.
4.1.4
Clinical Background
Five phase 1 clinical studies have been conducted in healthy subjects: a first-in-human study to 
determine the pharmacokinetic (PK) profiles of TAK-831 oral suspension after single-rising dose 
(SRD) and multiple-rising dose (MRD) administration, as well as the relative bioavailability and 
effect of food on the PK of the T1 tablet formulation of TAK-831 (TAK-831-1001); and a study to 
demonstrate DAO target engagement in the brain as measured by positron emission tomography 
(PET) (TAK-831-1003). Plasma D-serine levels, TAK-831 plasma concentrations and safety were 
also evaluated. Since these studies were conducted, a single dose PK and food-effect, 
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bioavailability study with the T2 tablet formulation (TAK-831-1004) has completed active dosing, 
and a study examining additional escalating multiple doses of TAK-831 higher than those 
achieved in the TAK-831-1001 study was initiated and is ongoing (TAK-831-1005).
After both single and multiple dosing with TAK-831 (Study TAK-831-1001), increases in the area 
under the effect curve from time 0 to 24 hours of D-serine were dose-dependent; changes in 
D-serine were noticeably higher after multiple daily doses of TAK-831 400 mg than after multiple 
daily doses of TAK-831 30, 100, and 200 mg. Single oral doses of TAK-831 temporally increased 
plasma concentrations of D-serine in the PET study (TAK-831-1003); the results are similar to 
those obtained from Study TAK-831-1001.
TAK-831 was safe and well tolerated in doses studied in the 103 healthy subjects dosed with active 
drug in studies TAK-831-1001 and TAK-831-1003. Headache was the most common 
treatment-emergent adverse event (TEAE) potentially related to treatment. Headaches were mild 
to moderate in intensity and generally self-limiting. The rate of postural dizziness in 
TAK-831-treated subjects did not markedly differ from the rate observed in placebo-treated 
subjects. There were no concerning trends in laboratory, electrocardiogram (ECG), or vital sign 
data.
TAK-831-1004 was a phase 1, randomized, open-label, single-dose, 2-period crossover study 
designed to characterize the pharmacokinetics (PK) of a single dose of 400 mg of TAK-831 and 
assess the effect of food on the bioavailability of TAK-831 400 mg when administered as 4 100 mg 
oral tablets of the T2 formulation in 15 healthy adult subjects. In the TAK-831-1004 study, there 
was only a single adverse event (AE) of mild upper respiratory tract infection, judged to be 
unrelated to study treatment. One subject met criteria for orthostatic hypotension at a single time 
point without an accompanying report of a dizziness AE. There were no concerning trends in 
laboratory, ECG, or vital sign data. TAK-831 given as T2 tablet coadministered with the 
nutritional drink (Ensure Plus) increased mean Cmax and AUC∞values by 35% and 21%, 
respectively. Treatment with a single oral dose of 400mg TAK-831 T2 formulation temporally 
increased plasma concentration of D-serine, similar to the results obtained in the Study 
TAK-831-1001. The magnitude and kinetics of the change in plasma D-serine was similar when 
the drug was administered in either water or Ensure.
TAK-831-1005 is an ongoing investigator and subject blinded, sponsor unblinded, 
placebo-controlled clinical study progressively assessing independent cohorts of healthy subjects 
to continue evaluation of the safety, tolerability, PK, and pharmacodynamics (PD) of escalating 
multiple doses of TAK-831 at doses higher than those achieved in the TAK-831-1001 study. The 
following study information is preliminary and is based on blinded AE data reported by the 
investigator and blinded safety endpoint data in study TAK-831-1005. Although not expected, 
these data are subject to change upon finalization following study monitoring, source data 
verification, and discrepancy query management prior to database lock. At this time, 2 cohorts 
with 8 subjects each (6 TAK-831 and 2 placebo) have completed treatment at dose levels of 600 
mg QD (T2 tablet formulation) or 800 mg QD (oral suspension) administered first as a single dose, 
and then administered for up to 14 days of multiple dosing. In addition to standard safety 
assessments, subjects in these cohorts underwent catheterized CSF collection for a 24 hour period 
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starting prior to dosing on Day 1 single dose treatment and on Day 14 of multiple dose treatment. 
Nausea and post-lumbar puncture syndrome were the most common treatment-emergent AEs; 
nausea in the absence of post-lumbar puncture syndrome was reported by one subject in each 
cohort. All episodes of nausea were mild in intensity and self-limiting. Two subjects in each cohort 
met categorical criteria for orthostatic hypotension on at least one assessment; none of these 
findings were associated with an AE of dizziness. There were no concerning trends in laboratory, 
ECG, or vital sign data collected in these cohorts. 
Following once-daily dosing, mean plasma exposures of TAK-831 were higher (Cmax: 1.3-fold and 
AUC: 1.8-fold) when dosed as an oral suspension than as T2 tablets. Geometric mean Cmax values 
were 1466 and 1976 ng/mL with 600 mg QD (T2 tablet formulation) and 800 mg QD (oral 
suspension), respectively. Mean steady-state exposures (AUCt) over the 24-hour dosing interval 
were on average 4993 and 8853 ng.hr/mL for the respective 600 mg and 800 mg QD dosing 
cohorts. The mean 24-hour TAK-831 PK profile in CSF was parallel to that of plasma and 
observed TAK-831 CSF concentrations were well in agreement with the TAK-831 unbound 
fraction in plasma. After both single and multiple dosing with TAK-831, there was a notable 
increase in the area under the effect curve from time 0 to 24 hours of CSF D-serine for both the 
600 mg T2 and 800 mg oral suspension treatment groups when compared to placebo; changes in 
CSF D-serine were noticeably higher after multiple doses of TAK-831 than after administration of 
a single dose of TAK-831. The magnitude of the increase in the area under the effect curve for CSF 
D-serine was similar for both the 600 mg T2 and 800 mg oral suspension, suggesting that the 
maximal PD effect in the CSF was achieved at drug exposures attained with the 600 mg T2 dose 
and 800 mg suspension.
Overall, the emerging safety data from the TAK-831-1004 and TAK-831-1005 studies are 
consistent with the data collected in prior clinical studies and do not alter the risk profile of the 
compound. 
The safety data from healthy subjects cannot be directly generalized for patients with FRDA. 
However, no safety signal has manifested that would prevent additional studies in healthy subjects 
or in subjects with FRDA. 
The clinical efficacy of TAK-831 has not been studied.
4.2
Rationale for the Proposed Study
Phase 1 studies have demonstrated acceptable PK characteristics and no safety issues to date. This 
study will be the first phase 2 study to test the efficacy and safety of TAK-831 in subjects with
FRDA. The literature suggests that D-serine is a critical mediator of glutamate receptor–dependent 
functions of the cerebellum and was shown to reduce ataxia in animal model of spinocerebellar 
ataxia [3]. As a DAO inhibitor that increases D-serine in the cerebellum, TAK-831 has the 
potential to increase NMDA-dependent glutamatergic signaling. One disease state that could be 
treated through this mechanism is FRDA. TAK-831 showed efficacy in a mouse model of FRDA 
with single doses and dosed daily for 15 days at 3 mg/kg. 
There is currently no cure or approved effective treatment for FRDA [14]. Thus, there is a great 
need to identify and develop effective therapies for patient populations with ataxia. The current 
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phase 2 study in subjects with FRDA will be the first to explore the potential benefits of TAK-831 
in this population. 
4.3
Benefit/Risk Profile 
The proposed phase 2 study is being conducted to evaluate the efficacy, safety, PD effects, and PK 
of 2 dose levels of oral TAK-831 in adult subjects with FRDA for up to 84 days. The proposed 
doses of TAK-831 have been selected based on PK data from the SRD/MRD studies 
(TAK-831-1001 and TAK-831-1005), brain target occupancy data from the PET study 
(TAK-831-1003), CSF D-serine data from the TAK-831-1005 study, and safety data from all 
clinical studies after oral administration of TAK-831 in healthy subjects described above. The 
dose and study duration of TAK-831 used in prior studies have not resulted in a safety signal that 
would prevent additional studies in subjects with FRDA. 
Potential risks, and risk mitigation measures to be implemented in studies with TAK-831, are 
described below. These measures are based on what is known about the mechanism of action of 
TAK-831, nonclinical data, the phase 1 studies conducted to date, and general considerations in 
the development of new chemical entities. These procedures may be modified during the study if 
necessary based on evaluation of any additional clinical or nonclinical safety data.

Acute hypersensitivity/anaphylactic reactions to new chemical entities are always a possible 
risk in any clinical study. Appropriate procedures should be used to manage such possible 
risks. 

Subjects with a risk of suicide according to the investigator’s clinical judgment (eg, per the 
Columbia-Suicide Severity Rating Scale [C-SSRS]) [16,17] or who have made a suicide 
attempt in the previous 6 months, will be excluded from studies with TAK-831. Subjects 
should be monitored for any signs of suicidal ideation or behaviors, and appropriate 
psychiatric interventions or other precautions should be instituted, if warranted.

Emesis and diarrhea were reported in laboratory animals exposed to TAK-831. If a subject 
develops emesis or diarrhea, the investigator should assess the clinical status. For mild emesis 
or diarrhea that is self-limited, the subject should be encouraged to increase fluid intake. 
Hydration status should be assessed with physical examination and vital signs, including 
orthostatic pulse and blood pressure measurements. For more severe emesis or diarrhea, where 
the subject has had more than 3 episodes and signs and symptoms of dehydration are present 
(ie, lightheadedness, vertigo, syncope, and/or orthostatic changes in blood pressure or pulse 
are present), measurement of serum electrolytes, blood urea nitrogen, and creatinine, as well as 
the consideration of more aggressive hydration, including the administration of an appropriate 
parenteral solution, should be undertaken.

Eosinophilic intranuclear inclusion bodies (EIIBs) were observed in the proximal tubule 
epithelium of the kidneys at doses of ≥10 mg/kg/day in rats. The EIIBs were not accompanied 
by apparent necrosis, inflammation, or impaired renal function and were not considered 
adverse. Similar findings have been reported in the literature and are considered to be 
species-specific to the rat [18]. Creatinine will be measured in the clinical studies.
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
Postural hypotension and dizziness were observed in prior studies in healthy subjects. 
However, the incidence of dizziness in subjects treated with TAK-831 and placebo was 
similar. In addition, 2 subjects who received 250 mg TAK-831 showed blood pressure 
variations consistent with orthostatic hypotension without clinical symptoms. These 
measurements were taken at the Study Exit Visit and were considered not-related to TAK-831. 
As FRDA patients experience gait disturbance, motor dysfunction, and thus are susceptible to 
fall, subjects should be instructed to take appropriate precautionary measures to prevent falling 
while under treatment with TAK-831. Additionally, subjects with current history of 
symptomatic orthostatic hypotension will be excluded from the study.

Study procedure–specific risks include issues relating to the requirement for fasting (which 
may lead to AEs of lightheadedness or stomach cramps) as well as blood collection for safety 
assessment/PK monitoring (venipuncture may cause bruising), and the placement.
The investigator has discretion to use his/her clinical judgment as to whether to allow a subject to 
proceed in the study or whether to unblind the subject in order to determine his/her treatment 
allocation. These cases would normally be discussed with the sponsor beforehand, but that is not 
an absolute requirement in case of medical emergency, and the clinical needs of the individual 
subject will always take precedence.
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective of the study is to evaluate the efficacy of TAK-831 versus placebo on upper 
extremity (arms and hands) motor function and manual dexterity, as measured by the 9-hole peg 
test (9-HPT).
5.1.2
Secondary Objectives

To evaluate the efficacy of TAK-831 versus placebo on Activities of Daily Living (ADL), as 
measured by the ADL component of the Friedreich Ataxia Rating Scale (FARS), and those 
items that are related to upper limb function.

To evaluate the efficacy of TAK-831 versus placebo on neurological function, as measured by 
the modified FARS neurological examination (mFARS-neuro) total score. 

To evaluate the efficacy of TAK-831 versus placebo on lower extremity motor function, as 
measured by the Timed 25-Foot Walk (T25FW).

To evaluate the efficacy of TAK-831 versus placebo on limb ataxia, as measured by the 
composite of the T25FW and 9-HPT.

To evaluate the efficacy of TAK-831 versus placebo on visual acuity, as measured by the 
low-contrast letter acuity (LCLA) testing with Sloan charts.

To evaluate the efficacy of TAK-831 versus placebo on global improvement, as measured by 
the Clinical Global Impression-Improvement (CGI-I).

To evaluate the efficacy of TAK-831 versus placebo on global improvement, as measured by
the Patient Global Impression-Improvement (PGI-I).

To evaluate the efficacy of TAK-831 versus placebo on upper extremity functional 
improvement, as measured by the CGI-I.

To evaluate the efficacy of TAK-831 versus placebo on upper extremity functional 
improvement, as measured by the PGI-I.

To evaluate the efficacy of TAK-831 versus placebo on global severity, as measured by the 
Clinical Global Impression-Severity (CGI-S).

To evaluate the efficacy of TAK-831 versus placebo on global severity, as measured by the 
Patient Global Impression-Severity (PGI-S).

To evaluate the efficacy of TAK-831 versus placebo on upper extremity functional severity, as 
measured by the CGI-S.

To evaluate the efficacy of TAK-831 versus placebo on upper extremity functional severity, as 
measured by the PGI-S.
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!
To evaluate the safety and tolerability of TAK-831.
5.1.3
Exploratory Objectives
!
To evaluate the efficacy of TAK-831 versus placebo on speech, as measured by digital 
assessments.
!
To evaluate the efficacy of TAK-831 versus placebo on motor function such as gait, balance, 
and upper limb coordination, as measured by digital sensors.
!
To evaluate the PK and PD (plasma D-serine and L-serine levels and D-serine:Total serine 
ratios), and explore the relationships between TAK-831 exposures and D- and L-serine levels 
or selected measures of efficacy.
!
To correlate plasma D-serine and L-serine levels, and D-serine:Total serine ratios with clinical 
parameters of disease status.
!
To quantify subject-perceived meaningful change in upper limb function, as evaluated by the 
Exit Interview. 
5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoint for this study is the change from Baseline to Week 12 in the inverse of the 
time to complete the 9-HPT (9-HPT-1) after treatment with TAK-831, compared with placebo.
5.2.2
Secondary Endpoints
!
The change from Baseline to Weeks 2, 7, and 12 on the ADL component of the FARS, after 
treatment with TAK-831, compared with placebo. 
!
The change from Baseline to Weeks 2, 7, and 12 on the ADL component upper limb function 
items (ADL items 3 to 5) of the FARS, after treatment with TAK-831, compared with placebo. 
!
The change from Baseline to Weeks 2 and 7 on the 9-HPT-1 after treatment with TAK-831, 
compared with placebo.
!
The change from Baseline to Weeks 2, 7, and 12 on the ADL individual items after treatment 
with TAK-831, compared with placebo.
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
The change from Baseline to Weeks 2, 7, and 12 on the mFARs-neuro total score after 
treatment with TAK-831, compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on the mFARS-neuro subscales and 
individual items after treatment with TAK-831, compared with placebo. 

The change from Baseline to Weeks 2, 7, and 12 on the T25FW after treatment with TAK-831, 
compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on the 9-HPT and T25FW composite score 
after treatment with TAK-831, compared with placebo.

Percentage of subjects whose 9-HPT completion time is reduced by at least 15% and at least 
20% from Baseline.

The change from Baseline to Weeks 2, 7, and 12 on LCLA test score after treatment, compared 
with placebo.

The change from Baseline to Weeks 2, 7, and 12 on CGI-I (global change) after treatment with 
TAK-831, compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on PGI-I (global change) after treatment with 
TAK-831, compared with placebo. 

The change from Baseline to Weeks 2, 7, and 12 on CGI-I (upper extremity functional change) 
after treatment with TAK-831, compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on PGI- I (upper extremity functional change) 
after treatment with TAK-831, compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on CGI-S (global severity) after treatment 
with TAK-831, compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on PGI-S (global severity) after treatment 
with TAK-831, compared with placebo. 

The change from Baseline to Weeks 2, 7, and 12 on CGI-S (upper extremity functional 
severity) after treatment with TAK-831, compared with placebo. 

The change from Baseline to Weeks 2, 7, and 12 on PGI-S (upper extremity functional 
severity) after treatment with TAK-831, compared with placebo.
5.2.3
Safety Endpoints

AEs, clinical laboratory assessments, ECG measures, changes in physical examinations and 
vital signs after treatment with TAK-831, compared with placebo.

Assessment of suicidal ideation and behavior as measured by the C-SSRS at Screening, 
Baseline, and all other timepoints after treatment with TAK-831, compared with placebo.
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5.2.4
Exploratory Endpoints

The change from Baseline to Weeks 2, 7, and 12 on the digital speech assessment after 
treatment with TAK-831, compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on the digital motor sensors measurements 
such as gait, stability and upper limb coordination after treatment with TAK-831, compared 
with placebo.

The change from Baseline to Weeks 2, 7, and 12 on TAK-831 plasma D-serine and L-serine 
levels and D-serine:Total serine ratios after treatment with TAK-831, compared with placebo.

Percent of subjects reporting a meaningful change in upper limb function from Baseline to 
Week 12 after treatment with TAK-831, compared with placebo, as evaluated by the Exit 
Interview.

Correlation of change in 9-HPT with that of patient reported improvement of change in upper 
limb function, such as ADL items 3 to 5 and PGI.

TAK-831 plasma concentration.
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
TAK-831-1501 is a phase 2, randomized, double-blind, placebo-controlled, parallel-arm study 
designed to evaluate the efficacy, safety, PD effects, and PK of 2 dose levels of oral TAK-831 in 
adult subjects with FRDA. 
The study will include a Screening Period (Days -28 to -2), a Training Period (Day -1), Treatment 
(Days 1 to 84), a Phone Exit Interview (within 7 days from the last dose of study medication of the 
Double-Blind Treatment Period or within 7 days of notification of termination for the Early 
Termination Visit), and a Safety Follow-up Phone Call (7 to 17 days after last dose of study drug).
Approximately 65 subjects who meet the study criteria during Screening will be invited to attend 
training to minimize practice effects on performance-based efficacy assessments on Day -1. On 
Day 1, subjects who continue to meet inclusion and none of the exclusion criteria will be 
randomized in a 2:1:2 ratio to TAK-831 high dose, TAK-831 low dose, or placebo, respectively. 
(If the rate of early withdrawal is substantially greater than predicted, then an increase to the 
number of randomized subjects may be considered.) Randomization will be stratified by 
ambulation status (ambulatory vs. nonambulatory).
The study will be conducted in approximately 6 or more specialized academic neurological 
clinical centers in the United States with expertise in, and access to, patients with FRDA.
Subjects will receive twice daily (BID) study drug dosing or placebo from Day 1 through Day 84. 
Clinic visits during the treatment period include Day 1, end of Weeks 2, 7, and 12. Clinical 
assessments, blood collections, and laboratory tests will be conducted at specific time points per 
the schedule of study procedures (Appendix A). A semistructured Exit Interview will be 
conducted by phone to provide an in-depth, qualitative evaluation of the subject experience and 
subject-perceived change due to treatment, and a Safety Follow-up Phone Call will be conducted
(Table 6.a). 
Table 6.a
Schematic of Study Design
Screening
Efficacy 
Assessment 
Training
Treatment (TAK-831 high dose, 
TAK-831 low dose, or placebo)
Phone Exit 
Interview
Safety Follow-up 
Phone Call (a)
Randomization, 
Baseline, and 
Dosing
Efficacy, PK, PD, and 
Safety Assessments
Days
-28 to -2
Day -1
Day 1
Day 14 (±3 days), 
Day 49 (±3 days), 
Day 84 (±2 days)
≤7 days after 
Final Visit or 
termination
7 to 17 days after 
last dose
(a) The Follow-up Phone Call will occur 7 to 17 days after the last dose of study drug by telephone unless subject 
report concerning AEs. In these cases, subjects will be brought back into the clinic for re-evaluation at the 
investigator’s discretion.
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in 
Appendix A.
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Figure 6.a
Schematic of Study Design
6.2
Justification for Study Design, Dose, and Endpoints
TAK-831 is a selective inhibitor of DAO. Inhibition of DAO leads to higher D-serine levels in the 
plasma, CSF, and cerebellum of animal models. D-serine enhances glutamate receptor–mediated 
mechanisms that may be impaired or contribute to cerebellar dysfunction symptoms, such as 
ataxia. Increasing D-serine levels by way of inhibition of its catabolizing enzyme DAO may 
improve motor symptoms and HRQoL of patients with cerebellar dysfunction. Accordingly, the 
focus of this study is to target and mitigate symptoms of cerebellar dysfunction in subjects with 
FRDA.
6.2.1
Justification of Study Design and Subject Population
The double-blind, placebo-controlled study design is appropriate to assess the objectives of this
study. Clinical outcome assessment measures including performance-based, clinician-reported, 
and patient-reported outcome measures will be evaluated. The inclusion of a placebo group allows 
for the evaluation of efficacy and safety objectives related to TAK-831. Placebo tablets will match 
the TAK-831 tablets for blinding purposes. 
Nonclinical studies in mice models of FRDA suggest potential efficacy of TAK-831 in improving 
motor coordination or function symptomatically. TAK-831 is hypothesized to treat ataxia 
symptomatically in a broad range of FRDA patients at various stages of disease progression, 
including patients who are ambulatory and nonambulatory.
In this initial efficacy study in the FRDA population, including a broad population (rather than 
limiting the population to ambulatory or nonambulatory, for example) will help identify subgroups 
Days -1, 1
(Visits 2, 3)
Day 84 
(Visit 6)
Screening
Randomization & 
First Dose (Day 1)
Screening
Double-blind
12 weeks
FRDA Subjects
TAK-831 High Dose BID
Placebo
Day -28 to -2 
(Visit 1)
Last Diose 
Visit
TAK-831 Low Dose BID
Day 14
(Visit 4)
Day 49
(Visit 5)
Safety
Follow-up
phone call
(7-17 days
afer last dose)
Exit 
Interview  
(<7 days 
after last 
dose)
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that may benefit better from the treatment, and therefore inform future studies. Overall mobility 
can be scored by using the Functional Ataxia Staging (total score range from 0 to 6). Stage 1 
patients show minimal signs detected by the physician during Screening, patients can run or jump 
without loss of balance, and there is no disability. Sensory ataxia is more prominent than limb 
ataxia in this stage, likely due to a developmental pathology in combination with the progressive 
pathology of dorsal root ganglia and dorsal columns. It is unlikely that TAK-831 will dramatically 
improve sensory ataxia symptoms of FRDA in stage 1, based on the hypothesized mechanism of 
action. Stage 6 patients are confined to a wheelchair or bed and have total dependency for all 
ADLs. These patients might be too severe to respond with meaningful improvement to 
symptomatic drug treatment. It is likely that the disease severity in stages 2 to 5 is severe enough to 
result in a measurable improvement in function.
The duration of treatment for this study is 12 weeks. Although TAK-831 is anticipated to act 
symptomatically with a relatively rapid onset of action (based on its mechanism of action and the 
nonclinical data), a duration of 12 weeks was chosen for Study TAK-831-1501 to better 
characterize the onset of action as well as the maintenance of effect of the drug. Twelve weeks is 
the maximum treatment duration supported by currently available TAK-831 nonclinical 
toxicology data.
The sample size of 65 subjects being randomized in a 2:1:2 ratio to TAK-831 high dose, TAK-831 
low dose, or placebo, respectively, was based on the following assumptions. It was assumed that 
approximately 60 subjects (93%) will complete 12 weeks and be evaluable on the primary 
endpoint. Assuming an effect size of 0.6 for each dose, this approach gives 77% power for at least 
1 dose to be deemed superior to placebo and 54% power for both doses. The effect size was chosen 
based on expert advice that a treatment effect equivalent to preventing or reversing 2 years of 
decline due to FRDA would be clinically meaningful. Using published data [19], the target effect 
size should be approximately 0.6 for each endpoint.
6.2.2
Justification of Dose
The doses of TAK-831 (300 mg and 75 mg BID) selected for the current study are based on PK 
data from the SRD/MRD study (TAK-831-1001) and brain target occupancy data from the PET 
study (TAK-831-1003), PK and food effect study (TAK-831-1004), CSF D-serine study 
(TAK-831-1005), and safety data from all clinical studies after oral administration of TAK-831 in 
healthy subjects. Preliminary PK/PD modeling analyses showed that the high dose regimen 
resulted in steady-state exposures associated with peak target occupancy of >90%. The lower dose 
is to provide at least 3-fold exposure difference from the high dose to understand the relationship 
between TAK-831 and response relationship. In addition, CSF D-serine levels at 600 mg QD 
using T2 tablet and 800 mg suspension produced similar level of CSF D-serine, suggesting that 
600 mg QD produced levels of D-serine approaching maximal DAO inhibition in the brain. These 
2 doses (300 and 75 mg BID) may allow characterization of an exposure-response relationship 
with PD or efficacy measures in adult subjects with FRDA. Subjects will be instructed to take 
3 tablets by mouth 2 times a day in the fasted condition (at least 1 hour before or after a meal) or 
with a light meal (less than 600 calories total with <30% from fat). This will keep the TAK-831 
exposure at levels that have been shown to be well tolerated in healthy subjects. 
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6.2.3
Justification of Measurements
6.2.3.1
Primary Outcome Measure: 9-HPT
The 9-HPT is a quantitative performance-based measure of timed upper extremity (arm and hand) 
function and manual dexterity. The 9-HPT was developed in the 1970s as a performance-based 
measure of upper limb dexterity [20]. This measure has been used extensively in stroke and 
Parkinson’s disease patients and is the gold standard test recommended by the MS Outcome 
Assessments Consortium for measuring manual dexterity in multiple sclerosis [21]. The 9-HPT 
has been used more recently in FRDA[19,22] and is recommended as the best performance-based 
measure of upper limb function for inclusion in clinical studies of FRDA [23].
Participants pick up pegs 1 at a time (9 in total), using 1 hand only, and place them into holes on the 
board as quickly as possible, in any order until all holes are filled. Then, without pausing, 
participants remove the pegs 1 at a time and return them as quickly as possible. Each participant 
performs this task twice with each hand separately. Results on both tests are then averaged for an 
overall task completion time. The 9-HPT quantifies the speed at which participants put all of the 
pegs in and take them out again. 
The 9-HPT is a useful measure of upper limb function in FRDA and has established reliability in 
FRDA as well as normative reference values to assist with score interpretation [24-26]. This 
measure correlates with neurological disability and disease duration as well as other 
performance-based measures in FRDA [27]. Additional analysis of natural history data based on 
the Friedreich Ataxia Clinical Outcome Measures Study (FACOMS) show a correlation of 9-HPT 
with ADL total scores and subscores that reflect functions such as cutting food and handling 
utensils, dressing, and hygiene (personal communications with Jennifer Farmer from Friedreich 
Ataxia Research Alliance and Dr. David Lynch).
The 9-HPT is the optimal choice for the primary endpoint in this study as determined by the 
relevance of impairment in upper limb function to FRDA patients, likely impact of TAK-831, the 
broad study population, and greater precision and accuracy in outcome measurement over other 
measures including the T25FW, visual acuity tests, mFARS, and ADL as indicated by FACOMS 
data [19], and from author personal communication. Anchor- and distribution-based methods in 
accordance with Food and Drug Administration (FDA) guidance [28] will be used to derive a 
responder definition for the 9-HPT in the study population (see Section 13.1.3.1).
6.2.3.2
Secondary Outcome Measure: 
ADL
FARS ADL scale has a total score range of 0 to 36 (higher scores represent greater 
severity/dependency). Each ADL subscale is scored from 0 (normal) to 4 (severe 
disability/inability to carry out activity independently). The 9 ADL subscales include speech, 
swallowing, cutting food and handling utensils, dressing, personal hygiene, falling, walking, 
quality of sitting position, and bladder function. Note items 3 to 5 are directly related to upper limb 
function [29,30].
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mFARS-neuro
The FARS neurological examination is based on neural substrates affected in FRDA including 
bulbar, upper limb, lower limb, peripheral nerve, and upright stability/gait functions (maximum 
scores of 11, 36, 16, 26, and 36, respectively; maximum deficit=125) [29,31]. A functional staging 
was incorporated with a total score ranging from 0 to 6 (higher scores represent greater disability). 
The mFARS-neuro is the modified version of the FARS neurological examination that excludes 
the peripheral nerve component and bulbar assessment item 1-2. The mFARS-neuro has 
demonstrated clinical utility in FRDA and is considered a better functional assessment than the 
FARS as it separates out the functional assessment from assessment of neurological signs. It is a 
clinician-rated measure. In this study, the entire FARS neurological examination will be 
performed and the mFARS-neuro will be extracted after data entry.
T25FW
The T25FW is a quantitative performance-based measure of mobility and leg function used in 
ambulatory FRDA patients. This measure exhibited the highest correlation with accelerometer 
measures and is considered the most accurate measure of ambulation in FRDA [27,32]. The 
subject is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as 
quickly as possible, but safely. The time is calculated from the initiation of the instruction to start 
and ends when the subject has reached the 25-foot mark. The task is immediately administered 
again by having the subject walk back the same distance. Subjects may use assistive devices when 
doing this task.
The T25FW is a useful measure of lower limb function in ambulatory FRDA patients and 
correlates with disease status and duration as well as other performance-based measures in FRDA 
(including the 9-HPT) [27].
T25FW and 9-HPT Composite Measure
The T25FW and 9-HPT will be evaluated together as a performance-based composite measure of 
limb ataxia which has been shown to be a reliable assessment of function in FRDA [30]. The 
composite measure is created using the basic methods used in the MSFC [33]. In brief, raw scores 
from each test are tabulated and converted to test-specific Z scores by subtracting the cohort mean 
from the raw score, and then dividing by the cohort SD to create a Z score for the test. The inverse 
is taken for the 9-HPT (9-HPT-1). The composite Z scores will be created by subtracting Z-score 
for T25FW from the Z-score for 9-HPT-1.
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LCLA
The LCLA test provides a simple and reliable clinical outcome assessment measure for evaluating 
visual dysfunction, a highly prevalent manifestation, in FRDA [34]. Testing will be performed 
binocularly using Low-Contrast Sloan Letter Charts at different contrast levels. 
Clinical Global Impression (CGI-I, CGI-S)
The Clinical Global Impression Scale (CGI) provides an overall clinician-determined summary 
measure that takes into account all available information, including knowledge of the subject’s 
history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the 
subject’s ability to function.
The CGI comprises 2 companion 1-item measures evaluating the following: (a) CGI-S, severity of 
psychopathology from 1 to 7 and (b) CGI-I, improvement from the initiation of treatment on a 
similar 7-point scale. 
The CGI-S will be administered at baseline and at various time points to assess overall severity and 
severity of upper extremity function.
Patient Global Impression (PGI-I, PGI-S)
The PGI rating scales capture global efficacy as perceived by the subject and provide “anchors” to 
determine clinically-relevant effects.
The PGI-S requires the subject to rate his/her disease severity at the time of assessment on a 
5-point scale ranging from normal to extremely severe.
The PGI-I measures improvement due to treatment relative to Baseline on a 7-point scale ranging 
from 1 (very much improved) to 7 (very much worse). 
The PGI-S and the PGI-I will be administered similarly to the CGI-S and CGI-I.
6.2.3.3
Exploratory Outcome Measures
Digital Quantification of Gait (for Ambulatory Patients Only), Upper Body Stability, and Upper 
Limb Movement
The use of digital devices, such as the Lab Mobility Test, provides means of objective measures of 
subject’s gait and stability to explore the effect of TAK-831 treatment. This work will be of an 
exploratory nature to assess utility of digital measurements of disease activity in ataxia. Data from 
this exploratory measurement will not be included in the clinical database.
Digital Assessments of Speech
Each subject will be asked to complete a speech battery suitable for measuring components of 
speech and voice resulting from ataxia. Speech data will be analyzed objectively using acoustic 
analysis software. This assessment is of an exploratory nature and will be used to evaluate the 
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effect of TAK-831 on voice characteristics in ataxia [35]. Please refer to the Redenlab study 
manual for additional details. 
Subject Exit Interview
A semistructured, qualitative subject Exit Interview is planned. The key objectives of the Exit 
Interview are as follows:

To understand the subject experience with FRDA (including symptoms and day-to-day 
impacts), previous management of symptoms, and treatment expectations.

To understand the most relevant and important outcomes that subjects desire so that 
meaningful treatment from the subject perspective can be better understood.

To evaluate the subject-perceived meaningfulness of change in upper limb function due to 
TAK-831 (given the planned primary endpoint).

To determine the overall perception of treatment with TAK-831.
The interviews will be conducted over the phone within 7 days from the last dose of study 
medication of the double-blind Treatment Period or within 7 days of notification of termination for 
the Early Termination Visit. Experienced interviewers from a third-party research organization 
will conduct the interviews. All interviewers will be blinded to treatment assignment and 
interviews will be audio-recorded pending subject consent.
D-Serine Levels
Plasma D-serine levels could be used as a biomarker for peripheral inhibition of DAO enzyme. PD 
parameters will be determined from the concentration-time profiles for all evaluable subjects. 
Actual sampling times, rather than scheduled sampling times, will be used in all computations 
involving sampling times. 
6.3
Premature Termination or Suspension of Study or Study Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied that 
require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a change in the known risk/benefit profile for the TAK-831, such that the risk is no 
longer acceptable for subjects participating in the study. 

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety. 

Subjects experience any of the Takeda Medically Significant List events.
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
Abnormal liver function:
–
Two or more subjects experience alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) elevations >5× the upper limit of normal (ULN) in the absence of 
a concomitant bilirubin increase.*
–
One or more subjects experience ALT and/or AST elevations >3×ULN in the presence of a 
total bilirubin increase >2×ULN or an international normalized ratio (INR) >1.5 without 
findings of cholestasis or other alternate etiology to explain the elevations (ie, “Hy’s Law 
cases”).
–
Two or more subjects experience ALT and/or AST elevations >3×ULN with the 
appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash, and/or eosinophilia (>5%).
*Note that the study may be terminated early prior to full attainment of these criteria (eg, if just 1 
subject experiences 1 of these events) if warranted by safety data from the other subjects dosed in 
the study to date.
6.3.2
Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s)
In the event that the sponsor, an institutional review board (IRB), or regulatory authority elects to 
terminate or suspend the study or the participation of a study site, a study-specific procedure for 
early termination or suspension will be provided by the sponsor; the procedure will be followed by 
applicable study sites during the course of termination or study suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to randomization.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study: 
1. In the opinion of the investigator, the subject is capable of understanding the informed consent, 
and capable of understanding and complying with protocol requirements.
2. The subject signs and dates a written, informed consent. 
3. The subject is an adult male or female aged 18 to 55 years, inclusive, at the time of informed 
consent.
4. The subject has a genetically-confirmed diagnosis (homozygous for GAA repeat expansions in 
the FXN in the affected range of FRDA or a compound heterozygous expansion with a point 
mutation or deletion), with an established disease stage of 2 to 5, inclusive, as determined by 
the Functional Staging for Ataxia, at Screening.
5. The subject is able to complete the 9-HPT test in ≤150 seconds at Screening.
6. The subject weighs ≥43 kg and has a body mass index (BMI) between 16.0 and 40.0 kg/m2, 
inclusive at Screening.
7. A male subject who is nonsterilized* and sexually active with a female partner of childbearing 
potential* agrees to use barrier method of contraception (eg, condom with spermicide cream or 
jelly)* from signing of informed consent throughout the duration of the study and for 95 days 
after last dose. The male subject agrees to advise the female partner to use a highly 
effective/effective method of contraception.*
8. A female subject is of nonchildbearing potential or, a female subject of childbearing potential* 
who is sexually active with a nonsterilized* male partner agrees to use 2 highly 
effective/effective methods of contraception* from signing of informed consent throughout the 
duration of the study and for 35 days after the last dose.
*Definitions and highly effective methods of contraception are defined in Section 9.1.11 and 
reporting responsibilities are defined in Section 9.1.12.
9. Female subjects of childbearing potential must have a negative serum pregnancy test at 
Screening.
10. The subject is able to swallow study drug in tablet form.
11. If a subject requires a caregiver to accompany him/her during the study for clinic visits, a 
caregiver and backup caregivers should be available.
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7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1. The subject has received a diagnosis of ataxic syndromes other than FRDA.
2. The subject has, based on medical history and judgment of the investigator, uncontrolled, 
clinically significant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, 
gastrointestinal, or endocrine disease (including uncontrolled diabetes) or other abnormality 
(other than the disease being studied), which may impact the ability of the subject to participate 
or potentially confound the efficacy and safety evaluation. The subject has medical history or 
conditions that, in the opinion of the investigator, may interfere with study conduct or clinical 
assessments.
3. The subject has received treatment with other experimental therapies within the last 30 days or 
5x half-lives, whichever is longer, prior to the first dose of study drug.
4. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in the conduct of this study 
(eg, spouse, parent, child, sibling) or may consent under duress.
5. The subject has a history of cancer, except squamous cell carcinoma or basal cell carcinoma 
that have been treated or excised, or in situ cervical cancer that has been in remission for ≥5 
years prior to first dose of study drug.
6. The subject is known to have a history of having been infected with human immunodeficiency 
virus (HIV), hepatitis B virus, or hepatitis C virus.
7. Urine drug screen positive for drugs of abuse at Screening or, except for a prescribed drug 
allowed by the protocol at Screening. Cannabinoid use is not permitted either recreationally or 
medically. 
8. The subject has a known hypersensitivity to any component of the formulation of TAK-831.
9. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse within 1 year prior to Screening.
10. The subject has taken any excluded medication, or has had insufficient washout of medications 
as listed in the Excluded/Allowed Medications, Procedures, and Treatments table listed in 
Section 7.3 or is unable or unwilling to discontinue medications as required by the protocol.
11. The subject is considered by the investigator to be at imminent risk of suicide or injury to self, 
others, or property or subjects who within the past year prior to Screening have attempted 
suicide or have positive answers on item 4 or 5 on the C-SSRS, life-time version, at Screening 
or Day 1.
12. The subject has clinically significant cardiac abnormalities at Screening that, in the opinion of 
the investigator, makes the subject unsuitable for enrollment, including but not limited to heart 
failure meeting criteria for class IV insufficiency by the New York Heart Association or 
documented ejection fraction <40%.
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13. The subject has a QT interval with Fridericia correction method (QTcF) >450 msec (males) or 
>470 msec (females), confirmed with 1 repeat testing, at Screening or Day -1.
14. If male, the subject intends to donate sperm during the course of this study or for 95 days after 
the last dose of study drug.
15. If female, the subject is of childbearing potential and lactating, pregnant (positive 
prerandomization serum pregnancy test), or plans to become pregnant before participating in 
the study, during the study, or within 35 days after last dose of the study drug, or intending to 
donate ova during such time period.
16. The subject has a history of neuroleptic malignant syndrome, water intoxication, or paralytic 
ileus or other conditions that may interfere with absorption of study medication.
17. The subject has 1 or more laboratory values outside the normal range that are considered by the 
investigator to be clinically significant at the Screening Visit; or the subject has any of the 
following at the Screening Visit: a serum creatinine value >1.5 times the ULN, a total serum 
total bilirubin value >1.5×ULN, or a serum ALT or AST value >2×ULN. 
18. The subject has current history of symptomatic orthostatic hypotension.
7.3
Excluded Medications, Supplements, and Dietary Products
The following are excluded:

Inhibitors for uridine 5'-diphosphate-glucuronosyltransferase (UGT) enzymes (Probenecid 
and valproic acid) should be excluded for 14 days prior to dosing. 

Subjects must be instructed not to start any medications during the study, including 
over-the-counter products, without first consulting with the investigator. Occasional use of 
acetaminophen and aspirin are allowed.

Disallowed agents with CNS effects including but not limited to stimulants, lithium, or 
monoamine-oxidase inhibitor antidepressant agents, dextromethorphan, memantine, 
amantadine, antipsychotics medications. See Table 7.a for details.

Sedative or hypnotic medication at equivalent doses greater than lorazepam 2 mg should not be 
used within 24 hours of the conduct of any clinical assessments. 

Other agents with CNS effects may be allowed after consultation with the study sponsor or 
sponsor's designee.
Table 7.a provides a list of excluded and allowed medications. This table however is not a 
comprehensive list and consultation with sponsor/representative might be warranted.
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Table 7.a
Excluded/Allowed Medications and Treatments
Drug Class
Disallowed (X) During the Study 
(sections without X indicate no restriction)
Chronic Use
Episodic Use
Comments or Exceptions
Inhibitors for UGT enzymes (Probenecid and 
valproic acid)
X
X
Wash-out for at least 14 days prior to 
randomization
Any investigational drug
X
X
Must have completed clinical trial and 
stopped investigational drug 30 days before 
Screening or 5 half-lives, whichever is longer
Dextromethorphan, memantine, amantadine, or 
other glutamatergic drugs
X
X
Wash-out of at least 3 weeks prior to 
randomization and approval for patient 
inclusion by sponsor/representative
Psychotropic agents not otherwise specified 
(including but not limited to stimulants, 
tryptophan, melatonin)
X
X
Wash-out of at least 3 weeks prior to 
randomization and approval for patient 
inclusion by sponsor/representative
Antipsychotics
X
X
Excluded
Narcotic analgesics
X
X
Except chronic use on stable dose for at least 
30 days prior to randomization 
Anticonvulsants (gabapentin, pregabalin or 
related drugs)
X
X
Except chronic use on stable dose for at least 
30 days prior to randomization for the 
management of pain. Phenytoin is excluded. 
All other anticonvulsants need approval for 
inclusion by sponsor.
Antidepressant SSRIs, SNRIs
X
Except chronic use on stable dose for at least 
8 weeks prior to randomization and 
consultation with sponsor/representative
Herbal remedies, which are psychoactive (eg, St. 
Johns Wort, kava kava, valerian, ginkgo biloba, 
melatonin), OTC (e.g., caugh syrup)
X
X
All OTC excluded. Patients should be 
instructed to consult with PI regarding prior 
to starting any medications
Sedatives/hypnotics 
X
X
Except as described in Section 7.3
Muscle relaxants including but not limited to 
baclofen, tizanidine, 4 aminopyridine
X
X
Except chronic use on stable dose for at least 
14 days prior to randomization
Antiparkinsonian drugs including dopamine 
agonists
X
X
Except chronic use on stable dose for at least 
14 days prior to randomization
Benzodiazepines
X
X
Except chronic use on stable dose for at least 
14 days prior to randomization
MAOI=monoamine oxidase inhibitor, NSAIDs=nonsteroidal anti-inflammatory drugs, OTC=over-the-counter, 
RIMA=reversible inhibitor of monoamine oxidase type A, SNRI=serotonin–norepinephrine reuptake inhibitor, 
SSRI=selective serotonin reuptake inhibitor.
7.4
Diet, Fluid, Activity Control
Subjects will maintain their regular routine of exercise and physical therapy or speech therapy.
Alcohol intake will be restricted to no more than 1 unit in 1 occasion and less than 3 units per 
week. One unit is equivalent to a half-pint of beer or 1 single measure of spirits or 1 small glass of 
wine. Subject will not drink alcohol with 24 hours of the conduct of any clinical assessments. 
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7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the electronic case report form (eCRF) using the following categories. For 
screen failure subjects, refer to Section 9.1.18.
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires early 
termination because continued participation imposes an unacceptable risk to the subject’s 
health or the subject is unwilling to continue because of the PTE or AE.

Liver function test (LFT) abnormalities:
Study drug should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.10), if the following circumstances occur at any 
time during study drug treatment:
–
ALT or AST >8×ULN, or
–
ALT or AST >5×ULN and persists for ≥2 weeks, or
–
ALT or AST >3×ULN in conjunction with elevated total bilirubin >2×ULN or 
INR >1.5, or
–
ALT or AST >3×ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).

ECG abnormalities
–
QTcF > 500 ms
2. Significant protocol deviation. The discovery postrandomization that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued participation 
poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documentation.
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal because of 
an AE should not be recorded in the “voluntary withdrawal” category; similarly, lack of 
efficacy should not be recorded in the “voluntary withdrawal” category).
5. Study termination. The sponsor, IRB, or regulatory agency terminates the study.
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6. Pregnancy. The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.12.
7. Severe gastrointestinal intolerance. The subject develops severe gastrointestinal intolerance 
that cannot be ameliorated by supportive treatment.
8. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
Early Termination Visit. Discontinued or withdrawn subjects will not be replaced.
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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Study Drug and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term study drug refers to all or any of the drugs defined below.
8.1.1.1
Study Drug
TAK-831 100 mg, 25 mg, and matching placebo tablets will be provided as unmarked, round, 
yellow-red, film-coated tablets for oral administration. TAK-831 is manufactured by Takeda 
Pharmaceuticals, Osaka, Japan.
The TAK-831 100 mg, 25 mg, and matching placebo tablets will be supplied in round, 
high-density polyethylene, 150 cc, round white bottles with child resistant caps. Each bottle will 
contain 180 tablets and will be labeled with a single-panel, double-blind label. The label will 
include pertinent study information and appropriate country-specific regulatory caution 
statements.
8.1.1.2
Sponsor-supplied Drug
Sponsor-supplied drugs referenced in other sections of the protocol include the following: 
TAK-831 100 mg, 25 mg, and matching placebo tablets.
8.1.2
Storage
Study drug must be kept in an appropriate, limited-access, secure place until it is used or returned 
to the sponsor or designee for destruction. Study drug must be stored under the conditions 
specified on the label, and remain in the original container until dispensed. A daily temperature log 
of the drug storage area must be maintained every working day.
8.1.3
Dose and Regimen
Treatment doses and regimens for the study are provided in Table 8.a.
Table 8.a
Dose and Regimen
Treatment 
Group
Dose
Treatment Description
Active
Placebo
Placebo
Placebo BID
Zero active tablets
3 TAK-831 placebo tablets
Low dose
TAK-831 75 mg BID
3 TAK-831 25 mg tablets 
Zero TAK-831 placebo tablets
High dose
TAK-831 300 mg BID
3 TAK-831 100 mg tablets
Zero TAK-831 placebo tablets
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8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of study drug, to or by a 
study subject, at a dose above that which is assigned to that individual subject according to the 
study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on AE CRF(s) according to Section 10.0.
Serious adverse events (SAEs) associated with overdose should be reported according to the 
procedure outlined in Section 10.2.2.
In the event of drug overdose, the subject should be treated symptomatically. 
8.2
Study Drug Assignment and Dispensing Procedures
If sponsor-supplied drug TAK-831 100 mg, 25 mg, or placebo tablets are lost or damaged, the site 
can request a replacement from interactive response technology (IRT).
At the first and subsequent drug-dispensing visits, the investigator or designee will access the IRT 
to request study drug for a subject. The medication identification (ID) number of the study drug to 
be dispensed will be provided by the IRT.
8.3
Randomization Code Creation and Storage 
The designee of the sponsor will generate the randomization schedule. All randomization 
information will be stored in a secured area, accessible only by authorized personnel.
8.4
Study Drug Blind Maintenance 
The study drug blind will be maintained using the IRT.
8.5
Unblinding Procedure
The study drug blind shall not be broken by the investigator unless information concerning the 
study drug is necessary for the medical treatment of the subject. All study assessments and 
causality assessment should be performed, if possible, prior to unblinding. In the event of a 
medical emergency, if possible, the medical monitor should be contacted before the study drug 
blind is broken to discuss the need for unblinding.
For unblinding a subject, the study drug blind can be obtained by the investigator, by accessing the 
IRT.
The sponsor must be notified as soon as possible if the study drug blind is broken. The date, time, 
and reason the blind is broken must be recorded in the source documents and the same information 
(except the time) must be recorded on the eCRF.
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If any site personnel are unblinded, study drug must be stopped immediately and the subject must 
be withdrawn from the study.
8.6
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being destroyed or returned to the 
sponsor or designee.
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance with 
the protocol and is dispensed only to subjects enrolled in the study. To document appropriate use 
of sponsor-supplied drug TAK-831 100 mg, 25 mg, and matching placebo tablets, the investigator 
or designee must maintain records of all sponsor-supplied drug delivery to the site, site inventory, 
dispensation and use by each subject, and return to the sponsor or designee.
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, and the 
medication is in good condition. If quantity and conditions are acceptable, investigator or designee 
should acknowledge the receipt of the shipment by signing bottom half of the packing list and by 
recording in IRT. If there are any discrepancies between the packing list versus the actual product 
received, Takeda must be contacted to resolve the issue. The packing list should be filed in the 
investigator’s essential document file.
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to:

Continuously monitoring expiration dates if expiry date is provided to the investigator or 
designee. 

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the drug lot/medication ID/job number used to prepare 
each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The IRT will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
The investigator or designee must record the current inventory of all sponsor-supplied drugs, 
TAK-831 100 mg, 25 mg, and matching placebo tablets on a sponsor-approved drug 
accountability log. The following information will be recorded at a minimum: protocol number 
and title, name of investigator, site identifier and number, description of sponsor-supplied drugs, 
date and amount dispensed including initials, seal, or signature of the person dispensing the drug, 
and the date and amount returned to the site by the subject, including the initials, seal, or signature 
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of the person receiving the sponsor-supplied drug. The log should include all required information 
as a separate entry for each subject to whom sponsor-supplied drug is dispensed. 
All study drug not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug accountability log.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 
drugs are destroyed or returned to the sponsor or its designee for destruction. The investigator or 
designee will retain a copy of the documentation regarding sponsor-supplied drug accountability, 
return, and/or destruction, and originals will be sent to the sponsor or designee.
The investigator will be notified of any expiry date or retest date extension of sponsor-supplied 
drug during the study conduct. On expiry date notification from the sponsor or designee, the site 
must complete all instructions outlined in the notification, including segregation of expired 
sponsor-supplied drug for return to the sponsor or its designee for destruction.
In the event of expiry date extension of sponsor-supplied drug already at the study site, 
sponsor-supplied drugs may be relabeled with the new expiry date at that site. In such cases, 
Takeda or its designee will prepare additional labels, certificates of analyses, and all necessary 
documentation for completion of the procedure at the sites. 
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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures to be performed and data to be collected. For 
each procedure, subjects are to be assessed by the same investigator or site personnel whenever 
possible. The Schedule of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed, including requesting that a subject fast for laboratory 
evaluations.
A unique subject identification number (site number plus subject number) will be assigned to each 
subject at the time that informed consent is obtained; this subject number will be used throughout 
the study. 
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth, sex, Hispanic ethnicity, race as 
described by the subject, height, weight, alcohol use, reproductive status, and smoking status of the 
subject at Screening.
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to FRDA (including age at disease onset) that resolved at or prior to 
signing of informed consent. Ongoing conditions are considered concurrent medical conditions 
(see Section 9.1.9).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria.
9.1.3
Physical Examination Procedure
A baseline physical examination (defined as the assessment prior to the first dose of study drug) 
will consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular 
system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; 
(7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) other. 
All subsequent physical examinations should assess clinically significant changes from the 
assessment prior to first dose examination.
Property of Takeda: For non-commer
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Any abnormal finding on a pretreatment physical examination assessment must be assessed as not 
clinically significant or clinically significant by the investigator and recorded in the source 
document and eCRF. All clinically significant findings/changes will be recorded as a pretreatment 
event (PTE) or concurrent medical condition in the source document and in the eCRF described in 
Section 10.0. 
On subsequent examinations, any abnormal change from the baseline physical examination must 
be assessed as not clinically significant or clinically significant by the investigator and recorded in 
the source document and eCRF. Any clinically significant change or new diagnosis as a result of a 
clinically significant change, as determined by the investigator, will be recorded as an AE in the 
source document and on the PTE/AE page of the eCRF. 
Neurological exams: FARS neurological exam will substitute for the standard neurological exams. 
FARS includes neurological signs that specifically reflect neural substrates affected in FRDA. 
Based on a neurological examination, bulbar, upper limb, lower limb, peripheral nerve, and 
upright stability/gait functions are assessed. See Section 9.1.7.
9.1.4
Weight, Height, and BMI
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off (not applicable for subjects who are in wheelchairs and their weight can be obtained by 
alternative methods or based on medical history). The BMI is calculated at Screening using metric 
units with the formula below. Height is recorded in centimeters without decimal places, and 
weight is collected in kilograms (kg) with 1 decimal place. BMI should be derived as follows:
Metric
BMI =
	
 ()
	
 ()
Note that although height is reported in centimeters, the formula uses meters for height; meters can 
be determined from centimeters by dividing by 100. Thus, for example, if height=176 cm 
(1.76 meters) and weight=79.2 kg, then BMI=79.2/1.762=25.56818 kg/m2.
The values should be reported to 1 decimal place by rounding. Thus, in the above example BMI 
would be reported as 25.6 kg/m2.
9.1.5
Vital Sign Procedure
Vital signs will include oral body temperature, respiratory rate, sitting blood pressure (systolic and 
diastolic, resting more than 5 minutes), and pulse (beats per minute).
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within 0.5 hour before or after the scheduled blood draw. 
If vital signs are abnormal, a repeat measurement may be performed and recorded approximately 
15 minutes after the first measurement. 
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9.1.6
Other Safety Measurements
The C-SSRS will be administered at all timepoints including Screening and Baseline. The C-SSRS 
was developed by researchers at Columbia University as a tool to help systematically assess 
suicidal ideation and behavior in subjects during participation in a clinical trial of centrally acting 
drugs.
The C-SSRS is composed of 3 questions addressing suicidal behavior and 5 questions addressing 
suicidal ideation, with subquestions assessing the severity. The tool is administered via interview 
with the subject (by a trained operator/interviewer). If possible, the same interviewer should be 
used throughout the study for the same subject. All events such as suicidal ideations or behaviors 
should be reported as AEs [36].
9.1.7
Primary and Secondary Efficacy Measurements
The sequence of efficacy assessment should take into consideration of subject fatigue and morning 
dosing time of study drug. In particular, the 9-HPT and digital speech recording should be done 
first among the assessments and procedures, and around or between 2-4 hours after the morning 
dose of the study drug unless stated otherwise in the Schedule of Study Procedures For example, 
on Day 1 assessments will all be conducted before dosing the subjects. 
The following assessments will be administered by a neurologist who has experience with the 
FARS. Each site will also have a trained neurologist to serve as back-up to the primary neurologist. 
However, it is strongly recommended that the same neurologist assess the same subjects at each 
visit throughout the study, as much as possible. The time of the day for the assessment should be 
consistent throughout the study as much as possible (eg, all mornings or a rough window of time). 

FARS neurological exam.

CGI-S (global severity).

CGI-I (global improvement).

CGI-S (upper extremity functional severity).

CGI-I (upper extremity functional improvement).
The following assessments will be administer by qualified study personnel (nurse, study 
coordinator) appointed by the principal investigator. Each should have a record of successful 
completion of the required training, and have experience in FRDA or ataxia clinical trials. Each 
site should also have a back-up administrator meeting the same requirements. However, it is 
strongly recommended that the same administrator assess the same subjects at the various visits 
throughout the study, as much as possible. The time of the day for the assessment should be 
consistent throughout the study as much as possible (eg, all mornings or a rough window of time). 

9-HPT.

T25FW (for ambulatory subjects only. This will be done with the digital sensors for gait 
assessment).
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
LCLA test.

Digital speech assessment.

Digital balance and upper limb assessment.

C-SSRS.
The following assessments are patient-reported outcome measures:

FARS ADL.

PGI-S (global severity).

PGI-I (global improvement). 

PGI-S (upper extremity functional severity).

PGI-I (upper extremity functional improvement).
9.1.8
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study drug. These may be prescribed 
by a physician or obtained by the subject over the counter. Concomitant medication is not provided 
by the sponsor. At each study visit, subjects will be asked whether they have taken any medication 
other than the study drug (used from signing of informed consent through the end of the study), 
and all medication including vitamin supplements, over-the-counter medications, and oral herbal 
preparations, must be recorded in the eCRF. Documentation will include generic medication 
name, dose, unit, frequency, route of administration, start and end dates, and reason for use.
9.1.9
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, ECG, or physical 
examination abnormalities noted at the screening examination. The condition (ie, diagnosis) 
should be described.
9.1.10
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. Details of these 
procedures and required safety monitoring will be given in the laboratory manual. Section 9.4
describes procedures for specimen handling.
The tests that will be performed for each clinical laboratory specimen are listed in Table 9.a.
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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
RBCs
WBCs with differential (% 
and absolute)
Hemoglobin
Hematocrit
Platelets 
ALT
Albumin
Alkaline phosphatase
AST
Total bilirubin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
γ-Glutamyl transferase
Potassium
Sodium
Glucose
Chloride
Bicarbonate
Calcium
pH
Specific gravity
Protein
Glucose
Blood 
Nitrite
Ketones
Bilirubin
Urobilinogen
Leukocyte esterase
Microscopic Analysis: (a)
Erythrocytes/RBCs/high 
power field
Leukocytes/WBCs/high 
power field
Epithelial cells, casts, etc
Serum
Urine
Female subjects of childbearing potential only:
hCG (for pregnancy) at Screening and ET visit.
FSH 
Urine drug screen including amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, methamphetamine, 
opiates. 
Female subjects of childbearing potential only:
hCG (for pregnancy) at Visits 2, 4, 5, and 6.
ET=early termination, FSH=follicle-stimulating hormone, GGT=-glutamyl transferase, hCG=human chorionic 
gonadotropin, RBC=red blood cell, WBC=white blood cell.
(a) Microscopic examination of sediment to be performed only if the dipstick results are positive.
The central laboratory will perform laboratory tests for hematology, serum chemistry, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible for 
reviewing and filing these results.
If subjects experience ALT or AST >3×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed preferably 
within 48 to 72 hours and no later than 7 days after the abnormality was noted (please refer to 
Section 10.2.3 for reporting requirements related to abnormal LFT results).
If ALT or AST remains elevated >3×ULN on these 2 consecutive occasions, the investigator must 
contact the Medical Monitor for consideration of additional testing, close monitoring, possible 
discontinuation of study drug, discussion of the relevant subject details, and possible alternative 
etiologies. The abnormality should be recorded as an AE (please refer to Section 10.2.3 for 
reporting requirements related to abnormal LFT results).
The investigator or designee is responsible for transcribing or attaching laboratory results to the 
eCRF. The investigator will maintain a copy of the laboratory accreditation and the reference 
ranges for the laboratory used.
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Laboratory reports must be signed and dated by the principal investigator indicating that the report 
has been reviewed and any abnormalities have been assessed for clinical significance. Any 
abnormalities identified prior to first dose of study drug will require clear and complete 
documentation in the source documents as to the investigator’s assessment of not clinically 
significant before proceeding with enrollment or randomization.
All clinically significant laboratory abnormalities must be recorded as a PTE/AE in the subject’s 
source documents and on the appropriate eCRF. A clinically significant laboratory abnormality 
that has been verified by retesting will be followed until the abnormality returns to an acceptable 
level or a satisfactory explanation has been obtained. 
9.1.11
Contraception and Pregnancy Avoidance Procedure
9.1.11.1 Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and for 95 days after last 
dose of study drug, nonsterilized** male subjects who are sexually active with a female partner of 
childbearing potential* must use barrier contraception (eg, condom with spermicidal cream or 
jelly). In addition, they must be advised not to donate sperm during this period. The male subject 
must agree to advise the female partner to use additional contraception as shown in the list 
containing highly effective/effective contraception in Section 9.1.11.3.
9.1.11.2 Female Subjects and Their Male Partners
From signing of informed consent, throughout the duration of the study, and for 35 days after last 
dose of study drug, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use 2 highly effective/effective methods of contraception (from 
the list in Section 9.1.11.3). 
In addition they must be advised not to donate ova during this period.
9.1.11.3 Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A woman is considered a woman of childbearing potential, ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses 
for 12 months without an alternative medical cause. A high FSH level in the postmenopausal range 
(FSH >40 IU/L) may be used to confirm a postmenopausal state in younger women (eg, those 
<45 year old) or women who are not using hormonal contraception or hormonal replacement 
therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.
** Sterilized males should be at least 1 year post–bilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
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The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this study, where devices containing hormones are excluded, the only acceptable 
methods of contraception are:

Nonhormonal methods: 
–
Intrauterine device.
–
Bilateral tubal occlusion. 
–
Vasectomized partner (provided that partner is the sole sexual partner of the study 
participant and that the vasectomized partner has received medical assessment of 
the surgical success. 
–
True sexual abstinence, only if this is in line with the preferred and usual lifestyle of 
the subject. True abstinence is defined as refraining from heterosexual intercourse 
during the entire period of the study, from 1 month prior to the first dose until 
35 days after last dose.
–
Cervical cap with spermicide and male condom.
–
Diaphragm with spermicide and male condom.
–
Sponge with spermicide and male condom.
2. Double-barrier methods are acceptable for this study if used each time the subject has 
intercourse. 
Acceptable double-barrier methods (each time the subject has intercourse):

Cap (plus spermicidal cream or jelly) PLUS male condom and spermicide.

Diaphragm (plus spermicidal cream or jelly) PLUS male condom and spermicide.
3. Unacceptable methods of contraception are:

Hormonal methods.

Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.
4. Subjects will be provided with information on highly effective/effective methods of 
contraception as part of the subject informed consent process and will be asked to sign a 
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consent form stating that they understand the requirements for avoidance of pregnancy, 
donation of ova, and sperm donation during the course of the study.
5. During the course of the study, regular urine hCG pregnancy tests will be performed only for 
women of childbearing potential and all subjects (male and female) will receive continued 
guidance with respect to the avoidance of pregnancy as part of the study procedures. Such 
guidance should include a reminder of the following:
a) Contraceptive requirements of the study.
b) Reasons for use of barrier methods (ie, condom) in males with pregnant partners.
c) Assessment of subject compliance through questions such as:
i. Have you used the contraception consistently and correctly since the last visit?
ii. Have you forgotten to use contraception since the last visit?
iii. Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)
iv. Is there a chance you could be pregnant?
6. In addition to a negative serum or urine hCG pregnancy test at Screening, female subjects of 
childbearing potential must also have confirmed menses in the month before first dosing (no 
delayed menses), and a negative urine hCG pregnancy test on Day -1. Additional pregnancy 
testing will also be conducted during the study.
9.1.12
Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug (TAK-831) should be immediately discontinued. In addition, any 
pregnancies in the partner of a male subject during the study or within 95 days after the last dose, 
should also be recorded following authorization from the subject’s partner.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
Subjects randomized to placebo need not be followed.
If the female subject or female partner of a male subject agrees to the primary care physician being 
informed, the investigator should notify the primary care physician that the female subject/female 
partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of the study drug the subject received (blinded or unblinded, as applicable).
All pregnancies, including female partners of male subjects, in subjects on active study drug will 
be followed up to final outcome, using the pregnancy form. Pregnancies will remain blinded to the 
study team. The outcome, including any premature termination, must be reported to the sponsor. 
An evaluation after the birth of the child will also be conducted.
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9.1.13
ECG Procedure
Standard 12-lead ECGs will be recorded. When an ECG is scheduled at the same time as the blood 
draws or vital signs, then the blood draws and vital signs will take priority and the ECG will be 
obtained within 0.5 hours before or after the scheduled blood draw or vital sign assignment. If an 
ECG coincides with a meal, the ECG will take precedence followed by the meal.
All 12-lead ECG machines will be supplied by the study site. Subjects should be in a supine 
position following an approximate 5-minute rest period for ECG recordings. Should technical 
difficulties occur during recording of the ECG, a reasonable attempt should be made to repeat the 
ECG shortly after the failed attempt.
The investigator (or a qualified observer at the study site who should have access to a cardiology 
consult) will manually interpret the ECG using 1 of the following categories: within normal limits, 
abnormal but not clinically significant, or abnormal and clinically significant. The time that the 
ECG was performed will be recorded. The following parameters will be calculated automatically 
by the ECG machine and recorded on the eCRF: heart rate, RR interval, PR interval, QT interval, 
QRS interval, QT interval with Bazett correction method, and QTcF interval. QTcF interval may 
be calculated manually by the study site. The QTcF interval is calculated as shown below:
 = 
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One copy of the 12-lead ECG with the physician’s signature and date of assessment will be filed 
with the source documents and captured in the appropriate eCRF. If the original ECG is printed on 
thermal paper, the ECG report must be photocopied and certified. The photocopy will be filed with 
the original ECG in the source. The study site uses a fully validated ECG system. The investigator 
assessment is recorded electronically within this system.
All ECGs will be recorded at the time points detailed in the Schedule of Study Procedures 
(Appendix A). 
9.1.14
PGx Sample Collection
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9.1.15
PK Sample Collection and Analysis 
Serial blood samples (one 4-mL sample per scheduled time) for PK analysis of TAK-831 plasma 
concentrations will be collected into chilled Vacutainers containing the anticoagulant K2EDTA, 
according to the schedule shown in Appendix A.
The actual date and time of each PK sample collection as well as the date and time of study drug 
dosing for the most recent dose will be recorded accurately in the eCRF.
Instructions for sample collection, processing and shipment are provided in the laboratory manual.
9.1.15.1 Bioanalytical Methods
Plasma concentrations of TAK-831 will be measured by a validated high-performance liquid 
chromatography (HPLC) with tandem mass spectrometry method.
9.1.16
PD Sample Collection and Analysis
Serial blood samples (one 6-mL sample per scheduled time) for PD (D- and L-serine) analysis of 
TAK-831 will be collected into chilled Vacutainers containing the anticoagulant K2EDTA, 
according to the schedule shown in in Appendix A.
The actual date and time of sample collection, time since last dose was administered, and time 
since last meal will be recorded on the source document and eCRF.
Instructions for sample collection, processing and shipment are provided in the laboratory manual.
9.1.16.1 Bioanalytical Methods
Plasma concentrations of D- and L-serine will be measured by a validated HPLC with tandem 
mass spectrometry assay method.
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9.1.17
PD Parameters of D- and L-Serine
PD parameters will be determined from the concentration-time profiles for all evaluable subjects. 
Actual sampling times, rather than scheduled sampling times, will be used in all computations 
involving sampling times. 
9.1.18
Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent.
If the subject is withdrawn at the Screening Visit, the investigator should complete the eCRF. The 
IRT should be contacted as a notification of screen failure.
The primary reason for screen failure is recorded in the eCRF using the following categories:

PTE/AE.

Did not meet inclusion criteria or did meet exclusion criteria (specify reason). 

Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal (specify reason).

Study termination.

Other (specify reason).
Subject identification numbers assigned to subjects who fail screening should not be used again. 
Subjects can only be rescreened after approval by the sponsor. 
9.1.19
Documentation of Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment phase.
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF.
All measurements will be recorded on the source documents and in the eCRF.
9.2
Monitoring Subject Treatment Compliance
Subjects will be required to bring study drug containers/unused study drugs to each dispensing site 
visit. 
If a subject is persistently noncompliant with the study drug (80% of the allocated study drug for 
the period since the last visit), it may be appropriate to withdraw the subject from the study. All 
subjects should be reinstructed about the dosing requirement during study contacts. The authorized 
study personnel conducting the re-education must document the process in the subject source 
records.
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9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A.
Assessments should be completed at the designated visits.
9.3.1
Screening
Subjects will be screened as specified in Appendix A. Subjects will be screened in accordance with 
predefined inclusion and exclusion criteria as described in Section 7.0. See Section 9.1.18 for 
procedures for documenting screen failures.
9.3.2
Study Entrance/Randomization
Randomization will take place as described in Appendix A.
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized using the IRT, as described in Section 8.2. 
Subjects will be instructed on when to take the first dose of study drug as described in Section 6.1. 
The procedure for documenting screen failures is provided in Section 9.1.18.
9.3.3
Treatment Phase
Study-related procedures will be conducted according to the Schedule of Study Procedures in 
Appendix A.
9.3.4
Interim Phone Calls
Interim phone calls will be performed at the time specified in Appendix A. 
9.3.5
Safety Follow-up Phone Call or Early Termination
The final safety phone call will be performed at the time specified in Appendix A or at the Early 
Termination Visit. 
For all subjects receiving study drug, the investigator must complete the End of Study eCRF page.
9.3.6
Exit Interview Phone Call
A semistructured Exit Interview will be conducted by phone as specified in Appendix A.
9.3.7
Post Study Care
Study drug will not be available upon completion of the subject’s participation in the study. The 
subject should be returned to the care of a physician and standard therapies as required.
9.4
 
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9.5
Blood Volume
Approximate blood volumes to be collected for each subject are shown in Table 9.b. 
Table 9.b
Approximate Blood Volume
Sample Type
Sample Volume 
(mL)
Number of Samples (a)
Total Volume 
(mL)
Screening and 
Day -1
Treatment Period
Clinical laboratory 
(hematology and serum 
chemistry) 
21
1
2
63
PK 
4
1
5
24
PD (D- and L-serine)
6
1
3
24
Total approximate blood sampling volume (mL)
117
(a) Does not include blood draws at any unscheduled visits.
For each subject, the maximum volume of blood collected at any single visit is approximately 
37 mL, and the approximate total volume of blood for the study is 117 mL.
Direct venipuncture is recommended for all blood collections: if a catheter is used, then use the 
saline lock (catheter) for the blood draws without the extra tubing (eg, BD Insyte Autoguard 
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#381434 [needle] and ICU Medical, Inc Clave Connector #PM30-2381 or similar). Any other 
method will need to be approved by the sponsor. 
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10.0
PRETREATMENT EVENTS AND AES
10.1
Definitions
10.1.1
PTEs
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study drug; it 
does not necessarily have to have a causal relationship with study participation.
10.1.2
AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory value), symptom, or disease temporally associated with the use of a drug whether or not 
it is considered related to the drug.
10.1.3
Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered PTEs or 
AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study drug or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG findings are only considered to be PTEs or AEs if they 
are judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory or ECG re-test and/or continued monitoring of an abnormal value or finding is not 
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considered an intervention. In addition, repeated or additional noninvasive testing for 
verification, evaluation or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent medical condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study drug) or an AE 
(worsening or complication occurs after start of study drug). Investigators should ensure that 
the event term recorded captures the change in the condition (eg, “worsening of…”).

If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy) any 
occurrence of an episode should only be captured as a PTE/AE if the condition becomes more 
frequent, serious or severe in nature. Investigators should ensure that the AE term recorded 
captures the change in the condition from Baseline (eg, “worsening of…”).

If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be recorded as a PTE/AE if occurring to a 
greater extent to that which would be expected. Investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after the start of study drug, 
the worsening or complication should be recorded as an AE. Investigators should ensure that 
the AE term recorded captures the change in the PTE (eg, “worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study
drug, the worsening or complication should be recorded as a new AE. Investigators should 
ensure that the AE term recorded captures the change in the condition (eg, “worsening of…”).
Changes in intensity of AEs /Serious PTEs:

If the subject experiences changes in intensity of an AE/serious PTE, the event should be 
captured once with the maximum intensity recorded.
Preplanned procedures (surgeries or interventions):

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 
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worsening of the condition should be recorded as a PTE or an AE. Complications resulting 
from any planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing illness 
and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of 
the eCRF.
10.1.4
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
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Table 10.a
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Acute liver failure
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by a 
medicinal product
Convulsive seizure
Pulmonary fibrosis 
Hepatic necrosis
Spontaneous abortion / stillbirth and fetal death
Malignant hypertension
Pulmonary hypertension
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia
Anaphylactic shock
Acute renal failure
Toxic epidermal necrolysis/Stevens-Johnson syndrome Neuroleptic malignant syndrome / malignant hyperthermia
Note: Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered as 
“Important Medical Events” satisfying SAE reporting requirements.
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5
Intensity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.6
Causality of AEs
The relationship of each AE to study drug(s) will be assessed using the following categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant medications and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant medications and concurrent treatments.
10.1.7
Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.
The relationship should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as Not Related. 
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10.1.8
Start Date
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or investigator.
10.1.9
Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but with 
sequelae, or the subject died.
10.1.10 Frequency 
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous.
10.1.11 Action Concerning Study Drug

Drug withdrawn – a study drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not Applicable – a study drug was stopped for a reason other than the particular AE eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped before 
the onset of the AE.

Dose Reduced – the dose was reduced due to the particular AE.

Dose Interrupted – the dose was interrupted due to the particular AE.
10.1.12 Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE.

Recovering/Resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to Baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”.

Not recovered/not resolved—there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/PTE state remaining “Not 
recovered/not resolved”.

Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis.

Fatal – the AEs/PTEs which are considered as the cause of death. 
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
Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1
Collection and Reporting of AEs
10.2.1.1 PTE and AE Collection Period
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study drug (Visit 3) or 
until screen failure. For subjects who discontinue prior to study drug administration, PTEs are 
collected until the subject discontinues study participation.
Collection of AEs will commence from the time that the subject is first administered study drug 
(Visit 3). Routine collection of AEs will continue until the follow-up phone call.
10.2.1.2 PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or there is a satisfactory explanation for the change. 
Nonserious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study drug or 
not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or until there is a satisfactory explanation for the 
changes observed. All PTEs and AEs will be documented in the PTE/AE page of the eCRF, 
whether or not the investigator concludes that the event is related to the drug treatment. The 
following information will be documented for each event:
1. Event term.
2. Start and stop date. The timing of the AE in relation to first dose of study drug (predose or 
postdose) will be indicated if the AE occurs on the first day of dosing.
3. Frequency.
4. Intensity.
5. Investigator’s opinion of the causal relationship between the event and administration of study 
drug(s) (related or not related) (not completed for PTEs).
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.
7. Action concerning study drug (not applicable for PTEs).
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8. Outcome of event.
9. Seriousness.
The Exit Interview and the ADL component of FARS will not be used as a primary means to 
collect AEs. However, should the investigator become aware of a potential AE through the 
information collected with this instrument, proper follow-up with the subject for medical 
evaluation should be undertaken. Through this follow-up if it is determined that an AE not 
previously reported has been identified, normal reporting requirements should be applied.
10.2.2
Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
A Takeda SAE form must be completed, in English, and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:
A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study drug.

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of Serious PTEs will follow the procedure described for SAEs.
10.2.3
Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.10 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Takeda SAE form (as per Section 10.2.2).
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10.3
Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form (or provide other written documentation) and 
fax it within 24 hours of receipt. Copies of any relevant data from the hospital notes (eg, ECGs, 
laboratory tests, discharge summary, postmortem results) should be sent to the addressee, if 
requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.3.1
Safety Reporting to Investigators, IRBs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the FDA, European 
Medicines Agency, investigators, and IRBs, as applicable, in accordance with national regulations 
in the countries where the study is conducted. Relative to the first awareness of the event by/or 
further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory 
authorities as expedited report within 7 days for fatal and life-threatening events and 15 days for 
other serious events, unless otherwise required by national regulations. The sponsor will also 
prepare an expedited report for other safety issues where these might materially alter the current 
benefit-risk assessment of a study drug/sponsor supplied drug or that would be sufficient to 
consider changes in the study drug/sponsor supplied drug administration or in the overall conduct 
of the trial. The study site also will forward a copy of all expedited reports to his or her IRB.
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11.0
STUDY-SPECIFIC COMMITTEES
This study does not include endpoints related to assessing mortality or major adverse health 
outcomes, and the study population is not at risk of serious safety events given the clinical 
characteristics of the disorder and known trajectory of disease progression. In addition, as 
summarized in Section 4.1.4, TAK-831 has been well tolerated and safe across the full range of 
doses examined in clinical studies, and there have not been any safety findings that indicate the 
need for an independent Data Monitoring Committee (DMC). 
However, in addition to the ongoing review of blinded safety data by the sponsor and designee 
during the conduct of this study, the sponsor will establish an internal DMC independent of the 
study and project team to periodically review unblinded safety data during conduct of this study to 
complement the routine safety monitoring approach for compounds at this stage of development. 
The functions and procedures of the committee will be outlined in a DMC Charter. 
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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent medical conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization Drug Dictionary.
12.1
CRFs (Electronic)
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply study sites with access to eCRFs. The sponsor will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor and regulatory authorities. 
eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
The principal investigator must review the eCRFs for completeness and accuracy and must e-sign 
the appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility 
for the accuracy and authenticity of all data entered on the eCRFs.
The eCRFs will be reviewed for completeness and acceptability at the study site during periodic 
visits by the sponsor or its designee. The sponsor or its designee will be permitted to review the 
subject’s medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. The 
completed eCRFs are the sole property of the sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the sponsor. 
After lock of the clinical study database or submission of the eCRFs to the sponsor, any change of, 
modification of, or addition to the data on eCRFs should be made by the investigator with use of 
change and modification records of eCRFs (Data Clarification Form) provided by the sponsor. The 
principal investigator must review the Data Clarification Form for completeness and accuracy, and 
must sign and date the form.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long term legibility. Furthermore, The 
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International Council for Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to retain 
essential documents specified in ICH E6 (Section 8) until at least 2 years after the last approval of 
a marketing application for a specified drug indication being investigated or, if an application is 
not approved, until at least 2 years after the investigation is discontinued and regulatory authorities 
are notified. In addition, ICH E6 Section 4.9.5 states that the study records should be retained until 
an amount of time specified by applicable regulatory requirements or for a time specified in the 
study site agreement between the investigator and sponsor.
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of treatment 
assignments. This document will provide further details regarding the definition of analysis 
variables and analysis methodology to address all study objectives.
A blinded data review will be conducted prior to unblinding of treatment assignments. This review 
will assess the accuracy and completeness of the study database, subject evaluability, and 
appropriateness of the planned statistical methods.
Multiplicity across doses will be controlled for the primary endpoint as described in 
Section 13.1.3.1. Multiplicity will not be controlled for the secondary endpoints.
13.1.1
Analysis Sets
13.1.1.1
Full Analysis Set
The full analysis set (FAS) will include all subjects who were randomized and received at least 
1 dose of the study drug for the treatment period. In FAS efficacy summaries, subjects will be 
analyzed by the treatment to which they were randomized.
13.1.1.2
Safety Analysis Set
The Safety Analysis Set will include all randomized subjects who receive at least 1 dose of 
double-blind study medication. In safety summaries, subjects will be analyzed according to the 
treatment they received.
13.1.1.3
PD Analysis Set
The PD analysis set will consist of subjects who receive at least 1 dose of double-blind study 
medication and who have a Baseline D-serine and L-serine plasma concentration measurement 
and at least corresponding 1 postdose plasma concentration measurement.
13.1.1.4
Per-Protocol Set
The per-protocol set will include all FAS subjects who had no major protocol violations.
13.1.2
Analysis of Demographics and Other Baseline Characteristics
Demographics and baseline characteristics including age, gender, race, BMI, and medical history 
will be listed and summarized by each treatment group and overall based on the FAS. 
Baseline values for efficacy assessments will also be summarized by each treatment group and 
overall based on the FAS.
For continuous variables, comparability of treatment groups will be assessed using an analysis of 
variance with treatment and pooled site as factors. For discrete variables, comparability will be 
assessed using the Cochran-Mantel-Haenszel general association test, stratified by pooled site. 
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13.1.3
Efficacy Analysis
13.1.3.1 Primary Efficacy Analysis
The primary endpoint for this study is the change from Baseline to Week 12 in the inverse of the 
time to complete the 9-HPT (9-HPT-1) after treatment with TAK-831, compared with placebo.
The primary analysis of change from Baseline in 9-HPT-1 will be based on the FAS. Comparisons 
between TAK-831 and placebo will be made over all assessed time points using estimates from a 
mixed model for repeated measures (MMRM) with Baseline 9-HPT-1 as a covariate; pooled site, 
visit, treatment, and ambulation status (randomization factor) as fixed factors; and 
treatment-by-visit and 9-HPT-1 by-visit interactions. Based on a Missing at Random Assumption, 
this analysis will be performed using observed case data only. The effect at each time point for 
each treatment is allowed to vary freely and an unstructured covariance matrix is assumed. If the 
model does not converge, other covariance structures (unstructured, compound symmetry, 
2-Toeplitz, etc) will be considered. A suite of appropriate sensitivity analyses will be specified in 
the SAP.
Since 2 doses of TAK-831 are compared to placebo, multiplicity will be controlled at the Holm’s 
method. The dose with the smaller p-value will be tested at the one-sided 0.05 level, then dose with 
the larger p-value will be tested at the one-sided 0.10 level only if the smaller p-value is 
significant. This procedure will control the overall type I error rate at the one-sided 0.10 level. The 
one-sided alternative hypothesis is that the mean time to complete the 9-HPT is shorter on the 
TAK-831 arm compared to placebo.
Subgroup analyses will be conducted according to ambulation status and Baseline D-serine 
concentration.
13.1.3.2 Secondary Efficacy Analysis
Analysis of secondary efficacy endpoints will be based on the FAS. For these endpoints, which are 
continuous change from Baseline endpoints, comparisons between TAK-831 and placebo will be 
based on similar methodology to that described for the primary efficacy analysis. For binary or 
ordinal endpoints, Cochran-Mantel-Haenszel tests will be used with ambulation status at 
randomization as a stratification factor. For binary or ordinal endpoints, missing data will be 
imputed as no change from Baseline. For each secondary endpoint, the 1-sided alternative 
hypothesis is that TAK-831 is superior to placebo in the clinically favorable direction, for 
example, a lower mean score on the FARS ADL scale.
Analysis of exploratory efficacy endpoints will be described in the SAP.
13.1.4
PK and PD Modeling Analysis
Plasma concentrations of TAK-831 will be listed for each subject and summarized by each time 
point for each dose of the study.
Individual concentration-time data will be pooled to describe the population PK of TAK-831. As 
data permit, a nonlinear mixed effects modeling approach (NONMEM software) will be used to 
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assess TAK-831 exposure. PK information generated in this study will be further utilized in 
subsequent population PK-PD analyses. The relationships between TAK-831 plasma 
concentrations and drug response (D- or L-serine plasma levels and/or selected measures of 
efficacy) will be explored. As appropriate, historical data may be used in this analysis to increase 
the robustness of the model and precision of estimated parameters. Details of the modeling 
approach will be provided in a separate analysis plan, and the results of these analyses may be 
reported separately.
13.1.5
PD Analysis 
For each regimen, the concentrations of D-serine, L-serine, and the ratio of D-serine to total serine 
with change and percent change from Baseline will be summarized at each time point of each dose 
level using descriptive statistics. In addition, mixed effects regression models will be fitted to the 
change from Baseline in these concentrations. Pairwise comparisons between the test regimens 
(high dose, low dose and placebo) will be made and the CIs for the difference in the LS means will 
be constructed for selected time points. Additional details and further analyses will be specified in 
the SAP. (See also Section 13.1.4.)
13.1.6
Safety Analysis
Analysis of safety variables will be based on the safety analysis set.
13.1.6.1 Analysis of AEs
All AEs will be coded using MedDRA. Data will be summarized using preferred term and primary 
system organ class. AEs that are reported more than once by a subject during the same period will 
be counted only once for that subject and period at the maximum severity.
13.1.6.2 Analysis of Other Safety Assessments
Other safety endpoints include:

Laboratory values.

Vital signs.

Weight.

ECGs.

Physical examination findings.
Absolute values and changes from Screening/Baseline in clinical laboratory tests, vital signs, 
weight and ECG parameters will be summarized for each treatment group at all visits assessed 
using descriptive techniques. Physical examination findings will also be summarized for each 
treatment group. Values outside the reference ranges and markedly abnormal laboratory values 
will be flagged and tabulated.
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13.1.7
Responder Analysis
A responder analysis to estimate the responder definition/threshold for the 9-HPT will be 
conducted. The methods used will be based on recommended methods presented in the FDA PRO 
guidance [28].
The main responder analysis will use patient global ratings, as measured by the PGI-I, on the 
change in upper limb function as the anchor. Other patient and clinician global ratings for upper 
limb function (PGI-S, CGI-S, CGI-I) will be candidate measures as supportive anchors. All 
anchors will be reviewed for appropriateness. FARS ADL items 3 to 5 will also be considered. 
The basis of the threshold for meaningful change in the main responder analysis will correspond to 
the mean (or median) change score on the 9-HPT from Baseline to Week 12 corresponding to 
Improvement on the PGI-I for upper limb function. Supportive responder thresholds will be 
estimated similarly using the CGI-I for upper limb function and also estimated based on a 
one-category improvement on the PGI-S and CGI-S.
A distribution-based method based on one-half SD at Baseline, which corresponds to a moderate 
effect size, will also be estimated to provide a supportive responder threshold estimate [37-39].
Additional analyses will explore if a patient-reported improvement in upper limb function is 
meaningful from the patient perspective, as captured by the Exit Interview. 
Application of the main and supportive responder definitions will be done by comparing the 
percentage of responders on the 9-HPT between TAK-831and placebo groups at Week 12.
Responder analyses will be replicated for each time point assessed (eg, Weeks 2 and 7).
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
Approximately 65 subjects will be randomized in a 2:1:2 ratio for the placebo, low, and high dose 
respectively. It is assumed that approximately 60 subjects (92%) will complete 12 weeks and be 
evaluable on the primary endpoint. If the rate of early withdrawal is substantially greater than 
predicted, then an increase to the number of randomized subjects may be considered. 
Assuming an effect size of 0.6 for each dose, there will be 77% power for at least 1 dose to be 
deemed superior to placebo and 54% power for both doses (overall alpha=0.10, 1-sided). 
Validated software (EAST 6.3, Cytel Inc.) was used to determine the power. The effect size was 
chosen based on the premise that a treatment effect equivalent to preventing or reversing 2 years of 
decline due to FDRA would be clinically meaningful. Using published data [19], the target effect 
size is approximately 0.6 for the 9-HPT.
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator guarantees access to source documents by the sponsor or its designee contract 
research organization and by the IRB or independent ethics committee (IEC).
All aspects of the study and its documentation will be subject to review by the sponsor or sponsor’s 
designee (as long as blinding is not jeopardized), including but not limited to the Investigator’s 
Binder, study drug, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the informed consent 
forms), and review of eCRFs and associated source documents. It is important that the investigator 
and other study personnel are available during the monitoring visits and that sufficient time is 
devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations noted in the subject’s source documents. In the 
event of a significant deviation, the site should notify the sponsor or its designee (and IRB or ethics 
committee, as required). Significant deviations include, but are not limited to, those that involve 
fraud or misconduct, increase the health risk to the subject, or confound interpretation of primary 
study assessment. 
The investigator should document all protocol deviations via the eCRF.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator guarantees access for quality assurance auditors to all study 
documents as described in Section 14.1.
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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable regional regulatory requirements and align his or her conduct in 
accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB
IRBs must be constituted according to the applicable requirements of each participating region. 
The sponsor or designee will require documentation noting all names and titles of members who 
make up the respective IRB. If any member of the IRB has direct participation in this study, 
written notification regarding his or her abstinence from voting must also be obtained. Those 
Americas sites unwilling to provide names and titles of all members due to privacy and conflict of 
interest concerns should instead provide a Federal Wide Assurance Number or comparable 
number assigned by the US Department of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB for 
the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of the 
informed consent form, a copy of the Exit Interview protocol, and, if applicable, subject 
recruitment materials and/or advertisements and other documents required by all applicable laws 
and regulations, must be submitted to a central or local IRB for approval. The IRB’s written 
approval of the protocol and subject informed consent must be obtained and submitted to the 
sponsor or designee before commencement of the study (ie, before shipment of the 
sponsor-supplied drug or study specific screening activity). The IRB approval must refer to the 
study by exact protocol title, number, and version date; identify versions of other documents 
(eg, informed consent form) reviewed; and state the approval date. The sponsor will notify site 
once the sponsor has confirmed the adequacy of site regulatory documentation and, when 
applicable, the sponsor has received permission from competent authority to begin the study. 
Study sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent form, 
recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB, and submission of the investigator’s final status report to IRB. All IRB approvals 
and relevant documentation for these items must be provided to the sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and sponsor.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
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applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
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15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical trial database or documentation via a subject identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit the monitor or the sponsor’s designee, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs to review the subject’s original medical records (source data or documents), 
including, but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and autopsy 
reports. Access to a subject’s original medical records requires the specific authorization of the 
subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the study site agreement, any public disclosure 
(including publicly accessible websites) related to the protocol or study results, other than study 
recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The investigator needs to obtain a prior written approval from the sponsor to publish any 
information from the study externally such as to a professional association.
15.4.2
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
Property of Takeda: For non-commercial use only and subject to the applicable Ter
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contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor. 
Any investigator who objects to the sponsor providing this information to callers must provide the 
sponsor with a written notice requesting that their information not be listed on the registry site.
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov and/or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the sponsor 
or sponsor’s designee.
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16.0
REFERENCES
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regulates cerebellar LTD and motor coordination through the delta2 glutamate receptor. Nat 
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7. Pandolfo M. Friedreich ataxia: the clinical picture. J Neurol 2009;256 Suppl 1:3-8.
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16. Sham PC, Gottesman, II, MacLean CJ, Kendler KS. Schizophrenia: sex and familial 
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22. Feys P, Lamers I, Francis G, Benedict R, Phillips G, LaRocca N, et al. The Nine-Hole Peg Test 
as a manual dexterity performance measure for multiple sclerosis. Mult Scler 
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23. Corben LA, Tai G, Wilson C, Collins V, Churchyard AJ, Delatycki MB. A comparison of 
three measures of upper limb function in Friedreich ataxia. J Neurol 2010;257(4):518-23.
24. Mathiowetz V, Weber K, Kashman N, Volland G. Adult norms for the nine hole peg test of 
finger dexterity. Occup Ther J Res 1985;5(1):24-38.
25. Oxford Grice K, Vogel KA, Le V, Mitchell A, Muniz S, Vollmer MA. Adult norms for a 
commercially available Nine Hole Peg Test for finger dexterity. Am J Occup Ther 
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26. Wang YC, Bohannon RW, Kapellusch J, Garg A, Gershon RC. Dexterity as measured with the 
9-Hole Peg Test (9-HPT) across the age span. J Hand Ther 2015;28(1):53-9; quiz 60.
27. Lynch DR, Farmer JM, Wilson RL, Balcer LJ. Performance measures in Friedreich ataxia: 
potential utility as clinical outcome tools. Mov Disord 2005;20(7):777-82.
28. Psychopharmacolgic Drugs Advisory Committee (PDAC) meeting of the June 9-10, 2009. 
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29. Subramony SH, May W, Lynch D, Gomez C, Fischbeck K, Hallett M, et al. Measuring 
Friedreich ataxia: Interrater reliability of a neurologic rating scale. Neurology 
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30. Lynch DR, Farmer JM, Tsou AY, Perlman S, Subramony SH, Gomez CM, et al. Measuring 
Friedreich ataxia: complementary features of examination and performance measures. 
Neurology 2006;66(11):1711-6.
31. Friedman LS, Farmer JM, Perlman S, Wilmot G, Gomez CM, Bushara KO, et al. Measuring 
the rate of progression in Friedreich ataxia: implications for clinical trial design. Mov Disord 
2010;25(4):426-32.
32. Fahey MC, Corben L, Collins V, Churchyard AJ, Delatycki MB. How is disease progress in 
Friedreich's ataxia best measured? A study of four rating scales. J Neurol Neurosurg 
Psychiatry 2007;78(4):411-3.
33. Cutter GR, Baier ML, Rudick RA, Cookfair DL, Fischer JS, Petkau J, et al. Development of a 
multiple sclerosis functional composite as a clinical trial outcome measure. Brain 1999;122 ( 
Pt 5):871-82.
34. Lynch DR, Farmer JM, Rochestie D, Balcer LJ. Contrast letter acuity as a measure of visual 
dysfunction in patients with Friedreich ataxia. J Neuroophthalmol 2002;22(4):270-4.
35. Vogel AP, Wardrop MI, Folker JE, Synofzik M, Corben LA, Delatycki MB, et al. Voice in 
Friedreich Ataxia. J Voice 2017;31(2):243 e9- e19.
36. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from 
three multisite studies with adolescents and adults. Am J Psychiatry 2011;168(12):1266-77.
37. Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in health-related quality of 
life: the remarkable universality of half a standard deviation. Med Care 2003;41(5):582-92.
38. McLeod LD, Coon CD, Martin SA, Fehnel SE, Hays RD. Interpreting patient-reported 
outcome results: US FDA guidance and emerging methods. Expert Rev Pharmacoecon 
Outcomes Res 2011;11(2):163-9.
39. Wyrwich KW, Krishnan S, Poon JL, Auguste P, von Maltzahn R, Yu R, et al. Interpreting 
important health-related quality of life change using the Haem-A-QoL. Haemophilia 
2015;21(5):578-84.
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Appendix A
Schedule of Study Procedures
Screening
Baseline and Treatment Period 
Phone Exit 
Interview
Safety 
Phone 
Follow-up
Early 
Termination 
Visit
Clinic Visit
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Study Day
Within 28 
days
-1
1 (a)
2-13
(home)
14
(±3) 
days
15-48 
(home)
49
(±3)
days
50- 83
(home)
84
(±2)
days
≤7 days 
after Visit 6 
or 
termination
7-17 days 
after last 
dose
Informed consent 
X
Randomization
X
Inclusion/exclusion criteria
X
X
X
Demographics and medical 
history
X
Medication history 
X
Concurrent medical 
conditions 
X
Physical examination
X
X
X
Height and BMI (Screening 
only), weight 
X
X
X
Clinical laboratory tests (b)
X
X
X
X
Urine drug screen
X
FSH
X
Urinalysis 
X
X
X
X
Pregnancy test (hCG) (c)
X
X
X
X
X
X
Footnotes are on last table page.
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Screening
Baseline and Treatment Period 
Phone Exit 
Interview
Safety 
Phone 
Follow-up
Early 
Termination 
Visit
Clinic Visit
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Study Day
Within 28 
days
-1
1 (a)
2-13
(home)
14
(±3) 
days
15-48 
(home)
49
(±3) 
days
50- 83
(home)
84
(±2) 
days
≤7 days 
after Visit 6 
or 
termination
7-17 days 
after last 
dose
ECG
X
X
X
FARS Functional Staging 
for Ataxia
X
Vital signs (a)
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
Dispense study medication 
(d)
X
X
X
Study drug dosing (d)
X
X
X
X
X
X
X (e)
PTE/AE assessment (a) 
X
X
X
X
X
X
X
X
X
X
X
Interim phone calls (f)
X
X
X
PK blood collection (h)
X
X
X
X
X
X
PD blood collection (D- and 
L-serine) (i)
X
X
X
X
X
9-HPT (j) (k) (l)
X
X
X
X
X
X
X
FARS ADL (j)
X
X
X
X
X
X
FARS-neuro (j) (l)
X
X
X
X
X
X
X
T25FW and digital gait with 
sensors (j) (l)
X
X
X
X
X
X
X
Footnotes are on last table page.
Property of Takeda
X
da: For non-c
ercial use only and subject to the applicable Terms of Use
le
Phone Ex
hone 
Interv
Inte
ab
ap
it 6
ap
ap
ap
- 83
83
(home)
ome
84
8
(±
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TAK-831
Study No. TAK-831-1501
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Protocol Incorporating Amendment No. 01
06 October 2017
Screening
Baseline and Treatment Period 
Phone Exit 
Interview
Safety 
Phone 
Follow-up
Early 
Termination 
Visit
Clinic Visit
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Study Day
Within 28 
days
-1
1 (a)
2-13
(home)
14
(±3) 
days
15-48 
(home)
49
(±3) 
days
50- 83
(home)
84
(±2) 
days
≤7 days 
after Visit 6 
or 
termination
7-17 days 
after last 
dose
Digital speech assessment 
(j) (l)
X
X
X
X
X
X
X
Digital balance and upper 
limb assessment (j) (l)
X
X
X
X
X
X
X
Low contrast letter acuity (j) 
(l)
X
X
X
X
X
X
CGI-S (overall severity) (j) 
(l)
X
X
X
X
X
CGI-I (overall 
improvement) (j) (l)
X
X
X
X
CGI-S (upper extremity 
functional severity) (j) (l)
X
X
X
X
X
CGI-I (upper extremity 
functional improvement) (j) 
(l)
X
X
X
X
PGI-S (overall severity)
X
X
X
X
X
PGI-I (overall 
improvement) (l)
X
X
X
X
PGI-S (upper extremity 
functional severity)
X
X
X
X
X
PGI-I (upper extremity 
functional improvement) (l)
X
X
X
X
Exit Interview (m)
X
X
Footnotes are on last table page.
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Study No. TAK-831-1501
Page 88 of 114
Protocol Incorporating Amendment No. 01
06 October 2017
Note: The Follow-up phone call will occur 7 to 17 days after the last dose of study drug by telephone unless subject report concerning AEs. In these cases, subjects 
will be brought back into the clinic for re-evaluation at the investigator’s discretion.
(a) On Day 1 (Visit 3), subjects will complete all efficacy and safety baseline assessment before dosing. After all baseline assessment and procedures, subjects will 
be dosed in the clinic and will remain in the clinic for approximately 3 to 4 hours after dosing. During this time, subjects will be observed or monitored by clinic staff 
for any unexpected serious or severe AEs. Vital signs/AEs should be taken twice during this time, one around 1 to 2 hours postdose and one before patients are 
discharged. As noted in Section 1.1, all subjects will be provided with emergency medical contact information cards. They will be allowed to take a break for lunch 
in the vicinity of the clinic, if necessary. Prior to going to the hotel, vital signs will be recorded and all AEs recorded. A responsible clinician will review AEs and 
vital signs before sending the patients to hotels/homes. 
(b) Clinical laboratory samples will be collected under nonfasting conditions.
(c) Urine test only except at Screening and Safety Follow-up/ET visit.
(d) Specific instructions: Subjects will be instructed to take 3 tablets by mouth two times a day in the fasted condition (at least 1 h before or after a meal) or with a 
light meal (less than 600 calories total with <30% from fat). 
(e) On Day 84, subjects will only get the morning dose as their last dose.
(f) Interim phone calls will be conducted on Day 2, approximately at end of Week 1 and at the midpoints between Visits 4 and 5 and Visits 5 and 6. Subjects will be 
asked how they are doing and whether they are taking the drugs BID as directed. Reported AEs and concomitant medications will be captured in the source 
documents and eCRF. All questions will be addressed.
(g) 
(h) Blood samples for the determination of concentrations of TAK-831 will be collected as shown below in the Schedule of Samples. One blood sample will be 
collected for subjects at the early termination visit. The sampling schedule may change based on emerging data but will not exceed the number of planned samples 
(N=10). 
(i) Blood samples for PD will be collected immediately following the first PK sample collection for each visit a PD sample is to be collected per the Schedule of 
Samples.
(j) The efficacy assessments should be conducted by the same administrator throughout the entire study for a particular subject, as much as possible. 
(k) The 9-HPT assessment consists of 2 trials of dominant hand, followed by 2 trials of nondominant hand. The 9-HPT assessment will be repeated twice with at 
least 1 hour in between the 2 sets of 9-HPT assessments. 
(l) Sequence and timing of assessments will consider patient fatigue. The first set of 9-HPT and digital speech should be conducted first. In addition, during 
treatment period, subjects will be taking the drugs at home/hotel. This will be followed by other assessment/procedures. Timing of efficacy assessments should also 
be taken into consideration. During the treatment period (Visits 4-7), 9-HPT and digital speech should be assessed approximately 2-4 hours after the morning dose.  
All assessments should be approximately 2 to 6 hours post morning dose. Note for Visit 5, blood samples for PK and PD will be collected 1 to 2 hours post morning 
dose which the subjects takes at home/hotel and the collection of blood sample can be the first procedure on that day.
(m) A semistructured subject Exit Interview will be conducted by phone within 7 days from the last dose of study medication of the Double-Blind Treatment Period 
or within 7 days of notification of termination for the Early Termination Visit.
Property of Takeda: For non-commercial us
ly and subject to the applicable Terms of Use
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concernin
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TAK-831
Study No. TAK-831-1501
Page 89 of 114
Protocol Incorporating Amendment No. 01
06 October 2017
Schedule of Samples
Visit
Visit 1 
(Screening)
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Early 
Termination 
Visit
Day(s)
-28 to -2
-1
1
14
(±3)
49
(±3)
84
(±2)
Clinical laboratory samples
X
X
X
X
PK blood collection
Predose
0.25 and 
2 hours 
postdose
1-2 hours post 
morning dose
At the end of the 
visit >4 hours after 
morning dose
At the end of the visit 
>4 hours after 
morning dose
X
PD blood collection (D-
and L-serine)
Predose
1-2 hours post 
morning dose
At the end of the 
visit >4 hours after 
morning dose
At the end of the visit 
>4 hours after 
morning dose
X
Property of Takeda: For non-commercial use only and su
t to the applicable Terms of Use
le
lic
ap
9
(±3)
(±3)
he
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ose
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Protocol Incorporating Amendment No. 01
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study-related procedures, including study-specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH, and local 
regulations, are met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization Section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
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Study No. TAK-831-1501
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Protocol Incorporating Amendment No. 01
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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Study No. TAK-831-1501
Page 92 of 114
Protocol Incorporating Amendment No. 01
06 October 2017
Appendix C
Elements of the Subject Informed Consent 
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
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Protocol Incorporating Amendment No. 01
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19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 
legally acceptable representative may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study drug(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
Property of Takeda: For non-commercial use only and subject 
pplicable Terms of Use
or 
ures for 
es for 
will be in
will be 
o the sub
the s
ubject’s p
ject
n the inf
the in
he contem
cont
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TAK-831
Study No. TAK-831-1501
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Protocol Incorporating Amendment No. 01
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e) that the subject’s identity will remain confidential in the event that study results are 
published.
25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from Screening throughout the duration of the study, and for 35 days after last dose. 
Regular pregnancy tests will be performed throughout the study for all female subjects of 
childbearing potential. If a subject is found to be pregnant during study, study drug will be 
discontinued and the investigator will offer the subject the choice to receive unblinded 
treatment information.
26. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study, and for 95 days after 
last dose. If the partner or wife of the subject is found to be pregnant during the study, the 
investigator will offer the subject the choice to receive unblinded treatment information.
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.
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Protocol Incorporating Amendment No. 01
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Appendix D
Investigator Consent to Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study drug.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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TAK-831
Study No. TAK-831-1501
Page 96 of 114
Protocol Incorporating Amendment No. 01
06 October 2017
Appendix E
Detailed Description of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment No. 01 are indicated. 
The corresponding text has been revised throughout the protocol.
Change 1: Revision of study procedures (reduce the number of visits and blood draws, and update 
the randomization scheme).
The primary changes occur in Section 6.1 Study Design.
Initial 
wording:
...
The study will include a Screening Period (Days -28 to -2), a Training Period to 
minimize practice effect on efficacy assessment (Day -1), treatment (Days 1 to 84), 
a follow-up clinic visit (~1-2 weeks after last administration of study drug), and a 
subject Exit Interview (conducted over the phone within 7 days from the last dose of 
study medication of the Double-Blind Treatment Period or within 7 days of 
notification of termination for the Early Termination Visit) will be based on the last 
visit of the last subject. In addition, several interim phone calls will also be 
conducted.
Approximately 65 subjects who meet the study criteria during Screening will be 
invited to attend training to minimize practice effects on performance-based 
efficacy assessments on Day -1. On Day 1, subjects who continue to meet inclusion 
and none of the exclusion criteria will be randomized in a 2:1:2 ratio to TAK-831 
high dose, TAK-831 low dose, or placebo, respectively. (If the rate of early 
withdrawal is substantially greater than predicted, then an increase to the number of 
randomized subjects may be considered.) Randomization will be stratified by 
ambulation status (ambulatory vs. nonambulatory). The first 5 subjects will be 
randomized to either placebo or TAK-831 low dose in a 2:3 ratio; the randomization 
ratio for the remaining 60 subjects will be adjusted to approximate a 2:1:2 ratio 
overall.
The study will be conducted in approximately 4 or more specialized academic 
neurological clinical centers in the United States with expertise in, and access to, 
patients with FRDA.
Subjects will receive twice daily (BID) study drug dosing or placebo from Day 1 
through Day 84. Clinic visits during the treatment period include Day 1, Day 2, end 
of Week 2, end of Week 7, and end of Week 12. Clinical assessments, blood 
collections, and laboratory tests will be conducted at specific time points per the 
schedule of study procedures (Appendix A). A follow-up safety assessment visit 
will be conducted and a separate semistructured subject Exit Interview will be 
conducted by phone to provide an in-depth, qualitative evaluation of the subject 
experience and subject-perceived change due to treatment (Table 6.a). 
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TAK-831
Study No. TAK-831-1501
Page 97 of 114
Protocol Incorporating Amendment No. 01
06 October 2017
Amended or 
new wording:
...
The study will include a Screening Period (Days -28 to -2), a Training Period to 
minimize practice effect on efficacy assessment (Day -1), treatment (Days 1 to 84), 
a follow-up clinic visit (~1-2 weeks after last administration of study drug), and a 
subject phone Exit Interview (conducted over the phone within 7 days from the last 
dose of study medication of the Double-Blind Treatment Period or within 7 days of 
notification of termination for the Early Termination Visit) will be based on the last 
visit of the last subject. In addition, several interim phone calls will also be 
conducted. and a Safety Follow-up Phone Call (7 to 17 days after last dose of 
study drug).
Approximately 65 subjects who meet the study criteria during Screening will be 
invited to attend training to minimize practice effects on performance-based 
efficacy assessments on Day -1. On Day 1, subjects who continue to meet inclusion 
and none of the exclusion criteria will be randomized in a 2:1:2 ratio to TAK-831 
high dose, TAK-831 low dose, or placebo, respectively. (If the rate of early 
withdrawal is substantially greater than predicted, then an increase to the number of 
randomized subjects may be considered.) Randomization will be stratified by 
ambulation status (ambulatory vs. nonambulatory). The first 5 subjects will be 
randomized to either placebo or TAK-831 low dose in a 2:3 ratio; the randomization 
ratio for the remaining 60 subjects will be adjusted to approximate a 2:1:2 ratio 
overall.
The study will be conducted in approximately 46 or more specialized academic 
neurological clinical centers in the United States with expertise in, and access to, 
patients with FRDA.
Subjects will receive twice daily (BID) study drug dosing or placebo from Day 1 
through Day 84. Clinic visits during the treatment period include Day 1, Day 2, end 
of Week 2, end of Week 7, and end of Week 12. Clinical assessments, blood 
collections, and laboratory tests will be conducted at specific time points per the 
schedule of study procedures (Appendix A). A follow-up safety assessment visit 
will be conducted and a separate semistructured subject Exit Interview will be 
conducted by phone to provide an in-depth, qualitative evaluation of the subject 
experience and subject-perceived change due to treatment, and a Safety Follow-up 
Phone Call will be conducted (Table 6.a). 
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Table 6.a Schematic of Study Design.

Figure 6.a Schematic of Study Design.
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Study No. TAK-831-1501
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Protocol Incorporating Amendment No. 01
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
5.2.2 Secondary Endpoints

5.2.4 Exploratory Endpoints

Appendix A
Schedule of Study Procedures.
Rationale for change: To reduce patient burden by making the original Day 2 in clinic visit and 
follow up visit to be conducted by phone. By following up with the subjects by phone, the 
investigators still have the liberty to invite the subjects for an in person clinical visit if concerning 
AE is reported, thus better balance the patient burden and evaluation of tolerability and safety. 
Additional safety and tolerability study data support the testing of the compound in the FRDA 
population and randomization across the high dose and low dose groups.
Change 2 Revision of TAK-831 dose.
The primary changes occur in Section 6.2.2 Justification of Dose:
Initial 
wording:
6.2.2
Justification of Dose
The doses of TAK-831 (200 mg BID and 20 mg BID) selected for the current study 
are based on PK data from the SRD/MRD study (TAK-831-1001) and brain target 
occupancy data from the PET study (TAK-831-1003), and safety data from both 
clinical studies after oral administration of TAK-831 (suspension) in healthy 
subjects. Preliminary PK/PD modeling analyses showed that the high dose regimen 
resulted in steady-state exposures associated with peak target occupancy of >90%, 
while the low dose regimen produced daily exposures associated with peak target 
occupancy of >50%. These 2 doses may allow characterization of an 
exposure-response relationship with PD or efficacy measures in adult subjects with 
FRDA. Of note, the study drug will be administered as a tablet, which exhibits lower 
oral bioavailability and higher variability relative to the oral suspension. Nutritional 
drinks (Ensure Plus) are proposed to be used in this rare disease population which 
may have difficulty with swallowing. It is anticipated that TAK-831 exposure may 
increase with food when TAK-831 T2 tablets are administered. Nutritional drinks 
can be easily standardized and can potentially increase drug exposure without 
requiring subjects to have repeated high fat diet over a long duration, which may not 
be well tolerated for some subjects. Therefore, a phase 1 study to evaluate the effect 
of food (a nutritional drink) on the PK of a T2 tablet formulation of TAK-831 in 
healthy subjects (TAK-831-1004) is currently planned to ensure the projected 
TAK-831 steady-state exposures can be achieved for optimal target occupancy, 
while remaining within the range of those observed at doses up to 400 mg daily 
dose, which were found to be safe.
Amended or 
new wording:
6.2.2 Justification of Dose
The doses of TAK-831 (200 mg BID300 and 2075 mg BID) selected for the current 
study are based on PK data from the SRD/MRD study (TAK-831-1001) and brain 
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target occupancy data from the PET study (TAK-831-1003), PK and food effect 
study (TAK-831-1004), CSF D-serine study (TAK-831-1005), and safety data 
from bothall clinical studies after oral administration of TAK-831 (suspension) in 
healthy subjects. Preliminary PK/PD modeling analyses showed that the high dose 
regimen resulted in steady-state exposures associated with peak target occupancy of 
>90%, while the low dose regimen produced daily exposures associated with peak 
target occupancy of >50%. These 2 doses The lower dose is to provide at least 
3-fold exposure difference from the high dose to understand the relationship 
between TAK-831 and response relationship. In addition, CSF D-serine levels 
at 600 mg QD using T2 tablet and 800 mg suspension produced similar level of 
CSF D-serine, suggesting that 600 mg QD produced levels of D-serine 
approaching maximal DAO inhibition in the brain. These 2 doses (300 mg BID 
and 75 mg BID) may allow characterization of an exposure-response relationship 
with PD or efficacy measures in adult subjects with FRDA. Of note, the study drug 
will be administered as a tablet, which exhibits lower oral bioavailability and higher 
variability relative to the oral suspension. Nutritional drinks (Ensure Plus) are 
proposed to be used in this rare disease population which may have difficulty with 
swallowing. It is anticipated that TAK-831 exposure may increase with food when 
TAK-831 T2 tablets are administered. Nutritional drinks can be easily standardized 
and can potentially increase drug exposure without requiring subjects to have 
repeated high fat diet over a long duration, which may not be well tolerated for some 
subjects. Therefore, a phase 1 study to evaluate the effect of food (a nutritional 
drink) on the PK of a T2 tablet formulation of TAK-831 in healthy subjects 
(TAK-831-1004) is currently planned to ensure the projected TAK-831 steady-state 
exposures can be achieved for optimal target occupancy, while remaining within the 
range of those observed at doses up to 400 mg daily dose, which were found to be 
safe. Subjects will be instructed to take 3 tablets by mouth two times a day in 
the fasted condition (at least 1 h before or after a meal) or with a light meal 
(less than 600 calories total with <30% from fat). This will keep the TAK-831 
exposure at levels that have been shown to be well tolerated in healthy subjects.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 8.1.1.1 Study Drug.

Section 8.1.1.2 Sponsor-supplied Drug.

Table 8.a Dose and Regimen.

Section 8.2 Study Drug Assignment and Dispensing Procedures.

Section 8.6 Accountability and Destruction of Sponsor-Supplied Drugs.
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Rationale for change: Additional clinical studies in healthy volunteers and understanding CSF 
D-serine levels in relationship withTAK-831 dose indicate that a 600 mg daily dose produced 
nearly maximal pharmacological effect. This provided better precision in recommending the high 
dose.  The lower dose is adjusted to provide at least 3-fold exposure difference from the high dose 
to understand the relationship between TAK-831 PK and response.
Change 3: Recatagorizing of objectives and endpoints related to Activities of Daily Living.
The primary changes occur in Section 5.1 Objectives and Section 5.2 Endpoints:
Initial 
wording:
5.1.2 Key Secondary Objective
The key secondary objective of the study is to evaluate the efficacy of TAK-831 
versus placebo on Activities of Daily Living (ADL), as measured by the ADL 
component of the Friedreich Ataxia Rating Scale (FARS).
5.1.3 Other Secondary Objectives
The secondary objectives of the study are:
...
5.2.2. Key Secondary Endpoint
The key secondary endpoint for this study is the change from Baseline to Week 12 
on the ADL component of the FARS after treatment with TAK-831, compared with 
placebo.
5.2.3 Other Secondary Endpoints
....

The change from Baseline to Day 2, Weeks 2 and 7 on the 9-HPT after treatment 
with TAK-831, compared with placebo.

The change from Baseline to Weeks 2 and 7 on the ADL individual items after 
treatment with TAK-831, compared with placebo.
....
5.2.4 Exploratory Endpoints
....
Amended or 
new wording:
5.1.2 Key Secondary ObjectiveObjectives

The key secondary objective of the study is toTo evaluate the efficacy of 
TAK-831 versus placebo on Activities of Daily Living (ADL), as measured by 
the ADL component of the Friedreich Ataxia Rating Scale (FARS), and those 
items that related to upper limb function.
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5.1.3 Other Secondary Objectives
The secondary objectives of the study are.
...
5.2.2. Key Secondary EndpointEndpoints
!
The key secondary endpoint for this study is the change from Baseline to Week 
12 on the ADL component of the FARS after treatment with TAK-831, 
compared with placebo.
5.2.3 Other Secondary Endpoints
Other secondary endpoints for this study as follows:
!
The change from Baseline to Day 2, Weeks 2 and 7 on the 9-HPTWeeks 2, 7, 
and 12 on the ADL component upper limb function items (ADL items 3 to 
5) of the FARS, after treatment with TAK-831, compared with placebo. 
!
The change from Baseline to Weeks 2 and 7 on the 9-HPT-1 after treatment 
with TAK-831, compared with placebo.
!
The change from Baseline to Weeks 2, 7, and 12 on the ADL individual items 
after treatment with TAK-831, compared with placebo.
....
!
Percentage of subjects whose 9-HPT completion time is reduced by at least 
15% and at least 20% from Baseline.
....
5.2.4 Exploratory Endpoints
....
The following sections also contain this change:
!
Section 2.0 STUDY SUMMARY.
!
Section 13.1 Statistical and Analytical Plans.
Rationale for change: While the ADL is important, the probability of detecting significant 
change in this study of short duration is low and therefore it is recategorized as one of the 
secondary endpoints.
Property of Taked
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Change 4: Clarification of endpoints related to the 9-hole peg test.
The primary changes occur in Section 5.2 Endpoints:
Initial 
wording:
5.2.1 Primary Endpoint
The primary endpoint for this study is the change from Baseline to Week 12 in the 
time (in seconds) to complete the 9-HPT after treatment with TAK-831, compared 
with placebo.
...
5.2.3 Other Secondary Endpoints
Other secondary endpoints for this study as follows:

The change from Baseline to Day 2, Weeks 2 and 7 on the 9-HPT after treatment 
with TAK-831, compared with placebo.
...
5.2.5 Exploratory Endpoints
Exploratory endpoints for this study as follows:
...
Amended or 
new wording:
5.2.1 Primary Endpoint
The primary endpoint for this study is the change from Baseline to Week 12 in the 
inverse of the time (in seconds) to complete the 9-HPT (9-HPT-1) after treatment 
with TAK-831, compared with placebo.
...
5.2.32 Other Secondary Endpoints
Other secondary endpoints for this study as follows:

The change from Baseline to Day 2, Weeks 2 and 7 on the 9-HPT-1 after 
treatment with TAK-831, compared with placebo.
...

Percentage of subjects whose 9-HPT completion time is reduced by at least 
15% and at least 20% from Baseline.
...
5.2.54 Exploratory Endpoints
Exploratory endpoints for this study as follows:
...
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The following sections also contain this change:
Section 2.0 STUDY SUMMARY.
Rationale for change: To clarify details on endpoints.
Change 5: Revision and clarification of study entry criteria.
The primary changes occur in Section 7.1 Inclusion Criteria and Section 7.2 Exclusion Criteria:
Initial 
wording:
7.1 Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry 
into the study: 
1. In the opinion of the investigator, the subject is capable of understanding and 
complying with protocol requirements.
2. The subject signs and dates a written, informed consent. If written consent is not 
possible due to physical incapacity, written consent on behalf of the participant 
will be sought from the participant’s relatives or caregivers (or from a legally 
acceptable representative).
...
7.2 Exclusion Criteria
...
2. The subject has uncontrolled, clinically significant neurologic, cardiovascular, 
pulmonary, hepatic, renal, metabolic, gastrointestinal, or endocrine disease 
(including uncontrolled diabetes) or other abnormality (other than the disease 
being studied), which may impact the ability of the subject to participate or 
potentially confound the efficacy and safety evaluation. The subject has medical 
history or conditions that, in the opinion of the investigator, may interfere with 
study conduct or clinical assessments.
...
5. The subject has a history of cancer, except basal cell carcinoma or in situ 
cervical cancer that has been in remission for ≥5 years prior to first dose of study 
drug.
6. The subject is known to be currently infected or have been infected with human 
immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus.
Property of Takeda: For no
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7. The subject has a positive urine drug result for drugs of abuse (defined as any 
illicit drug use without a valid prescription or medical need) at Screening.
...
9. The subject has a history of drug abuse (defined as any illicit drug use) or a history 
of alcohol abuse (defined as regular consumption of 3 or more units per day on 1 
occasion per week or 7 or more units in any given week) within 1 year prior to 
Screening. One unit is equivalent to a half-pint of beer or 1 single measure of 
spirits or 1 small glass of wine.
...
11. The subject is considered by the investigator to be at imminent risk of suicide or 
injury to self, others, or property or subjects who within the past year prior to 
Screening have attempted suicide or have positive answers on item 4 or 5 on the 
Columbia Suicide Severity Rating Scale (C-SSRS, life-time version) at 
Screening or Day 1.
...
17. The subject has 1 or more laboratory values outside the normal range that are 
considered by the investigator to be clinically significant at the Screening Visit; 
or the subject has any of the following at the Screening Visit: a serum creatinine 
value >1.5 times the ULN. A total serum total bilirubin value >1.5×ULN. A
serum ALT or AST value >2×ULN, or prolactin ≥100 ng/mL.
Amended or 
new wording:
7.1 Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry 
into the study: 
1. In the opinion of the investigator, the subject is capable of understanding the 
informed consent, and capable of understanding and complying with protocol 
requirements.
2. The subject signs and dates a written, informed consent. If written consent is not 
possible due to physical incapacity, written consent on behalf of the participant 
will be sought from the participant's relatives or caregivers (or from a legally 
acceptable representative). 
...
7.2 Exclusion Criteria
...
2. The subject has, based on medical history and judgment of the investigator,
uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, 
hepatic, renal, metabolic, gastrointestinal, or endocrine disease (including 
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uncontrolled diabetes) or other abnormality (other than the disease being 
studied), which may impact the ability of the subject to participate or potentially 
confound the efficacy and safety evaluation. The subject has medical history or 
conditions that, in the opinion of the investigator, may interfere with study 
conduct or clinical assessments.
...
5. The subject has a history of cancer, except squamous cell carcinoma or basal 
cell carcinoma that have been treated or excised, or in situ cervical cancer that 
has been in remission for ≥5 years prior to first dose of study drug.
6. The subject is known to be currently infected or have a history of having been 
infected with human immunodeficiency virus (HIV), hepatitis B virus, or 
hepatitis C virus.
7. The subject has a Urine drug screen positive urine drug result for drugs of 
abuse (defined as any illicitat screening or, except for a prescribed drug use 
without a valid prescription or medical need)allowed by the protocol at 
Screening. Cannabinoid use is not permitted either recreationally or 
medically. 
...
9. The subject has a history of drug abuse (defined as any illicit drug use) or a history 
of alcohol abuse (defined as regular consumption of 3 or more units per day on 1 
occasion per week or 7 or more units in any given week) within 1 year prior to 
Screening. One unit is equivalent to a half-pint of beer or 1 single measure of 
spirits or 1 small glass of winewithin 1 year prior to Screening.
...
11. The subject is considered by the investigator to be at imminent risk of suicide or 
injury to self, others, or property or subjects who within the past year prior to 
Screening have attempted suicide or have positive answers on item 4 or 5 on the 
Columbia Suicide Severity Rating Scale (C-SSRS, life-time version) at 
Screening or Day 1.
...
17. The subject has 1 or more laboratory values outside the normal range that are 
considered by the investigator to be clinically significant at the Screening Visit; 
or the subject has any of the following at the Screening Visit: a serum creatinine 
value >1.5 times the ULN. A, a total serum total bilirubin value >1.5×ULN. Aor 
a serum ALT or AST value >2×ULN, or prolactin ≥100 ng/mL.
18. The subject has current history of symptomatic orthostatic hypotension.
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The following sections also contain this change:
Section 2.0 STUDY SUMMARY.
Rationale for change: To clarify study entrance criteria. In addition, squamous cell carcinomas
with excision that have been treated or excised are added to the exceptions of exclusion. To 
reduced patient risk of falling, subjects with current history of symptomatic orthostatic 
hypotension are excluded.
Change 6: Clarification of excluded medications and products.
The primary changes occur in Section 7.3 Excluded Medications, Supplements, and Dietary 
Products and Section 7.4 Diet, Fluid, Activity Control:
Initial 
wording:
Section 7.3 Excluded Medications, Supplements, and Dietary Products
...
Table 7.a
Excluded/Allowed Medications and Treatments.

Psychotropic agents not otherwise specified (including stimulants, tryptophan, 
melatonin and dopamine agonists)

Herbal remedies, which are psychoactive (eg, St. John's Wort, kava kava, 
valerian, ginkgo biloba, melatonin)

Muscle relaxants

Antiparkinson drugs
Section 7.4 Diet, Fluid, Activity Control
Subjects will maintain their regular routine of exercise and physical therapy or 
speech therapy.
Alcohol intake will be restricted to no more than 1 unit in 1 occasion and less than 3 
units per week. One unit is equivalent to a half-pint of beer or 1 single measure of 
spirits or 1 small glass of wine.
Amended or 
new wording:
Section 7.3 Excluded Medications, Supplements, and Dietary Products
...
Table 7.a
Excluded/Allowed Medications and Treatments.

Psychotropic agents not otherwise specified (including but not limited to
stimulants, tryptophan, melatoninand dopamine agonists)

Herbal remedies, which are psychoactive (eg, St. John's Wort, kava kava, 
valerian, ginkgo biloba, melatonin), OTC (e.g., cough syrup)

Muscle relaxants including but not limited to baclofen, tizanidine, 4 
aminopyridine
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
Antiparkinson drugsAntiparkinsonian drugs including dopamine agonists
Section 7.4 Diet, Fluid, Activity Control
Subjects will maintain their regular routine of exercise and physical therapy or 
speech therapy.
Alcohol intake will be restricted to no more than 1 unit in 1 occasion and less than 3 
units per week. One unit is equivalent to a half-pint of beer or 1 single measure of 
spirits or 1 small glass of wine. Subject will not drink alcohol with 24 hours of 
the conduct of any clinical assessments.
Rationale for change: To clarify excluded medications and products.
Change 7: Revision of statistical analysis.
The primary changes occur in Section 13.1.2 Analysis of demographics and other baseline 
characteristics and Section 13.1.3.1 Primary Efficacy Analysis
Initial 
wording:
13.1.2 Analysis of demographics and other baseline characteristics
Demographics and baseline characteristics including age, gender, race, BMI, and 
medical history will be listed and summarized by each treatment group and overall 
based on all randomized subjects.
Baseline values for efficacy assessments will also be summarized by each treatment 
group and overall based on all randomized subjects.
....
13.1.3.1 Primary Efficacy Analysis
The primary endpoint to be measured is the change from Baseline in the time (in 
seconds) to complete the 9-HPT at 12 weeks. An inverse transform will be used to 
reduce skewness. The primary efficacy comparison will be the comparison between
TAK-831 and placebo in change from Baseline in the time to complete the 9-HPT at 
12 weeks.
....
13.1.3.2 Secondary Efficacy Analysis
Analysis of secondary efficacy endpoints will be based on the FAS. For these 
endpoints, which are continuous change from Baseline endpoints, comparisons 
between TAK-831 and placebo will be based on similar methodology to that 
described for the primary efficacy analysis. However, for the CGI-I and PGI-I 
endpoints the corresponding Baseline severity scores (CGI-S or PGI-S, 
respectively) will be used as the Baseline covariate in the MMRM and analysis of 
covariance models. For each secondary endpoint, the 1-sided alternative hypothesis 
is that TAK-831 is superior to placebo in the clinically favorable direction, for 
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example, a lower mean score on the FARS ADL scale.
Amended or 
new wording:
13.1.2 Analysis of demographics and other baseline characteristics
Demographics and baseline characteristics including age, gender, race, BMI, and 
medical history will be listed and summarized by each treatment group and overall 
based on all randomized subjects.the FAS. 
Baseline values for efficacy assessments will also be summarized by each treatment 
group and overall based on all randomized subjectsthe FAS.
....
13.1.3.1 Primary Efficacy Analysis
The primary endpoint to be measuredfor this study is the change from Baseline to 
Week 12 in the inverse of the time (in seconds) to complete the 9-HPT at 12 weeks. 
An inverse transform will be used to reduce skewness. The primary efficacy 
comparison will be the comparison between(9-HPT-1) after treatment with
TAK-831 and, compared with placebo in change from Baseline in the time to 
complete the 9-HPT at 12 weeks.
....
13.1.3.2 Secondary Efficacy Analysis
Analysis of secondary efficacy endpoints will be based on the FAS. For these 
endpoints which are continuous change from Baseline endpoints, comparisons 
between TAK-831 and placebo will be based on similar methodology to that 
described for the primary efficacy analysis. However, for the CGI-I and PGI-I 
endpoints the corresponding Baseline severity scores (CGI-S or PGI-S, 
respectively) will be used as the Baseline covariate in the MMRM and analysis of 
covariance models.For binary or ordinal endpoints, Cochran-Mantel-Haenszel 
tests will be used with ambulation status at randomization as a stratification 
factor. For binary or ordinal endpoints, missing data will be imputed as no 
change from Baseline. For each secondary endpoint, the 1-sided alternative 
hypothesis is that TAK-831 is superior to placebo in the clinically favorable 
direction, for example, a lower mean score on the FARS ADL scale.
Rationale for change: To update statistical analysis.
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Change 8: Inclusion of the summary of clinical data from Studies TAK-831-1004 and 
TAK-831-1005.
The primary changes occur in Section 4.1.4 Clinical Background.
Initial 
wording:
4.1.4 Clinical Background
Two phase 1 clinical studies have been conducted in healthy subjects: a 
first-in-human study to determine the pharmacokinetic (PK) profiles of TAK-831 
oral suspension after single-rising dose (SRD) and multiple-rising dose (MRD) 
administration, as well as the relative bioavailability and effect of food on the PK of 
the T1 tablet formulation of TAK-831 (TAK-831-1001); and a study to demonstrate 
DAO target engagement in the brain as measured by positron emission tomography 
(PET) (TAK-831-1003). Plasma D-serine levels, TAK-831 plasma concentrations 
and safety were also evaluated. There is an ongoing clinical study, TAK-831-1004, 
to study the food (nutritional drink) effect of T2 tablet formulation.
...
4.3
Benefit/Risk Profile 
The literature suggests that D-serine is a critical mediator of glutamate receptor–
dependent functions of the cerebellum [2]. As a DAO inhibitor that increases 
D-serine in the cerebellum, TAK-831 has the potential to increase 
NMDA-dependent glutamatergic signaling. One disease state that could be treated 
through this mechanism is FRDA. TAK-831 showed efficacy in a mouse model of 
FRDA with single doses and dosed daily for 15 days at 3 mg/kg. 
...
The proposed phase 2 study is being conducted to evaluate the efficacy, safety, PD 
effects, and PK of 2 dose levels of oral TAK-831 in adult subjects with FRDA for up 
to 84 days. The proposed doses of TAK-831 have been selected based on PK data 
from the SRD/MRD study (TAK-831-1001), brain target occupancy data from the 
PET study (TAK-831-1003), and safety data from both clinical studies after oral 
administration of TAK-831 (suspension) in healthy subjects as a single dose up to 
750 mg (TAK-831-1001 and TAK-831-1003) or for 13 days as a multiple dose up to 
400 mg/day (TAK-831-1001). The dose and study duration of TAK-831 used in 
prior studies have not resulted in a safety signal that would prevent additional 
studies. 
Potential risks, and risk mitigation measures to be implemented in studies with 
TAK-831, are described below. These measures are based on what is known about 
the mechanism of action of TAK-831, nonclinical data, and the 2 phase 1 studies 
conducted to date. These procedures may be modified during the study if necessary 
based on evaluation of any additional clinical or nonclinical safety data.
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...
•
Postural hypotension and dizziness were observed in prior studies in healthy 
subjects, although the incidence for subjects treated with TAK-831 and placebo 
was similar. As FRDA patients experience gait disturbance, motor dysfunction, 
and thus are susceptible to fall, subjects should be carefully monitored for 
possible orthostatic hypotensive effects of TAK-831 administration. 
Additionally, subjects should be instructed to take appropriate precautionary 
measures to prevent falling while under treatment with TAK-831.
...
Amended or 
new wording:
4.1.4 Clinical Background
Two Five phase 1 clinical studies have been conducted in healthy subjects: a 
first-in-human study to determine the pharmacokinetic (PK) profiles of TAK-831 
oral suspension after single-rising dose (SRD) and multiple-rising dose (MRD) 
administration, as well as the relative bioavailability and effect of food on the PK of 
the T1 tablet formulation of TAK-831 (TAK-831-1001); and a study to demonstrate 
DAO target engagement in the brain as measured by positron emission tomography 
(PET) (TAK-831-1003). Plasma D-serine levels, TAK-831 plasma concentrations 
and safety were also evaluated. There is an ongoing clinical study, TAK-831-1004, 
to study the food (nutritional drink) effect of T2 tablet formulation.Since these 
studies were conducted, a single dose PK and food-effect, bioavailability study 
with the T2 tablet formulation (TAK-831-1004) has completed active dosing, 
and a study examining additional escalating multiple doses of TAK-831 higher 
than those achieved in the TAK-831-1001 study was initiated and is ongoing 
(TAK-831-1005).
...
TAK-831-1004 was a phase 1, randomized, open-label, single-dose, 2-period 
crossover study designed to characterize the PK of a single dose of 400 mg of 
TAK-831 and assess the effect of food on the bioavailability of TAK-831 400 
mg when administered as four 100 mg oral tablets of the T2 formulation in 15 
healthy adult subjects. In the TAK-831-1004 study, there was only a single AE 
of mild upper respiratory tract infection, judged to be unrelated to study 
treatment. One subject met criteria for orthostatic hypotension at a single time 
point without an accompanying report of a dizziness AE. There were no 
concerning trends in laboratory, ECG, or vital sign data. TAK-831 given as T2 
tablet coadministered with the nutritional drink (Ensure Plus) increased mean 
Cmax and AUC∞values by 35% and 21%, respectively. Treatment with a single 
oral dose of 400mg TAK-831 T2 formulation temporally increased plasma 
concentration of D-serine, similar to the results obtained in the Study 
TAK-831-1001. The magnitude and kinetics of the change in plasma D-serine 
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was similar when the drug was administered in either water or Ensure. 
TAK-831-1005 is an ongoing investigator and subject blinded, sponsor 
unblinded, placebo-controlled clinical study progressively assessing 
independent cohorts of healthy subjects to continue evaluation of the safety, 
tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of 
escalating multiple doses of TAK-831 at doses higher than those achieved in 
the TAK-831-1001 study. The following study information is preliminary and 
is based on blinded adverse event data reported by the investigator and 
blinded safety endpoint data in study TAK-831-1005. Although not expected, 
these data are subject to change upon finalization following study monitoring, 
source data verification, and discrepancy query management prior to 
database lock. At this time, two cohorts with 8 subjects each (6 TAK-831 and 2 
placebo) have completed treatment at dose levels of 600 mg QD (T2 tablet 
formulation) or 800 mg QD (oral suspension) administered first as a single 
dose, and then administered for up to 14 days of multiple dosing. In addition to 
standard safety assessments, subjects in these cohorts underwent catheterized 
CSF collection for a 24 hour period starting prior to dosing on Day 1 single 
dose treatment and on Day 14 of multiple dose treatment. Nausea and 
post-lumbar puncture syndrome were the most common treatment-emergent 
AEs; nausea in the absence of post-lumbar puncture syndrome was reported 
by one subject in each cohort. All episodes of nausea were mild in intensity and 
self-limiting. Two subjects in each cohort met categorical criteria for 
orthostatic hypotension on at least one assessment; none of these findings were 
associated with an AE of dizziness. There were no concerning trends in 
laboratory, ECG, or vital sign data collected in these cohorts. 
Following once-daily dosing, mean plasma exposures of TAK-831 were higher 
(Cmax: 1.3-fold and AUC: 1.8-fold) when dosed as an oral suspension than as 
T2 tablets. Geometric mean Cmax values were 1466 and 1976 ng/mL with 600 
mg QD (T2 tablet formulation) and 800 mg QD (oral suspension), respectively. 
Mean steady-state exposures (AUCt) over the 24-hour dosing interval were on 
average 4993 and 8853 ng.hr/mL for the respective 600 mg and 800 mg QD 
dosing cohorts. The mean 24-hour TAK-831 PK profile in CSF was parallel to 
that of plasma and observed TAK-831 CSF concentrations were well in 
agreement with the TAK-831 unbound fraction in plasma. After both single 
and multiple dosing with TAK-831, there was a notable increase in the area 
under the effect curve from time 0 to 24 hours of CSF D-serine for both the 
600 mg T2 and 800 mg oral suspension treatment groups when compared to 
placebo; changes in CSF D-serine were noticeably higher after multiple doses 
of TAK-831 than after administration of a single dose of TAK-831. The 
magnitude of the increase in the area under the effect curve for CSF D-serine 
was similar for both the 600 mg T2 and 800 mg oral suspension, suggesting 
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that the maximal PD effect in the CSF was achieved at drug exposures attained 
with the 600mg T2 dose  and 800 mg suspension
Overall, the emerging safety data from the TAK-831-1004 and TAK-831-1005 
studies are consistent with the data collected in prior clinical studies and do 
not alter the risk profile of the compound.
...
The literature suggests that D-serine is a critical mediator of glutamate receptor–
dependent functions of the cerebellum and was shown to reduce ataxia in animal 
model of spinocerebellar ataxia [2]. As a DAO inhibitor that increases D-serine in 
the cerebellum, TAK-831 has the potential to increase NMDA-dependent 
glutamatergic signaling. One disease state that could be treated through this 
mechanism is FRDA. TAK-831 showed efficacy in a mouse model of FRDA with 
single doses and dosed daily for 15 days at 3 mg/kg. 
4.3 Benefit/Risk Profile 
The proposed phase 2 study is being conducted to evaluate the efficacy, safety, PD 
effects, and PK of 2 dose levels of oral TAK-831 in adult subjects with FRDA for up 
to 84 days. The proposed doses of TAK-831 have been selected based on PK data 
from the SRD/MRD studystudies (TAK-831-1001 and TAK-831-1005), brain 
target occupancy data from the PET study (TAK-831-1003), CSF D-serine data 
from the TAK-831-1005 study, and safety data from bothall clinical studies after 
oral administration of TAK-831 (suspension) in healthy subjects as a single dose up 
to 750 mg (TAK-831-1001 and TAK-831-1003) or for 13 days as a multiple dose up 
to 400 mg/day (TAK-831-1001).described above. The dose and study duration of 
TAK-831 used in prior studies have not resulted in a safety signal that would 
prevent additional studies. in subjects with FRDA.
Potential risks, and risk mitigation measures to be implemented in studies with 
TAK-831, are described below. These measures are based on what is known about 
the mechanism of action of TAK-831, nonclinical data, and the 2 phase 1 studies 
conducted to date, and general considerations in the development of new 
chemical entities. These procedures may be modified during the study if necessary 
based on evaluation of any additional clinical or nonclinical safety data.
...

Postural hypotension and dizziness were observed in prior studies in healthy 
subjects, although. However, the incidence forof dizziness in subjects treated 
with TAK-831 and placebo was similar. In addition, 2 subjects who received 
250 mg TAK-831 showed blood pressure variations consistent with 
orthostatic hypotension without clinical symptoms. These measurements 
were taken at the Study exit visit and were considered not-related to 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-831
Study No. TAK-831-1501
Page 113 of 114
Protocol Incorporating Amendment No. 01
06 October 2017
TAK-831. As FRDA patients experience gait disturbance, motor dysfunction, 
and thus are susceptible to fall, subjects should be carefully monitored for 
possible orthostatic hypotensive effects of TAK-831 administration. 
Additionally, subjects should be instructed to take appropriate precautionary 
measures to prevent falling while under treatment with TAK-831. Additionally, 
subjects with current history of postural hypotension will be excluded from 
the study.
Rationale for change: To provide the most current clinical data available for TAK-831.
Change 9: Engagement of an internal DMC to review unblinded safety data.
The primary changes occur in Section 11.0 STUDY-SPECIFIC COMMITTEES.
Initial 
wording:
11.0 STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, clinical endpoint 
committee, or adjudication committee will be used in this study.
Amended or 
new wording:
11.0 STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, clinical endpoint 
committee, or adjudication committee will be used in this study.
This study does not include endpoints related to assessing mortality or major 
adverse health outcomes, and the study population is not at risk of serious 
safety events given the clinical characteristics of the disorder and known 
trajectory of disease progression. In addition, as summarized in Section 4.1.4, 
TAK-831 has been well tolerated and safe across the full range of doses 
examined in clinical studies, and there have not been any safety findings that 
indicate the need for an independent Data Monitoring Committee (DMC).
However, in addition to the ongoing review of blinded safety data by the 
sponsor and designee during the conduct of this study, the sponsor will
establish an internal DMC independent of the study and project team to 
periodically review unblinded safety data during conduct of this study to 
complement the routine safety monitoring approach for compounds at this 
stage of development. The functions and procedures of the committee will be 
outlined in a DMC Charter. 
Rationale for change: To coordinate the monitoring of safety and tolerability data for the 
TAK-831 compound, together with other upcoming clinical trials in the schizophrenia population.
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TAK-831
Study No. TAK-831-1501
Page 114 of 114
Protocol Incorporating Amendment No. 01
06 October 2017
Change 10: Personnel change
The primary changes occur in Section 1.1 and Section 1.2
Initial 
wording:
Section 1.1
Section 1.2
Amended or 
new wording:
Section 1.1
Section 1.2
Rationale for change: To update personnel responsibilities.
PPD
PPD
PPD
PPD
Property of Takeda: For non-com
: To upd
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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Arm Study to Evaluate 
Efficacy, Tolerability, and Pharmacokinetics of Multiple Doses of Oral TAK-831 in Adult Subjects 
With Friedreich Ataxia
NCT Number: NCT03214588
SAP Approve Date: 01 February 2019
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information or 
company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-831-1501
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Arm Study to 
Evaluate Efficacy, Tolerability, and Pharmacokinetics of Multiple Doses of Oral TAK-831 
in Adult Subjects With Friedreich Ataxia
PHASE 2
Version: Final
Date: 01 February 2019
Prepared by:
Based on:
Protocol Version: Amendment 1
Protocol Date: 06 October 2017
Propert  of Takeda: F
Protoco
Proto
Pro
Pr
mercial use only and subject to the applicable Terms of Use
Parallel
Parall
ltiple Do
iple D
Ataxia
Ataxi
ion
on: : Fin
Fin
: 01 Feb
01 F
PPD


TAK-831-1501
Page 2 of 27
Statistical Analysis Plan 
01 February 2019
1.1
Approval Signature
Electronic signature can be found on the last page of this document.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-831-1501
Page 3 of 27
Statistical Analysis Plan 
01 February 2019
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signature....................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Exploratory Objectives ..............................................................................................8
4.4
Study Design .............................................................................................................8
5.0
ANALYSIS ENDPOINTS.............................................................................................10
5.1
Primary Endpoint.....................................................................................................10
5.2
Secondary Endpoints ...............................................................................................10
5.3
Safety Endpoints......................................................................................................11
5.4
Exploratory Endpoints .............................................................................................11
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................12
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................13
7.1
General Principles....................................................................................................13
7.1.1
Study Definitions ...............................................................................................13
7.1.2
Conventions for Missing Adverse Event Dates...................................................14
7.1.3
Conventions for Missing Concomitant Medication Dates...................................14
7.1.4
Grouping of Sites...............................................................................................14
7.2
Analysis Sets ...........................................................................................................14
7.2.1
Full Analysis Set................................................................................................14
7.2.2
Safety Analysis Set ............................................................................................15
7.2.3
PD Analysis Set .................................................................................................15
7.2.4
PK Analysis Set .................................................................................................15
7.3
Disposition of Subjects ............................................................................................15
7.4
Demographic and Other Baseline Characteristics.....................................................15
7.5
Medical History and Concurrent Medical Conditions...............................................16
7.6
Medication History and Concomitant Medications...................................................16
7.7
Study Drug Exposure and Compliance.....................................................................16
7.8
Efficacy Analysis.....................................................................................................17
7.8.1
Primary Efficacy Endpoint.................................................................................17
7.8.2
Secondary Efficacy Endpoints............................................................................18
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-831-1501
Page 4 of 27
Statistical Analysis Plan 
01 February 2019
7.8.3
Exploratory Endpoints .......................................................................................19
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................19
7.9.1
Pharmacokinetic Analysis ..................................................................................19
7.9.2
Pharmacodynamic Analysis ...............................................................................19
7.10
Other Outcomes.......................................................................................................19
7.11
Safety Analysis........................................................................................................20
7.11.1 Adverse Events ..................................................................................................20
7.11.2 Clinical Laboratory Evaluations .........................................................................21
7.11.3 Vital Signs .........................................................................................................22
7.11.4 12-Lead ECGs ...................................................................................................22
7.11.5 Other Observations Related to Safety.................................................................23
7.12
Interim Analysis ......................................................................................................23
7.13
Changes in the Statistical Analysis Plan...................................................................23
8.0
REFERENCES..............................................................................................................24
LIST OF IN-TEXT TABLES
Table 4.a
Schematic of Study Design ..................................................................................9
LIST OF APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values .................25
Appendix B
Criteria for Abnormal Vital Signs ......................................................................26
Appendix C
Criteria for Out-of-Range Values for the 12-Lead ECG Parameters....................27
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-831-1501
Page 5 of 27
Statistical Analysis Plan 
01 February 2019
3.0
LIST OF ABBREVIATIONS
Term
Definition
%CV
coefficient of variation
9-HPT
9-hole peg test
ADaM
Analysis Data Model
ADL
Activities of Daily Living
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC∞
area under the concentration-time curve from time 0 to infinity
BID
twice daily
BMI
body mass index
CGI
Clinical Global Impression Scale
CGI-I
Clinical Global Impression-Improvement 
CGI-S
Clinical Global Impression-Severity 
Cmax
maximum observed concentration
C-SSRS
Columbia-Suicide Severity Rating Scale
ECG
electrocardiogram, electrocardiographic
eCRF
electronic case report form 
FARS
Friedreich Ataxia Rating Scale
FAS
full analysis set
FRDA
Friedreich ataxia
GGT
gamma-glutamyl transferase
MAV
markedly abnormal value
MedDRA
Medical Dictionary for Regulatory Activities
mFARS
modified Friedreich Ataxia Rating Scale 
mFARS-neuro
modified Friedreich Ataxia Rating Scale neurological examination
MMRM
mixed model for repeated measures
PD
pharmacodynamic(s)
PGI-I
Patient Global Impression-Improvement
PGI-S
Patient Global Impression-Severity
PK
pharmacokinetic(s)
PMM
pattern mixture model
PT
preferred term
PTE
pretreatment event
QTc
QT interval with correction
QTcF
QT interval with Fridericia correction method 
SAE
serious adverse event
SD
standard deviation
SDTM
Study Data Tabulation Model
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-831-1501
Page 6 of 27
Statistical Analysis Plan 
01 February 2019
Term
Definition
SOC
system organ class
SI
International System of Units
T25FW
Timed 25-Foot Walk
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
WHODrug
World Health Organization Drug Dictionary
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-831-1501
Page 7 of 27
Statistical Analysis Plan 
01 February 2019
4.0
OBJECTIVES
4.1
Primary Objectives
The primary objective of the study is to evaluate the efficacy of TAK-831 versus placebo on 
upper extremity (arms and hands) motor function and manual dexterity, as measured by the 9-
hole peg test (9-HPT).
4.2
Secondary Objectives

To evaluate the efficacy of TAK-831 versus placebo on Activities of Daily Living (ADL), as 
measured by the ADL component of the Friedreich Ataxia Rating Scale (FARS), and those 
items that are related to upper limb function. 

To evaluate the efficacy of TAK-831 versus placebo on neurological function, as measured 
by the modified FARS neurological examination (mFARS-neuro) total score. 

To evaluate the efficacy of TAK-831 versus placebo on lower extremity motor function, as 
measured by the Timed 25-Foot Walk (T25FW).

To evaluate the efficacy of TAK-831 versus placebo on limb ataxia, as measured by the 
composite of the T25FW and 9-HPT.

To evaluate the efficacy of TAK-831 versus placebo on visual acuity, as measured by the 
low-contrast letter acuity (LCLA) testing with Sloan charts.

To evaluate the efficacy of TAK-831 versus placebo on global improvement, as measured by 
the Clinical Global Impression-Improvement (CGI-I).

To evaluate the efficacy of TAK-831 versus placebo on global improvement, as measured by
the Patient Global Impression-Improvement (PGI-I).

To evaluate the efficacy of TAK-831 versus placebo on upper extremity functional 
improvement, as measured by the CGI-I.

To evaluate the efficacy of TAK-831 versus placebo on upper extremity functional 
improvement, as measured by the PGI-I.

To evaluate the efficacy of TAK-831 versus placebo on global severity, as measured by the 
Clinical Global Impression-Severity (CGI-S).

To evaluate the efficacy of TAK-831 versus placebo on global severity, as measured by the 
Patient Global Impression-Severity (PGI-S).

To evaluate the efficacy of TAK-831 versus placebo on upper extremity functional severity, 
as measured by the CGI-S.

To evaluate the efficacy of TAK-831 versus placebo on upper extremity functional severity, 
as measured by the PGI-S.

To evaluate the safety and tolerability of TAK-831.
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TAK-831-1501
Page 8 of 27
Statistical Analysis Plan 
01 February 2019
4.3
Exploratory Objectives
!
To evaluate the efficacy of TAK-831 versus placebo on speech, as measured by digital 
assessments.
!
To evaluate the efficacy of TAK-831 versus placebo on motor function such as gait, balance, 
and upper limb coordination, as measured by digital sensors.
!
To evaluate the PK and PD (plasma D-serine and L-serine levels and D-serine:Total serine 
ratios), and explore the relationships between TAK-831 exposures and D- and L-serine levels 
or selected measures of efficacy.
!
To correlate plasma D-serine and L-serine levels, and D-serine:Total serine ratios with 
clinical parameters of disease status.
!
To quantify subject-perceived meaningful change in upper limb function, as evaluated by the 
Exit Interview. 
4.4
Study Design
TAK-831-1501 is a phase 2, randomized, double-blind, placebo-controlled, parallel-arm study 
designed to evaluate the efficacy, safety, PD effects, and PK of 2 dose levels of oral TAK-831 in 
adult subjects with FRDA. 
The study will include a Screening Period (Days -28 to -2), a Training Period (Day -1), 
Treatment (Days 1 to 84), a Phone Exit Interview (within 7 days from the last dose of study 
medication of the Double-Blind Treatment Period or within 7 days of notification of termination 
for the Early Termination Visit), and a Safety Follow-up Phone Call (7 to 17 days after last dose 
of study drug).
Approximately 65 subjects who meet the study criteria during Screening will be invited to attend 
training to minimize practice effects on performance-based efficacy assessments on Day -1. On 
Day 1, subjects who continue to meet inclusion and none of the exclusion criteria will be 
randomized in a 2:1:2 ratio to TAK-831 high dose, TAK-831 low dose, or placebo, respectively. 
(If the rate of early withdrawal is substantially greater than predicted, then an increase to the 
number of randomized subjects may be considered.) Randomization will be stratified by 
ambulation status (ambulatory vs. nonambulatory).
The study will be conducted in approximately 6 or more specialized academic neurological 
clinical centers in the United States with expertise in, and access to, patients with FRDA.
Property of Takeda: For non-commercial 
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TAK-831-1501
Page 9 of 27
Statistical Analysis Plan 
01 February 2019
Subjects will receive twice daily (BID) study drug dosing or placebo from Day 1 through Day 
84. Clinic visits during the treatment period include Day 1, end of Weeks 2, 7, and 12. Clinical 
assessments, blood collections, and laboratory tests will be conducted at specific time points per 
the schedule of study procedures (Protocol Appendix A). A semi-structured Exit Interview will 
be conducted by phone to provide an in-depth, qualitative evaluation of the subject experience 
and subject-perceived change due to treatment, and a Safety Follow-up Phone Call will be 
conducted (Table 4.a). 
Table 4.a
Schematic of Study Design
Screening
Efficacy 
Assessment 
Training
Treatment (TAK-831 high dose, 
TAK-831 low dose, or placebo)
Phone Exit 
Interview
Safety Follow-up 
Phone Call (a)
Randomization, 
Baseline, and 
Dosing
Efficacy, PK, PD, and 
Safety Assessments
Days
-28 to -2
Day -1
Day 1
Day 14 (±3 days), 
Day 49 (±3 days), 
Day 84 (±2 days)
≤7 days after 
Final Visit or 
termination
7 to 17 days after 
last dose
(a) The Follow-up Phone Call will occur 7 to 17 days after the last dose of study drug by telephone unless subject 
report concerning AEs. In these cases, subjects will be brought back into the clinic for re-evaluation at the 
investigator’s discretion.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-831-1501
Page 10 of 27
Statistical Analysis Plan 
01 February 2019
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
The primary endpoint for this study is the change from Baseline to Week 12 in the inverse of the 
time to complete the 9-HPT (9-HPT-1) after treatment with TAK-831, compared with placebo.
5.2
Secondary Endpoints

The change from Baseline to Weeks 2, 7, and 12 on the ADL component of the FARS, after 
treatment with TAK-831, compared with placebo. 

The change from Baseline to Weeks 2, 7, and 12 on the ADL component upper limb function 
items (ADL items 3 to 5) of the FARS, after treatment with TAK-831, compared with 
placebo. 

The change from Baseline to Weeks 2 and 7 on the 9-HPT-1 after treatment with TAK-831, 
compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on the ADL individual items after treatment 
with TAK-831, compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on the mFARs-neuro total score after 
treatment with TAK-831, compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on the mFARS-neuro subscales and 
individual items after treatment with TAK-831, compared with placebo. 

The change from Baseline to Weeks 2, 7, and 12 on the T25FW after treatment with TAK-
831, compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on the 9-HPT and T25FW composite score 
after treatment with TAK-831, compared with placebo.

Percentage of subjects whose 9-HPT completion time is reduced by at least 15% and at least 
20% from Baseline.

The change from Baseline to Weeks 2, 7, and 12 on LCLA test score after treatment, 
compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on CGI-I (global change) after treatment 
with TAK-831, compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on PGI-I (global change) after treatment 
with TAK-831, compared with placebo. 

The change from Baseline to Weeks 2, 7, and 12 on CGI-I (upper extremity functional 
change) after treatment with TAK-831, compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on PGI- I (upper extremity functional 
change) after treatment with TAK-831, compared with placebo.
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TAK-831-1501
Page 11 of 27
Statistical Analysis Plan 
01 February 2019

The change from Baseline to Weeks 2, 7, and 12 on CGI-S (global severity) after treatment 
with TAK-831, compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on PGI-S (global severity) after treatment 
with TAK-831, compared with placebo. 

The change from Baseline to Weeks 2, 7, and 12 on CGI-S (upper extremity functional 
severity) after treatment with TAK-831, compared with placebo. 

The change from Baseline to Weeks 2, 7, and 12 on PGI-S (upper extremity functional 
severity) after treatment with TAK-831, compared with placebo.
5.3
Safety Endpoints

AEs, clinical laboratory assessments, ECG measures, changes in physical examinations and 
vital signs after treatment with TAK-831, compared with placebo.

Assessment of suicidal ideation and behavior as measured by the C-SSRS at Screening, 
Baseline, and all other timepoints after treatment with TAK-831, compared with placebo.
5.4
Exploratory Endpoints

The change from Baseline to Weeks 2, 7, and 12 on the digital speech assessment after 
treatment with TAK-831, compared with placebo.

The change from Baseline to Weeks 2, 7, and 12 on the digital motor sensors measurements 
such as gait, stability and upper limb coordination after treatment with TAK-831, compared 
with placebo.

The change from Baseline to Weeks 2, 7, and 12 on TAK-831 plasma D-serine and L-serine 
levels and D-serine:Total serine ratios after treatment with TAK-831, compared with 
placebo.

Percent of subjects reporting a meaningful change in upper limb function from Baseline to 
Week 12 after treatment with TAK-831, compared with placebo, as evaluated by the Exit 
Interview.

Correlation of change in 9-HPT with that of patient reported improvement of change in upper 
limb function, such as ADL items 3 to 5 and PGI.

TAK-831 plasma concentration.
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TAK-831-1501
Page 12 of 27
Statistical Analysis Plan 
01 February 2019
6.0
DETERMINATION OF SAMPLE SIZE
Approximately 65 subjects will be randomized in a 2:1:2 ratio for the placebo, low, and high 
dose respectively. It is assumed that approximately 60 subjects (92%) will complete 12 weeks 
and be evaluable on the primary endpoint. If the rate of early withdrawal is substantially greater 
than predicted, then an increase to the number of randomized subjects may be considered. 
Assuming an effect size of 0.6 for each dose, there will be 77% power for at least 1 dose to be 
deemed superior to placebo and 54% power for both doses (overall alpha=0.10, 1-sided). 
Validated software (EAST 6.3, Cytel Inc.) was used to determine the power. The effect size was 
chosen based on the premise that a treatment effect equivalent to preventing or reversing 2 years 
of decline due to FDRA would be clinically meaningful. Using published data (Patel et al., 2016 
[2]), the target effect size is approximately 0.6 for the 9-HPT.
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
Baseline values are defined as the last observed value before the first dose of study medication.
All confidence intervals, statistical tests, and resulting P-values will be reported as 2-sided and 
will be assessed at α=0.05 significance level unless otherwise specified. P-values will be rounded 
to 3 decimal places prior to assessment of statistical significance.
Unless otherwise stated, means and medians will be presented to 1 more decimal place than the 
recorded data. The standard deviations (SDs) will be presented to 2 more decimal places than the 
recorded data. Confidence intervals about a parameter estimate will be presented using the same 
number of decimal places as the parameter estimate.
Continuous data will be summarized using the following descriptive statistics: number of 
subjects (N), mean, standard deviation (SD), median, minimum, and maximum, where 
appropriate. Where indicated, the coefficient of variation (%CV) and geometric mean will also 
be included in the summary of continuous data. Categorical data will be summarized using the 
number and percent of subjects for each category, where appropriate.
Unless otherwise stated, Baseline is defined as the last observed value before the first dose of 
study medication.
As applicable, summaries will be presented by treatment arm, TAK-831 overall and overall. 
Where appropriate, variables will be summarized descriptively by study visit.
All data analyses and figures will be generated using SAS System® Version 9.4 or higher.
7.1.1
Study Definitions
7.1.1.1
Definition of Study Days
Study Day 1 is defined as the date on which a subject is administered their first dose of the 
medication. Other study days are defined relative to the Study Day 1 with Day 1 being Study 
Day 1 and Day -1 being the day prior to Study Day 1.
7.1.1.2
Definition of Study Visit Windows
A windowing convention will be used to determine the analysis value for a given study visit that 
applies to observed data. For each visit, a window will be defined such that the lower and upper 
bounds of each window is generally the midpoint between 2 consecutive study visits. 
More than 1 result for a parameter may be obtained in a visit window. In such an event, the result 
with the date closest to the scheduled visit day will be used. In the event of 2 observations 
equidistant to the scheduled visit day, the later of the observations will be used.
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7.1.2
Conventions for Missing Adverse Event Dates
Incomplete adverse event (AE) start dates will be imputed to determine the relationship between 
the start date and the informed consent date, as well as the start date and the first dose date of the 
double-blind study medication. Incomplete AE dates will be presented as they are in the listings.
The following methods will be used to impute incomplete start dates of AEs:

If only the month and year of the start date are available and the month and year are different 
than the month and year of the first dose of double-blind study medication or the stop date is 
prior to the first dose of study medication, then the first day of the month will be used for the 
start date. If only the month and year of the start date are available and the month and year 
are the same as the month and year of the first dose of double-blind study medication and the 
stop date is not prior to the date of first dose, then the date of first dose will be used for the 
start date.

If only the year of the start date is available and the year is different than the year of the first 
dose of double-blind study medication or the stop date is prior to the first dose of study 
medication, then January 1st will be used for start date. If only the year of the start date is 
available and the year is the same as the year of the first dose of double-blind study 
medication and the stop date is not prior to the date of first dose, then the date of first dose 
will be used for start date.
7.1.3
Conventions for Missing Concomitant Medication Dates
If start date and stop date are missing, medication will be assumed to occur both prior and 
concomitantly.
7.1.4
Grouping of Sites
Before unblinding the data, study sites that are considered small (< 5 subjects for analysis) will 
be pooled with geographically similar sites to minimize artifacts in the statistical analyses from 
imbalances in subject counts within the sites. 
The pooling will start first within each state; if it is still small, other states within the same 
geographical region will also be considered. If possible, sites will only be pooled with sites from 
within the same general US geographic region.
The pooling of the sites will be reviewed before the final analysis. 
7.2
Analysis Sets
7.2.1
Full Analysis Set
The full analysis set (FAS) will include all subjects who were randomized and received at least 
1 dose of the study drug for the treatment period. In FAS efficacy summaries, subjects will be 
analyzed by the treatment to which they were randomized.
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7.2.2
Safety Analysis Set
The Safety Analysis Set will include all randomized subjects who receive at least 1 dose of double-
blind study medication. In safety summaries, subjects will be analyzed according to the treatment 
they received.
7.2.3
PD Analysis Set
The PD analysis set will consist of subjects who receive at least 1 dose of double-blind study 
medication and who have a Baseline D-serine and L-serine plasma concentration measurement 
and at least corresponding 1 postdose plasma concentration measurement.
7.2.4
PK Analysis Set
The PK analysis set will consist of subjects who receive at least 1 dose of double-blind study 
medication and who have any available plasma concentration data.
7.3
Disposition of Subjects
Disposition of all screened subjects (denominator) will be tabulated (count and percent); there 
will be no inferential analysis of subject disposition data.
Summaries will be presented by treatment arm, TAK-831 overall and overall. 
Disposition of all randomized subjects will be tabulated: 

All subjects received at least one dose of study drug (denominator).

Subjects who completed the study.

Subjects who prematurely discontinued study.
Primary reasons for discontinuation of study and study treatment as entered on the electronic 
case report form (eCRF), will be tabulated. Reasons for discontinuation include death, adverse 
event, significant protocol deviation, lost to follow-up, withdrawal by subject, study termination
by sponsor, pregnancy, severe gastrointestinal intolerance and other. The date of first dose, date 
of last dose, duration of treatment and the reason for premature discontinuation of study 
drug/study visit will be presented for each subject in listings. 
Disposition of screen failure subjects will be summarized descriptively. Primary reasons for 
failure will be summarized and will be presented in a data listing.
Significant protocol deviation will be summarized by type.
7.4
Demographic and Other Baseline Characteristics
Demographics and baseline characteristics including age at screening, age at disease onset, 
gender, race, and BMI will be listed and summarized by each treatment group and overall based 
on the FAS. 
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Baseline values for efficacy assessments will also be summarized by each treatment group and 
overall based on the FAS.
For continuous variables, comparability of treatment groups will be assessed using an analysis of 
variance with treatment and pooled site as factors. For discrete variables, comparability will be 
assessed using the Cochran-Mantel-Haenszel general association test, stratified by pooled site. 
The statistical test for race will only be conducted if < 90% subjects report the same race. 
7.5
Medical History and Concurrent Medical Conditions
Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Drug Regulatory Activities (MedDRA, version 21 or higher) coding system. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to FRDA (including age at disease onset) that resolved at or prior 
to signing of informed consent. Ongoing conditions are considered concurrent medical 
conditions.
All medical history and concurrent medical condition data will be listed by site (study center) 
and subject number. The listing will contain subject identifier, treatment, system organ class 
(SOC), preferred term (PT), start and end dates (if not ongoing), and the verbatim term.
Medical history and concurrent medical conditions will be listed and summarized by system 
organ class and preferred term for each treatment group and overall based on the FAS. 
7.6
Medication History and Concomitant Medications
Medication history information to be obtained includes any medication relevant to eligibility 
criteria. Concomitant medication is any drug given in addition to the study drug. 
All medication history and concomitant medications will be listed by site (study center) and 
subject number. The listings will contain subject identifier, treatment, World Health 
Organization Drug Dictionary (WHODrug) preferred medication name, dose, unit, frequency, 
route, start date, stop date, whether the medication was ongoing, and reason for use. Medication 
history and concomitant medications will be summarized for each treatment group and overall 
based on the FAS. No inferential statistics will be presented. 
Medication history and concomitant medications will be coded using the WHODrug Version 
01March 2017 or higher.
7.7
Study Drug Exposure and Compliance
Duration of exposure is defined as [date of the last dose of study medication - date of first dose 
of study medication + 1]. Compliance will be defined as {(number of tablets dispensed – number 
of tablets returned)/(duration of exposure in days x 2 x 3)} x 100%. Duration of exposure and 
compliance will be summarized for each treatment group and overall based on the FAS. The 
duration of exposure will be summarized as a continuous variable.
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7.8
Efficacy Analysis
Two 9-HPT assessments are conducted at each assessment date, with each assessment consisting 
of two trials for each hand. The 9-HPT-1 endpoint will be computed as follows for each 
assessment, using the formula from the Multiple Sclerosis Functional Composite Administration 
and Scoring Manual (Fischer et al, 2001 [1]):
1) For the dominant hand, compute the mean of the two trials, and take the reciprocal
2) Do the same for the non-dominant hand
3) Take the average of the two reciprocals
For descriptive summaries of the 9-HPT, the overall value for each subject will be defined as the 
inverse of the 9-HPT-1 (as computed above). Except where otherwise noted, the analyses 
described herein will be on the data from the first assessment.
Descriptive statistics (mean and SD) for change in the 9-HPT-1 will be displayed with at least 5 
digits after the decimal point.
7.8.1
Primary Efficacy Endpoint
The primary endpoint for this study is the change from Baseline to Week 12 in the inverse of the 
time to complete the 9-HPT (9-HPT-1) after treatment with TAK-831, compared with placebo. 
The primary analysis of change from Baseline in 9-HPT-1 will be based on the FAS. 
Comparisons between TAK-831 and placebo will be made over all assessed time points using 
estimates from a mixed model for repeated measures (MMRM) with Baseline 9-HPT-1 as a 
covariate; pooled site, visit, treatment, and ambulation status (randomization factor) as fixed 
factors; and treatment-by-visit and Baseline 9-HPT-1-by-visit interactions. Based on a Missing at 
Random Assumption, this analysis will be performed using observed case data only. The effect 
at each time point for each treatment is allowed to vary freely and an unstructured covariance 
matrix is assumed. If the model does not converge, other covariance structures will be considered 
in the following order, from most generous to most parsimonious: Toeplitz, compound 
symmetry, and Toeplitz with two bands.
Since 2 doses of TAK-831 are compared to placebo, multiplicity will be controlled at the Holm’s 
method. The dose with the smaller p-value will be tested at the one-sided 0.05 level, then dose 
with the larger p-value will be tested at the one-sided 0.10 level only if the smaller p-value is 
significant. This procedure will control the overall type I error rate at the one-sided 0.10 level. 
The one-sided alternative hypothesis is that the mean time to complete the 9-HPT is shorter on 
the TAK-831 arm compared to placebo.
Subgroup analyses will be conducted according to ambulation status, Baseline D-serine 
concentration (< median of randomized subjects and ≥ median), sex, categorical age at Screening 
(<35 and ≥35 years of age), and baseline mFARS-neuro total score (< median of randomized 
subjects and ≥ median). In addition, a subgroup analysis by race (white vs. non-white) will be 
conducted if at least 20% of randomized subjects are non-white.
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As a sensitivity analysis, a method for missing value imputation based on pattern mixture models 
(PMM) will be implemented using standard SAS STAT procedures. It is assumed that after 
discontinuation from the study, subjects receiving a TAK-831 dose will exhibit the same future 
evolution of the disease as subjects on the placebo treatment. The missing 9-HPT-1 score in the 
TAK-831 dose arm will be imputed using placebo-based pattern mixture models. This method 
uses sequential regression and multiple imputation methodology to impute missing values for 
visits after a subject’s discontinuation from the study in the placebo arm. Then based on the 
available data from placebo subjects, the missing values from active treatment arm will be 
imputed using pattern mixture models until missing values at all visits are imputed.
The primary endpoint will then be analyzed using ANCOVA, with pooled center, stratification 
factor, and treatment as fixed factors, and Baseline 9-HPT-1 as a covariate, based on the multiply-
imputed data. 
In addition, the primary analysis will be conducted with the average of Screening and Baseline 9-
HPT-1 included in the model instead of Baseline 9-HPT-1. 
The primary analysis will also be conducted using the second set of 9-HPT assessments at each 
timepoint. Both sets of 9-HPT assessments will be summarized descriptively at all timepoints. 
The 9-HPT and 9-HPT-1 will be plotted longitudinally for each subject. Up to 10 subjects from 
the same treatment group can be displayed on the same plot.
7.8.2
Secondary Efficacy Endpoints
Analysis of secondary efficacy endpoints will be based on the FAS. For these endpoints, which 
are continuous change from Baseline endpoints, comparisons between TAK-831 and placebo 
will be based on similar methodology to that described for the primary efficacy analysis. For 
binary or ordinal endpoints, Cochran-Mantel-Haenszel tests will be used with ambulation status 
at randomization as a stratification factor. For binary or ordinal endpoints, missing data will be 
imputed as no change from Baseline. For each secondary endpoint, the 1-sided alternative 
hypothesis is that TAK-831 is superior to placebo in the clinically favorable direction, for 
example, a lower mean score on the FARS ADL scale.
The time-weighted average of the change from baseline in 9-HPT-1 at Weeks 2, 7, and 12 will be 
summarized for each treatment group. Specifically, the change from baseline will be weighted 
according to the number of days since the first dose (at Week 2) or the previous post-baseline 
observation (at Weeks 7 and 12).
The T25FW assessment will be consist of up to 2 trials at each assessment. If both are 
conducted, the average of the 2 trials will be used in the analysis. 
The 9-HPT-1 and T25FW composite score will be created using the methods in Fischer et al 
(2001). In brief, raw scores from each test will be converted to test-specific Z scores by 
subtracting the cohort mean from the raw score, and then dividing by the cohort SD. The cohort 
mean and SD will be computed from the Baseline value, pooling all treatment arms. The 
composite Z scores will be created by subtracting Z-score for T25FW from the Z-score for 9-
HPT-1.
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The T25FW and the inverse of the T25FW will be plotted longitudinally for each subject. Up to 
10 subjects from the same treatment group can be displayed on the same plot. Plotting symbols 
will be used to indicate what type of assistive device, if any, a subject used at each assessment.
Multiplicity will not be controlled for the secondary endpoints.
7.8.3
Exploratory Endpoints
The analysis of the digital speech and motor endpoints will be described in a separate analysis 
plan. 
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
Plasma concentrations of TAK-831 will be listed for each subject and summarized by each time 
point for each dose of the study.
Individual concentration-time data will be pooled to describe the population PK of TAK-831. As 
data permit, a nonlinear mixed effects modeling approach (NONMEM software) will be used to 
assess TAK-831 exposure. PK information generated in this study will be further utilized in 
subsequent population PK-PD analyses. The relationships between TAK-831 plasma 
concentrations and drug response (D- or L-serine plasma levels and/or selected measures of 
efficacy) will be explored. As appropriate, historical data may be used in this analysis to increase 
the robustness of the model and precision of estimated parameters. Details of the modeling 
approach will be provided in a separate analysis plan, and the results of these analyses may be 
reported separately. 
7.9.2
Pharmacodynamic Analysis
For each regimen, the concentrations of D-serine, L-serine, and the ratio of D-serine to total 
serine with change will be summarized at each time point of each dose level using descriptive 
statistics. In addition, a mixed effects regression model will be fitted to the change from Baseline 
in these concentrations. Comparisons between TAK-831 and placebo will be made over all 
assessed time points using estimates from a MMRM with serine (D-, L-, ratio) as a covariate; 
visit and treatment as fixed factors; and treatment-by-visit and Baseline-by-visit interactions. 
Pairwise comparisons between each pair of test regimens (high dose, low dose and placebo) will 
be made and the CIs for the difference in the LS means will be constructed for Days 14, 49, and 
84. In addition, the percent change from Baseline will be summarized at Day 84.
See also Section 7.9.1.
7.10
Other Outcomes
The CGI-I, PGI-I, CGI-S, and PGI-S endpoints, including both global and upper extremity 
function endpoints, will be summarized using descriptive statistics.
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The statistical details of the Responder Analysis (Protocol Section 13.1.7) will be included in a 
separate analysis plan.
7.11
Safety Analysis
Analysis of safety variables will be based on the safety analysis set.
7.11.1 Adverse Events
Verbatim terms will be coded by SOC and PT using MedDRA (version 20.0 or later).
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has
signed informed consent to participate in a study but prior to administration of any study drug; it
does not necessarily have to have a causal relationship with study participation.
Treatment-emergent adverse events (TEAEs) will be defined as any sign, symptom, syndrome, 
or new illness, regardless of relationship to study drug, that occur after the first dose of study 
drug and up to 3 days (onset date – last date of dose + 1 ≤3) after the last dose of study drug or 
early termination. In the protocol they are referred to simply as adverse events, but the term 
TEAE is used in this document and the resulting outputs for consistency with other TAK-831 
studies.
TEAEs are recorded in the eCRF as being related or not related to study drug and study 
procedure. TEAEs that are recorded as related to study drug and/or study procedure will be 
summarized separately. TEAEs will also be presented by intensity/severity (mild, moderate, and 
severe). Serious TEAEs, TEAEs leading to study drug discontinuation, and TEAEs leading to 
death will also be summarized using SOC and PT. 
When calculating the frequency and percentage of subjects who reported TEAEs, a subject will 
be counted only once for each SOC or PT when multiple TEAEs are coded to the same SOC or 
PT. For the intensity or relatedness summaries, if a subject reports multiple TEAEs coded to the 
same SOC or PT, the TEAE with maximum intensity or strongest relationship will be included in 
the summary.
AEs with missing intensity will be listed as such in the AE listings, however, will be summarized 
as severe in summary tables. If the relationship of an event is missing, the relationship for the 
event will be considered to have been related.
In general, AEs will be tabulated at the following levels: overall summary (subjects with at least 
1 AE in any dose or regimen), the MedDRA SOC, and the MedDRA PT. The tables will include 
the number and percentage (N[%]) of subjects. Summary tables that will be generated will 
include, but may not be limited to:

Overview of Treatment-Emergent Adverse Events 

Treatment-Emergent Adverse Events by System Organ Class and Preferred Term

Treatment-Emergent Adverse Events by Preferred Term
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
Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 

Most Frequent (>5% or N>2) Non-Serious Adverse Events by System Organ Class and 
Preferred Term

Relationship of Treatment-Emergent Adverse Events to Study Drug by System Organ Class 
and Preferred Term

Drug-Related Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term 

Drug-Related Treatment-Emergent Adverse Events by Preferred Term

Intensity of Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 

Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by System 
Organ Class and Preferred Term

Pretreatment Adverse Events by System Organ Class and Preferred Term
In addition, subject mappings for the TEAEs by SOC and PT will be generated.
Data listings will be provided for PTEs, TEAEs, TEAEs leading to study drug discontinuation, 
liver function abnormalities, SAEs, and AEs that resulted in death. AEs happened after 3 days 
post the last dose of the study drug will be listed as well.
Summaries will be presented by treatment arm, TAK-831 overall and overall.
7.11.2 Clinical Laboratory Evaluations
Clinical laboratory tests will be assessed using the Safety Set and will be evaluated and presented 
using International System of Units (SI) units unless otherwise stated. Refer to Protocol Section 
9.1.10 as well as the schedule of the events for a list of all clinical laboratory tests.
All laboratory test parameters will be displayed in individual subject data listings. For test results 
not in SI units, the conversion to SI units will be done in the derived SDTM and ADaM datasets 
using the known conversion factors. If necessary, SI units from the central laboratory may be 
converted to Takeda’s preferred SI units in the derived SDTM and ADaM datasets. All 
summaries and analyses will be based on the values using these preferred SI units.
Only observations within 3 days of the last dose of study drug will be included in the tables. No 
inferential statistics will be presented unless otherwise stated.
Descriptive statistics (N, mean, SD, median, minimum, and maximum) for the observed and 
change from baseline values will be presented. Study baseline will be used for change from 
baseline. Note that “character” urinalysis tests will only be listed.
Laboratory MAVs, identified by the criteria defined in Appendix A, will be tabulated. If a 
subject has a MAV for a particular laboratory test, all visits for that subject for that parameter 
will be listed. The number and percentage of subjects with at least 1 postdose markedly abnormal 
laboratory test result will be summarized. The mapping of the subjects who meet the MAV 
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criteria will be listed as a table. All observations, including ones at unscheduled visits, will be 
included in the MAV evaluation and summaries.
Listings of all clinical safety laboratory data will be provided in Appendix 16.2. Laboratory data 
outside of the normal reference range will be indicated in the listings. In addition, MAVs will be 
flagged. The listing will include site number, subject identifier, age, gender, treatment group, 
study visit, and sample collection date.
7.11.3 Vital Signs
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be used to 
summarize vital sign parameters at baseline, each post-baseline visit, and change from baseline 
to each post-baseline visit. Only observations within 3 days of the study drug will be included in 
the tables.
Vital sign MAVs, identified by the criteria defined in Appendix B, will be tabulated. If a subject 
has a MAV for a particular vital signs parameter, all visits for that subject for that parameter will 
be listed. The number and percentage of subjects with at least 1 postdose markedly abnormal 
vital signs measurement will be summarized. The mapping of the subjects who meet the MAV 
criteria will be listed as a table. All observations, including ones at unscheduled visits, will be 
included in the MAV evaluation and summaries.
Listings of all vital signs data will be provided in Appendix 16.2. Vital sign MAVs will be 
flagged in the listings. The listing will include site number, subject identifier, age, gender, 
treatment group, study visit, and sample collection date.
7.11.4 12-Lead ECGs
Descriptive statistics (N, mean, SD, median, minimum, and maximum) of ECG parameters, 
including heart rate, PR interval, RR interval, QRS interval, QT interval, and QTc interval 
(Fredericia’s and Bazett’s corrections), will be presented for baseline, each post-baseline visit, 
and change from baseline to each post-baseline visit. Only the scheduled measurements will be 
included in the summary. Only observations within 3 days of the study drug will be included in 
the tables. No inferential statistics will be presented.
ECG MAVs, identified by the criteria defined in Appendix C, will be tabulated. If a subject has a 
MAV for a particular 12-lead ECG parameter, all visits for that subject for that parameter will be 
listed. The number and percentage of subjects with at least 1 postdose markedly abnormal 12-
lead ECG measurement will be summarized. The mapping of the subjects who meet the MAV 
criteria will be listed as a table. All observations, including ones at unscheduled visits, will be 
included in the MAV evaluation and summaries.
Overall ECG interpretation category (normal, abnormal not clinically significant, abnormal 
clinically significant) is collected by eCRF at baseline and at each scheduled post-baseline visit. 
Shifts in ECG interpretation will be presented as cross-tabulations (baseline versus each post-
baseline visit) of numbers of subjects with normal, abnormal not clinically significant, and 
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abnormal clinically significant interpretations with missing, if applicable, and total categories by 
regimen.
Listings of all 12-lead ECG data will be provided in Appendix 16.2. MAVs will be flagged in the 
listings. The listing will include site number, subject identifier, age, gender, treatment group, 
study visit, and sample collection date.
The Frederica-corrected QT interval (QTcF) will be derived using the formula in Section 9.1.13 
of the protocol. The Frederica-corrected QT interval (QTcB) will be derived using the following 
formula:
 =  
√

.
7.11.5 Other Observations Related to Safety
Suicidality assessments (C-SSRS) will also be summarized for each treatment group. Subjects 
with elevated liver function test values will also be summarized.
7.12
Interim Analysis
No interim analysis of efficacy is planned.
The sponsor established an internal DMC independent of the study and project team to 
periodically review unblinded safety data during conduct of this study to complement the routine 
safety monitoring approach for compounds at this stage of development. The functions and 
procedures of the committee were outlined in a DMC Charter. 
7.13
Changes in the Statistical Analysis Plan 
Although change in CGI-I and PGI-I were included as endpoints in the protocol, CGI-I and PGI-
I were not collected at baseline since these endpoints are not meaningful prior to treatment. 
Therefor the CGI-I or PGI-I value at the given timepoint rather than the change will be analyzed.
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8.0
REFERENCES
1. Fischer JS, Jak AJ, Kniker JE, Rudick RA, Cutter G. Multiple Sclerosis Functional 
Composite administration and scoring manual, Revised. October 2001. National Multiple 
Sclerosis Society.
2. Patel M, Isaacs CJ, Seyer L, Brigatti K, Gelbard S, Strawser C, et al. Progression of 
Friedreich ataxia: quantitative characterization over 5 years. Ann Clin Transl Neurol 
2016;3(9):684-94.
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Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values 
Hematology—Criteria for Markedly Abnormal Values
Parameter
Unit
Low Abnormal
High Abnormal
Hemoglobin
Both 
< 0.8 × LLN
> 1.2 × ULN
Hematocrit
Both
< 0.8 × LLN
> 1.2 × ULN
RBC count 
Both
< 0.8 × LLN 
> 1.2 × ULN
WBC count 
Both 
<0.5 x LLN
>1.5 x ULN
Platelet count
Conventional
<75 x 103/L
>600 x 103/L
SI
<75 x 109/L
>600 x 109/L
LLN=lower limit of normal, RBC=red blood cell, ULN=upper limit of normal, WBC=white blood cell. 
Serum Chemistry—Criteria for Markedly Abnormal Values
Parameter
Unit 
Low Abnormal
High Abnormal
ALT
Both
--
>3x ULN
AST
Both
--
>3x ULN
GGT
Both
--
>3x ULN
Alkaline phosphatase
Both
--
>3x ULN
Total bilirubin
Conventional
--
>2.0 mg/dL
SI
--
>34.2 mol/L
Albumin
Conventional 
<2.5 g/dL
--
SI 
<25 g/L
--
Total protein
Both
<0.8x LLN
>1.2x ULN
Creatinine
Conventional 
--
>2.0 mg/dL
SI
>177 mol/L
Blood urea nitrogen
Conventional 
>30 mg/dL
SI
>10.7 mmol/L
Sodium
Conventional
<130 mEq/L
>150 mEq/L
SI
<130 mmol/L
>150 mmol/L
Potassium
Conventional
<3.0 mEq/L
>6.0 mEq/L
SI
<3.0 mmol/L
>6.0 mmol/L
CPK
Both
--
>5x ULN
Glucose
Conventional
< 50 mg/dL
>350 mg/dL
SI
< 2.8 mmol/L
>19.4 mmol/L
ALT=alanine aminotransferase, AST=aspartate aminotransferase, CPK=creatine phosphokinase, GGT=-glutamyl 
transferase, LLN=lower limit of normal, ULN=upper limit of normal.
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TAK-831-1501
Page 26 of 27
Statistical Analysis Plan 
01 February 2019
Appendix B
Criteria for Abnormal Vital Signs
Parameter
Unit
Lower Criteria
Upper Criteria
Pulse
Bpm
<50 
>120
Systolic blood pressure
mm Hg
<85
>180 
Diastolic blood pressure
mm Hg
<50
>110
Body temperature
oC
< 35.6
>37.7
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TAK-831-1501
Page 27 of 27
Statistical Analysis Plan 
01 February 2019
Appendix C
Criteria for Out-of-Range Values for the 12-Lead ECG Parameters
Parameter
Lower Criteria
Upper Criteria
Heart rate
<50 beats per minute
>120 beats per minute
PR
≤80 milliseconds
≥200 milliseconds
QT Interval
≤300 milliseconds
≥460 milliseconds
QTcB Interval
≤300 milliseconds
≥500 milliseconds OR 
≥30 milliseconds change from baseline and
≥450 milliseconds
QTcF Interval
≤300 milliseconds
≥500 milliseconds OR 
≥30 milliseconds change from baseline and
≥450 milliseconds
QRS
≤80 milliseconds
≥180 milliseconds
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