Clinical trial NCT04334317
Conditions: Parkinson Disease Healthy Participants
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2020-10-21; Completion date: 2023-02-27
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
It is hoped that TAK-071 will help people with Parkinson's disease to walk with better balance. The main aim of the study is to check if there is a difference in how participants walk after treatment with TAK-071. Another aim is to see if it improves how participants think and remember.

At the first visit, the study doctor will check who can take part. Participants who can take part will be picked for 1 of 2 groups by chance.

Both groups will have 2 treatments but in a different order. The treatments are TAK-071 tablets or placebo. In this study, a placebo will look like the TAK-071 but will not have any medicine in it.

One group will take TAK-071 for 6 weeks, have at least a 3-week break, then take a placebo for 6 weeks. The other group will take a placebo for 6 weeks, have at least a 3-week break, then take TAK-071 for 6 weeks. The participants will not know the order of their 2 treatments, nor will their study doctors. This is to help make sure the results are more reliable.

The participants will visit the clinic at the beginning and end of each treatment for a check-up. 14 days after the 2nd treatment, clinic staff will telephone the participants for a final check-up.

Detailed description:
The drug being tested in this study is TAK-071. TAK-071 is being tested to treat people with PD who have cognitive impairment and are at risk for falls and who are not concurrently taking acetylcholinesterase inhibitors. The study will look at the efficacy and safety of TAK-071 in participants with PD who take TAK-071 versus placebo.

The study will also evaluate the PK of TAK-071 in healthy participants (sentinel cohort) older than 55 years.

The study will enroll approximately 74 participants. An initial sentinel cohort of 10 healthy participants will be included to estimate age effects. Participants aged 56 to 75 years will be randomly assigned in 3:1 ratio to one of the two treatments:

* Sentinel Cohort: TAK-071 7.5 mg
* Sentinel Cohort: Placebo

Enrolment for participants aged 40 to ≤ 85 years in the main study will start simultaneously with sentinel cohort. Based on PK, safety, and physiologically based PK modelling data from sentinel cohort, dosing will be decided for the remaining participants. Participants with maximum age of 66 to 85 years, inclusive, will be enrolled at a dose of 5 mg, and the dose for subjects aged 40 to 65 years, inclusive, will be 7.5 mg. All participants will be asked to take one tablet at the same time each day throughout the study.

The remaining participants aged 40 years to \<=85 years will be randomly assigned in 1:1 ratio to one of two treatment sequences in crossover design:

* TAK-071 + Placebo
* Placebo + TAK-071

The study will be conducted in the United States. The minimum time to participate in this study is approximately 15 weeks. Participants will make multiple visits to the clinic and will have home assessments during the third Week of each 6-week treatment period, and will be contacted by telephone at 14 days after completion of the last period for a follow-up assessment.

Arms: arm 1: TAK-071 placebo-matching tablets, orally, once daily for up to first 6 weeks in Period 1, followed by ≥3 weeks washout period, followed by TAK-071 tablets, orally, once daily for up to next 6 weeks in Period 2. arm 2: TAK-071 tablets, orally, once daily for up to first 6 weeks in Period 1, followed by ≥3 weeks washout period, followed by TAK-071 placebo-matching tablets, orally, once daily for up to next 6 weeks in Period 2. arm 3: A single dose of TAK-071 placebo-matching mg, tablet, orally, on Day 1. arm 4: A single dose of TAK-071 ≤ 7.5 milligrams (mg), tablet, orally, on Day 1.
Interventions: intervention 1: TAK-071 intervention 2: Placebo
Intervention descriptions: intervention 1: TAK-071 tablet. intervention 2: TAK-071 placebo-matching tablet.

Protocol documents:
Prot_000.pdf: 
NCT Number: NCT04334317
Title: A Randomized, Double-blind, Placebo-Controlled, 2-Period Crossover, 
Phase 2 Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of Oral TAK-071 in Parkinson Disease Patients With 
Cognitive Impairment and an Elevated Risk of Falls
Study Number: TAK-071-2002
Document Version and Date: Amendment 4.0, 07 September 2021
Certain information within this document has been redacted (ie, specific content is masked 
irreversibly from view) to protect either personally identifiable information or company 
confidential information. 
Clinical Study Protocol


1 REVIEW, 13 DECEMBER 2019DRAFT 1 REVIEW, 13 DECEMBER 20191.0 TITLE 
PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
A Randomized, Double-blind, Placebo-Controlled, 2-Period Crossover, Phase 2 Study to 
Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of 
Oral TAK-071 in Parkinson Disease Patients With Cognitive Impairment and an Elevated 
Risk of Falls
TAK-071 for Falls and Cognition in Parkinson Disease
Sponsor:
Takeda Development Center Americas, Inc. 
95 Hayden Avenue 
Lexington MA 02421
Study Number:
TAK-071-2002
IND Number:
146849
EudraCT Number:
Not Applicable
NCT Number
NCT04334317
Compound:
TAK-071
Date:
07 September
2021
Version/Amendment 
Number:
Amendment 4
Amendment History
Date
Amendment Number
Region
07 September 2021
Amendment 4
United States
18 January 2021
Amendment 3
United States
12 August 2020
Amendment 2
United States
06 July 2020
Amendment 1
United States
16 March 2020
Initial version
United States
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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1.0
ADMINISTRATIVE INFORMATION
1.1
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 (ICH) E6 (R2) Good Clinical Practice (GCP): 
Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer can be found on the signature page.
Electronic Signatures are provided on the last page of this document.
, MD PhD
or delegate
Date
, PhD
Quantitative Clinical Pharmacology
Date
Statistics and Quantitative Sciences 
Date
, MD
, 
Neuroscience Therapeutic Area Unit
Date
9/8/2021


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CONFIDENTIAL
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.

ICH E6 (R2) GCP: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events (SAEs) defined in Section 10.2
of this protocol.

Terms outlined in the study site agreement.

Responsibilities of the investigator (Appendix D).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix F 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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1.2
Contacts
Takeda Development Center Americas, Inc. (TDCA)–sponsored investigators 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
Cognizant
FAX: 800-963-6290
Medical Monitor
(medical advice on protocol and study drug)
PPD
Phone: 800-201-8725
Responsible Medical Officer 
(carries overall responsibility for the conduct of the 
study)
, MD PhD
95 Hayden Avenue 
Lexington MA 02421


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CONFIDENTIAL
1.3
Protocol Amendment 4 Summary of Changes
This section describes the changes in reference to the Protocol Incorporating Amendment No. 4.
Amendment 4 is mainly necessitated by the pharmacokinetic (PK), safety, and physiologically 
based PK modeling of data from the sentinel cohort completed at a designated site. Additional 
clarifications have been made to the excluded and allowed medications and treatments, entry
criteria, and other items to avoid protocol deviations.
The primary reasons for this amendment are to:

Allow enrollment of older subjects with Parkinson disease aged 66 to 85 years, inclusive, at a 
dose level of TAK-071 5 mg. Subjects aged 40 to 65 years, inclusive, will continue to receive 
TAK-071 at a dose level of 7.5 mg.

Change the suggested study entry criteria for investigator assessment of fall history, cognitive 
impairment, prior history of stable antiparkinsonian medication, and prior history of deep brain 
stimulation (DBS) device implantation.

Prohibit use of acetylcholinesterase inhibitors administration during study and modify study 
entry and use criteria for other medications and treatments.

Clarify visit windows for Study Visit days.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only, 
and are not captured in the following table.
Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by 
Change
Description of Each Change and Rationale
Location
Description
Rationale
1
Section 2.0, Study Summary: 
Study Design / Dose Levels:
Section 4.2, Benefit/Risk 
Profile
Section 6.1, Study Design, 
Main Study
Allowed enrollment of older 
individuals aged 66 to 85 years, 
inclusive, at a dose level of 
TAK-071 5 mg. 
Clarified that individuals aged 40 
to 65 years, inclusive, will 
continue to receive TAK-071 at a 
dose level of 7.5 mg. The 
TAK-071 dose level for this age 
group was specified as 7.5 mg 
(rather than ≤7.5 mg).
PK, safety, and physiologically 
based PK modeling of data from 
the completed sentinel cohort 
allowed for expansion of the 
main cohort to include 
participants up to 85 years of 
age, inclusive. The modeling 
also provided justification for 
dose level specification by age.


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Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by 
Change
Description of Each Change and Rationale
Location
Description
Rationale
2
Section 2.0, Study Summary: 
Subject Population
Section 6.1, Study Design, 
Main Study
Section 8.2, Study Drug 
Assignment and Dispensing 
Procedures
Removed enrollment procedures 
and related discussion for the 
sentinel cohort and for initial 
sentinel cohort data review and 
modeling.
Completion of the sentinel 
cohort and corresponding 
analysis.
3
Section 6.3.3, Dose 
Justification
Section 7.1, Inclusion 
Criteria (#3)
Section 8.2, Study Drug 
Assignment and Dispensing 
Procedures
Clarified upper limit of age range 
of study subjects, changing to 85 
years, inclusive.
PK, safety, and physiologically 
based PK modeling of data from 
the completed sentinel cohort 
allowed for expansion of the 
main cohort to include 
participants up to 85 years of 
age, inclusive.
4
Section 2.0, Study Summary: 
Main Criteria for Inclusion
Section 7.1, Inclusion 
Criteria (#6) 
Changed suggested fall history 
criteria (ie, elevated risk of falls) 
to at least 1 fall in the last 12 
months with continued elevated 
risk of falls per investigator 
judgment. 
Clarified that investigator 
judgment on fall risk may be 
informed by such information as, 
but not limited to, history, 
physical examination and/or a 
score ≥2 on item 3.10 on 
Movement Disorders Society–
Unified Parkinson’s Disease 
Rating Scale Part III.
Provides additional emphasis on 
investigator determination of fall 
history and provide suggested 
criteria. Increases study 
feasibility.
5
Section 2.0, Study Summary: 
Main Criteria for Inclusion
Section 6.3.1, Subject 
Selection Considerations
Section 7.1, Inclusion 
Criteria (#7)
Changed permissible Montreal 
Cognitive Assessment score range 
from 11 to 26, inclusive (rather 
than 17 to 24), for assessment of 
cognitive impairment and specify 
completion of cognitive 
assessments at screening (rather 
than randomization) for 
assessment of cognitive 
impairment (as specified in the 
study manual).
Provides additional more 
specific and more widely 
applicable criteria for assessment 
of cognitive impairment. 
Increases study feasibility.


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Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by 
Change
Description of Each Change and Rationale
Location
Description
Rationale
6
Section 2.0, Study Summary: 
Main Criteria for Inclusion
Section 7.1, Inclusion 
Criteria (#10)
Clarified period for study entry 
assessment of stable 
antiparkinsonian medication as at 
least 30 days before 
randomization (rather than 
screening).
Clarification.
7
Section 2.0, Study Summary: 
Main Criteria for Exclusion
Section 7.2, Exclusion 
Criteria (#6)
Specified period for DBS device 
implantation as within the past 
year and for stable setting as ≥2 
months, if safe to do so and if the 
presence of DBS will not impact 
study assessments, and if further 
changes in DBS settings are not 
anticipated for the duration of 
study participation, per 
investigator judgment.
Provides additional context 
regarding criteria for prior use of 
DBS device for investigator.
Increase study feasibility.
8
Section 7.2, Exclusion 
Criteria (#10)
Specified repeat screening 
laboratory test for inaccurate 
values.
Clarification.
9
Section 2.0, Study Summary: 
Subject Population
Section 4.2, Benefit/Risk 
Profile
Table 7.a, Excluded and 
Allowed Medications and 
Treatments
Clarified that acetylcholinesterase 
inhibitors, including donepezil, 
rivastigmine, and galantamine,
are not permitted. 
Risk of seizure with 
co-administration of TAK-071, 
based on data from nonclinical 
toxicology studies.
10
Table 7.a, Excluded and 
Allowed Medications and 
Treatments
Clarified that vaccination for 
coronavirus disease 2019 vaccine 
is allowed.
Clarification.
11
Table 7.a, Excluded and 
Allowed Medications and 
Treatments
Added exception for mirabegron 
among excluded anticholinergic 
drugs.
Allows subjects to use 
mirabegron.
12
Table 7.a, Excluded and 
Allowed Medications and 
Treatments
Clarified washout period for 
excluded antipsychotic drugs ie, 
at least 30 days before 
randomization and approval for 
study entry.
Clarification.


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Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by 
Change
Description of Each Change and Rationale
Location
Description
Rationale
13
Table 7.a, Excluded and 
Allowed Medications and 
Treatments
Allowed the use of antipsychotic 
drugs, nonbenzodiazepine 
hypnotics, and muscle relaxants
under some circumstances. 
Emphasized that anticonvulsants 
in Table 7.b are never allowed.
Clarified use of muscle relaxants 
under some circumstances if the 
total daily dose has been relatively 
stable from 30 days before 
randomization to the end of the 
study.
Clarification.
14
Table 7.a, Excluded and 
Allowed Medications and 
Treatments
Allowed episodic use of 
antidepressants, herbal remedies 
that are psychoactive, 
over-the-counter drugs, and 
antiparkinsonian drugs under 
some circumstances. 
Clarification.
15
Table 7.a, Excluded and 
Allowed Medications and 
Treatments
Allowed episodic use of 
melatonin for subjects with REM 
(rapid eye movement) sleep 
behavior disorder and/or insomnia 
under described conditions.
Clarification.
16
Section 6.3.3, Dose 
Justification
Appendix H, Sentinel Cohort 
(Healthy Subjects) Only
Presented justification for 
expanding enrollment of older 
participants from the sentinel 
cohort analysis.
Clarified by pharmacologist.
17
Section 2.0, Study Summary: 
Statistical Considerations
Changed the area under the 
concentration-time curve (AUC) 
PK parameter for the sentinel 
cohort to AUC from time 0 to 24 
hours (AUC24).
Clarified by pharmacologist.


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Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by 
Change
Description of Each Change and Rationale
Location
Description
Rationale
18
Appendix A, Schedule of 
Study Procedures, Main 
Study (Su.bjects With PD): 
Table A-1, Period 1
(footnotes a, b, c)
Clarified that screening 
assessments should be completed 
within the screening period.
Clarified that assessments at Visit 
2 (Period 1 baseline) may be split 
across 2 days and should be 
completed on or before Day 3.
Clarified that assessments at Visit 
4 (Period 1 last day of treatment 
period or early termination) may 
be split across 2 days and should 
occur within the visit window.
Clarification. Increase study 
feasibility.
19
Appendix A, Schedule of 
Study Procedures, Main 
Study (Su.bjects With PD): 
Table A-1, Period 1 and 
Table A -2, Period 2
(footnote a)
Clarified that assessments at Visit 
5 (Period 2 baseline) and Visit 7 
(Period 2 last day of treatment 
period or early termination visit) 
may be split across 2 days and 
should occur within the visit 
window. 
Clarification. Increase study 
feasibility.


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Approval....................................................................................................................2
1.2
Contacts.....................................................................................................................4
1.3
Protocol Amendment 4 Summary of Changes............................................................5
2.0
STUDY SUMMARY ....................................................................................................16
3.0
STUDY REFERENCE INFORMATION ......................................................................21
3.1
Study-Related Responsibilities.................................................................................21
3.2
Coordinating Investigator.........................................................................................21
3.3
List of Abbreviations ...............................................................................................22
4.0
INTRODUCTION.........................................................................................................24
4.1
Background and Rationale .......................................................................................24
4.1.1
Falls in PD.......................................................................................................24
4.1.2
Cognitive Impairment in PD ............................................................................25
4.1.3
Impairments in Speech in PD...........................................................................25
4.1.4
Nonclinical Data..............................................................................................25
4.1.5
Differentiation From AChEIs and Other M1 PAMs..........................................26
4.2
Benefit/Risk Profile .................................................................................................27
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................27
5.1
Objectives................................................................................................................28
5.1.1
Primary Objectives ..........................................................................................28
5.1.2
Secondary Objectives ......................................................................................28
5.1.3
Exploratory/Additional Objectives...................................................................28
5.2
Endpoints.................................................................................................................29
5.2.1
Primary Endpoint.............................................................................................29
5.2.2
Secondary Endpoints .......................................................................................29
5.2.3
Safety Endpoints..............................................................................................30
5.2.4
Exploratory Endpoints .....................................................................................30
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................31
6.1
Study Design, Main Study .......................................................................................31
6.2
Contingency Measures Due to COVID-19 Pandemic or Other Unavoidable 
Circumstances..........................................................................................................33
6.3
Justification for Study Design, Endpoints, and Dose ................................................33
6.3.1
Subject Selection Considerations .....................................................................33
6.3.2
Justification for Digital Endpoints....................................................................34


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6.3.3
Dose Justification ............................................................................................34
6.4
Premature Termination or Suspension of Study or Study Site...................................35
6.4.1
Criteria for Premature Termination or Suspension of the Study........................35
6.4.2
Criteria for Premature Termination or Suspension of Study Sites.....................36
6.4.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites..............................................................................36
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............36
7.1
Inclusion Criteria .....................................................................................................36
7.2
Exclusion Criteria ....................................................................................................37
7.3
Excluded/Allowed Medications and Treatments.......................................................39
7.4
Diet, Fluid, and Activity Control..............................................................................44
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................45
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................46
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................46
8.1
Study Drug and Materials ........................................................................................46
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling ..................................46
8.1.1.1
Study Drug ..............................................................................................46
8.1.1.2
Sponsor-Supplied Drug............................................................................47
8.1.2
Storage ............................................................................................................47
8.1.3
Dose and Regimen...........................................................................................47
8.1.4
Overdose .........................................................................................................47
8.2
Study Drug Assignment and Dispensing Procedures ................................................47
8.3
Randomization Code Creation and Storage..............................................................48
8.4
Study Drug Blind Maintenance................................................................................48
8.5
Unblinding Procedure..............................................................................................48
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................49
9.0
STUDY PLAN ..............................................................................................................49
9.1
Study Procedures.....................................................................................................49
9.1.1
Informed Consent Procedure............................................................................50
9.1.1.1
DNA Analysis Informed Consent Procedure............................................50
9.1.2
Demographics, Medical History, and Medication History Procedure................50
9.1.3
Physical Examination Procedure......................................................................50
9.1.4
Neurological Examination Procedure...............................................................51
9.1.5
Weight, Height, and BMI.................................................................................51
9.1.6
Vital Sign Procedure........................................................................................51
9.1.7
MoCA (Subjects With PD Only)......................................................................51


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9.1.8
Pharmacodynamic Measurements....................................................................51
9.1.8.1
Pharmacodynamic Measurements Related to Gait....................................52
9.1.8.2
Pharmacodynamic Measurements Related to Cognition...........................53
9.1.8.3
Other Pharmacodynamic Measures..........................................................55
9.1.8.4
Biomarkers ..............................................................................................56
9.1.9
Documentation of Concomitant Medications ...................................................57
9.1.10
Documentation of Concurrent Medical Conditions...........................................57
9.1.11
Maximum Blood Volumes (Subjects With PD Only) .......................................57
9.1.12
Procedures for Clinical Laboratory Samples ....................................................57
9.1.13
Contraception and Pregnancy Avoidance Procedure ........................................59
9.1.13.1
Male Subjects and Their Female Partners ................................................59
9.1.13.2
Female Subjects and Their Male Partners ................................................59
9.1.13.3
Definitions and Procedures for Contraception and Pregnancy Avoidance
................................................................................................................59
9.1.14
Pregnancy........................................................................................................61
9.1.15
ECG Procedure................................................................................................62
9.1.16
Assessment of Suicidal Ideation and Behavior.................................................62
9.1.17
Sample Collection for DNA Analysis ..............................................................62
9.1.18
Plasma Sample for Circulating Biomarkers......................................................63
9.1.19
Blood Samples for PK Analysis.......................................................................63
9.1.20
Bioanalytical Methods .....................................................................................63
9.1.21
PK Parameters .................................................................................................63
9.1.22
Documentation of Screen Failure.....................................................................63
9.1.23
Documentation of Randomization....................................................................64
9.1.24
Alternative Approaches to Study Procedures and Data Collection Due to 
COVID-19 or Other Unavoidable Circumstances.............................................64
9.2
Monitoring Subject Treatment Compliance..............................................................65
9.3
Schedule of Observations and Procedures................................................................65
9.3.1
Screening.........................................................................................................66
9.3.2
Treatment Period .............................................................................................66
9.3.2.1
Baseline/Randomization ..........................................................................66
9.3.2.2
Treatment and Washout Periods...............................................................67
9.3.3
Final Visit or Early Termination ......................................................................67
9.3.4
Follow-up........................................................................................................67
9.3.5
Post Study Care ...............................................................................................67
9.4
Biological Sample Retention and Destruction ..........................................................67


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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................68
10.1
Definitions...............................................................................................................68
10.1.1
PTEs................................................................................................................68
10.1.2
AEs .................................................................................................................68
10.1.3
Additional Points to Consider for PTEs and AEs .............................................68
10.1.4
SAEs ...............................................................................................................70
10.1.5
Intensity of PTEs and AEs ...............................................................................71
10.1.6
Causality of AEs..............................................................................................72
10.1.7
Relationship to Study Procedures.....................................................................72
10.1.8
Start Date.........................................................................................................72
10.1.9
Stop Date.........................................................................................................72
10.1.10 Frequency........................................................................................................72
10.1.11 Action Concerning Study Drug........................................................................72
10.1.12 Outcome..........................................................................................................72
10.2
Procedures...............................................................................................................73
10.2.1
Collection and Reporting of AEs .....................................................................73
10.2.1.1
PTE and AE Reporting ............................................................................73
10.2.2
Collection, Reporting, and Acknowledgment of SAEs.....................................74
10.2.3
Reporting of Abnormal LFTs...........................................................................75
10.3
Follow-up of SAEs ..................................................................................................75
10.3.1
Safety Reporting to Investigators, IRBs, and Regulatory Authorities................75
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................76
12.0
DATA HANDLING AND RECORDKEEPING............................................................76
12.1
eCRFs......................................................................................................................76
12.2
Record Retention .....................................................................................................77
13.0
STATISTICAL METHODS..........................................................................................77
13.1
Statistical and Analytical Plans ................................................................................77
13.1.1
Analysis Sets ...................................................................................................77
13.1.1.1
Safety Analysis Set..................................................................................77
13.1.1.2
PK Analysis Set.......................................................................................78
13.1.1.3
Pharmacodynamic Analysis Set ...............................................................78
13.1.2
Analysis of Demographics and Other Baseline Characteristics.........................78
13.1.3
Pharmacodynamic Analysis (Subjects With PD)..............................................78
13.1.4
PK Analysis.....................................................................................................78
13.1.5
Other Analyses (Subjects With PD) .................................................................79


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13.1.6
Safety Analysis................................................................................................79
13.2
Interim Analysis, Sentinel Analysis, and Criteria for Early Termination...................79
13.3
Determination of Sample Size (Subjects With PD)...................................................79
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................80
14.1
Study-Site Monitoring Visits ...................................................................................80
14.2
Protocol Deviations..................................................................................................80
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................81
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................81
15.1
IRB..........................................................................................................................81
15.2
Subject Information, Informed Consent, and Subject Authorization .........................82
15.3
Subject Confidentiality ............................................................................................83
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................83
15.4.1
Publication and Disclosure...............................................................................83
15.4.2
Clinical Trial Registration................................................................................84
15.4.3
Clinical Trial Results Disclosure......................................................................84
15.5
Insurance and Compensation for Injury....................................................................84
16.0
REFERENCES..............................................................................................................84
LIST OF IN-TEXT TABLES
Table 7.a
Excluded and Allowed Medications and Treatments ..........................................39
Table 7.b
Strong and Moderate CYP3A Inducers and Inhibitors........................................43
Table 9.a
Primary Specimen Collection.............................................................................56
Table 9.b
Clinical Laboratory Tests...................................................................................58
Table 9.c
Overview of Main Study Schedule (Subjects With PD)......................................66
Table 10.a
Takeda Medically Significant AE List................................................................71
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design, Main Study ............................................................32


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LIST OF APPENDICES
Appendix A
Schedule of Study Procedures, Main Study (Su.bjects With PD) ........................87
Appendix B
Schedule of At-Home Speech Tests (Subjects With PD) ....................................93
Appendix C
Schedule of Samples Across Both Periods, Main Study......................................94
Appendix D
Responsibilities of the Investigator.....................................................................95
Appendix E
Elements of the Subject Informed Consent.........................................................97
Appendix F
Investigator Consent to Use of Personal Information........................................100
Appendix G
Amendment History.........................................................................................101
Appendix H
Sentinel Cohort (Healthy Subjects) Only..........................................................117


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2.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc. (TDCA)
Compound:
TAK-071
Title of Protocol: A Randomized, Double-blind, 
Placebo-Controlled, 2-Period Crossover, Phase 2 Study to 
Evaluate the Efficacy, Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of Oral 
TAK-071 in Parkinson Disease Patients With Cognitive 
Impairment and an Elevated Risk of Falls
IND No.: 146,849
EudraCT No.:
Not Applicable
Study Number: TAK-071-2002
Phase: 2
Study Design, Main Study:
This is a phase 2, randomized, double-blind, placebo-controlled, 2-period, 2-treatment crossover study to evaluate the 
efficacy, safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of TAK-071 when administered orally 
once daily (QD) in subjects with Parkinson disease (PD) and evidence of cognitive impairment who are at risk for falls
and who are not concurrently taking acetylcholinesterase inhibitors. In parallel with the main cohort, healthy subjects 
will participate in the sentinel cohort portion of the study as described below.
Approximately 64 male and female subjects, aged 40 to 85 years, inclusive, will be enrolled at up to 25 sites in the 
United States.
The main study will consist of a ≤6-week screening period, two 6-week double-blind treatment periods separated by a 
≥3-week washout period, at-home assessments during the third week of each 6-week treatment period, and a safety 
follow-up call approximately 14 days after the last dose of study drug.
At the screening visit (Visit 1), subjects who provide informed consent will proceed with screening procedures. 
Subjects who meet a current diagnosis of PD, as defined by Movement Disorders Society (MDS) clinical diagnostic 
criteria for PD, will then be given additional assessments as specified in the schedule of study procedures.
On Day 1, subjects who continue to meet inclusion and none of the exclusion criteria will be randomized 1:1 to 
treatment with TAK-071 or placebo.
Subjects will receive TAK-071 or placebo QD from Day 1 through Day 42 of each period. Clinic visits include Day 1 
and Weeks 6, 9, and 15. Clinical assessments, blood collections, and laboratory tests will be conducted at specific time 
points per the schedule of study procedures.
A safety follow-up call will be conducted at Day 21, Day 84, and 14 days after completion of the last period.
The end of the study will be the date of the last visit of the last subject for safety follow-up, ie, the safety follow up call.
The figure shows a schematic of the main study (all subjects with PD):
PBO: placebo; Rand: randomization.


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Study Design, Sentinel Cohort:
An initial sentinel cohort of healthy subjects will be enrolled at designated site(s), in parallel with enrollment of PD 
patients in the main cohort. Approximately 10 healthy subjects of either sex, aged 56 to 75 years, inclusive, will 
initially be randomized 3:1 to TAK-071 7.5 mg versus placebo. After analysis of data from these subjects, additional 
subjects may be enrolled, including subjects over age 75. Enrollment of the sentinel cohort will conclude when 
sufficient data are available to characterize the PK in older subjects, as determined by the sponsor.
Healthy subjects will be selected on the basis of safety considerations. Of particular importance is exclusion on the 
basis of seizure risk factors, medical disease, and hepatic or renal impairment that may influence the PK of TAK-071.
Assessments for healthy subjects will be limited to safety, tolerability, rich PK sampling, and samples for DNA 
(optional) and biomarkers.
After the PK, safety, and physiologically based PK modeling data from the sentinel cohort have been assessed, a 
decision will be made about the dose for the remaining subjects with PD to be enrolled in the main study. If older 
subjects are expected to remain below the exposure caps (potentially at a lower dose), they will also be enrolled. The 
maximum subject age and dose may be modified after analysis of data from the sentinel cohort. Update: At the 
completion of the sentinel cohort, based on PK modeling, a decision was made by the sponsor to allow enrollment of 
subjects aged 66 to 85 years, inclusive, at a dose of 5 mg. The dose for subjects aged 40 to 65 years, inclusive, will 
continue to be 7.5 mg.
The figure shows a schematic of the sentinel cohort (healthy subjects).
In unavoidable circumstances (eg, a widespread disease outbreak or natural disaster) that impact the ability to conduct 
study procedures according to the Schedule of Study Procedures, contingency measures may be implemented. The 
United States Food and Drug Administration issued guidance on the management of clinical trials during the 
coronavirus disease 2019 (COVID-19) pandemic 
(fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-medical-produ
cts-during-covid-19-public-health-emergency. Accessed 12 June 2020). Hospital, local, state and national restrictions 
designed as precautions to ensure the rights, safety and wellbeing of study subjects during the COVID-19 pandemic 
have also been established. These restrictions may also prevent conduct of study procedures according to the Schedule 
of Study Procedures. Alternative approaches to study procedures and data collection for the current study are 
described.
Objectives for Subjects With PD
Primary Objectives
The primary objectives for subjects with PD are:

To evaluate the efficacy of TAK-071 versus placebo on gait dysfunction, as measured by gait variability during a 
2-minute walk test.

To evaluate the safety and tolerability of TAK-071.
Rand
PBO
TAK-071
Follow -up
Screening
Single dose PK
and safety evaluation
≤6 weeks
168 hours
14 ± 2 days


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Secondary Objectives
The secondary objectives for subjects with PD are:

To evaluate the efficacy of TAK-071 versus placebo on cognition globally, as determined by a cognitive profile 
including attention, executive functioning, and memory.

To evaluate the PK of TAK-071.
Objectives for Healthy Subjects
The primary objective for healthy subjects is to evaluate the PK of TAK-071 in healthy subjects older than 55 years.
The secondary objective for healthy subjects is to evaluate the safety and tolerability of TAK-071 in healthy subjects 
older than 55 years.
Subject Population:
In the main study: Subjects diagnosed with PD who have cognitive impairment and a history of falls, aged 40 years 
to 85 years, inclusive. Subjects must not be taking acetylcholinesterase inhibitors.
In the sentinel cohort: Healthy subjects aged 56 to 75 years, inclusive, will initially be enrolled. 
Number of Subjects:
In the main study, approximately 64 subjects with PD to 
ensure at least 42 completers. Each subject with PD will 
receive both treatments in a crossover manner: TAK-071 or 
placebo.
In the sentinel cohort, initially approximately 10 subjects. 
Additional subjects may subsequently be enrolled. Healthy 
subjects will receive a single dose of TAK-071 or placebo.
Number of Sites:
Up to 25 sites in the United States.
Dose Levels:
For subjects with PD:
- Aged 40 to 65 years, inclusive: 7.5 mg TAK-071 or 
placebo, QD. 
- Aged 66 to 85 years, inclusive: 5 mg TAK-071 or placebo, 
QD.
For healthy subjects: A single dose of 7.5 mg TAK-071 or 
placebo.
Route of Administration:
Oral
Duration of Treatment:
For subjects with PD: Two 6-week treatment periods.
For healthy subjects: A single dose.
Period of Evaluation:
For subjects with PD: 17 weeks, plus screening 
period of 1 to 42 days (23 weeks maximum total).
For healthy subjects: 22 days plus screening period of 
1 to 42 days.
Main Criteria for Inclusion:
For subjects with PD: Male and female subjects aged 40 to 85 years, inclusive. Subjects with PD (identified by MDS 
clinical diagnostic criteria) who have Hoehn and Yahr stage ≥2 and <4 at screening, have had at least 1 PD-related fall 
in the 12 months before screening, are at continued risk of falls per investigator judgment, have evidence of cognitive 
impairment (Montreal Cognitive Assessment [MOCA] score between 11 and 26, inclusive), can complete cognitive 
assessments at screening (as specified in the study manual), are able to walk without aid for 2 minutes while doing 
serial 3 subtraction, are on stable antiparkinsonian medication for at least 30 days before randomization and able to 
remain on stable dosage during study, and have a study partner involved in care of the subject at least 2 hours per day 
who is willing to supervise and assist the subject with medication administration and to complete fall assessments.
Subjects must not be taking acetylcholinesterase inhibitors.
Please note that subjects who have dementia with Lewy body (DLB)(ie, dementia was diagnosed before onset of 


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motor symptoms or up to 1 year after onset of motor symptoms) are eligible for this study consistent with the MDS 
clinical diagnostic criteria for PD.
For healthy subjects: Male and female subjects aged 56 to 75 years, inclusive. 
Main Criteria for Exclusion:
For subjects with PD: Parkinsonism not due to primary PD; orthostatic hypotension judged to preclude safe 
participation in the study; prior neurosurgical intervention for PD (with the exception of deep brain stimulation [DBS] 
device implanted ≥1 year prior to screening with stable settings for ≥2 months and further changes in DBS settings not 
anticipated); dyskinesia of sufficient severity to interfere with digital gait assessments or other study aspects; 
excessive daytime sleepiness of sufficient severity to interfere with participation in the cognitive and gait assessments; 
fall-related institutionalization or hospital admission (not including emergency room visit) between screening and first 
baseline visit.
For subjects with PD and healthy subjects: Medical problems (other than PD) that significantly interfere with 
balance, gait, or completion of the study; significant risk factors for seizures; depression or other psychiatric disorder 
of sufficient severity to interfere with participation in the study; at risk of suicide. Additional major exclusions will 
include orthostatic hypotension, estimated glomerular filtration rate (eGFR) <60 mL/min (calculated using the 
Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation; subjects not meeting the eGFR<60 
mL/min or orthostasis criteria may remain eligible, conditional on agreement between sponsor and investigator); a 
serum total bilirubin value >1.2 × upper limit of normal (ULN); a serum ALT or AST value >1.2 × ULN. Subjects 
with a positive hepatitis B surface antigen test result or known or suspected active hepatitis C infection are also 
excluded.
Endpoints for Subjects With PD:
Primary Endpoint:
The primary endpoint for subjects with PD is the change from baseline in gait variability during a 2-minute walk on a 
10-meter walkway after 6 week treatment with TAK-071 compared with placebo.
Secondary Endpoints:
The secondary efficacy endpoint for subjects with PD is the change from baseline in a global cognition profile 
consisting of attention (Sustained Attention Test [SAT], Symbol Digit Modalities Test [SDMT]), executive function 
(Cogstate Groton Maze Learning Test, Cogstate One Back Test), and memory (Cogstate International Shopping List 
Test, Cogstate One Card Learning Test) after 6 week treatment with TAK-071 compared with placebo.
The PK endpoints for subjects with PD are:

Observed concentration at the end of a dosing interval (Ctrough) of TAK-071 in subjects with PD (Day 42 of 
Period 1 and Period 2 only).

Maximum observed concentration (Cmax) and area under the concentration-time curve (AUC) of TAK-071 in 
subjects with PD.

Time of first occurrence of Cmax (tmax).
Safety Endpoints:
The safety endpoints for subjects with PD are:

Adverse events (AEs).

Clinical laboratory evaluations.

Electrocardiograms (ECGs).

Physical examinations.

Suicidal ideation and behavior as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS).

Movement Disorders Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) to evaluate for 
worsening of motor or nonmotor symptoms.
Endpoints for Healthy Subjects:
Primary Endpoints:


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The primary endpoints for healthy subjects are the following PK parameters for TAK-071:

Cmax.

tmax.

Area under the concentration-time curve from time 0 to 24 hours (AUC24).

Area under the concentration-time curve from time 0 to the last quantifiable concentration (AUClast).

Area under the concentration-time curve from time 0 to infinity (AUCinf).
Safety Endpoints:
The safety endpoints for healthy subjects are:

AEs.

Clinical laboratory evaluations.

ECGs.

Physical examinations.

Suicidal ideation and behavior as measured by the C-SSRS.
Statistical Considerations:
For subjects with PD, the primary outcome, the change from baseline in gait variability during a 2-minute walk test, 
will be analyzed using a linear mixed effect model with a random factor for subject and fixed factors for treatment, 
period, and sequence. Baseline covariates will be included in the model as appropriate.
The effect of treatment on the overall cognitive battery will be analyzed using a linear mixed effects model with 
random effects for subjects for each cognitive test, fixed factors for treatment, test, period, and sequence. The 
comparison of the number of falls for placebo versus TAK-071 will be analyzed using a generalized linear mixed 
effects model with a random factor for subjects, fixed factors for treatment, period, and sequence.
Drug effects on change from baseline for all endpoints will be assessed using 1-sided tests. In all analyses the 
interaction terms and covariates will be added as appropriate.
For healthy subjects, analysis will focus on PK (eg, Cmax, tmax, AUCinf, and AUC24).
Sample Size Justification:
For subjects with PD, a sample size of 42 completers will be sufficient to detect a statistically significant (α = 0.05, 
1-sided) decrease in gait variability during walking for TAK-071 versus placebo. We expect to detect a minimum 
effect size of 0.32 (Cohen d) in the reduction of gait variability. For the sample size calculation, the study power was 
assumed to be 80%.
Given the proposed study sample size and 80% power, a minimum detectable operational effect size for the cognitive 
battery (α = 0.1, 1-sided) will be 0.49. The correlations between cognitive tests are assumed to be 0.5. The minimum 
detectable (α = 0.1, 1-sided) effect size in the number of falls will be approximately 0.3. For all calculations, the 
within-person correlation was assumed to be 0.65.
For healthy subjects (sentinel cohort), a sample size of approximately 10 subjects at a 3:1 ratio is considered to be 
likely sufficient to adequately describe single-dose PK and safety.


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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 
Contract Research Organization Obligations Listing, located in the trial master file. The vendors 
identified in the listing 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
Abbreviation
Definition
AChEI
acetylcholinesterase inhibitor
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC24
area under the concentration-time curve from time 0 to 24 hours
AUC24,ss
area under the concentration-time curve from time 0 to 24 hours at steady state
AUCinf
area under the concentration-time curve from time 0 to infinity
AUClast
area under the concentration-time curve from time 0 to the last quantifiable concentration
BMI
body mass index
CFR
Code of Federal Regulations
CGI-S/I
Clinical Global Impression-Severity/Improvement
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration 
Cmax
maximum observed concentration
Cmax,ss
maximum observed concentration at steady state
COVID-19
coronavirus disease 2019
C-SSRS
Columbia-Suicide Severity Rating Scale
Ctrough
observed concentration at the end of a dosing interval
CYP
cytochrome P-450
DBS
deep brain stimulation
DLB
dementia with Lewy body
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
ESS
Epworth Sleepiness Scale
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
ICH
International Conference on Harmonisation
ID
identification (number)
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
IWRS
interactive web response system
LBD
Lewy body dementia


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Abbreviation
Definition
LFT
liver function test
MCI
mild cognitive impairment
MDS
Movement Disorders Society
MDS-UPDRS
Movement Disorders Society–Unified Parkinson’s Disease Rating Scale
MedDRA
Medical Dictionary for Regulatory Activities
MoCA
Montreal Cognitive Assessment
mRNA
messenger ribonucleic acid
NBM
nucleus basalis of Meynert
NfL
neurofilament light chain
OR
odds ratio
PAM
positive allosteric modulator
PBPK
physiologically based PK
PD
Parkinson disease
PDD
Parkinson disease dementia
PGI-S/I
Patient Global Impression-Severity/Improvement
PK
pharmacokinetic(s)
PT
Preferred Term
PTE
pretreatment event
QD
once daily
QTcF
QT interval with Fridericia correction
SAE
serious adverse event
SAP
statistical analysis plan
SAT
Sustained Attention Test
SDMT
Symbol Digit Modalities Test
SOC
System Organ Class
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
tmax
time of first occurrence of Cmax
TUG
Timed Up and Go test
ULN
upper limit of normal


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4.0
INTRODUCTION
4.1
Background and Rationale
TAK-071 is a first-in-class muscarinic M1 positive allosteric modulator (M1 PAM) proposed for 
the reduction of falls and improvement of cognition in Parkinson disease (PD).
4.1.1
Falls in PD
Falls are a common cause of morbidity and mortality in patients with PD. The cause of falls is 
multifactorial and involves interactions between environmental, motor, and cognitive factors.
Multiple lines of evidence suggest that falls are in part a consequence of the simultaneous loss of 
dopaminergic and cholinergic transmission associated with PD. PD is associated with a substantial 
loss of cholinergic fibers, which has been demonstrated using acetylcholinesterase positron 
emission tomography, as well as postmortem histopathological analyses. Cortical cholinergic 
deficits are significant in early PD and are correlated with cognitive decline in patients with PD 
and are more severe than in Alzheimer disease [1]. Modelling of PD-related falls in animal models 
has demonstrated that loss of striatal dopamine synergizes with cholinergic neuron loss in the basal 
forebrain to impair gait and increase falls.
There is clinical evidence that cholinergic drugs may reduce fall risk in patients with PD. The 
largest published study to date (n = 130, [2] showed that rivastigmine reduced step time variability, 
a correlate of fall risk, and the risk of falling was lowered by approximately 50% with 6 months of 
treatment. A smaller study (n = 23, [3]) showed that donepezil, an acetylcholinesterase inhibitor 
(AChEI), also reduced the risk of falls or near falls by approximately 50%. Li et al [4] studied 176 
Chinese patients with PD who were randomized to placebo or rivastigmine, another AChEI. 
Changes in cognition and fall incidence were compared between the 2 groups. Patients with mild 
cognitive impairment (MCI) (odds ratio [OR] = 2.5) or dementia (OR = 5.5) fell significantly 
more than patients with intact cognition. Rivastigmine improved cognition and reduced the 
number of falls relative to placebo (OR = 0.3). However, these studies suffer from significant 
methodological flaws. A recent publication [5] reported that donepezil did not improve balance in 
patients with PD.
Although these findings are somewhat supportive regarding AChEIs, efficacy has not been 
conclusively demonstrated. TAK-071 can selectively activate M1 receptors without interfering 
with the temporal dynamics of ACh signaling, which plays a critical role in specific cognitive 
functions such as attention. AChEIs instead cause a tonic increase of ACh, with nonselective direct 
agonism at all muscarinic receptor subtypes while disrupting the temporal dynamics of ACh 
signaling, which is believed to cause adverse effects and may obscure the procognitive effects of 
M1 receptor activation.


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4.1.2
Cognitive Impairment in PD
Most patients with PD will develop dementia, either at least 1 year after the onset of motor 
symptoms (termed Parkinson disease dementia [PDD]) or less than 1 year after the onset of motor 
symptoms (termed dementia with Lewy body [DLB]). The term Lewy body dementia (LBD) 
encompasses both PDD and DLB. Currently, many experts in the field believe that there are few 
fundamental biological differences between these conditions and the term LBD will, therefore, be 
used here.
LBD has a major impact on functioning, cost of care, and quality of life. Before the development 
of LBD, patients initially experience MCI. In addition to the direct impact on functioning, 
cognitive impairment in patients with PD also significantly increases the risk for falls as described 
above.
Patients with PD show early and marked degeneration of the cholinergic system including a loss of 
cholinergic fibers from the nucleus basalis of Meynert (NBM), which mainly supplies the cortex, 
and the pedunculopontine nucleus, which mainly supplies the basal ganglia, thalamus, brainstem, 
and rostral spinal cord. The degeneration of the NBM in particular is strongly related to cognitive 
impairment in PD. As noted in Section 4.1.4, nonclinical data from NBM-lesioned rats is 
supportive of potential efficacy with respect to cognitive impairment.
TAK-071 could be valuable in the treatment of patients with PD through reducing fall risk and/or 
improving cognition, both unmet needs for patients. Therefore, the present study will evaluate 
both.
4.1.3
Impairments in Speech in PD
Speech difficulties occur in up to 90% of patients with PD over the course of the disease and 
significantly affect their social interactions and quality of life. Speech impairment in PD is likely 
the result of the combined effect of impaired motor control and cognitive deficits. In PD, a 
reduction in dopamine is associated with the cardinal motor symptoms of tremor, slowness of 
movement (bradykinesia) and muscle rigidity (stiffness). However, dopamine replacement 
therapy showed inconsistent effects on speech performance, suggesting the contribution of 
alternative neurotransmitters during speech processing. The vocal apparatus is under motor control 
and is therefore impacted by the loss of cholinergic projections observed in PD. Moreover, 
previous studies reported language processing deficits are associated with cognitive dysfunction in 
PD [6]. The role of the cholinergic system in cognition has been well established. Therefore, it is 
plausible that TAK-071, through enhancing cholinergic function, will improve both motor control 
and cognitive function in patients with PD, and consequentially speech function. Analysis of 
speech in patients with PD will provide data that are complementary to measures of walking and 
other complex motor tasks.
4.1.4
Nonclinical Data
Nonclinical studies suggest that TAK-071 may improve cognitive performance including working 
memory, recognition memory, and attention.


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In Y-maze and the novel object recognition tests, TAK-071 improved working memory deficits 
and recognition memory, respectively, at 0.1 and 0.3 mg/kg in miR-137 Tg mice.
The neural activation pattern of TAK-071 measured by c-fos mapping in rodents was very similar 
to that of xanomeline, an M1/M4 agonist that previously showed efficacy for cognition in AD and 
schizophrenia but was limited by adverse events (AEs), while donepezil was not effective in this 
assay.
TAK-071 also significantly improved attentional function (measured by the Sustained Attention 
Test [SAT]) in rats with partial basal forebrain cholinergic lesions at doses as low as 0.1 mg/kg, a 
model where AChEIs are ineffective [7]. These findings are highly significant because the lesions 
in this model mirror the loss of cholinergic fibers in PD and because performance on this task is 
correlated with gait abnormalities and falls in a rat model of PD [8,9]. These data strongly support 
the potential of TAK-071 for falls and cognitive impairment in PD, as well as its differentiation 
from AChEIs.
Overall, these data suggest that TAK-071 is a promising therapy for cognitive impairment and falls 
in PD, and these data also provide important insights regarding differentiation from existing 
cholinergic therapies.
4.1.5
Differentiation From AChEIs and Other M1 PAMs
There is a strong scientific basis for the notion that M1 PAMs may be superior to AChEIs for falls 
and cognition. It has been established that ACh signals through slow “tonic” release as well as fast 
“phasic” release. Phasic ACh plays a critical role in the modulation of attention and other frontal 
cognitive functions that may be critical for cognitive gait control. AChEIs chronically elevate 
synaptic ACh levels, which may impair phasic signaling, whereas M1 PAMs such as TAK-071 do 
not disrupt these temporal dynamics and support phasic signaling.
Previous nonclinical evidence has strongly supported the synergistic effect of cholinergic lesions 
on dopaminergic deficits in falls in a rat model of PD [7]. Rats with dual cholinergic-dopaminergic 
lesions have clearly shown more frequent falls than rats with either cholinergic or dopaminergic 
lesions. Moreover, the attention performance and falls were only correlated in these animals with 
dual lesions. Therefore, enhancement of cholinergic function may have a positive impact not only 
on cognition, but also falls in PD. Whereas AChEIs are ineffective in this dual-lesion model, 
TAK-071 significantly improves attentional performance, which strongly supports the prediction 
that TAK-071 can support phasic ACh signaling to improve cognition, and by inference cognitive 
control of gait.
TAK-071 has distinct pharmacology from other M1 PAMs. For example, Merck’s selective M1
PAM MK-7622 has a higher binding cooperativity (α-value: 511, where α is the fold increase of 
ACh affinity for its binding site due to the effects of the PAM) than TAK-071 (α-value: 199). 
Higher binding cooperativity has been shown to be strongly related to poor gastrointestinal 
tolerability in nonclinical studies [10]. TAK-071, but not MK-7622, showed synergy with 
donepezil in the scopolamine-induced cognitive deficit model. Taken together with other 
nonclinical studies comparing these drugs, these data strongly suggest that TAK-071 affects 
receptor signaling differently from MK-7622 and has distinct in vivo pharmacology.


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4.2
Benefit/Risk Profile
TAK-071 is a highly selective cholinergic muscarinic M1 receptor PAM. Nonclinical data indicate 
that cortical cholinergic deficits are associated with cognitive decline and falls in PD models, and 
clinical studies suggest that cholinergic drugs may reduce fall risk in patients with PD. There is 
therefore a scientific rationale for exploring the potential of TAK-071 to improve cognitive 
function and decrease falls in patients with PD. However, clinical benefit of TAK-071 has not been 
established because the product has only been tested in phase 1 studies in healthy subjects.
Nonclinical toxicology studies showed convulsions in rats and monkeys and neurotoxicity in rats 
at high doses. Consequently, clinical doses are limited to those expected to result in plasma 
TAK-071 exposures of no more than 600 ng/mL and 14,000 h*ng/mL for maximum observed 
concentration (Cmax) and area under the concentration-time curve from time 0 to 24 hours (AUC24), 
respectively. This allows up to a 7.5 mg once daily (QD) clinical dose. After 7.5 mg QD doses, the 
projected maximum observed concentration at steady state (Cmax,ss) and area under the 
concentration-time curve from time 0 to 24 hours at steady state (AUC24,ss) are 549 ng/mL and 
12,900 h*ng/mL, respectively, in subjects 18 to 55 years old, within the exposure limits. In 
addition, TAK-071 must not be coadministered with an acetylcholinesterase inhibitor (eg, 
donepezil, rivastigmine, galantamine) because of the potential to cause convulsions based on 
data from nonclinical toxicology studies.
In phase 1 clinical studies, a total of 139 healthy subjects 18 to 55 years old have received at least 
1 dose of TAK-071. There were no SAEs or deaths reported. Review of all available clinical safety 
data indicates that TAK-071 is generally safe and well tolerated.
Information from the completed phase 1 studies, together with the nonclinical toxicity studies in 
rats and monkeys, indicates that the benefit-risk balance for TAK-071 is deemed acceptable at the 
proposed dose of 7.5 mg. Clinical dosing of TAK-071 with donepezil and other AChEIs is not 
supported.
Please see the investigator’s brochure for more details regarding the safety profile of TAK-071.
Exploratory biomarker analysis, including DNA, plasma, cerebrospinal fluid, and exosome protein 
and nucleic acid analysis may be conducted to investigate the contribution of genetic and other 
biological factor variance on drug response, for example, its efficacy and safety.
5.0
STUDY OBJECTIVES AND ENDPOINTS
This section details the objectives and endpoints for the main study, ie, for subjects with PD.
For the sentinel cohort (ie, healthy subjects), please refer to Appendix H.


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5.1
Objectives
5.1.1
Primary Objectives
The primary objectives for subjects with PD are:

To evaluate the efficacy of TAK-071 versus placebo on gait dysfunction, as measured by gait 
variability during a 2-minute walk test.

To evaluate the safety and tolerability of TAK-071.
5.1.2
Secondary Objectives
The secondary objectives for subjects with PD are:

To evaluate the efficacy of TAK-071 versus placebo on cognition globally, as determined by a 
cognitive profile including attention, executive functioning, and memory.

To evaluate the pharmacokinetics (PK) of TAK-071.
5.1.3
Exploratory/Additional Objectives
The exploratory/additional objectives for subjects with PD are:

To evaluate the efficacy of TAK-071 versus placebo on specific cognitive tests that measure 
domains including attention, executive functioning, and memory.

To evaluate the efficacy of TAK-071 versus placebo on gait parameters during a 2-minute 
walk test in the presence versus absence of cognitive loading.

To evaluate the efficacy of TAK-071 versus placebo on gait variability and double support 
time during a 2-minute walk test in the presence versus absence of cognitive loading.

To evaluate the efficacy of TAK-071 versus placebo on self-directed turns during a 2-minute 
walk test in the presence versus absence of cognitive loading.

To evaluate the efficacy of TAK-071 versus placebo on cued 180-degree turns during walking.

To evaluate the efficacy of TAK-071 versus placebo on functional mobility, as measured by 
time to complete the Timed Up and Go test (TUG).

To evaluate the efficacy of TAK-071 versus placebo on postural stability, as measured by 
postural sway with eyes open and closed.

To evaluate the efficacy of TAK-071 versus placebo on speech production based on in-clinic 
assessments.

To evaluate the efficacy of TAK-071 versus placebo on speech production as assessed in the 
home.

To evaluate the efficacy of TAK-071 versus placebo on in-home activity as measured by a 
wearable pendant sensor in the home.


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
To evaluate the efficacy of TAK-071 versus placebo on fall frequency as assessed using a 
wearable pendant sensor in the home.

To evaluate the efficacy of TAK-071 versus placebo on fall frequency as assessed using a 
study partner–reported falls diary.

To evaluate the efficacy of TAK-071 versus placebo on subjective daytime sleepiness as 
assessed by the Epworth Sleepiness Scale (ESS).

To evaluate the efficacy of TAK-071 versus placebo on global improvement, as measured by 
the Clinical Global Impression-Improvement (CGI-I), Clinical Global Impression-Severity 
(CGI-S), Patient Global Impression-Improvement (PGI-I), and Patient Global 
Impression-Severity (PGI-S).

To evaluate the impact of TAK-071 versus placebo on motor functioning, as measured by 
MDS-UPDRS Part 3 and on other aspects of PD by MDS-UPDRS Parts 1, 2, and 4.

To evaluate the relationship between specific blood-based biomarkers including neuronally 
derived exosomal M1 receptor and synaptic marker messenger ribonucleic acid (mRNA) 
expression with clinical scales of cognition, gait, balance, and MDS-UPDRS subscales as well 
as treatment response.

To evaluate genomic predictors of treatment response and adverse effects to TAK-071.

To evaluate the relationship of pharmacodynamic endpoints to disease characteristics.

The ratio of plasma 4-beta-hydroxycholesterol to cholesterol and the relationship to plasma 
TAK-071 area under the concentration-time curve (AUC) may be analyzed.
5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoint for subjects with PD is the change from baseline in gait variability during a 
2-minute walk on a 10-meter walkway after 6-week treatment with TAK-071 compared with 
placebo.
5.2.2
Secondary Endpoints
The secondary efficacy endpoint for subjects with PD is the change from baseline in a global 
cognition profile consisting of attention (SAT, Symbol Digit Modalities Test [SDMT]), executive 
function (Cogstate Groton Maze Learning Test, Cogstate One Back Test), and memory (Cogstate 
International Shopping List Test, Cogstate One Card Learning Test) after 6-week treatment with 
TAK-071 compared with placebo.
The PK endpoints for subjects with PD are:

Ctrough of TAK-071 in subjects with PD (Day 42 of Period 1 and Period 2 only).

Cmax and AUC of TAK-071 in subjects with PD.


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
tmax.
5.2.3
Safety Endpoints
The safety endpoints for subjects with PD are:

AEs.

Clinical laboratory evaluations.

Electrocardiograms (ECGs).

Physical examinations.

Suicidal ideation and behavior as measured by the Columbia-Suicide Severity Rating Scale 
(C-SSRS).

MDS-UPDRS (to evaluate for worsening of motor or nonmotor symptoms).
5.2.4
Exploratory Endpoints
The exploratory pharmacodynamic endpoints for subjects with PD are:

Audio recordings to verify serial subtraction performance during the 2-minute walk after 
6-week treatment with TAK-071 compared with placebo.

Change from baseline on cognitive performance on individual cognitive tests (SAT, SDMT, 
Groton Maze Learning Test, Cogstate One-Back Test, Cogstate International Shopping List 
Test, Cogstate One Card Learning Test) after 6 weeks of treatment with TAK-071 compared 
with placebo.

Change from baseline on gait parameters in the presence versus absence of cognitive loading 
during a 2-minute walk on a 10-meter walkway after 6-week treatment with TAK-071 
compared with placebo.

Change from baseline in gait variability and double support time in the presence versus 
absence of cognitive loading during a 2-minute walk after 6-week treatment with TAK-071 
compared with placebo.

Change from baseline in self-directed turns in the presence versus absence of cognitive loading
during a 2-minute walk test after 6-week treatment with TAK-071 compared with placebo.

Change from baseline in cued 180 degree turns after 6-week treatment with TAK-071 
compared with placebo.

Change from baseline in the completion time of the TUG after 6-week treatment with 
TAK-071 compared with placebo (average of 3 trials).

Change from baseline in postural sway with eyes open and eyes closed during a 30-second 
balance test after 6-week treatment with TAK-071 compared with placebo.


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
Change from baseline on speech performance after 3- and 6-week treatment with TAK-071 
compared with placebo.

Change from baseline in in-home activity measured by a wearable pendant sensor during 
6-week treatment with TAK-071 compared with placebo.

Change from baseline in number of falls measured by a wearable pendant sensor during 
6-week treatment with TAK-071 compared with placebo.

Change from baseline in number of falls and number of near-falls measured by a falls diary 
during 6-week treatment with TAK-071 compared with placebo.

Change from baseline on the ESS after 6-week treatment with TAK-071 compared with
placebo.

Change from baseline on the CGI-S and PGI-S after 6-week treatment with TAK-071 
compared with placebo.

Values of CGI-I and PGI-I after 6-week treatment with TAK-071 compared with placebo.

Change from baseline on MDS-UPDRS Part 3 scores (including individual motor assessments 
in Parts 3.1-3.18, impact of dyskinesia, and the Hoehn and Yahr scale) and on MDS-UPDRS 
Parts 1, 2, and 4 scores after 6-week treatment with TAK-071 compared with placebo.

Plasma biomarkers including neuronally derived exosomal M1 receptor mRNA, amyloid, tau, 
neurofilament light chain (NfL), biomarkers of synaptic integrity, and potentially additional 
blood-based biomarkers.

DNA samples will be used to assess potential variability in drug response and safety.

Relationship of pharmacodynamic endpoints to disease characteristics.

The relationship of the ratio of plasma 4-beta-hydroxycholesterol/cholesterol with plasma 
TAK-071 AUC may be analyzed.
6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design, Main Study
This section describes the main study (subjects with PD). For the healthy subject cohort, please see 
Appendix H.
This is a phase 2, randomized, double-blind, placebo-controlled, 2-period, 2-treatment crossover 
study to evaluate the efficacy, safety, tolerability, PK, and pharmacodynamics of TAK-071 when
administered orally QD in subjects with PD and evidence of cognitive impairment who are at risk 
for falls and who are not concurrently taking acetylcholinesterase inhibitors.
Approximately 64 male and female subjects, aged 40 to 85 years, inclusive, will be enrolled at up 
to 25 sites in the United States.


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The main study will consist of a ≤6-week screening period, two 6-week double-blind treatment 
periods separated by a ≥3-week washout period, at-home assessments during the third week of 
each 6-week treatment period, and a safety follow-up call approximately 14 days after the last dose 
of study drug.
At the screening visit (Visit 1), subjects who provide informed consent will proceed with screening 
procedures. Subjects who meet a current diagnosis of PD, as defined by MDS clinical diagnostic 
criteria for PD, will then be given additional assessments as specified in the schedule of study 
procedures (Appendix A).
On Day 1, subjects who continue to meet inclusion and none of the exclusion criteria will be 
randomized 1:1 to treatment with TAK-071 or placebo.
Subjects will receive TAK-071 or placebo QD from Day 1 through Day 42 of each period. Clinic 
visits include Day 1 and Weeks 6, 9, and 15. Clinical assessments, blood collections, and 
laboratory tests will be conducted at specific time points per the schedule of study procedures 
(Appendix A).
A safety follow-up call will be conducted on Day 21, Day 84, and 14 days after completion of the 
last period.
The end of the study will be the date of the last visit of the last subject for safety follow-up, ie, the 
safety follow-up call.
A schematic of the main study design is included as Figure 6.a. A detailed schedule of study 
procedures is provided in Appendix A.
Figure 6.a
Schematic of Study Design, Main Study
PBO: placebo; Rand: randomization.
While subjects with PD (initially restricted to those aged 40 to 65 years, inclusive) are being 
enrolled in the main study, a sentinel cohort of healthy subjects will be enrolled in parallel at 
designated sites (see Appendix H).
After the PK, safety, and physiologically based PK modeling data from the sentinel cohort have 


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been assessed, a decision will be made by the sponsor about the dose for the remaining subjects
with PD to be enrolled in the main study. If older subjects are expected to remain below the 
exposure caps, they will also be enrolled. The maximum subject age and dose may be modified 
after analysis of data from the sentinel cohort. Update: At the completion of the sentinel cohort, 
based on PK modeling, a decision was made by the sponsor to allow enrollment of subjects aged 
66 to 85 years, inclusive, at a dose of 5 mg. The dose for subjects aged 40 to 65 years, inclusive, 
will continue to be 7.5 mg.
6.2
Contingency Measures Due to COVID-19 Pandemic or Other Unavoidable 
Circumstances
This section applies to all study subjects.
In unavoidable circumstances (eg, a widespread disease outbreak or natural disaster) that impact 
the ability to conduct study procedures according to the schedule of study procedures 
(Appendix A), contingency measures may be implemented. In March 2020, the United States 
Food and Drug Administration (FDA) issued guidance on the management of clinical trials during 
the coronavirus disease 2019 (COVID-19) pandemic 
(fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-conduct-clinical-t
rials-medical-products-during-covid-19-public-health-emergency. Accessed 12 June 2020). 
Hospital, local, state and national restrictions designed as precautions to ensure the rights, safety 
and wellbeing of study subjects during the COVID-19 pandemic have also been established. These 
restrictions may also prevent conduct of study procedures according to the Schedule of Procedures. 
Alternative approaches to study procedures and data collection for the current study are described 
in Section 9.1.24.
6.3
Justification for Study Design, Endpoints, and Dose
This section applies to the main study (subjects with PD).
6.3.1
Subject Selection Considerations
Consistent with our focus on fall prevention, we are selecting subjects with PD who are at elevated 
risk of falling based on a history of falls. On the other hand, subjects who are at advanced stages of 
PD will not be able to complete gait assessments. Subjects with Hoehn and Yahr stage ≥2 and <4 
will, therefore, be selected for this study to ensure that PD severity is significant but not to the 
extent that the gait assessments become impossible. Furthermore, cognitive impairment is a risk 
factor for falls, and it is important to select subjects with sufficient cognitive impairment to avoid 
ceiling effects so that efficacy for cognition and improvement of gait via effects on cognition can 
be observed. On the other hand, very significant cognitive impairment will make following 
instructions and completing assessments difficult. Given these considerations, subjects who score 
between 11 and 26 on the Montreal Cognitive Assessment (MoCA) and who complete the 
cognition assessments at screening will therefore be selected.


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6.3.2
Justification for Digital Endpoints
Fall risk is correlated with several aspects of gait, including gait variability measured using stride 
and step time variability. Stride and step time variability are variables that can be measured with 
high precision using digital gait assessments in the clinic and are believed to reflect cognitive gait 
control; gait variability is a more appropriate primary endpoint for small initial patient studies, 
such as the present study, than actual falls.
The wearable pendant sensor generates 2 endpoints, in-home activity and number of falls. In-home 
activity is measured by calculating the number of steps taken by the patient every 15 minutes 
throughout the day from the raw sensor data. Hourly, daily, and weekly activity is then calculated 
from this step count data. Number of falls is measured using a proprietary algorithm to detect a fall 
from the raw sensor data. If a fall is detected, the time stamp of the fall is recorded and transmitted 
immediately, and the raw sensor data before and after the fall is saved locally on the device for 
offline analysis. Daily, weekly, and monthly number of falls are then calculated on the basis of the 
time-stamped falls.
6.3.3
Dose Justification
TAK-071 has been tested in human phase 1 clinical studies in healthy subjects 18 to 55 years old 
(197 subjects total, 139 dosed with TAK-071). After single (1 to 160 mg) and multiple (3 to 15 mg 
QD) oral doses of TAK-071, systemic exposure (Cmax and AUC) to TAK-071 increased in only a 
slightly less than dose proportional manner. TAK-071 demonstrated a long half-life of 46 to 
61 hours and reasonable brain penetration after oral dose. TAK-071 was well tolerated, with no 
deaths or SAEs. There was 1 discontinuation due to headache and 1 severe treatment-emergent 
adverse event (TEAE) of syncope. Both subjects were on TAK-071 and the AEs resolved. No 
clinical concerns were raised by laboratory tests, ECG, physical examination, or bowel function 
assessment.
The simulated exposure predictions for a 7.5 mg QD dose in humans, which is the dose proposed 
for this study in PD, yield a Cmin exposure (ie, 432 ng/mL) that is 6.0-fold the rat Cmax exposure at 
0.1 mg/kg (ie, 72 ng/mL), the predicted efficacious dose from the cholinergic lesion model. 
Therefore, there is ample margin to test the efficacy of TAK-071 in humans.
The subjects selected for this study are older than those in phase 1 clinical studies, 40 to 85 years, 
inclusive, versus 18 to 55 years, inclusive. The potential exposure difference was assessed through 
an initial preliminary physiologically based PK (PBPK) modeling of phase 1 PK data using 
SimCyp Simulator, and the model projection indicated an increase of less than 25% in mean 
exposure measures (Cmax and AUC) for a 7.5 mg QD dose for older subjects of 40 to 75 years, 
inclusive, versus subjects of 18 to 55 years, inclusive. For subjects aged 40 to 75 years, inclusive, 
SimCyp simulations predict a geometric mean Cmax,ss of 580 ng/mL and a geometric mean 
AUC24,ss of 11,100 hr*ng/mL. Higher exposure was achieved by multiple doses of up to 15 mg in 
the phase 1 clinical studies and was determined to be safe and well tolerated.
To study the age effect and ensure safety for older subjects, an initial small sentinel cohort of 
healthy subjects aged 56 to 75 years, inclusive, was enrolled with rich PK sampling after a single 
dose (at designated site[s]; see Appendix H). The PBPK model developed from the sentinel cohort 


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data suggest that subjects 40 to 65 years can continue to receive TAK-071 7.5 mg QD. A lower 
dose of TAK-071 5 mg QD is recommended for subjects 66 to 85 years to keep the exposure under 
the exposure cap, ie, 600 ng/mL for Cmax,ss and 14,000 hr*ng/mL for AUC24,ss. Based on these 
results, a decision was made to expand the main cohort to include subjects with PD aged 66 to 85 
years, inclusive, at a dose of 5 mg. Of note, the PBPK modeling projections of geometric mean 
Cmax,ss and AUC24,ss are below the exposure caps. For subjects aged 40 to 65 years, inclusive, the 
projections of geometric mean Cmax,ss and AUC24,ss at a dose of 7.5 mg are 586 ng/mL and 
11,663 hr*ng/mL, respectively. For subjects aged 66 to 85 years, inclusive, the projections of 
geometric mean Cmax,ss and AUC24,ss at a dose of 5 mg for TAK-071 are 556 ng/mL and 11,624 
hr*ng/mL, respectively.
After the PK, safety, and physiologically based PK modeling data from the sentinel cohort have 
been assessed, a decision will be made about the dose for the remaining subjects with PD to be 
enrolled. If older subjects are expected to remain below the exposure caps, they will also be 
enrolled. The maximum subject age and dose may be modified after analysis of data from the 
sentinel cohort.
6.4
Premature Termination or Suspension of Study or Study Site
This section applies to all subjects.
6.4.1
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 benefit-risk profile for TAK-071, such that the risk is no 
longer acceptable for subjects participating in the study.

One or more subjects experience a seizure that in the opinion of the investigator is related to 
TAK-071.

The following events occur regarding liver function:
–
Two or more subjects experience alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) elevations >5 × 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%).


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6.4.2
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.
6.4.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites
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.
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed before randomization.
7.1
Inclusion Criteria
This section applies to the main study (subjects with PD). Criteria for the sentinel cohort (healthy 
subjects) are described in Appendix H.
1. The subject (or, when applicable, the subject’s legally acceptable representative) signs an 
informed consent form indicating that the subject has been informed of the procedures to be 
followed, the experimental nature of the therapy, alternatives, potential benefits, side effects, 
risks, and discomforts.
2. The subject has a study partner who in the opinion of the investigator is sufficiently involved in 
the daily care of the subject to provide reliable information on falls, and assist the subject with 
at-home assessments, medication compliance, and attending study visits. Study partners who 
live with the subject are strongly preferred, but must spend at least 2 hours per day with the 
subject. The study partner must be willing to supervise and assist with medication 
administration and complete fall assessments on a daily basis during the study.
3. The subject is an outpatient of either sex aged between 40 and 85 years, inclusive, at the time of 
consent. 
4. The subject has a diagnosis of PD according to MDS clinical diagnostic criteria for PD. 
Subjects with DLB (ie, dementia diagnosed before onset of motor symptoms or up to 1 year 
after onset of motor symptoms) are also eligible, consistent with MDS clinical diagnostic 
criteria for PD.
5. The subject has Hoehn and Yahr stage ≥2 and <4 at the screening visit (bilateral involvement 
without impaired balance to mild to moderate bilateral disease with some postural instability 
but physically independent).
6. The subject has elevated risk for falls as indicated by at least 1 fall in the last 12 months before 
the screening visit based on the Fall History Assessment where in the opinion of the 


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investigator the falls were a consequence of PD, and who are at continued elevated risk of falls 
per investigator judgment. Investigator judgment on fall risk may be informed by information 
such as, but not limited to, history, physical examination and/or a score ≥2 on item 3.10 on 
MDS-UPDRS Part III.
7. The subject has evidence of cognitive impairment as indicated by a MoCA score between 
11 and 26, inclusive, and additionally can complete the cognitive assessments at screening (as 
specified in the study manual).
8. The subject has the ability to follow study instructions according to the investigator’s 
judgement.
9. The subject can walk without aid for 2 minutes while doing serial 3 subtraction (with site staff 
ensuring subject safety in case of falls). Subjects who require aids for walking can be included 
as long as they can complete the walk test without aid.
10. The subject has been on stable antiparkinsonian medication for at least 30 days before 
randomization and, in the opinion of the investigator, is expected to be able to remain at a 
stable dosage during the study without addition of new medications during the study.
11. A male subject who is nonsterilized and sexually active with a female partner of childbearing 
potential is eligible to participate if he agrees to use barrier method of contraception (ie, 
condom with or without spermicide) from signing of informed consent throughout the duration 
of the study and for 102 days after the last dose.
12. Female subjects are eligible to participate if a) not pregnant or nursing, and b) of 
nonchildbearing potential or agree to use highly effective contraception from signing of 
informed consent throughout the duration of the study and for 42 days after last dose of study 
drug.
7.2
Exclusion Criteria
This section applies to the main study (subjects with PD). Criteria for the sentinel cohort (healthy 
subjects) are described in Appendix H.
Any subject who meets any of the following criteria will not qualify for entry into the study.
1. In the opinion of the investigator, the subject’s parkinsonism is not due to primary PD.
2. The subject has orthostatic hypotension (defined as a decline in systolic blood pressure of 
20 mm Hg or a decline in diastolic blood pressure of 10 mm Hg on standing measured within 1 
minute of standing after being supine for at least 5 minutes). Subjects not meeting this criterion 
may be eligible if the principal investigator and the sponsor agree that the subject can safely 
participate in the study.
3. The subject has body mass index (BMI) less than 18 or greater than 40.
4. The patient has dyskinesia of sufficient severity to interfere with digital gait assessments 
during visits (as defined by MDS-UPDRS section 4.1 “Time spent with dyskinesias” and/or 
section 4.2 “Functional Impact of Dyskinesias” scores >2), and in the opinion of the 


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investigator the patient’s dyskinesia is likely to interfere with the digital gait assessments or 
other aspects of the study.
5. In the opinion of the investigator the patient has excessive daytime sleepiness of sufficient 
severity to interfere with participation in the cognitive and gait assessments.
6. The subject has received neurosurgical intervention for PD (eg, pallidotomy, thalamotomy) or 
has had a deep brain stimulation (DBS) device placed within the past year. Individuals who 
had a DBS implanted ≥1 year ago and have had stable settings for ≥2 months may participate if 
safe to do so, if the presence of DBS will not impact study assessments, and if further changes 
in DBS settings are not anticipated for the duration of study participation, per investigator 
judgment.
7. The subject has other medical problems (neurological, visual, orthopedic, psychiatric) that in 
the opinion of the investigator may significantly interfere with balance or gait, or interfere with 
completion of the study or interpretation of study endpoints.
8. The subject has significant risk factors for seizures (a history of seizures as an adult, a history 
of brain injury, or other risk factors deemed relevant by the investigator).
9. The subject has significant medical disease (renal, cardiac, endocrine, pulmonary, etc) based 
on medical history, physical examination, ECG, or laboratory evaluations, and/or in the 
opinion of the investigator the subject is otherwise unlikely to be medically able to participate 
in the study due to any reason including having a disorder that may interfere with drug 
absorption, distribution, metabolism, or excretion.
10. The subject has any of the following at the screening visit: estimated glomerular filtration rate 
(eGFR) (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) 
<60 mL/min; QT interval with Fridericia correction method (QTcF) >450 msec for male 
subjects and >470 msec for female subjects; a serum total bilirubin value >1.2 × ULN; a serum 
ALT or AST value >1.2 × ULN. Subjects with a positive hepatitis B surface antigen test result 
or known or suspected active hepatitis C infection are also excluded. Note: Subjects with 
positive hepatitis C virus (HCV) serology may be enrolled if quantitative polymerase chain 
reaction for HCV RNA is negative, to exclude active hepatitis C infection, and the investigator 
agrees that the subject can safely participate in the study. Subjects with eGFR <60 mL/min 
may be eligible if the investigator and the sponsor agree that the subject may safely participate 
in the study. Any screening laboratory test may be repeated if the investigator believes that a 
value is inaccurate.
11. In the opinion of the investigator the patient suffers from depression or other psychiatric 
disorder of sufficient severity to interfere with completion of the study or interpretation of the 
endpoints.
12. The subject has suffered from a substance use disorder (other than tobacco-use disorder) 
within the past 1 year before the first dose of study medication, or in the opinion of the 
investigator the subject’s current or past use of substances may interfere with performance on 
the cognitive, motor, or other assessments.


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13. The subject is considered by the investigator to be at imminent risk of suicide or injury to self, 
others, or property, or the subject has attempted suicide within the past year before screening. 
Subjects who have positive answers on item number 4 or 5 on the C-SSRS (based on the past 
year) before randomization are excluded.
14. The subject is unwilling or unable to discontinue taking cholinesterase inhibitors and/or 
moderate or strong CYP 3A4 inhibitors or inducers at least 30 days before randomization.
15. The subject is taking warfarin.
16. The subject has received any investigational compound that, in the opinion of the investigator 
or sponsor, may not have completely washed out before the screening visit.
17. The subject has received TAK-071 in the past.
18. The subject is an immediate family member, study site employee, or in a dependent 
relationship with a study site employee who is involved in the conduct of this study (eg, spouse, 
parent, child, sibling).
19. The subject has donated 400 mL or more of his or her blood volume within 90 days before the 
start of the screening visit.
20. The subject has a known hypersensitivity to any component of the formulation of TAK-071.
21. The subject has a fall-related institutionalization or hospital admission that occurs during the 
period between screening and the first baseline visit (not including emergency room visit).
7.3
Excluded/Allowed Medications and Treatments
This section applies to all subjects.
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator.
Excluded and allowed medications and treatments are shown in Table 7.a.
Table 7.a
Excluded and Allowed Medications and Treatments
Allowed Under 
Some 
Circumstances (See 
Comments)
Episodic Use
Comments or Exceptions
Acetylcholinesterase 
inhibitors
Not allowed
Not allowed
Acetylcholinesterase inhibitors are not permitted due to 
risk of seizure with coadministration of TAK-071. This 
class includes donepezil (Aricept), rivastigmine (Exelon), 
and galantamine (Razadyne). Washout of at least 30 days 
before randomization.


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Table 7.a
Excluded and Allowed Medications and Treatments
Allowed Under 
Some 
Circumstances (See 
Comments)
Episodic Use
Comments or Exceptions
COVID-19 vaccine 
(any FDA-approved 
manufacturer)
Allowed (see 
comments)
N/A
COVID-19 vaccination is allowed and recommended but 
should not be administered within 48 hours of any study 
visit, including home visits, if possible, to avoid 
complicating the assessment of AEs.
If the vaccination cannot be scheduled at another time, a 
reasonable attempt should be made to reschedule the 
study visit. If this is not feasible, both the vaccination and 
the study visit should proceed as scheduled, and the 
investigator should notify the sponsor.
Any investigational 
drug
Not allowed
Not allowed
Must have completed clinical study and stopped 
investigational drug 90 days before screening or 
5 half-lives, whichever is longer.
Anticholinergic drugs
Not allowed 
(exception: 
mirabegron is 
allowed)
Not allowed
Washout of at least 30 days before randomization. 
Although most drugs for overactive bladder have 
anticholinergic mechanisms of action and are excluded, 
mirabegron is permitted for this indication.
Stimulants
Not allowed
Not allowed
Washout of at least 30 days before randomization and 
approval for subject inclusion by sponsor/representative.
Antipsychotics
Allowed under some 
circumstances (see 
comments)
Not allowed
Not allowed: Antipsychotic drugs with significant 
interactions with cholinergic receptors (eg, clozapine, 
olanzapine) are not permitted. Washout of at least 30 days 
before randomization.
Allowed: Pimavanserin (at a dose of ≤34 mg QD) and 
quetiapine (at a dose of ≤250 mg total daily dose) for 
subjects who, in the opinion of the investigator, medically 
require treatment with an antipsychotic drug to safely 
complete the study, and the dose has been stable for at 
least 30 days before randomization. Other antipsychotic 
drugs may be permitted, conditional on agreement by the 
investigator and sponsor that the drug will not interfere 
with the study. Otherwise, washout of at least 30 days 
before randomization.
Narcotic analgesics
Not allowed
Not allowed
Washout of at least 30 days before randomization.


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Table 7.a
Excluded and Allowed Medications and Treatments
Allowed Under 
Some 
Circumstances (See 
Comments)
Episodic Use
Comments or Exceptions
Anticonvulsants
Allowed under some 
circumstances (see 
comments)
Not allowed
Allowed for non-seizure indication.
Not allowed: Subjects requiring anticonvulsants for 
seizure disorder or seizure risk factors are excluded 
from this study. Anticonvulsants listed in Table 7.b 
are never allowed.
May be allowed: Gabapentin and pregabalin at an FDA 
approved dose may be allowed if they are not being used 
for seizure disorder, the dose has been stable for at least 
30 days before randomization, and, in the opinion of the 
investigator and sponsor, the drug is unlikely to affect the 
outcome measures or subject safety in this study. The use 
of other anticonvulsants (except those in Table 7.b, which 
are never allowed) for indications unrelated to seizure 
disorder or seizure prophylaxis may be considered if the 
investigator and sponsor agree that the drug is unlikely to 
affect the outcome measures or subject safety in this 
study. Otherwise, washout of at least 30 days before 
randomization. 
Antidepressants 
Allowed under some 
circumstances (see 
comments)
Allowed under 
some circumstances 
(see comments)
Not allowed: Bupropion is excluded in all cases and 
requires washout at least 30 days prior to randomization. 
Nefazodone is excluded as a strong CYP3A4 inhibitor 
under all circumstances and must be stopped at least 30 
days before randomization. 
Allowed: Trazodone up to 100 mg at bedtime may also 
be used for insomnia, either as a stable dose or 
intermittently. Chronic use of other antidepressants is 
permitted as long as the dose is kept stable during the 
study. 
Herbal remedies that 
are psychoactive (eg, 
kava, valerian, ginkgo 
biloba)
Allowed under some 
circumstances (see 
comments)
Allowed under 
some circumstances 
(see comments)
Allowed: Herbal remedies may be permitted conditional 
on approval from the investigator and sponsor if they are 
judged to be unlikely to affect the outcome measures and 
are deemed to be safe. 
Not allowed: St. John’s wort is not permitted under any 
circumstances due to its activity as a CYP3A4 inducer 
and must be stopped at least 30 days before 
randomization. Any herbal remedies that are not 
permitted must be stopped at least 30 days before 
randomization.


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Table 7.a
Excluded and Allowed Medications and Treatments
Allowed Under 
Some 
Circumstances (See 
Comments)
Episodic Use
Comments or Exceptions
OTC (eg, cough 
syrup)
Allowed under some 
circumstances (see 
comments)
Allowed under 
some circumstances 
(see comments)
Allowed: The OTC analgesics acetaminophen, aspirin, 
ibuprofen, and naproxen at approved doses are allowed at 
approved (per label) doses. The OTC allergy medications 
fexofenadine, loratadine, and cetirizine are allowed at 
approved (per label) doses. Other OTC remedies are 
permitted as long as in the opinion of the investigator and 
sponsor the medication will not interfere with the study or 
pose a risk to subjects. 
Not allowed: OTC drugs with anticholinergic properties 
such as diphenhydramine are excluded under all 
circumstances and must be stopped at least 30 days 
before randomization. 
Melatonin
Allowed under some 
circumstances (see 
comments)
Allowed
Melatonin at doses of ≤10 mg at bedtime is permitted for 
subjects with REM sleep behavior disorder and/or 
insomnia as long as the dose is kept stable during the 
study and use has been relatively stable for at least 30 
days before randomization. Either consistent nightly or 
intermittent (as needed) nightly dosing is acceptable.
Cannabis and 
cannabis-derived 
products
Allowed under some 
circumstances (see 
comments)
Not allowed
Allowed if subjects have been using cannabis and 
cannabis-derived products at a relatively stable level for 
at least 30 days before randomization. Otherwise, 
washout of at least 30 days before randomization. 
Subjects must abstain from these products for at least 24 
hours before any study-related assessments.
Barbiturates
Not allowed
Not allowed
Washout at least 30 days before randomization.
Nonbenzodiazepine 
hypnotics (eg, 
zopiclone, 
eszopiclone, zaleplon, 
zolpidem, suvorexant)
Allowed under some 
circumstances (see 
comments)
Not allowed
Allowed if the total daily dose has been relatively stable 
from 30 days before randomization to the end of the 
study.
Muscle relaxants 
including but not 
limited to baclofen, 
tizanidine, 
4-aminopyridine
Allowed under some 
circumstances (see 
comments)
Not allowed
Allowed if the total daily dose has been relatively stable 
from 30 days before randomization to the end of the study 
and, in the opinion of the investigator and sponsor, the 
drug is unlikely to affect the outcome measures or subject 
safety in this study. Otherwise, washout of at least 30 
days before randomization.
Antiparkinsonian 
drugs
Allowed under some 
circumstances (see 
comments)
Allowed under 
some circumstances 
(see comments)
Allowed if the total daily dose has been relatively stable 
from 30 days before randomization to the end of the 
study. For medications that are occasionally taken as 
needed, or where the dosage is occasionally adjusted as 
needed, a judgment is to be made regarding the stability 
of dosing in collaboration with the sponsor.
Moderate/strong 
CYP3A inhibitor a
Not allowed
Not allowed
TAK-071 is primarily metabolized by CYP3A4; 
moderate and strong CYP3A inhibitors are excluded 
under all circumstances and must be stopped at least 30 
days prior to randomization.
Please note that subjects must not consume grapefruit or 
grapefruit juice, a CYP3A4 inhibitor, during the study.


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Table 7.a
Excluded and Allowed Medications and Treatments
Allowed Under 
Some 
Circumstances (See 
Comments)
Episodic Use
Comments or Exceptions
Moderate/strong 
CYP3A inducers a
Not allowed
Not allowed
TAK-071 is primarily metabolized by CYP3A4; 
moderate and strong CYP3A inducers are excluded under 
all circumstances and must be stopped at least 30 days 
prior to randomization.
Warfarin
Not allowed
Not allowed
TAK-071 is highly bound to plasma albumin, therefore 
warfarin is excluded. Other anticoagulants are allowed. 
Subjects taking warfarin must washout and start another 
anticoagulant at least 30 days before randomization
Benzodiazepines 
Allowed under some 
circumstances (see 
comments)
Not allowed
Benzodiazepines will be allowed as long as the dose has 
been stable for at least 30 days before randomization, the 
medication is used at night for insomnia and/or REM 
sleep behavior disorder, or for anxiety, and investigator 
and sponsor agree that the drug will not interfere 
substantially with the study endpoints.
Otherwise, benzodiazepines must be stopped at least 30 
days before randomization. 
CYP: cytochrome P-450; OTC: over-the-counter; QD: once daily; REM: rapid eye movement.
a Listed in Table 7.b.
Strong and moderate CYP3A inducers and inhibitors (Table 7.b) are excluded in all circumstances 
and must be stopped at least 30 days prior to randomization.
Table 7.b
Strong and Moderate CYP3A Inducers and Inhibitors
Class
Specific Drugs of Concern in Class
Strong CYP3A inhibitors
Antibiotics
Clarithromycin, telithromycin, troleandomycin
Antidepressants
Nefazodone
Antifungals
Itraconazole, ketoconazole, posaconazole, voriconazole
Antiprogestins
Mifepristone
Antivirals
Boceprevir, danoprevir/ritonavir, telaprevir, ombitasvir/paritaprevir/ 
ritonavir/dasabuvir (VIEKIRA PAK)
Diuretics
Conivaptan
Food products
Grapefruit juice (double strength)
Kinase inhibitors
Ceritinib, idelalisib, ribociclib
Pharmacokinetic enhancer
Cobicistat
Protease inhibitors
Indinavir, indinavir/ritonavir, lopinavir/ritonavir, nelfinavir, ritonavir, 
saquinavir, saquinavir/ritonavir, tipranavir/ritonavir
Treatments of AIDS
Elvitegravir/ritonavir


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Table 7.b
Strong and Moderate CYP3A Inducers and Inhibitors
Class
Specific Drugs of Concern in Class
Moderate CYP3A inhibitors
Antiarrhythmics
Dronedarone
Antibiotics
Ciprofloxacin, erythromycin
Antiemetics
Aprepitant, casopitant, netupitant
Antifungals
Fluconazole, isavuconazole, ravuconazole
Antineoplastic agents
Imatinib
Antiparkinsonians
Istradefylline
Antivirals
Faldaprevir, letermovir
Benzodiazepines
Tofisopam
Calcium channel blockers
Diltiazem, verapamil
Food products
Grapefruit juice
H2 receptor antagonists
Cimetidine
Herbal medications
Magnolia vine (Schisandra sphenanthera)
Immunosuppressants
Cyclosporine
Kinase inhibitors
Crizotinib, duvelisib, fedratinib, nilotinib
Protease inhibitors
Amprenavir, atazanavir, atazanavir/ritonavir, darunavir, darunavir/ritonavir
Strong CYP3A inducers
Antiandrogens
Apalutamide, enzalutamide
Antibiotics
Rifampin, rifapentine
Anticonvulsants
Carbamazepine, phenobarbital, phenytoin
Antilipemics
Avasimibe
Antineoplastics
Mitotane
Cancer treatments
Ivosidenib
Cystic fibrosis treatments
Lumacaftor
Herbal medications
St John’s wort
Moderate CYP3A inducers
Antibiotics
Nafcillin, rifabutin
Antidiarrheals
Telotristat ethyl
Antigout and uricosuric agents
Lesinurad
Antipsychotics
Thioridazine
Antivirals
Asunaprevir, beclabuvir, daclatasvir
Endothelin receptor antagonists
Bosentan
Kinase inhibitors
Dabrafenib, lorlatinib
Nonnucleoside reverse 
transcriptase inhibitors
Efavirenz, etravirine, lersivirine, talviraline
Other
Elagolix
Protease inhibitors
Lopinavir, ritonavir, tipranavir
Psychostimulants
Modafinil
Source: www.druginteraction.org. 
7.4
Diet, Fluid, and Activity Control
This section applies to all subjects.


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The subject should abstain from alcohol consumption for 24 hours before each study visit. In 
addition, subjects may not consume grapefruit or grapefruit juice during the study.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
This section applies to all subjects.
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 9.1.22.
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), 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 more than 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%).

Subject experiences any of the Takeda Medically Significant List events (see 
Section 10.1.4).
2. Significant protocol deviation. The discovery postrandomization that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, or 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 
documents.
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 due to an 
AE should not be recorded in the “voluntary withdrawal” category).


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5. 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 9.1.14.
6. Study termination by the sponsor.
7. Study termination by the IRB or regulatory agency.
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
This section applies to all subjects.
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 may be replaced.
If a subject discontinues from the study, a replacement subject may be enrolled, if deemed 
appropriate by the investigator and sponsor. The study site should contact the interactive web 
response system (IWRS) for the replacement subject’s treatment assignment and study number.
8.0
CLINICAL STUDY MATERIAL MANAGEMENT
This section applies to all subjects, except Section 8.1.3.
This section contains information regarding all medications and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of study material.
8.1
Study Drug and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
8.1.1.1
Study Drug
TAK-071 drug product will be supplied as film-coated tablets containing TAK-071 active 
pharmaceutical ingredient or matching placebo. Other ingredients will include typical 
pharmaceutical excipients (mannitol, microcrystalline cellulose, hydroxypropyl cellulose, sodium
starch glycolate, and magnesium stearate). The tablet coating is composed of typical 
pharmaceutical-grade coating components (hypromellose 2910, titanium dioxide, ferric oxide 
yellow, and ferric oxide red).
TAK-071 drug product or matching placebo will be supplied in white high-density polyethylene 
bottles with induction sealed caps. Bottle labels will bear the appropriate label text as required by 


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governing regulatory agencies. At a minimum, such text will include product name, product 
strength, number of tablets, and lot number.
8.1.1.2
Sponsor-Supplied Drug
Takeda will supply TAK-071 tablets and matching placebo.
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. Refer to pharmacy manual for 
additional storage- and return-related instructions and information.
8.1.3
Dose and Regimen
For the subjects with PD only: subjects who meet randomization criteria on Day 1 will be 
randomized to 1 of 2 treatment sequences consisting of daily treatment with 7.5 mg TAK-071 or 
placebo. Subjects will receive 7.5 mg TAK-071 or placebo dosed QD from Day 1 through Day 42 
of each period.
After the PK, safety, and physiologically based PK modeling data from the sentinel cohort 
(healthy subjects) have been assessed (see Appendix H), a decision will be made about the dose for 
the remaining subjects with PD to be enrolled in the main study. If older subjects are expected to 
remain below the exposure caps, they will also be enrolled. The maximum subject age and dose 
may be modified after analysis of data from the sentinel cohort.
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 the eCRF, 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 eCRF(s) according to Section 10.0.
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
Subjects will be assigned to receive their treatment according to the schedule allocated to each 
study site.


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Subjects with PD aged 40 to 85 years, inclusive, will be enrolled in the main study, with 1:1 
randomization to 7.5 mg TAK-071 QD versus placebo, in sequences of 4.
For the main study, subjects with PD will be randomized to 1 of 2 possible treatment sequences 
consisting of 2 periods and 2 treatments, alternating in a crossover fashion:

Subjects randomized to Sequence A will receive TAK-071 in the first 6-week period and 
crossover to placebo in the second 6-week period.

Subjects randomized to Sequence B will receive placebo in the first 6-week period and 
crossover to TAK-071 in the second 6-week period.
The investigator or the investigator’s designee will access IWRS at screening to obtain the subject 
study number. The investigator or the investigator’s designee will use the IWRS to randomize the 
subject into the study. During this contact, the investigator or designee will provide the necessary 
subject-identifying information, including the subject number assigned at screening. The 
medication identification (ID) number of the study drug to be dispensed will then be provided by 
the IWRS. If the sponsor-supplied drug is lost or damaged, the site can request a replacement from 
IWRS. (Refer to IWRS manual provided separately.) The tear-off portion of the medication label 
will be affixed to the Dispensing Log. At subsequent drug-dispensing visits, the investigator or 
designee will again access IWRS to request additional study drug for a subject.
8.3
Randomization Code Creation and Storage
The IWRS system 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 IWRS.
Since the maintenance of the blind may be compromised because of results from drug 
concentrations and/or pharmacodynamics assessments, such results should not be disclosed before 
blind breaking. In the event that results must be reported to the investigator before breaking the 
blind, all efforts should be made to maintain the blind (eg, as changing a medication ID number to 
avoid identification of subjects by the laboratory site personnel). Detailed procedures for 
measuring subject drug concentration levels, (including reporting results) are provided in the 
separately created procedure for directions on handling of biological samples for measuring drug 
concentrations.
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, before 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.


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For unblinding a subject, the study drug blind can be obtained by the investigator, by accessing the 
IWRS.
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.
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 returned to the sponsor or 
designee for destruction. Destruction at site will be permitted if/when a Standard Operating 
Procedure exists after requesting and receiving sponsor’s approval.
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,
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:

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the medication ID 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.

A site representative or unblinded pharmacy monitor, otherwise uninvolved with study 
conduct, will review the randomization schedule and subject dosing log before Day 1 dosing 
and after dosing to ensure all subjects received the correct dose of study drug,

Filing all study medication documentation in the investigator’s essential document file.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
Please see the Pharmacy Manual for additional details.
9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. They apply to all 
subjects except where indicated. 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 for the main study (subjects with PD) and Appendix H for the sentinel cohort (healthy 
subjects).


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9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained before the subject entering into the study, and before any 
protocol-directed procedures are performed.
A unique screening ID number will be generated by the IWRS and assigned to each subject after 
informed consent is signed and the site registers the subject in the IWRS; this ID number will be 
used throughout the study.
9.1.1.1
DNA Analysis Informed Consent Procedure
A separate informed consent form pertaining to collection, storage, and analysis of the sample 
must be obtained before collecting a blood sample for DNA analysis research for this study. The 
provision of consent to collect and analyze the sample for DNA analysis is independent of consent 
to the other aspects of the study. Providing a DNA sample is optional for this 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, 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 the disease under study that resolved at or before signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.10).
In addition, information on the subject’s PD history including symptoms and disease 
characteristics and history of falls over the past 6 months will be collected.
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 30 days before signing of informed consent.
9.1.3
Physical Examination Procedure
At screening and both baseline visits, a physical examination (defined as the assessment before 
first dose of study drug) will be conducted consisting 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) lymph nodes; and 
(10) other.
At the last visit of each period, (11) nervous system will be added to the examination.
All subsequent physical examinations should assess clinically significant changes from the 
assessment before first dose examination.


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9.1.4
Neurological Examination Procedure
A separate neurological examination will be performed and collected in the eCRF. This will 
include testing mental status, gait, cerebellar function, cranial nerves, upper and lower extremity 
motor strength, reflexes, and sensation.
9.1.5
Weight, Height, and BMI
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The BMI is calculated using metric units with the formula provided below. Height is recorded 
in centimeters without decimal places. Weight is collected in kilograms (kg) with 1 decimal place. 
BMI should be derived as:
Metric:
BMI = weight (kg)/height (m)2
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. Because the BMI is used as an exclusion criterion this 
determination must be made after rounding.
9.1.6
Vital Sign Procedure
The investigator will review all vital signs for real-time safety monitoring purposes. Vital signs 
will include body temperature (oral measurement), respiratory rate, supine blood pressure (systolic 
and diastolic, after lying down at least 5 minutes), supine pulse (beats per minute), standing blood 
pressure and pulse (systolic and diastolic blood pressure and pulse, measured within 1 minute after 
standing after supine measurements are taken).
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.
9.1.7
MoCA (Subjects With PD Only)
The MoCA is a cognitive screening examination designed to screen for MCI [11]. This 30-point 
test assesses 8 cognitive domains: attention and concentration, executive functions, memory, 
language, visuoconstructional skills, conceptual thinking, calculations, and orientation.
9.1.8
Pharmacodynamic Measurements
In the case of subjects with PD, all in-clinic assessments are to be performed during the subject’s 
On state after taking dopaminergic therapy. Assessments should be made within approximately the 
same time after a patient has taken their dopaminergic medication.
Please refer also to the study manual for the order in which gait and cognitive assessments should 
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Note: in unavoidable circumstances such as the COVID-19 pandemic, it may be necessary to 
administer clinical interviews and assessments using alternative approaches (please refer to 
Section 9.1.24). In some cases, audio/or video recording of subject interviews may not be possible. 
This will be documented in the study records.
9.1.8.1
Pharmacodynamic Measurements Related to Gait
This section applies only to the main study (subjects with PD).
9.1.8.1.1
Walk and Serial Subtraction Tests

Serial subtraction test. 
Serial subtraction tests are commonly used to measure attention and mental concentration [12]. 
Subjects in this study will perform a serial subtraction 3 test while sitting in a chair. Subjects 
will not be corrected during this testing. The total number of correct and incorrect numbers will 
be recorded.

2-minute walk (with cognitive load).
Subjects will be asked to walk at a self-selected comfortable pace back and forth along a 
10-meter long hallway for 2 minutes while conducting a serial subtraction 3 test. Subjects will 
complete turns at both ends of the hallway. Verbal reminders will be provided if subjects stop 
counting before completing the full 2-minute walk test. The total number of correct and 
incorrect numbers during subtraction will be recorded.

2-minute walk (no cognitive load).
Subjects will be asked to walk at a self-selected comfortable pace back and forth along a 
10-meter long hallway for 2 minutes. Subjects will complete turns at both ends of the hallway.
9.1.8.1.2
Cued 180° Turns
Subjects will be asked to walk at a self-selected comfortable pace back and forth along a 
10-meter-long hallway. At random times during their walk, the subjects will receive a verbal 
instruction to turn 180 degrees in a specific direction (left or right). After the turn, subjects will 
continue walking until they receive another instruction to turn. The total number of correct turns 
(turning in the direction instructed) will be recorded.
9.1.8.1.3
MDS-UPDRS Including Hoehn and Yahr Scale
MDS-UPDRS consists of 4 parts evaluating various aspects of PD through 65 items [13]. Part I 
evaluates nonmotor experiences of daily living and Part II evaluates motor experiences of daily 
living. Part III includes a set of motor examinations conducted by a clinician. Part IV assesses 
motor complications. Rater time for administrating the MDS-UPDRS is estimated to be 
approximately 30 minutes [14]. The Hoehn and Yahr scale is a 5-stage, descriptive ordinal scale 
that provides a general estimate of clinical aspects including objective signs (impairment) and 
functional deficits (disability) in PD [15]. Note that for this study the standard version rather than 
the modified version will be used.


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The scale will be evaluated by a clinician. The same rater should rate a subject on each visit during 
the course of the study. Of note, the distinction between stages 3 and stage 4 should be made in part 
based on whether the subject is too disabled to live alone. Subjects who cannot live independently 
should be rated as stage 4 or 5 (https://www.parkinson.org/Understanding-
Parkinsons/What-is-Parkinsons/Stages-of-Parkinsons).
9.1.8.1.4
Postural Sway
Subjects will be asked to stand still with feet slightly apart and hands hanging loosely at their sides 
for 30 seconds. The subjects will be instructed to either 1) look at a visual focal point on a wall or 
2) close their eyes during the test.
9.1.8.1.5
Speech Test
Subjects will be asked to complete tasks assessing various aspects of speech and language, 
including speech timing, voice quality, vocal control, breath support, sentence complexity, and 
idea density. Details will be available in the study manual.
9.1.8.1.6
TUG
Subjects will be asked to complete the standard TUG. Subjects will begin the test sitting in a chair. 
Subjects will then stand up from the chair, walk 3 meters as quickly and safely as possible, cross a 
line marked on the floor, turn around, walk back, and sit down again in the chair. This test will be 
repeated 3 times (only once at screening).
9.1.8.2
Pharmacodynamic Measurements Related to Cognition
This section applies only to the main study (subjects with PD).
Please refer to the Cogstate and Operation manuals for additional details on these assessments.
9.1.8.2.1
Cogstate International Shopping List Test
The International Shopping List test is a measure of verbal learning and memory and uses a 
well-validated list-learning paradigm. High-frequency, high-imagery, concrete nouns (items from 
a shopping list) are read to the subject by the test supervisor at the rate of 1 word every 2 seconds. 
Once all 12 words have been read, the subject is asked to recall as many of the words as he/she can 
as quickly as possible. The test supervisor records the words recalled by the subject on the testing 
device. When the subject can recall no more words, the same list is read a second time. The test 
supervisor records the words recalled by the subject on this trial. This is then repeated a third time. 
Delayed recall condition is also available for this test. The delayed recall condition requires the 
subject to recall the words from the list 10 to 30 minutes later without having the list read again. 
The software measures the number of correct responses as recorded by the test supervisor. It takes 
approximately 5 minutes to complete this test.


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9.1.8.2.2
Cogstate Modified Chase Test
The modified Chase test is administered prior to the first administration of the modified Groton 
Maze Learning test (screening visit) for additional subject familiarization. Subjects are required to 
“chase” a moving box around the grid for about 30 seconds, moving 1 box at a time without 
skipping boxes.
9.1.8.2.3
Cogstate Modified Groton Maze Learning Test
Modified Groton Maze Learning Test: The task begins with a chase task to allow subjects to 
become familiar with the task context. The subjects are shown a 10 × 10 grid of tiles on a computer 
touch screen. The subjects are instructed to ‘chase’ a moving tile around the grid. Once they 
understand the rules, they can proceed onto the timed chase test, where they must chase the target 
for 30 seconds. For the test, the subject is shown the same 10 × 10 grid of tiles on a computer touch 
screen. A 28-step pathway is hidden among these 100 possible locations. The start is indicated by 
the blue tile at the top left and the finish location is the tile with the red circles at the bottom right of 
the grid. The subjects are instructed to move 1 step from the start location and then to continue, 1 
tile at a time, toward the end (bottom right). The subjects move by touching a tile next to their 
current location with the stylus. After each move is made, the computer indicates whether this is 
correct by revealing a green checkmark (ie, this is the next step in the pathway), or incorrect by 
revealing a red cross (ie, this is not the next step in the pathway, or the subject has broken a rule, 
see below). If the choice was correct, the step in the pathway remains highlighted and the subjects 
must locate the next step in the pathway. If a choice was incorrect (ie, a red cross is revealed), the 
subjects must touch the last correct location (ie, the last green checkmark revealed) and then make 
a different tile choice to advance toward the end. While moving through the hidden maze, the 
subjects are required to adhere to 2 rules. First, the subjects cannot move diagonally or touch the 
same tile twice in succession. Second, the subjects cannot move backwards along the pathway (eg, 
move back to a location that displayed a green tick, but from which they have since moved). If the 
subjects choose a tile that is not part of the hidden pathway, but the tile choice is within the rules, 
this is recorded as a different type of error (eg, not a rule break). This could be due to chance (the 
first time through the maze) or due to misremembering the path on subsequent attempts. The 
subjects learn the 28-step pathway through the maze on the basis of this trial and error feedback. 
Once completed, the pathway of correct responses marked on the grid is extinguished and subjects 
are instructed to return to the start location and find the same pathway again. The process continues 
until subjects have completed 5 trials in total. There are 20 well-matched alternate forms for this 
task, and these are selected in pseudo-random order to ensure that no subject will complete the 
same hidden path until all 20 have been completed.
9.1.8.2.4
Cogstate One Card Learning Test
The One Card Learning test is a measure of visual learning and uses a well-validated pattern 
separation paradigm with playing card stimuli. In this test, the playing cards are identical to those 
found in a standard deck of 52 playing cards (without the joker cards). The subject is asked 
whether the card displayed in the center of the screen was seen previously in this test. The subject 


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responds by pressing the Yes or No key. The software measures the speed and accuracy of each 
response. It takes approximately 6 minutes to complete this test.
9.1.8.2.5
Cogstate One Back Test
The One Back test is a measure of working memory and uses a well-validated n-back paradigm 
with playing card stimuli. In this test, the playing cards are identical to those found in a standard 
deck of 52 playing cards (without the joker cards). The subject is asked whether the card displayed 
in the center of the screen is the same as the card presented immediately previously. The subject 
responds by pressing the Yes or No key. Because no card has been presented yet on the first trial, a 
correct first response is always No. The software measures the speed and accuracy of each 
response. It takes approximately 4 minutes to complete this test.
9.1.8.2.6
SDMT (Oral Version)
The oral version of the SDMT is administered by providing the subject with a sheet of paper at the 
top of which is printed the key containing (9 abstract symbols and 9 corresponding numbers). The 
key remains visible to the subject throughout the test. A sequence of 120 symbols (the first 10 
symbols are practice items) is presented in 8 rows below the key. In each row, empty boxes are 
located immediately below the boxes containing the symbols. The examiner, on a copy of the test 
sheet, records in the empty squares the numbers that the subject associates, orally, with the 
symbols. In the first test phase, the subject has to make 10 trial symbol-number associations 
without a time limit. The examiner will correct any errors made during this phase. After this 
learning phase, the test proper begins. The subject has to make as many associations as possible 
within the 90-second time limit. If the subject is able to complete all 110 associations before the 
time runs out, the test is stopped. The test score is the number of correct associations made by the 
subject in the time allowed.
9.1.8.2.7
SAT
The SAT is a measure of sustained attention that uses a signal detection paradigm. The subject 
indicates whether a small gray square has been presented on screen. The subject responds by 
pressing the Yes key when the gray square has been presented and No when it is not presented. A 
distractor condition is present in some trials, where the screen background flashes at a rapid rate 
and thereby makes it more difficult to determine whether the gray square has been presented. 
Performance is measured by calculating the total correct responses. It takes approximately 
11 minutes to complete the test.
9.1.8.3
Other Pharmacodynamic Measures
This section applies only to the main study (subjects with PD).
9.1.8.3.1
Global Impression Scales
The CGI [17] consist of 2 subscales: CGI-S and the CGI-I. The CGI-S assesses the clinician’s 
impression of the subject’s clinical condition. Both the CGI-I and CGI-S will be rated with respect 
to stability (gait, balance, falls) and cognition in separate assessments. The clinician should use 


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his/her total clinical experience with this subject population and rate the current severity of the 
subject’s illness on a 7-point scale ranging from 1) Normal, not at all ill to 7) Among the most 
extremely ill patients. This rating is based on observed and reported symptoms, behavior, and 
function in the past 7 days and should reflect the average severity level across the 7 days.
The CGI-I assesses the subject’s improvement (or worsening) on a 7-point scale ranging from 
1) Very much improved since the initiation of treatment to 7) Very much worse since the initiation 
of treatment. Each time the subject is seen after treatment has been initiated, the clinician compares 
the subject’s overall clinical condition to the 1-week period just before the initiation of medication 
use (baseline). The CGI-S score obtained at the baseline visit serves as a basis for making this 
assessment. In all cases, the assessment should be made independent of whether the clinician 
believes the improvement is drug-related or not.
Patient-reported global impression of severity and improvement (PGI-S and PGI-I, respectively) 
will be assessed [18]. PGI-I will be rated on a 7-point scale and PGI-S will be rated on a 6-point 
scale. Both the PGI-I and PGI-S will be rated with respect to stability (gait, balance, falls) and 
cognition in separate assessments.
9.1.8.3.2
ESS
ESS is a self-administered questionnaire to evaluate the level of excessive daytime sleepiness [19]. 
There are 8 questions measuring the subject’s usual chances of dozing off or falling asleep while 
engaged in 8 different activities. Each item will be rated on a 4-point scale (0-3). The total ESS 
score is the sum of all these 8 items with the range from 0 to 24.
9.1.8.4
Biomarkers
This section applies only to the main study (subjects with PD).
Primary specimen collection is outlined in Table 9.a.
Table 9.a
Primary Specimen Collection
No.
Specimen Name 
in Schedule of 
Study Procedures 
(Appendix A)
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of 
Intended Use
Sample Collection
1
Plasma samples 
circulating 
biomarkers
Plasma
Biomarker 
measurements
Mandatory
2
Blood sample for 
DNA
Blood
DNA
DNA 
measurements
Optional
3
Plasma samples for 
TAK-071 PK
Plasma
PK measurements
Mandatory
PK: pharmacokinetic.


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Plasma samples will be obtained for circulating biomarkers. Plasma biomarkers may include, but 
are not limited to, neuronally derived exosome M1 mRNA levels, amyloid, tau, NfL, and 
biomarkers of synaptic integrity.
Detailed information will be provided in the laboratory manual,
Blood samples will be obtained to assay for DNA-based and other plasma-based biomarkers. 
These include M1 receptor expression levels and the pharmacodynamic effects of TAK-071. 
Detailed information on the collection protocol and analytes will be provided in the laboratory 
manual.
9.1.9
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.
9.1.10
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 or 
neurological examination abnormalities noted at screening examination, according to the 
judgment of the investigator. The condition (ie, diagnosis) should be described.
9.1.11
Maximum Blood Volumes (Subjects With PD Only)
The maximum volume of blood at any single visit is approximately 27 mL and the maximum total 
volume of blood for the study is approximately 104 mL. See Appendix H for the sentinel cohort.
9.1.12
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. Laboratory 
samples will be taken on the days stipulated in Appendix A. It is not necessary that the subjects 
fast before these blood samples are collected. Additional laboratory safety tests may be added to 
blood samples previously drawn to obtain additional safety information at the investigator’s 
discretion (eg, adding creatinine kinase isoenzymes to a serum chemistry panel that was already 
drawn).
Details of these procedures and required safety monitoring will be given in the laboratory manual.
Table 9.b lists the tests that will be obtained for each laboratory specimen.


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Table 9.b
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Red blood cells
White blood cells with differential 
(absolute counts)
Hemoglobin
Hematocrit
Platelets
Coagulation
Prothrombin time/international 
normalized ratio
Activated partial thromboplastin 
time
Alanine aminotransferase
Albumin
Alkaline phosphatase
Aspartate aminotransferase
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
Microscopic analysis 
(only if positive dipstick 
results): white blood cells, 
red blood cells, epithelial 
cells, casts
Plasma
4β-Hydroxycholesterol and cholesterol
Ratio of 4β-hydroxycholesterol to cholesterol
Serum
Urine/Blood
Hemoglobin A1c
eGFR a
Hepatitis B surface antigen
Antibody to HCV; if positive, reflex qPCR for HCV 
viral RNA
Drug screen for amphetamines, barbiturates, 
benzodiazepines, cocaine, opiates, alcohol, and cotinine 
Urine pregnancy (optional substitute for serum pregnancy 
at baseline visits)
Female subjects: Serum human chorionic gonadotropin
Female subjects, if postmenopausal and not surgically 
sterile: FSH b
eGFR: estimated glomerular filtration rate; FSH: follicle-stimulating hormone; HCV: hepatitis C virus; qPCR: 
quantitative PCR.
a Calculated using Chronic Kidney Disease Epidemiology Collaboration equation.
b FSH level will be obtained for female subjects at screening if they are postmenopausal (ie, continuous amenorrhea of 
at least 1 year) and not surgically sterile. The result must be >40 IU/L for the subject to be enrolled.
The central laboratory will perform laboratory tests for hematology, serum chemistries, 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, gamma-glutamyl transferase, and INR) should be 
performed within a maximum of 7 days and preferably within 48 to 72 hours after the abnormality 
was noted. (Refer to Sections 7.5 and 10.2.3 for the appropriate guidance on reporting abnormal 
LFTs.)


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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).
9.1.13
Contraception and Pregnancy Avoidance Procedure
9.1.13.1
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and for 102 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 or without spermicidal 
cream or jelly). In addition, they must not donate sperm during this period. Women of childbearing 
potential who are partners of male subjects are also advised to use additional contraception as 
shown in the list containing highly effective contraception below.
*Women NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy, or tubal ligation) or who are postmenopausal (eg, defined 
as continuous amenorrhea of at least 12 months and a follicle-stimulating hormone (FSH)>40 
IU/L, confirmed before any study drug is implemented.
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate.
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign the consent form stating that they 
understand the requirements for avoidance of pregnancy during the course of the study and for 102 
days after the last dose of study drug.
9.1.13.2
Female Subjects and Their Male Partners
From signing of informed consent, throughout the duration of the study, and for 42 days after last 
dose of study drug, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use a highly effective method of contraception (from the list in 
Section 9.1.13.3).
In addition they must be advised not to donate ova during this period.
9.1.13.3
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, bilateral oophorectomy, and tubal ligation. A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause. A high 
follicle-stimulating hormone (FSH) level in the postmenopausal range (FSH >40 IU/L) may be 
used to confirm a postmenopausal state in younger women (eg, those <45 years old) or women 


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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.
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 medications and devices containing hormones are unacceptable, 
the acceptable methods are nonhormonal methods only:

Intrauterine device.

Bilateral tubal occlusion and bilateral tubal ligation.

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 42 days after last dose.
2. Unacceptable methods of contraception are:

Hormonal methods. Hormonal contraceptives are not considered to be highly effective 
contraceptives in the context of this study because the impact of TAK-071 on the 
metabolism of these drugs has not yet been studied. However, subjects taking these 
medications may continue to take them during the study as long as they are using a highly 
effective method of contraception listed above.

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, even if used with spermicidal jellies or creams and even with 
condom.
3. Subjects will be provided with information on highly effective methods of contraception as 
part of the subject informed consent process and will be asked to sign a consent form stating 
that they understand the requirements for avoidance of pregnancy, donation of ova, and sperm 
donation during the course of the study.


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4. During the course of the study, regular serum human chorionic gonadotropin (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 and sperm 
donation 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?
5. In addition to a negative serum hCG pregnancy test at screening, female subjects of 
childbearing potential must also have a negative urine dipstick hCG pregnancy test 1 day or the 
same day before receiving any dose of study medication.
9.1.14
Pregnancy
If any subject is found to be pregnant during administration of active study drug, for example, after 
baseline/Day 1 or within 42 days of the last dose of active study drug, she should be withdrawn and 
any sponsor-supplied drug should be immediately discontinued. The pregnancy should be reported 
immediately, using a pregnancy notification form, to the contact listed in Section 1.2.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of her 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 subject was 
participating in a clinical study at the time female subject/female partner of the subject became 
pregnant and provide details of the study drug the subject received (blinded or unblinded, as 
applicable).
All reported 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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9.1.15
ECG Procedure
The investigator will review all 12-lead ECG data, including estimates of ECG intervals, for 
real-time safety monitoring purposes, and an assessment of normality/abnormality will be 
recorded in the eCRF.
For both screening and safety ECGs, a standard 12-lead ECG will be recorded. The investigator (or 
a qualified observer at the study site) will 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 recorded 
on the eCRF from the subject’s ECG trace: heart rate, RR interval, PR interval, QT interval, QRS 
interval, QT interval with Fridericia correction, and QT interval with Bazett correction.
All stationary 12-lead ECG machines will be supplied by the site. Subjects should be in a supine 
position after an approximate 10-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.
One copy of the 12-lead ECG with the investigator’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.
If an ECG is scheduled at the same time as blood draws or vital signs, the ECG will be obtained 
within 0.5 hours before the scheduled blood draw/vital sign assessment. If an ECG coincides with 
a meal, the ECG will take precedence followed by the meal.
9.1.16
Assessment of Suicidal Ideation and Behavior
The C-SSRS was developed by researchers at Columbia University as a tool to 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.
9.1.17
Sample Collection for DNA Analysis
This section applies only to the main study (subjects with PD).
When optional sampling of whole blood for DNA analysis occurs, the subject must sign a special 
informed consent for the DNA sample.
DNA forms the basis for the genes that make the body produce proteins such as enzymes, drug 
transporters, or drug targets, and may be evaluated for the genetic contribution to how the drug is 
broken down or how the drug affects the body. Specific purposes of this study include:

Identifying genetic reasons why certain people respond differently to TAK-071.

Determining how TAK-071 affects the primary and secondary endpoints.


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
Generating information needed for research, development, and regulatory approval of tests to 
predict response to TAK-071.
See the laboratory manual for detailed instructions on collecting, handling, storing, and shipping 
DNA samples.
9.1.18
Plasma Sample for Circulating Biomarkers
This section applies only to the main study (subjects with PD).
Whole blood samples will be collected in the study and processed into plasma for analysis of 
circulating biomarkers. The plasma will be aliquoted into 2 samples.
All cells in the body release small extracellular vesicles called exosomes, and the cellular origin 
can be determined by enriching the exosomes using markers on their surface. Neuronally derived 
exosomes will be enriched from the plasma and used to explore muscarinic receptor M1 expression 
and other transcripts related to cholinergic tone. See the laboratory manual for detailed instructions 
on collecting, handling, storing, and shipping of plasma samples for circulating biomarkers.
9.1.19
Blood Samples for PK Analysis
Blood samples for PK analysis of plasma TAK-071 will be collected into chilled vacutainers 
containing anticoagulant K2EDTA according to the schedules in Appendix A and Appendix C.
9.1.20
Bioanalytical Methods
Plasma concentrations of TAK-071 will be measured by a validated method using 
high-performance liquid chromatography with tandem mass spectrometry.
9.1.21
PK Parameters
In the main study (subjects with PD), the plasma Cmax, observed concentration at the end of a 
dosing interval (Ctrough), and tmax of TAK-071 will be determined. See Appendix H for the sentinel 
cohort.
Actual sampling times, rather than scheduled sampling times, will be used in all data presentations.
9.1.22
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 
IWRS should be contacted as a notification of screen failure.
The primary reason for screen failure will be recorded in the eCRF using the following categories:

PTE/AE.

Did not meet entrance criteria (specify reason).

Significant protocol deviation.


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
Lost to follow-up.

Voluntary withdrawal (specify reason).

Study termination by sponsor.

Study termination by IRB or regulatory agency.

Other specify reason.
Screening ID numbers assigned to subjects who fail screening should not be reused.
Subjects who fail screening can be rescreened, with approval of the sponsor. They should be 
assigned a new screening ID number.
9.1.23
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.
9.1.24
Alternative Approaches to Study Procedures and Data Collection Due to 
COVID-19 or Other Unavoidable Circumstances
In unavoidable circumstances (eg, a widespread disease outbreak or natural disaster) that impact 
the ability to conduct study procedures according to the Schedule of Procedures (Appendix A), 
contingency measures may be implemented. In acknowledgement of FDA guidance 
(fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-conduct-clinical-t
rials-medical-products-during-covid-19-public-health-emergency. Accessed 12 June 2020), as 
well as study site, hospital, local, state, and national restrictions established during these kinds of 
circumstances, the following measures are being taken for the current study:

Other than the final visit, alternative methods for conducting subject visits (eg, telephone visits, 
video conferencing, or in-home study visits conducted by site personnel contingent upon local 
regulations) may be used per approval by the sponsor or designee.
–
Approval may be granted to omit collection of certain study assessments and visit windows 
may be extended.
–
When approval is given for a subject to miss an in-person study visit, a study site physician 
will speak directly with the subject by telephone or other medium (eg, a computer-based 
video communication) during each visit window to assess subject safety and overall 
clinical status.
–
At minimum, the study site physician or other qualified site personnel should conduct the 
following assessments within specified-visit window timeframes: AE assessments, 
documentation of concomitant medication, administration of C-SSRS, and an assessment 
of clinical symptoms.


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–
Other study assessments may be collected using an alternative method as feasible, and may 
involve audio or video recording where allowed by local regulation. In some cases, audio 
and/or video recording of subject interviews may not be possible. This will be documented 
in the study records.
–
Sites may seek approval to extend a visit window in order to conduct an on-site visit. 
Assessments that cannot be completed during the protocol-specified window will be 
considered missing data and such departures will be recorded in the study records.
–
The maximum interval between successive study visits may be no longer than 8 weeks.

The final visit should be performed in person. When it is not possible for the subject to come to 
the study site, the preferred alternative for the final visit is for qualified study site personnel to 
go to the subject’s residence and conduct the protocol-specified procedures in that location. 
Assessments collected at a subject’s residence should comply with applicable local 
regulations.
All subject discontinuations and alternative approaches to study procedures (ie, procedures not 
conducted per the Schedule of Procedures) due to the COVID-19 pandemic must be documented 
in the study records as related to COVID-19. Data collected using alternative methods may be 
handled differently in the final data analyses. This will be documented in the statistical analysis 
plan (SAP).
9.2
Monitoring Subject Treatment Compliance
This section applies only to the main study (subjects with PD). An electronic drug diary will be 
implemented in this study. Further details regarding this diary are provided in the study reference 
manual. Subjects also will be required to bring study drug packaging to each clinic visit, regardless 
of whether the study drug packaging is empty.
Noncompliance with study drug includes subjects who are <75% compliant between visits 
(including noncompliance as assessed via the electronic drug diary). If these criteria for 
noncompliance are met on more than 1 occasion during the study, the subject will be considered 
significantly out of compliance and the site investigator will need to discuss the subject’s 
continuation in the study with the sponsor (or designee). On the basis of the assessment of the 
investigator and sponsor (or designee), an out-of-compliance subject may be withdrawn from the 
study.
9.3
Schedule of Observations and Procedures
The detailed schedule for all study-related procedures for all evaluations in the main study 
(subjects with PD) is shown in Appendix A. Assessments should be completed at the designated 
visit/time points.
A brief overview of the study schedule is presented in Table 9.c.


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Table 9.c
Overview of Main Study Schedule (Subjects With PD)
Screening
6-Week Double-blind Treatment Period 
(Periods 1 and 2)
Washout
Follow-up 
Safety Phone 
Call
Baseline
At-Home 
Assessment
Last Day of 
Treatment 
Period or Early 
Termination
(Week 17)
Period 1 
Study Visit 
Number
1
2
3
4
(Study Day)
(Day -42 up to 
Day -1)
(Day 1)
(Day 21 ±2)
(Day 42 ±2)
(Day 43 to 
Day 63) a
Period 2 
Study Visit 
Number 
5
6
7
8
(Study Day)
(Day 64 ±2)
(Day 84 ±2)
(Day 105 ±2)
(Day 119)
a At least 3 weeks for washout.
The study schedule and specific visits for the sentinel cohort (healthy subjects) are described in 
Appendix H.
9.3.1
Screening
Subjects will be screened within 1 to 42 days before baseline/randomization. Subjects will be 
screened in accordance with predefined inclusion and exclusion criteria as described in Section 7.0. 
See Section 9.1.22 for procedures for documenting screen failures.
Procedures to be completed at screening are listed in Appendix A.
Subjects who fail screening can be rescreened, with approval of the sponsor. They should be 
assigned a new screening ID number.
9.3.2
Treatment Period
The 6-week treatment period begins with baseline/randomization, continues with 6 weeks of study 
medication, and ends on the last day of study medication (or early termination).
This is followed by a 3-week washout period, after which the treatment period is repeated.
9.3.2.1
Baseline/Randomization
Baseline/randomization will take place on study Day 1.
Procedures to be completed at baseline are listed 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 IWRS, as described in Section 8.2. 


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Subjects will be instructed on when to take the first dose of study drug as described in Section 6.1. 
The procedure for documenting randomization failures is provided in Section 9.1.23.
9.3.2.2
Treatment and Washout Periods
Procedures to be completed during each of the 2 treatment periods and the intervening washout 
period are listed in Appendix A.
9.3.3
Final Visit or Early Termination
The final visit will occur on the last day of treatment in treatment period 2 (or early termination).
Procedures to be completed at this visit are listed in Appendix A.
For all subjects receiving study drug, the investigator must complete the End of Study eCRF page.
9.3.4
Follow-up
The follow-up phone call occurs 14 days after the final visit or early termination.
9.3.5
Post Study Care
Study drug will not be available on 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
Biological Sample Retention and Destruction
Please refer to the sample management plan.
The sample will be labeled with a unique sample identifier similar to labeling in the main study but 
using a code that is different from the code attached to the health information and other clinical test 
results collected in the study. The sample and data are linked to personal health information with 
code numbers. This link means that the subject may be identified but only indirectly. The code 
numbers will be kept secure by or on behalf of the sponsor.
Subjects who consented and provided a sample for DNA analysis can withdraw their consent and 
request disposal of a stored sample at any time. The sponsor will be notified of consent 
withdrawal.
When a subject requests disposal of a stored sample during the retention period, the site will ask 
the vendor to destroy the sample via the sponsor according to the procedure. the vendor will 
destroy the sample in accordance with the procedure, and notify the site and sponsor. However, a 
sample may be retained if documentation (including medical records) identifying the subject 
donor has been destroyed and it is impossible to link the sample to any given subject.
Even if the sample can be linked to the subject, when DNA analysis has been conducted, the 
remaining samples will be destroyed and the results of DNA analysis of anonymized subject will 
be retained by the sponsor.


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The sponsor has put into place a system to protect the subject’s personal information to ensure 
optimal confidentiality and defined standard processes for sample and data collection, storage, 
analysis, and destruction.
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
This section applies to all subjects.
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 before 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 versus 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).


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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 are not 
considered an intervention. In addition, repeated or additional noninvasive testing for 
verification, evaluation or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (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. I 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.


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Preplanned procedures (surgeries or interventions):

Preplanned procedures (surgeries or therapies) that were scheduled before 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 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.
Overdose:
Cases of overdose with any medication without manifested side effects are NOT considered PTEs 
or AEs, but instead will be documented on 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
Blood and lymphatic system disorders
Pregnancy, puerperium, and perinatal conditions
Agranulocytosis
Spontaneous abortion 
Aplastic anaemia
Stillbirth and fetal death
Cardiac disorders
Renal and urinary disorders
Torsade de pointes
Acute renal failure
Ventricular fibrillation
Respiratory, thoracic, and mediastinal disorders
Ventricular tachycardia
Acute respiratory distress syndrome 
Hepatobiliary disorders
Acute respiratory failure
Acute liver failure
Pulmonary fibrosis 
Hepatic necrosis
Pulmonary hypertension
Immune system disorders
Skin and subcutaneous tissue disorders
Anaphylactic shock
Stevens-Johnson syndrome
Infections and infestations 
Toxic epidermal necrolysis
Confirmed or suspected endotoxin shock
Vascular disorders
Confirmed or suspected transmission of infectious 
agent by a medicinal product
Malignant hypertension
COVID-19
COVID-19 pneumonia
Nervous system disorders
Convulsive seizure
Malignant hyperthermia
Neuroleptic malignant syndrome
AE: adverse event.
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.


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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.
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.

Drug interrupted: the drug 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.


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
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.

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
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 baseline/Day 
1) or until screen failure. For subjects who discontinue before 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 
baseline/Day 1). Routine collection of AEs will continue until the follow-up safety phone call (≥14 
days after the last dose).
10.2.1.1
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 


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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 and time.
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).
8. Outcome of event.
9. Seriousness.
10.2.2
Collection, Reporting, and Acknowledgment of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
The preferred method of reporting SAEs is via the SAE eCRF page in the electronic data capture 
(EDC) system. If access to EDC is not feasible within 24 hours of receiving the event, a paper SAE 
form should be submitted via fax (see Section 1.2 for fax number).
If fax is used, site personnel need to confirm successful transmission of all pages and include an 
email address on the fax cover sheet so that an acknowledgment of receipt can be returned via 
email within 1 business day.
Email submission of SAE forms with a PDF attachment should only be used in the case where fax 
is not possible and EDC is not feasible within 24 hours of receiving the event,
In case of email, site personnel need to confirm successful transmission by awaiting an 
acknowledgment of the receipt via email within 1 business day,
If SAEs are reported via fax or by email, the EDC must be updated as soon as possible with the 
appropriate information,
The SAE 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 ID number.

Investigator’s name.

Name of the study drug.


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
Causality assessment.
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 LFTs
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, additional information on relevant recent 
history, risk factors, clinical signs and symptoms and results of any additional diagnostic tests 
performed will be recorded.
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 
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 9.1.11 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Takeda SAE form (per Section 10.2.2).
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 update the SAE form in the eCRF and provide other written documentation 
within 24 hours of receipt. However, as a back-up, if required, the SAE paper form should be 
completed, signed by the investigator, and transmitted within 24 hours to the attention of the 
contact listed in Section 1.2. Copies of any relevant data from the hospital notes (eg, ECGs, 
laboratory tests, discharge summary, postmortem results) should be sent to the attention of the 
contact listed in Section 1.2, 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, investigators, and IRBs.
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. 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 study. 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
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study. Data will be reviewed by the sponsor only.
12.0
DATA HANDLING AND RECORDKEEPING
This section applies to all subjects.
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
eCRFs
This study will use eCRFs.
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.
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.
Corrections eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. Reasons for significant corrections should also be included.
The principal investigator must review the eCRFs for completeness and accuracy and must 
electronically 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.
After the lock of the study database, any change of, modification of, or addition to the data on the 
eCRFs should be made by the investigator with use of change and modification records of the 
eCRFs. The principal investigator must review the data change for completeness and accuracy, 
and must sign and date.
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.


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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, ICH 
E6 (R2) Section 4.9.5 requires the investigator to retain essential documents specified in ICH E6 
(R2) (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 (R2) 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.
13.0
STATISTICAL METHODS
This section applies to all subjects unless otherwise indicated.
13.1
Statistical and Analytical Plans
A SAP will be prepared and finalized before database lock. This document will provide further 
details regarding the definition of analysis variables and analysis methodology to address all study 
objectives. Safety and PK analyses of the sentinel cohort will be conducted as described in a 
separate Internal Review Charter prior to that.
A blinded data review will be conducted before database lock. This review will assess the accuracy 
and completeness of the study database, subject evaluability, and appropriateness of the planned 
statistical methods.
13.1.1
Analysis Sets
13.1.1.1
Safety Analysis Set
The safety analysis set will include all subjects who were randomized and received at least 1 dose 
of the study drug. Subjects in this analysis set will be used for demographics, baseline 
characteristics, and safety summaries.


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13.1.1.2
PK Analysis Set
The PK analysis set will consist of subjects who receive at least 1 dose of study drug and who have 
at least 1 measurable plasma concentration of TAK-071.
13.1.1.3
Pharmacodynamic Analysis Set
The pharmacodynamic analysis set will consist of subjects who receive at least 1 dose of study 
drug and who have at least 1 evaluable postdose pharmacodynamic measure. All TAK-071 dose 
groups will be combined.
13.1.2
Analysis of Demographics and Other Baseline Characteristics
Demographics and baseline characteristics will be listed and summarized by each sequence group 
and overall using the safety analysis set.
13.1.3
Pharmacodynamic Analysis (Subjects With PD)
Summary statistics will be provided for the observed values of the efficacy measures at baseline 
and each of the postdose visits by treatment groups. Change from baseline will also be summarized 
with descriptive statistics by treatment groups.
The primary outcome, the change from baseline in gait variability during a 2-minute walk test, will 
be analyzed using a linear mixed effect model with a random factor for subject and fixed factors 
for treatment, period, and sequence. Baseline covariates will be included in the model as 
appropriate.
The effect of treatment on the overall cognitive battery will be analyzed using a linear mixed 
effects model with random effects for subjects for each cognitive test, fixed factors for treatment, 
test, period, and sequence. The comparison of the number of falls for placebo versus TAK-071 will 
be analyzed using a generalized linear mixed effects model with a random factor for subjects and 
fixed factors for treatment, period, and sequence.
To address the exploratory outcomes, the continuous endpoints will be analyzed using linear 
mixed effects models with a random factor for subject and fixed factors for treatment, period, and 
sequence.
Drug effects on change from baseline for all endpoints will be assessed using 1-sided tests. In all 
analyses the interaction terms and covariates will be added as appropriate. If the outcomes are 
positively skewed, a logarithmic transformation may be applied. All other statistical analyses of 
pharmacodynamic endpoints will be described in the SAP.
13.1.4
PK Analysis
Descriptive statistics will be used to summarize plasma concentrations over collection time. 
Individual plasma concentration data will be presented in data listings.
Descriptive statistics will also be used to summarize plasma PK parameters. Individual plasma PK 
parameters will be presented in data listings.


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13.1.5
Other Analyses (Subjects With PD)
Disease characteristics may be used as covariates in the statistical analyses of primary, secondary, 
and exploratory outcomes.
Other analyses may include, but are not limited to, the analysis of digital device data, such as 
wearable pendant sensor and/or digital gait assessment data; plasma biomarkers including 
neuronally derived exosome M1 mRNA levels, amyloid, tau, NfL, and biomarkers of synaptic 
integrity; and DNA-based biomarkers.
The statistical analyses of in-home activity and number of falls, collected by the wearable pendant 
sensor, will be described in detail in the SAP.
The analyses listed in this section will be performed if useful and appropriate. The corresponding 
data and the analyses results may not be included in the clinical study report.
13.1.6
Safety Analysis
AEs will be summarized using the safety analysis set.
All AEs will be coded using MedDRA. Data will be summarized using Preferred Term (PT) and 
primary System Organ Class (SOC).
TEAEs will be summarized by SOC and PT. The following summary tables will be included in the 
report: summary of TEAEs and drug-related AEs, relationship of AEs to study drug (related versus 
not related), severity of AEs, and related AEs.
Data listings will be provided for all AEs including TEAEs, AEs leading to study drug 
discontinuation, and SAEs.
Clinical laboratory variables, vital signs, and ECG parameters will be summarized with 
descriptive statistics for baseline, postdose, and change from baseline to postdose values.
Individual results of vital sign and ECG parameters that meet Takeda’s markedly abnormal criteria 
will be summarized and provided in the data listings. All vital sign data and all ECG data will be 
provided in the data listings.
13.2
Interim Analysis, Sentinel Analysis, and Criteria for Early Termination
No formal interim analysis is planned. The safety and PK review of the sentinel cohort will be 
described in detail in the Internal Review Charter. Stopping rules are described in Section 6.4.
13.3
Determination of Sample Size (Subjects With PD)
A sample size of 42 completers with PD will be sufficient to detect a statistically significant (α = 
0.05, 1-sided) decrease in gait variability during walking for TAK-071 versus placebo. We expect 
to detect a minimum effects size of 0.32 (Cohen d) in the reduction of gait variability, similar to 
that observed in [2]. For the sample size calculation, the study power was assumed to be 80%.
Given the proposed study sample size and 80% power, a minimum detectable operational effect 
size [20] for the cognitive battery (α = 0.1, 1-sided) will be 0.49. The correlations between 


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cognitive tests are assumed to be 0.5. The minimum detectable (α = 0.1, 1-sided) effect size in the 
number of falls will be approximately 0.3, similar to the effect size for the number of falls 
observed in the literature [2,3]. For all calculations, the within-person correlation for the primary 
and secondary outcomes was assumed to be 0.65 [3].
It is expected that approximately 64 subjects will be randomized to ensure at least 42 completers. 
During the study, blinded monitoring of the data will take place to evaluate assumptions regarding 
the distribution of key study variables. If necessary up to 70 subjects may be randomized. Details 
will be provided in the SAP.
14.0
QUALITY CONTROL AND QUALITY ASSURANCE
This section applies to all subjects.
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site (on-site and/or remote) 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.
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, such as the COVID-19 pandemic, the investigator 
should consult with the sponsor or designee (and IRB, 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 in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB, 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. A 
Protocol Deviation Form should be completed by the site and signed by the sponsor or designee for 
any significant deviation from the protocol.
The investigator should document all protocol deviations.


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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.
15.0
ETHICAL ASPECTS OF THE STUDY
This section applies to all subjects.
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 local or regional regulatory requirements and align his or her conduct in 
accordance with the “Responsibilities of the Investigator” that are listed in Appendix D. 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 state, federal and local requirements. 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 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, 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 and 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. Until the 
site receives notification no protocol activities, including screening, may occur.


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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 
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 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 and the sponsor before 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. 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 before 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 before subject entering 


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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.
Subjects who consented and provided sample for DNA analysis can withdraw their consent and 
request disposal of a stored sample at any time before analysis. Notify sponsor of consent 
withdrawal.
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 ID number. As permitted by all 
applicable laws and regulations, limited subject attributes, such as sex, age, or date of birth may be 
used to verify the subject and accuracy of the subject’s unique ID 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 


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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.
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 
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.
16.0
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Appendix A
Schedule of Study Procedures, Main Study (Su.bjects With PD)
Table A-1
Period 1
Screening a
6-Week Double-blind Treatment Period 
(Period 1)
Washout
Baseline b
At-home 
Assessment
Last Day of 
Treatment Period 
or Early 
Termination c
Study Visit Number
1
2
3
4
(Study Day)
(Day -42 up 
to Day -1)
(Day 1)
(Day 21 ±2)
(Day 42 ±2)
(Day 43 to Day 
63) d
Administrative Procedures
Informed consent
X
Inclusion/exclusion 
criteria
X
X
Demographics
X
Education and 
handedness
X
Medical history
X
Disease 
characteristics
X
Medication history
X
Concomitant 
medications
X
X
X
X
Fall history 
assessment
X
Clinical Procedures/Assessments
Vital signs, weight, 
and BMI
X
X
X
Height
X
MoCA
X
MDS UPDRS 
including Hoehn and 
Yahr scale
X
X
X
PTE/AE assessment
X
X
X
X
12-lead ECG
X
X
X
Physical examination 
without nervous 
system
X
X
Physical examination 
with nervous system
X
Neurological 
examination
X
X
C-SSRS
X
X
X
X
Serial subtraction test, 
seated
X
X
X
2-minute walk with no 
cognitive load
X
X


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Table A-1
Period 1
Screening a
6-Week Double-blind Treatment Period 
(Period 1)
Washout
Baseline b
At-home 
Assessment
Last Day of 
Treatment Period 
or Early 
Termination c
Study Visit Number
1
2
3
4
(Study Day)
(Day -42 up 
to Day -1)
(Day 1)
(Day 21 ±2)
(Day 42 ±2)
(Day 43 to Day 
63) d
2-minute walk under 
serial subtraction 
condition with audio 
recording to verify 
cognitive performance
X e
X
X
Cognition assessment 
f
X
X
X
Cued 180° turns
X
X
TUG g
X
X
X
Postural sway with 
eyes open and closed
X
X
Speech test (in clinic)
X
X
X
Speech test (at home)
See schedule in 
Appendix B for 
speech test
ESS
X
X
CGI-I/PGI-I
X
CGI-S/PGI-S
X
X
Compliance Procedures
Randomization
X
Dispense study drug
X
Confirm study drug 
compliance h
X
X
X
Collect remaining 
study drug
X
Provide wearable 
pendant sensor, 
electronic drug diary, 
and falls diary for 
at-home daily use
X
Confirm in-home 
wearable pendant 
sensor and electronic 
drug diary compliance
X
X
X
Collect wearable 
pendant sensor, 
electronic drug diary 
device, and falls diary
X (Only at early 
termination)


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Table A-1
Period 1
Screening a
6-Week Double-blind Treatment Period 
(Period 1)
Washout
Baseline b
At-home 
Assessment
Last Day of 
Treatment Period 
or Early 
Termination c
Study Visit Number
1
2
3
4
(Study Day)
(Day -42 up 
to Day -1)
(Day 1)
(Day 21 ±2)
(Day 42 ±2)
(Day 43 to Day 
63) d
Laboratory Procedures/Assessments
Clinical laboratory 
evaluations, including 
4β-hydroxycholestero
l and cholesterol
X
X
X
Urine drug and 
alcohol screen
X
X
X
Serum pregnancy test 
(hCG) i
X
X
X
HBsAg and anti-HCV
X
Plasma samples for 
circulating biomarkers 
j,k
X
X k
Blood sample for 
DNA (optional) j
X
Plasma samples for 
TAK-071 PK j,l
X
X
AE: adverse event; anti-HCV: antibody to hepatitis C virus; BMI: body mass index; C-SSRS: Columbia Suicide Severity Rating 
Scale; CGI-I/PGI-I: Clinical/Patient Global Impression-Improvement; ECG: electrocardiogram; ESS: Epworth Sleepiness Scale; 
HBsAg: hepatitis B surface antigen; hCG: human chorionic gonadotropin; MoCA: Montreal Cognitive Assessment; MDS UPDRS: 
Movement Disorder Society Unified Parkinson’s Disease Rating Scale; PD: Parkinson disease; PGI-S/CGI-S: Patient/Clinical 
Global Impression-Severity; PK: pharmacokinetic; PTE: pretreatment event; TUG: Timed Up and Go test.
a Screening assessments should be completed within the screening period.
b Assessments at Visit 2 (Period 1 baseline) may be split across 2 days and should be completed on or before Day 3.
c Assessments at Visit 4 (Period 1 last day of treatment period or early termination) may be split across 2 days and should occur 
within the visit window. 
d Washout is ≥3 weeks.
e The 2-minute walk at screening is done without audio recording.
f Assessments include Symbol Digit Modalities Test, Cogstate International Shopping List Test, Cogstate Modified Chase Test 
(only administered at screening visit), Cogstate Modified Groton Maze Learning Test, Cogstate One Card Learning Test, Cogstate 
One Back Test, Cogstate International Shopping List Test—Recall, and Sustained Attention Task.
g TUG: 1 trial at screening, 3 trials at each baseline and last/early termination visit.
h Drug compliance will be evaluated with an electronic drug diary.
i Pregnancy test is administered when applicable based on subject sex. For Baseline (Visit 2), urine pregnancy test may be used
instead of serum pregnancy.
j See Appendix C for timing of samples.
k Biomarker sample to be collected at Visit 4, but not early termination.
l Additional samples can be collected as needed.


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Table A-2
Period 2
6-Week Double-blind Treatment Period 
(Period 2)
Follow-up 
Safety Phone 
Call
Baseline a
At-home 
Assessment
Last Day of 
Treatment Period 
or Early 
Termination a
(Week 17)
Study Visit Number
5 a
6
7 a
8
(Study Day)
(Day 64 ±2)
(Day 84 ±2)
(Day 105 ±2)
(Day 119)
Administrative Procedures
Informed consent
Inclusion/exclusion criteria
X
Demographics
Medical history
Disease characteristics
Medication history
Concomitant medications
X
X
X
X
Fall history assessment
Clinical Procedures/Assessments
Vital signs, weight, and BMI
X
X
Height
MoCA
MDS UPDRS including Hoehn and 
Yahr scale
X
X
PTE/AE assessment
X
X
X
X
12-lead ECG
X
X
Physical examination without 
nervous system
X
Physical examination with nervous 
system
X
Neurological examination
X
C-SSRS
X
X
X
Serial subtraction test, seated
X
X
2-minute walk with no cognitive 
load
X
X
2-minute walk under serial 
subtraction condition with audio 
recording to verify cognitive 
performance
X
X
Cognition assessment b
X
X
Cued 180° turns
X
X
TUG c
X
X
Postural sway with eyes open and 
closed
X
X
Speech test (in clinic)
X
X


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Table A-2
Period 2
6-Week Double-blind Treatment Period 
(Period 2)
Follow-up 
Safety Phone 
Call
Baseline a
At-home 
Assessment
Last Day of 
Treatment Period 
or Early 
Termination a
(Week 17)
Study Visit Number
5 a
6
7 a
8
(Study Day)
(Day 64 ±2)
(Day 84 ±2)
(Day 105 ±2)
(Day 119)
Speech test (at home)
See schedule in 
Appendix B for 
speech test
ESS
X
X
CGI-I/PGI-I
X
CGI-S/PGI-S
X
X
Compliance Procedures
Randomization
X
Dispense study drug
X
Confirm study drug compliance d
X
X
X
Collect remaining study drug
X
Provide wearable pendant sensor, 
electronic drug diary, and falls 
diary for at-home daily use
X
Confirm in-home wearable pendant 
sensor and electronic drug diary 
compliance
X
X
X
Collect wearable pendant sensor, 
electronic drug diary device, and 
falls diary, (Visit 7 only)
X
Laboratory Procedures/Assessments
Clinical laboratory evaluations, 
including 4β-hydroxycholesterol 
and cholesterol
X
X
Urine drug and alcohol screen
X
X
Serum pregnancy test (hCG) e
X
X
HBsAg and anti-HCV
Plasma samples for circulating 
biomarkers f,g
X
X g
Blood sample for DNA (optional) f
Plasma sample for TAK-071 PK f,h
X
X
AE: adverse event; anti-HCV: antibody to hepatitis C virus; BMI: body mass index; C-SSRS: Columbia Suicide Severity Rating 
Scale; CGI-I/PGI-I: Clinical/Patient Global Impression-Improvement; ECG: electrocardiogram; ESS: Epworth Sleepiness Scale; 
HBsAg: hepatitis B surface antigen; hCG: human chorionic gonadotropin; MoCA: Montreal Cognitive Assessment; MDS UPDRS: 
Movement Disorder Society Unified Parkinson’s Disease Rating Scale; PD: Parkinson disease; PGI-S/CGI-S: Patient/Clinical 
Global Impression-Severity; PK: pharmacokinetic; PTE: pretreatment event; TUG: Timed Up and Go test.
a Assessments at Visit 5 (Period 2 baseline) and Visit 7 (Period 2 last day of treatment period or early termination visit) may be split 
across 2 days and should occur within the visit window. 


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Table A-2
Period 2
6-Week Double-blind Treatment Period 
(Period 2)
Follow-up 
Safety Phone 
Call
Baseline a
At-home 
Assessment
Last Day of 
Treatment Period 
or Early 
Termination a
(Week 17)
Study Visit Number
5 a
6
7 a
8
(Study Day)
(Day 64 ±2)
(Day 84 ±2)
(Day 105 ±2)
(Day 119)
b Assessments include Symbol Digit Modalities Test, Cogstate International Shopping List Test, Cogstate Modified Chase Test 
(only administered at screening visit), Cogstate Modified Groton Maze Learning Test, Cogstate One Card Learning Test, Cogstate 
One Back Test, Cogstate International Shopping List Test—Recall, and Sustained Attention Task.
c TUG: 1 trial at screening, 3 trials at each baseline and last/early termination visit.
d Drug compliance will be evaluated with an electronic drug diary.
e Pregnancy test is administered when applicable based on subject sex. For study visit 5 (Day 64), a urine pregnancy test may be 
used instead of serum pregnancy.
f See Appendix C for timing of samples.
g Biomarker sample to be collected at Visit 7, but not early termination.
h Additional samples can be collected as needed.


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Appendix B
Schedule of At-Home Speech Tests (Subjects With PD)
Period
Study Days for Morning Notification and 
At-Home Speech Assessment
Window for 
At-Home Speech Assessments
First
Days 19, 21, 23
Days 19-24
Second
Days 82, 84, 86
Days 82-87
No more than 1 assessment per day.
Notifications will be provided the morning of the assessment day. If the assessment is not done at that time, a second 
notification will be sent 1 hour later. The next morning, if the assessment is still not done, a third notification will be 
sent at same time of day as the first notification.


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Appendix C
Schedule of Samples Across Both Periods, Main Study
Subjects With PD
Visit
Visit 1 
(Screening)
Visit 2
Visit 4
Visit 5
Visit 7
Early Termin-
ation Visit
Day(s)
-42 to -1
1
42 (±2)
64 (±2)
105 (±2)
Clinical laboratory 
samples
X
X
X
X
X
X
Plasma samples 
for circulating 
biomarkers
Predose
2 hours
Predose
2 hours
Blood sample for 
DNA (optional)
Predose
Plasma sample for 
TAK-071 PK a
Predose; 
1 hour,
2 hours
Predose; 
1 hour,
2 hours, 
3 hours
Predose; 
1 hour,
2 hours
Predose; 
1 hour,
2 hours, 
3 hours
X
PD: Parkinson disease; PK: pharmacokinetic.


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Appendix D
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all 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, before 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/independent ethics 
committee (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.


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10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
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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Appendix E
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.
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 


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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. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so.
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) on 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
e) that the subject’s identity will remain confidential in the event that study results are 
published.


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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 42 days after the 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 the study, the study drug will 
be discontinued and the investigator will offer the subject the choice to receive unblinded 
treatment information.
26. Male subjects must use barrier or highly effective contraception (as defined in the informed 
consent) from signing the informed consent throughout the duration of the study, and for 102 
days after the 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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Appendix F
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.
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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Appendix G
Amendment History
Date
Amendment Number
Amendment Type (for regional 
Europe purposes only)
Region
07 September 2021
Amendment 4
Not applicable
United States
18 January 2021
Amendment 3
Not applicable
United States
12 August 2020
Amendment 2
Not applicable
United States
06 July 2020
Amendment 1
Not applicable
United States
16 March 2020
Initial version
Not applicable
United States
Protocol Amendment 3
The primary reasons for this amendment are to:

Add healthy subjects at the beginning of the study as a sentinel cohort for rich pharmacokinetic 
(PK) sampling, to be conducted at designated sites. Remove subjects with Parkinson disease 
(PD) from the sentinel cohort. To clarify procedures that are specific to each cohort, move 
information specific to the sentinel cohort to an appendix and remove sentinel cohort 
information from main text.

Allow initial subjects with PD to enroll in main study in parallel to when the sentinel cohort is 
running. These subjects must be ≤65 years old. Older subjects with PD may be enrolled 
pending the results of the sentinel cohort PK.

Remove cognitive load from the primary objective and endpoint. Add an 
exploratory/additional objective and endpoint around evaluation of gait parameters, and clarify 
that exploratory endpoints for change from baseline on gait parameters, gait variability, double 
support time, and self-directed turns are in the presence versus absence of cognitive loading.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only, 
and are not captured in the following table.
Protocol Amendment 3
Summary of Changes Since Amendment 2
Description of Each Change and Rationale
Sections Affected by Change
No.
Description
Rationale
Location
1
Lower dose may be used 
depending on pharmacokinetic 
(PK) results.
Clarify that proposed TAK-071 
dose is ≤7.5 mg and that the 
maximum subject age and dose 
may be modified after analysis of 
data from the sentinel cohort.
Section 4.2, Benefit/Risk Profile
Section 6.1, Study Design, Main 
Study
Section 8.1.3, Dose and Regimen
Section 8.2, Study Drug 
Assignment and Dispensing 
Procedures


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Protocol Amendment 3
Summary of Changes Since Amendment 2
Description of Each Change and Rationale
Sections Affected by Change
No.
Description
Rationale
Location
2
Given the inclusion criteria, some 
subjects may not be able to 
complete the task required to 
measure the original primary 
endpoint (2-minute walk with 
cognitive loading).
Remove cognitive load from 
primary objective and endpoint.
Section 2.0, Study Summary: 
Study Design
5.1.1, Primary Objectives
5.2.1, Primary Endpoint
13.1.3, Pharmacodynamic 
Analysis (Subjects With PD)
3
Examine the interaction of 
cognitive loading and treatment, 
which was removed from primary 
objectives and endpoint.
Clarify that exploratory endpoints 
for change from baseline on gait 
parameters, gait variability, 
double support time, and 
self-directed terms are in the 
presence versus absence of 
cognitive loading and treatment.
Add an exploratory/additional 
objective and endpoint around 
evaluation of gait parameters in 
presence versus absence of 
cognitive loading.
Change “presence and absence” of 
cognitive loading to “presence 
versus absence” in the exploratory 
objectives and endpoints.
5.1.3, Exploratory/Additional 
Objectives
5.2.4, Exploratory Endpoints
4
Separation of main study and 
sentinel cohort, where elements 
differ, makes protocol easier to 
follow.
Study sites enrolling only subjects 
with PD do not need to see 
instructions specific to healthy 
subjects.
Single PK site for healthy 
subjects, appendix will clarify 
procedures for them.
Remove sentinel cohort from main 
text.
Move sentinel cohort to new 
Appendix H with elements 
specific to sentinel cohort (healthy 
subjects).
Section 2.0, Study Summary
Section 5.2.2, Secondary 
Endpoints
Section 6.1, Study Design, Main 
Study
Section 6.3.3, Dose Justification
Section 8.2, Study Drug 
Assignment and Dispensing 
Procedures
Section 9.1.21, PK Parameters
Section 9.3 Schedule of 
Observations and Procedures
Appendix A, Schedule of Study 
Procedures, Main Study (Subjects 
With PD): Table A-1, Period 1
Appendix C, Schedule of Samples 
Across Both Periods, Main Study
Appendix H, Sentinel Cohort 
(Healthy Subjects) Only
5
Make age descriptions consistent.
Express all age ranges as 
“inclusive”.
Section 2.0, Study Summary
Section 6.1, Study Design, Main 
Study


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Protocol Amendment 3
Summary of Changes Since Amendment 2
Description of Each Change and Rationale
Sections Affected by Change
No.
Description
Rationale
Location
6
Data from healthy older subjects 
will be sufficient to extend the PK 
profile established in younger 
healthy adult subjects.
Designated site(s) will conduct the 
sentinel cohort, with rich PK 
sampling.
Add healthy subjects at the 
beginning of the study as a 
sentinel cohort for rich PK 
sampling, at designated site(s). 
Remove subjects with PD from the 
sentinel cohort.
Section 2.0, Study Summary
Section 6.1, Study Design, Main 
Study
Appendix A, Schedule of Study 
Procedures, Main Study (Subjects 
With PD)
7
Sentinel cohort data is needed 
before enrollment of older PD 
subjects can begin; there is no 
restriction on enrollment of PD 
subjects aged ≤65 years. 
Allow initial subjects with PD to 
enroll in main study in parallel to 
when the sentinel cohort is 
running. These subjects must be 
aged ≤65 years. Older subjects 
with PD may be enrolled pending 
the results of the sentinel cohort 
PK.
Section 2.0, Study Summary
Section 6.1, Study Design, Main 
Study
Section 6.3.3, Dose Justification
Section 8.1.3, Dose and Regimen
8
PK results from sentinel cohort 
and later subjects with PD may 
allow older subjects.
Remove age 85 years as upper 
limit.
Section 2.0, Study Summary
Section 6.1, Study Design, Main 
Study
Section 6.3.3, Dose Justification
Section 7.1, Inclusion Criteria (#3)
Section 8.1.3, Dose and Regimen
Section 8.2, Study Drug 
Assignment and Dispensing 
Procedures
9
Consistent with Movement 
Disorders Society clinical 
diagnostic criteria for PD.
Clarify that subjects with DLB are 
permitted.
Section 6.3.1, Subject Selection 
Considerations
7.1, Inclusion Criteria (#4)
10
Increase study feasibility.
Change the criteria for cognitive 
impairment to MOCA score of 17 
(rather than 18) to 24, inclusive.
Section 6.3.1, Subject Selection 
Considerations
Section 7.1, Inclusion Criteria (#7)
11
Does not intend capacity in the 
legal sense.
Clarify ability, rather than 
capacity, to follow instructions.
Section 7.1, Inclusion Criteria (#8)
12
Enable recruitment of some 
subjects with orthostasis who may 
still safely participate in study. 
Modify exclusion on the basis of 
orthostatic hypotension.
Section 7.2, Exclusion Criteria 
(#2)
13
Clarifies that both criteria defining 
dyskinesia severity must be met to 
exclude subject.
Expands investigator opinion to 
interference with more than digital 
gait assessments.
Change 
“scores >2), or in the opinion” to 
“scores >2), and in the opinion”.
Dyskinesia exclusion extended to 
interference with other aspects of 
study.
Section 7.2, Exclusion Criteria 
(#4)


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Study No. TAK-071-2002
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Protocol Incorporating Amendment No. 4
07 September 2021
CONFIDENTIAL
Protocol Amendment 3
Summary of Changes Since Amendment 2
Description of Each Change and Rationale
Sections Affected by Change
No.
Description
Rationale
Location
14
Enable recruitment of subjects 
who may still safely participate in 
study.
Modify exclusion on the basis of 
eGFR, QTcF, and HCV status.
Section 7.2, Exclusion Criteria 
(#10)
15
Other psychiatric disorders of 
sufficient severity could interfere 
with completion of the study or 
interpretation of the endpoints.
Expand exclusion from depression 
to depression or other psychiatric 
disorder.
Section 7.2, Exclusion Criteria 
(#11)
16
Substance use disorders with the 
exception of tobacco use disorder 
are an exclusion, as the later is not 
expected to interfere with the 
study.
Clarify that substance use 
disorders do not include 
tobacco-use disorder for purposes 
of exclusion.
Section 7.2, Exclusion Criteria 
(#12)
17
Subjects with emergency room 
visit due to fall may be safe to 
continue in the study.
Clarify that fall-related 
institutionalization or hospital 
admission does not include 
emergency room visit. 
Section 7.2, Exclusion Criteria 
(#21)
18
Add and clarify timing of 
vaccination.
Clarify that vaccination for 
COVID-19 is allowed provided it 
is not within 48 hours of a study 
visit.
Table 7.a, Excluded and Allowed 
Medications and Treatments
19
Allow subjects to use trazodone 
for insomnia.
Change antidepressant criterion in 
Table 7.a regarding trazodone.
Table 7.a, Excluded and Allowed 
Medications and Treatments
20
Allow if investigator and sponsor 
agree the drug will not interfere 
with the study.
Allow the use of antipsychotic 
drugs (aside from pimavanserin 
and quetiapine, which are already 
permitted) under some 
circumstances.
Table 7.a, Excluded and Allowed 
Medications and Treatments
21
Broaden conditions where 
anticonvulsants are acceptable.
Allow the use of anticonvulsants if 
not used for seizure disorder.
Table 7.a, Excluded and Allowed 
Medications and Treatments
22
Allow use of stable dose for 
insomnia, rapid eye movement 
sleep disorder, and anxiety.
Allow use of benzodiazepines 
under some circumstances.
Table 7.a, Excluded and Allowed 
Medications and Treatments
23
Clarify that nonbenzodiazepine 
hypnotics may be used if dose is 
relatively stable from 30 days 
before randomization to the end of 
the study, rather than requiring 
washout.
Allow the use of 
nonbenzodiazepine hypnotics 
under some circumstances.
Table 7.a, Excluded and Allowed 
Medications and Treatments
24
Clarify relationship of scale to 
independent living criterion.
Provide web reference for Hoehn 
and Yahr scale.
Section 9.1.8.1.3, MDS-UPDRS 
Including Hoehn and Yahr Scale
25
Match updates to schedule of 
assessments.
Update blood volume estimate.
Section 9.1.11, Maximum Blood 
Volumes (Subjects With PD Only)


TAK-071
Study No. TAK-071-2002
Page 105 of 125
Protocol Incorporating Amendment No. 4
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CONFIDENTIAL
Protocol Amendment 3
Summary of Changes Since Amendment 2
Description of Each Change and Rationale
Sections Affected by Change
No.
Description
Rationale
Location
26
Clarifies that these are 2 separate 
tests.
Clarify that samples for 
4β-hydroxycholesterol and
cholesterol will be collected.
Table 9.b, Clinical Laboratory 
Tests
27
Make criteria for female partners 
of male subjects consistent with 
criteria for female subjects.
Clarify that amenorrhea must be at 
least 12 months to determine if a 
female subject is not of 
childbearing potential.
Section 9.1.13.1, Male Subjects 
and Their Female Partners
28
Correct inadvertent omission.
Add tubal ligation to definitions 
and procedures of pregnancy 
avoidance.
Section 9.1.13.3, Definitions and 
Procedures for Contraception and 
Pregnancy Avoidance
29
Results of serum human chorionic 
gonadotropin test may not be 
available before dosing. female 
subjects could be perimenopausal 
and having irregular periods.
Rule out pregnancy with urine 
dipstick the previous or same day 
before receiving any dose of study 
medication. Remove requirement 
to confirm menses in month before 
first dose.
Table 9.b, Clinical Laboratory 
Tests
Section 9.1.13.3, Definitions and 
Procedures for Contraception and 
Pregnancy Avoidance
Appendix A, Schedule of Study 
Procedures, Main Study (Subjects 
With PD): Table A-1, Period 1 and 
Table A -2, Period 2
30
Paper CRFs do not exist for study.
Omit mention of paper CRFs.
Section 12.1, eCRFs
31
Clarified by statistician.
Change Blinded Data Review 
Manual to Internal Review 
Charter.
Section 13.1, Statistical and 
Analytical Plans
32
Clarification.
Delete assumption of 5% type I 
error for exploratory outcomes.
Section 13.1.3 Pharmacodynamic 
Analysis (Subjects With PD)
33
Consistent with contingency 
measures due to coronavirus 
disease 2019.
Clarify that site monitoring visits 
can be onsite or remote.
Section 14.1, Study-Site 
Monitoring Visits
34
Education and handedness 
will/may be used as covariates for 
analyses of pharmacodynamic 
measures.
Collect education and handedness 
at baseline (subjects with PD).
Appendix A, Schedule of Study 
Procedures, Main Study (Subjects 
With PD): Table A-1, Period 1
35
No audio recording will be used at 
screening walk test. 
Clarify walk test at screening.
Appendix A, Schedule of Study
Procedures, Main Study (Subjects 
With PD): Table A-1, Period 1
36
Clarify footnotes.
Correct footnotes in Appendices A 
and C.
Appendix A, Schedule of Study 
Procedures, Main Study (Subjects 
With PD): Table A-1, Period 1 and 
Table A -2, Period 2
Appendix C, Schedule of Samples 
Across Both Periods, Main Study


TAK-071
Study No. TAK-071-2002
Page 106 of 125
Protocol Incorporating Amendment No. 4
07 September 2021
CONFIDENTIAL
Protocol Amendment 3
Summary of Changes Since Amendment 2
Description of Each Change and Rationale
Sections Affected by Change
No.
Description
Rationale
Location
Clarify subject populations.
Throughout clarify that certain 
sections apply to sentinel, main, or 
all.
Global change.
Protocol Amendment 2
The primary reasons for this amendment were to:

Remove Amendment Type from Amendment History table on cover page.

Change maximum subject age to ≤65 years, with the option of increasing age limit later.

Allow up to 25 study sites.

Clarify that subjects who drop out of the sentinel cohort may be replaced, at sponsor’s 
discretion.

Replace modified Hoehn and Yahr scale with original Hoehn and Yahr scale.

Remove description of speech tasks.

Revise table of excluded medications.

Revise estimates of total blood volume.

Correct tests for 4β-hydroxycholesterol, cholesterol, and ratio of 4β-hydroxycholesterol to 
cholesterol to be plasma samples, not serum.

Correct sample collection information for plasma biomarkers.
Protocol Amendment 2
Summary of Changes Since Amendment 1
Description of Each Change and Rationale
Sections Affected by Change
Description
Rationale
Location
Remove Amendment Type from 
Amendment History table on cover 
page
Not applicable to US study.
Cover page.
Change maximum subject age to ≤65 
years, with the option of increasing 
the age limit later if pharmacokinetic 
and safety data permit.
FDA guidance.
Section 2.0, Study Summary: Study 
Design, Number of Sites
Section 6.1, Study Design
Allow up to 25 study sites.
Flexibility to add more sites.
Section 2.0, Study Summary: Study 
Design, Subject Population, Main 
Criteria for Inclusion
Section 6.1, Study Design


TAK-071
Study No. TAK-071-2002
Page 107 of 125
Protocol Incorporating Amendment No. 4
07 September 2021
CONFIDENTIAL
Protocol Amendment 2
Summary of Changes Since Amendment 1
Description of Each Change and Rationale
Sections Affected by Change
Description
Rationale
Location
Clarify that subjects who drop out of 
the sentinel cohort may be replaced, 
at sponsor’s discretion.
Replacement is not necessary in all 
cases.
Section 2.0, Study Summary: Study 
Design
Section 6.1, Study Design
Section 8.2, Study Drug Assignment 
and Dispensing Procedures
Section 13.3, Determination of 
Sample Size
Revise table of excluded medications 
to standardize all washout periods to 
30 days.
Simplify for sites. 
Table 7.a, Excluded and Allowed 
Medications and Treatments
Require antipsychotics pimavanserin 
and quetiapine to be at a steady dose 
30 days before randomization.
Clarified requirements.
Table 7.a, Excluded and Allowed 
Medications and Treatments
Allow gabapentin when it is used for 
neuropathic pain and the dose has 
been stable for at least 30 days before 
randomization.
Allow use of anticonvulsants for 
other indications such as migraine 
headache if the investigator and 
sponsor agree that the drug is 
unlikely to affect the outcome
measures.
Clarify permitted exceptions to 
exclusion of anticonvulsants.
Standardize prior dose requirements 
to 30 days before randomization.
Table 7.a, Excluded and Allowed 
Medications and Treatments
Permit antidepressants (except 
bupropion and nefazodone) if dose is 
kept stable during study and has been 
a stable dose for 30 days before 
randomization.
Standardize prior dose requirements 
to 30 days before randomization.
Table 7.a, Excluded and Allowed 
Medications and Treatments
Remove St John’s Wort from 
allowed herbal products.
Allow herbal remedies, conditional 
on approval from the investigator and 
sponsor.
As a cytochrome P-450 inhibitor, St 
John’s wort is excluded.
Allowed if judged unlikely to affect 
the outcome measures and are 
deemed safe.
Table 7.a, Excluded and Allowed 
Medications and Treatments
Permit use of over-the-counter 
(OTC) medications not otherwise 
listed under certain circumstances.
Investigator and sponsor judge the 
medication will not interfere with the 
study or pose a risk to subjects.
Table 7.a, Excluded and Allowed 
Medications and Treatments
Allow exceptions to melatonin use 
for certain conditions if use has been 
relatively stable for 30 days before 
randomization.
Standardize prior dose requirements 
to 30 days before randomization.
Table 7.a, Excluded and Allowed 
Medications and Treatments


TAK-071
Study No. TAK-071-2002
Page 108 of 125
Protocol Incorporating Amendment No. 4
07 September 2021
CONFIDENTIAL
Protocol Amendment 2
Summary of Changes Since Amendment 1
Description of Each Change and Rationale
Sections Affected by Change
Description
Rationale
Location
Clarify circumstances where use of 
cannabis and derived products is 
allowed; exclude episodic use.
Allows if subjects have been using 
cannabis and cannabis-derived 
products at a relatively stable dose 
and frequency for at least 30 days 
before randomization.
Table 7.a, Excluded and Allowed 
Medications and Treatments
Clarify that subjects taking warfarin 
must wash out and start another 
anticoagulant at least 30 days before 
randomization.
Subject safety.
Table 7.a, Excluded and Allowed 
Medications and Treatments
Clarify that benzodiazepines, when 
excluded, must be stopped at least 30 
days before randomization.
Clarifies washout requirements when 
excluded.
Table 7.a, Excluded and Allowed 
Medications and Treatments
Replace modified Hoehn and Yahr 
scale with original Hoehn and Yahr 
scale.
The standard Hoehn and Yahr was 
selected by the Movement Disorders 
Society to include in the Movement 
Disorders Society–Unified 
Parkinson's Disease Rating Scale 
(MDS-UPDRS). Use of the modified 
Hoehn and Yahr with the 
MDS-UPDRS could cause confusion 
at sites and lead to the wrong version 
being used.
Section 9.1.8.1.3, MDS-UPDRS 
Including Hoehn and Yahr Scale
Remove detailed table of speech 
tasks.
Table included errors. Material will 
be presented in study manual.
Section 9.1.8.1.5, Speech Test
Revise estimates of total blood 
volume.
Site advice.
Section 9.1.11, Procedures for 
Clinical Laboratory Samples
Correct tests for 
4β-hydroxycholesterol, cholesterol, 
and ratio of 4β-hydroxycholesterol to 
cholesterol.
Corrected to be plasma samples, not 
serum.
Table 9.b, Clinical Laboratory Tests
Update references.
Remove references that occurred in 
prior (Amendment 1) Summary of 
changes.
Removed reference to modified 
Hoehn and Yahr scale.
Section 16.0, REFERENCES 
Correct sample collection 
information for plasma biomarkers.
Remove collection at early 
termination visit.
Appendix A, Schedule of Study 
Procedures
Appendix C, Schedule of Samples 
Across Both Periods 
Add appendix of amendment history.
Takeda process requires history of 
prior amendments.
Appendix G, Amendment History


TAK-071
Study No. TAK-071-2002
Page 109 of 125
Protocol Incorporating Amendment No. 4
07 September 2021
CONFIDENTIAL
Protocol Amendment 1:
The primary reasons for this amendment were to:

Describe a sentinel cohort for age effects on PK, in which initial subjects enrolled have rich PK 
sampling. The results of single-dose and steady-state PK analyses from these subjects will be 
used to decide the dose, up to 7.5 mg, for the remaining subjects to be enrolled. Subjects up to 
age 85 could possibly be included in the future, based on these PK analyses.

Moved evaluation of PK from exploratory to secondary objectives.

Add sentinel cohort PK endpoints to the secondary endpoints.

Add evaluation of the ratio of plasma 4-beta-hydroxycholesterol to cholesterol and the
relationship to plasma TAK-071 area under the concentration-time curve (AUC) as an 
exploratory objective, and add the relationship of the ratio of plasma 
4-beta-hydroxycholesterol/cholesterol with plasma TAK-071 AUC as an exploratory 
endpoint.

Clarify inclusion criteria, exclusion criteria, and dose justification.

Clarify requirements in the excluded medications table, add a table of strong and moderate 
cytochrome P-450 (CYP)3A inhibitors and inducers, and exclude consumption of grapefruit 
and grapefruit juice.

Add orthostatic hypotension to vital sign procedures.

Add neurological examination.

Clarify descriptions of modified Hoehn and Yahr scale and cognitive assessments, add 
Cogstate Modified Chase Test, and include Symbol Digit Modalities Test (SDMT) in 
screening procedures.

Clarify that fasting before sample collection is not necessary and remove lactate 
dehydrogenase and glutamate dehydrogenase from serum chemistry tests. Add 
4β-hydroxycholesterol, cholesterol, and their ratio at baseline to the serum chemistry tests.

Modify serum chemistry tests with more conservative criteria regarding renal and hepatic 
function.

Increase stringency of contraceptive requirements for women of childbearing potential.

Add section on sample collection for circulating biomarkers.

Allow rescreening of subjects who fail screening, with sponsor permission.

Update Takeda Medically Significant Adverse Events list.

Provide for blinded safety and PK reviews.

Provide flexibility for subjects and investigators if procedures for data collection need to be 
modified due to the coronavirus disease 2019 (COVID-19) pandemic.


TAK-071
Study No. TAK-071-2002
Page 110 of 125
Protocol Incorporating Amendment No. 4
07 September 2021
CONFIDENTIAL

Reorganize Schedule of Study Procedures. Add an appendix with a schedule for at-home 
speech assessments. Update schedule of samples. Removed appendix on Preferred Gait and 
Cognitive Measurement Procedure Sequence. Renumbered appendices accordingly.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only, 
and are not captured in the following table. 
Protocol Amendment 1
Summary of Changes Since Original Protocol
Description of Each Change and Rationale
Sections Affected by Change
Description
Rationale
Location
Moved evaluation of 
pharmacokinetic (PK) from 
exploratory to secondary objectives.
Emphasize importance of PK in 
establishing dose.
Section 2.0, Study Summary: 
Secondary Objectives
Section 5.1.3, 
Exploratory/Additional Objectives
Section 5.1.2, Secondary Objectives
Add sentinel cohort PK endpoints to 
the secondary endpoints.
Clarify PK endpoints for sentinel 
cohort versus all other subjects.
Section 2.0, Study Summary: Study 
Design
Section 5.2.3, Secondary Endpoints
Describe a sentinel cohort for age 
effects on PK. The results of 
single-dose and steady-state PK 
analyses from these subjects will be 
used to decide the dose, 7.5 mg or 
lower, for the remaining subjects 
to be enrolled.
The results of single-dose and 
steady-state PK analyses from these 
subjects will be used to decide the 
dose, 7.5 mg or lower, for the 
remaining subjects to be enrolled. 
Depending on the sentinel cohort PK 
results, age-specific dosing may be 
used. At a later date, after sufficient 
PK data are available, whether 
subjects up to age 85 years are
expected to remain below the 
exposure caps will be determined. If 
so, subjects up to age ≤85 years may 
be enrolled.
Section 2.0, Study Summary: Study 
Design
Section 6.1, Study Design
Section 6.3.3, Dose Justification
Section 8.1.3, Dose and Regimen
Section 8.2, Study Drug Assignment 
and Dispensing Procedures
Section 9.1.20, PK Parameters
Section 13.1.4, PK Analysis
Appendix A, Schedule of Study 
Procedures
Appendix C, Schedule of Samples 
Across Both Periods
Allow for possible inclusion of 
subjects up to age 85 years at a 
future date, based on PK results in 
sentinel cohort.
To allow a greater age range of 
subjects.
Section 2.0, Study Summary: Study 
Design; Subject Population; Main 
Criteria for Inclusion
Section 6.1, Study Design
Section 6.3.3, Dose Justification
Section 7.1, Inclusion Criteria, 
criterion #3


TAK-071
Study No. TAK-071-2002
Page 111 of 125
Protocol Incorporating Amendment No. 4
07 September 2021
CONFIDENTIAL
Protocol Amendment 1
Summary of Changes Since Original Protocol
Description of Each Change and Rationale
Sections Affected by Change
Description
Rationale
Location
Provide potential modifications to 
account for the COVID-19 
pandemic.
To allow flexibility for subjects and 
investigative sites in data collection.
Section 2.0, Study Summary: Study 
Design
Section 6.2, Contingency Measures 
Due to COVID-19 Pandemic or 
Other Unavoidable Circumstances,
Section 9.1.8, Pharmacodynamic 
Measurements
Section 9.1.23, Alternative 
Approaches to Study Procedures and 
Data Collection Due to COVID-19 or 
Other Unavoidable Circumstances
Section 14.2, Protocol Deviations
Section 16.0, REFERENCES
Add to Study Summary, subjects are 
able to walk without aid for 2 
minutes while doing serial 3 
subtraction.
Makes summary consistent with 
inclusion criteria in Section 7.1, 
criterion #9.
Section 2.0, Study Summary: Main 
Criteria for Inclusion
Inclusion criterion #10, subjects 
stable on antiparkinsonian 
medication for 30 days (rather than 4 
weeks).
Standardize medication exclusions 
from 4 weeks to 30 days.
Section 2.0, Study Summary: Main 
Criteria for Inclusion
Section 7.1, Inclusion Criteria
Exclusion criterion #10, replace 
aspartate aminotransferase (AST) 
and alanine aminotransferase 
(ALT) > 2 × upper limit of normal 
(ULN) with >1.2 × ULN and replace 
serum creatinine >1.5 × ULN with 
estimated glomerular filtration 
rate (eGFR) (calculated using the 
Chronic Kidney Disease 
Epidemiology Collaboration 
[CKD-EPI] equation) <60 mL/min.
These values are more conservative 
than the original cutoff criteria.
Section 2.0, Study Summary: Main 
Criteria for Exclusion
Section 7.2, Exclusion Criteria, 
criterion #10
Add evaluation of the ratio of 
plasma 4-beta-hydroxycholesterol 
to cholesterol and the relationship 
to plasma TAK-071 area under the 
concentration-time curve (AUC) as 
an exploratory objective, and add the 
relationship of the ratio of plasma 
4-beta-hydroxycholesterol/cholester
ol with plasma TAK-071 AUC as an 
exploratory endpoint.
To evaluate the relationship of these 
parameters to TAK-071 exposure.
Section 5.1.3, 
Exploratory/Additional Objectives
Section 5.2.4, Exploratory Endpoints


TAK-071
Study No. TAK-071-2002
Page 112 of 125
Protocol Incorporating Amendment No. 4
07 September 2021
CONFIDENTIAL
Protocol Amendment 1
Summary of Changes Since Original Protocol
Description of Each Change and Rationale
Sections Affected by Change
Description
Rationale
Location
Clarify language about age in dose 
justification.
Change made to ensure subject 
safety.
Section 6.3.3, Dose Justification
Inclusion criterion #12, female 
subjects of childbearing potential 
must use highly effective 
contraception (rather than 
effective).
Highly effective is a more 
conservative requirement.
Section 7.1, Inclusion Criteria, 
criterion #12
Section 9.1.12, Contraception and 
Pregnancy Avoidance Procedure
Exclusion criterion #2, orthostatic 
hypotension definition reduces time 
after standing to 1 minute.
Juraschek et al [1] suggest that the 
1-minute time point is actually more 
predictive of adverse outcomes 
(including falls, which is of concern 
here).
Juraschek et al added to references.
Section 7.2, Exclusion Criteria, 
criterion #2
Section 9.1.6 Vital Sign Procedure
Section 16.0, REFERENCES 
Exclusion criterion #8, add other risk 
factors deemed relevant by the 
investigator to the definition of risk 
factors for seizures.
Clarify risk definition to allow 
investigator judgment.
Section 7.2, Exclusion Criteria, 
criterion #8
Remove use of Geriatric Depression 
Scale (GDS). Replace with exclusion 
criterion #11, in the opinion of the 
investigator the patient suffers 
from depression of sufficient 
severity to interfere with completion 
of the study or interpretation of the 
endpoints.
Investigator advice and literature [2].
Lopez et al added to references.
Yesavage et al deleted from 
references.
Section 7.2, Exclusion Criteria, 
criterion #11
Deletion of GDS (Short Form) from 
former Section 9.1.6.1
Deleted GDS from Appendix A, 
Table A-1, Period 1
Section 16.0, REFERENCES 
Exclusion criterion #12, revise to 
replace history of drug abuse or 
alcohol dependences with substance 
use disorder, and also exclude 
subjects whose current or past use 
of substances may interfere with 
performance on the cognitive, motor, 
or other assessments.
Broadens exclusion to activities that 
might interfere with assessments.
Section 7.2, Exclusion Criteria, 
criterion #12
Exclusion criterion #14, exclude 
subjects who cannot discontinue 
cholinesterase inhibitor and/or 
moderate or strong cytochrome 
P-450 3A4 inhibitor at least 30 days 
before randomization (rather than 
baseline visit).
These drugs will interfere with the 
metabolism of TAK-071 and must be 
excluded to ensure safety of subjects.
Section 7.2, Exclusion Criteria, 
criterion #14
Exclusion criterion #16, change 
washout period for prior 
investigational compounds from 90 
days to investigator judgement.
Allows exclusion of entities that may 
not have washed out in 90 days, such 
as monoclonal antibodies.
Section 7.2, Exclusion Criteria, 
criterion #16


TAK-071
Study No. TAK-071-2002
Page 113 of 125
Protocol Incorporating Amendment No. 4
07 September 2021
CONFIDENTIAL
Protocol Amendment 1
Summary of Changes Since Original Protocol
Description of Each Change and Rationale
Sections Affected by Change
Description
Rationale
Location
Allow benzodiazepines for subjects 
with REM sleep disorder.
Benzodiazepines are sometimes used 
by PD patients for this indication and 
may need to continue to take these 
medications during the study.
Table 7.a, Excluded and Allowed 
Medications and Treatments 
Allow melatonin for subjects with 
rapid eye movement (REM) behavior 
disorder and/or insomnia.
Melatonin has efficacy for REM 
behavior disorder and insomnia and 
is often used by Parkinson disease 
patients for these reasons.
Table 7.a, Excluded and Allowed 
Medications and Treatments
Allow the antipsychotics 
pimavanserin (at a dose of ≤34 mg 
once daily and quetiapine (at a dose 
of ≤250 mg total daily dose).
Allowed for subjects who in the 
opinion of the investigator medically 
require treatment with an 
antipsychotic drug to safely complete 
the study.
Table 7.a, Excluded and Allowed 
Medications and Treatments
Change sedatives/hypnotics to 2 
categories, barbiturates and 
nonbenzodiazepine hypnotics.
Provide more refined guidelines on 
allowed drug classes to improve 
clarity.
Table 7.a, Excluded and Allowed 
Medications and Treatments
Clarify anticholinergic exclusion to 
state that for overactive bladder, 
subjects may be treated with 
mirabegron, which works by a 
different mechanism.
Although most drugs for overactive 
bladder have anticholinergic 
mechanisms of action and are 
excluded, mirabegron does not and is 
permitted for this indication.
Table 7.a, Excluded and Allowed 
Medications and Treatments
Clarify which antidepressants are 
allowed and excluded.
Bupropion is excluded in all cases. 
Nefazodone is excluded as a strong 
CYP3A4 inhibitor under all 
circumstances and must be stopped at 
least 30 days before randomization. 
Chronic use of other antidepressants 
is permitted as long as the dose is 
kept stable during the study and the 
dose has been stable for at least 8 
weeks before randomization.
Table 7.a, Excluded and Allowed 
Medications and Treatments
Exclude consumption of grapefruit 
and grapefruit juice.
Grapefruit is a CYP3A4 inhibitor.
Table 7.a, Excluded and Allowed 
Medications and Treatments
Section 7.4, Diet, Fluid, and Activity 
Control
Make over-the-counter (OTC) 
drugs a separate category and clarify 
when they are allowed and excluded.
Rationale is to provide more refined 
guidelines on allowed drug classes. 
OTC drugs will be allowed if the 
investigator agrees on a case by case 
basis.
Table 7.a, Excluded and Allowed 
Medications and Treatments


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Protocol Amendment 1
Summary of Changes Since Original Protocol
Description of Each Change and Rationale
Sections Affected by Change
Description
Rationale
Location
Various drug categories: stable dose 
or washout requirements of 4 weeks 
modified to 30 days; washout criteria 
before screening changed to before 
randomization.
Criteria changed to be as uniform as 
possible across drug classes to 
minimize errors.
Table 7.a, Excluded and Allowed 
Medications and Treatments
Add table of strong and moderate 
CYP3A inducers and inhibitors.
Identifies these classes of drugs, 
which must be excluded in all 
circumstances and stopped at least 30 
days before randomization.
Table 7.b, Strong and Moderate 
CYP3A Inducers and Inhibitors
Add neurological examination with 
physical examination.
A focused neurological examination 
is needed to evaluate for potential 
exclusions and to ensure subject 
safety.
Section 9.1.3, Physical Examination 
Procedure
Section 9.1.4, Neurological 
Examination Procedure
Appendix A, Schedule of Study 
Procedures
Add orthostatic blood pressure to 
vital sign procedures.
Make consistent with exclusion 
criteria.
Section 9.1.6, Vital Sign Procedure
Clarify that Timed Up and Go test
at screening is only done once.
Distinguish screening from other 
visits.
Section 9.1.8.1, Pharmacodynamic 
Measurements Related to Gait
Appendix A, Schedule of Study 
Procedures
Clarify description of modified 
Hoehn and Yahr scale.
Describe scores of modified scale.
Add Bayés and Counihan [16] to 
reference list.
Section 9.1.8.1.3, MDS-UPDRS 
Including Hoehn and Yahr Scale
Section 16.0, REFERENCES
Define the stages of the modified 
Hoehn and Yahr Scale.
Clarify categories.
Section 9.1.8.1.3, MDS-UPDRS 
Including Hoehn and Yahr Scale 
Add description of Cogstate 
Modified Chase Test; add to 
schedule of procedures.
Test added to screening visit for 
practice.
Section 9.1.8.2, Pharmacodynamic 
Measurements Related to Cognition
Appendix A, Schedule of Study 
Procedures
Clarify description of Cogstate 
International Shopping List Test.
Add delayed recall condition.
Section 9.1.8.2, Pharmacodynamic 
Measurements Related to Cognition
Clarify description of Symbol Digit 
Modalities Test; add to schedule of 
procedures.
First 10 of 120 symbols in sequence 
are practice items.
Section 9.1.8.2, Pharmacodynamic 
Measurements Related to Cognition
Appendix A, Schedule of Study 
Procedures
Clarify description of Patient Global 
Impression (PGI) scales.
PGI-Improvement is rated on 7-point 
scale and PGI-Severity is rated on 
6-point scale.
Section 9.1.8.3.1 Global Impression 
Scales
Add that fasting before sample 
collection is not necessary.
Fasting not necessary.
Section 9.1.11, Procedures for 
Clinical Laboratory Samples


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Protocol Amendment 1
Summary of Changes Since Original Protocol
Description of Each Change and Rationale
Sections Affected by Change
Description
Rationale
Location
Revise estimate of maximum blood 
volumes to include separate estimate 
for subjects in sentinel cohort.
Sentinel cohort will have more PK 
samples taken.
Section 9.1.11, Procedures for 
Clinical Laboratory Samples
Add plasma 
4β-hydroxycholesterol, cholesterol, 
and their ratio to the laboratory tests 
at baseline
These tests may be used in the future 
if they prove useful in predicting 
TAK-071 PK.
Table 9.c, Clinical Laboratory Tests
Remove lactate dehydrogenase and 
glutamate dehydrogenase from 
serum chemistry tests.
Tests not necessary.
Table 9.c, Clinical Laboratory Tests
Replace serum creatinine clearance 
test with eGFR. 
More conservative indicator of renal 
function.
Table 9.c, Clinical Laboratory Tests
Add abstinence as acceptable 
contraception.
True abstinence (defined in section) 
is highly effective contraception.
Section 9.1.12.3, Definitions and 
Procedures for Contraception and 
Pregnancy Avoidance
Add section on sample collection for 
circulating biomarkers.
Distinguishes this sample from the 
optional sample for DNA.
Section 9.1.17, Plasma Sample for 
Circulating Biomarkers
Allow rescreening of subjects who 
have failed original screening, with 
sponsor permission.
Allows subjects who may have been 
mildly ill at original screening to be 
enrolled later.
Section 9.1.21, Documentation of 
Screen Failure
Section 9.3.1, Screening 
Update Takeda Medically 
Significant AE List.
Company-wide list has been updated 
to include COVID-19 and other 
conditions.
Table 10.a, Takeda Medically 
Significant AE List
Add blinded safety analysis to 
evaluation of sentinel cohort.
Change made to ensure subject 
safety.
Section 13.1, Statistical and 
Analytical Plans
Clarify that no formal interim 
analysis is planned and that blinded 
safety and available PK review of 
the sentinel cohort will be described 
in a manual.
Clarify intentions for review of data.
Section 13.2, Interim Analysis, 
Sentinel Analysis, and Criteria for 
Early Termination
Reorganize Appendix A to separate 
treatment Periods 1 and 2, add visits 
specific to sentinel cohort.
Clarify visits and procedures.
Appendix A, Schedule of Study 
Procedures
Correct window for Day 21, Day 84 
procedures from ±4 to ±2 days.
Make window consistent with other 
visits.
Appendix A, Schedule of Study 
Procedures
Add a new Appendix B for timing 
of at-home speech assessments; 
reordered appendices overall.
Clarify procedures.
Appendix B, Schedule of At-Home 
Speech Tests
Add separate row in Appendix C for 
plasma PK samples for the sentinel 
cohort.
The sentinel cohort will have rich PK 
sampling in Period 1
Appendix C, Schedule of Samples 
Across Both Periods


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Protocol Amendment 1
Summary of Changes Since Original Protocol
Description of Each Change and Rationale
Sections Affected by Change
Description
Rationale
Location
Remove Appendix D, Preferred Gait 
and Cognitive Measurement 
Procedure Sequence.
This material will be provided in a 
study manual.
Appendices.


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Appendix H
Sentinel Cohort (Healthy Subjects) Only
H.1
Objectives and Endpoints for Healthy Subjects
H.1.1 Objectives
H.1.1.1 Primary Objective
The primary objective for healthy subjects is to evaluate the PK of TAK-071 in healthy subjects
older than 55 years.
H.1.1.2 Secondary Objective
The secondary objective for healthy subjects is to evaluate the safety and tolerability of TAK-071
in healthy subjects older than 55 years.
H.1.2 Endpoints
H.1.2.1 Primary Endpoints
The primary endpoints for healthy subjects are the following PK parameters for TAK-071:

Cmax.

tmax.

AUC24.

Area under the concentration-time curve from time 0 to the last quantifiable concentration 
(AUClast).

AUCinf.
H.1.2.2 Safety Endpoints
The safety endpoints for healthy subjects are:

AEs.

Clinical laboratory evaluations.

ECG.

Physical examinations.

Suicidal ideation and behavior as measured by the C-SSRS.
H.2 STUDY DESIGN FOR SENTINEL COHORT (HEALTHY SUBJECTS)
An initial sentinel cohort of healthy subjects will be enrolled at designated site(s), in parallel with 
enrollment of PD patients in the main cohort. Approximately 10 healthy subjects of either sex, 
aged 56 to 75 years, inclusive, will be randomized 3:1 to TAK-071 versus placebo. After analysis 
of data from these subjects, additional subjects may be enrolled, potentially including subjects 
over age 75. Enrollment of the sentinel cohort will conclude when sufficient data are available to 


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characterize the PK in older subjects, as determined by the sponsor. Enrollment of the sentinel 
cohort will conclude when sufficient data are available to characterize the PK in older subjects, as 
determined by the sponsor.
Healthy subjects will be selected on the basis of safety considerations. Of particular importance is
exclusion on the basis of seizure risk factors, medical disease, and hepatic or renal impairment that 
may influence the PK of TAK-071.
Assessments for healthy subjects will be limited to safety, tolerability, rich PK sampling, and 
samples for DNA (optional) and biomarkers.
After the PK, safety, and physiologically based PK modeling data from the sentinel cohort have 
been assessed, a decision will be made about the dose for the remaining subjects with PD to be 
enrolled. If older subjects are expected to remain below the exposure caps, they will also be 
enrolled. The maximum subject age and dose may be modified after analysis of data from the 
sentinel cohort.
Figure H-2 shows a schematic of the sentinel cohort (healthy subjects).
Figure H-2
Schematic of Study Design for Subjects in the Sentinel Cohort (Healthy 
Subjects)
H.3 ENTRY CRITERIA
H.3.1 Inclusion Criteria for Healthy Subjects
All entry criteria, including test results, need to be confirmed before randomization.
13. The subject signs an informed consent form indicating that the subject has been informed of 
the procedures to be followed, the experimental nature of the therapy, alternatives, potential 
benefits, side effects, risks, and discomforts.
Rand
PBO
TAK-071
Follow -up
Screening
Single dose PK
and safety evaluation
≤6 weeks
168 hours
14 ± 2 days


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14. The subject is a healthy individual of either sex aged between 56 and 75 years, inclusive (for 
initial set of subjects in the sentinel cohort) at the time of consent. Older subjects may be 
enrolled after analysis of data from subjects aged 56 to 75 years, inclusive.
15. The subject has the ability to follow study instructions according to the investigator’s 
judgement.
16. A male subject who is nonsterilized and sexually active with a female partner of childbearing 
potential is eligible to participate if he agrees to use barrier method of contraception (ie, 
condom with or without spermicide) from signing of informed consent throughout the duration 
of the study and for 102 days after the last dose.
17. Female subjects are eligible to participate if a) not pregnant or nursing, and b) of 
nonchildbearing potential or agree to use highly effective contraception from signing of 
informed consent throughout the duration of the study and for 42 days after last dose of study 
drug.
H.3.2 Exclusion Criteria for Healthy Subjects
Any subject who meets any of the following criteria will not qualify for entry into the study.
22. The subject has BMI less than 18 or greater than 40.
23. The subject has other medical problems (neurological, visual, orthopedic, psychiatric) that in 
the opinion of the investigator may significantly interfere with completion of the study or 
interpretation of study endpoints.
24. The subject has significant risk factors for seizures (a history of seizures as an adult, a history 
of brain injury, or other risk factors deemed relevant by the investigator).
25. The subject has significant medical disease (renal, cardiac, endocrine, pulmonary, etc) based 
on medical history, physical examination, ECG, or laboratory evaluations, and/or in the 
opinion of the investigator the subject is otherwise unlikely to be medically able to participate 
in the study due to any reason including having a disorder that may interfere with drug 
absorption, distribution, metabolism, or excretion.
26. The subject has any of the following at the screening visit: estimated eGFR (CKD-EPI) 
<60 mL/min; QTcF >450 msec for male subjects and >470 msec for female subjects; a serum 
total bilirubin value >1.2 × ULN; a serum ALT or AST value >1.2 × ULN. Subjects with a 
positive hepatitis B surface antigen test result or known or suspected active hepatitis C 
infection are also excluded. Note: Subjects with positive HCV serology may be enrolled if 
quantitative polymerase chain reaction for HCV RNA is negative, to exclude active hepatitis C 
infection, and the investigator agrees that the subject can safely participate in the study. 
Subjects with eGFR <60 mL/min may be eligible if the investigator and the sponsor agree that 
the subject may safely participate in the study.


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27. In the opinion of the investigator the patient suffers from depression or other psychiatric 
disorder of sufficient severity to interfere with completion of the study or interpretation of the 
endpoints.
28. The subject has suffered from a substance use disorder (other than tobacco-use disorder) 
within the past 1 year before the first dose of study medication, or in the opinion of the 
investigator the subject’s current or past use of substances may interfere with completion of the 
study.
29. The subject is considered by the investigator to be at imminent risk of suicide or injury to self, 
others, or property, or the subject has attempted suicide within the past year before screening. 
Subjects who have positive answers on item number 4 or 5 on the C-SSRS (based on the past 
year) before randomization are excluded.
30. The subject is unwilling or unable to discontinue taking cholinesterase inhibitors and/or 
moderate or strong CYP 3A4 inhibitors or inducers at least 30 days before randomization.
31. The subject is taking warfarin.
32. The subject has received any investigational compound that, in the opinion of the investigator 
or sponsor, may not have completely washed out before the screening visit.
33. The subject has received TAK-071 in the past.
34. The subject is an immediate family member, study site employee, or in a dependent 
relationship with a study site employee who is involved in the conduct of this study (eg, spouse, 
parent, child, sibling).
35. The subject has donated 400 mL or more of his or her blood volume within 90 days before the 
start of the screening visit.
36. The subject has a known hypersensitivity to any component of the formulation of TAK-071.
H.4
Study Drug
Dose and regimen. Healthy subjects who meet randomization criteria on Day 1 will be randomized 
to a single dose of ≤7.5 mg TAK-071 or placebo.
Study Drug Assignment and Dispensing Procedures. The randomization will be to sequences in 
blocks of 3. Subjects will be assigned to receive their treatment according to the schedule allocated 
to each study site. Healthy subjects will be randomized 3:1 to a single dose of ≤7.5 mg QD 
TAK-071 or placebo, respectively (see Section 8.2).
H.5
PK Parameters.
In the sentinel cohort, single-dose tmax, Cmax, AUCinf, and area under the concentration-time curve 
from time 0 to 24 hours (AUC24) will be determined. Actual sampling times, rather than scheduled 
sampling times, will be used in all data presentations.


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H.6
Study Procedures
The schedule of study procedures for the sentinel cohort is shown in Table H-6.


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Table H-6
Schedule of Study Procedures, Sentinel Cohort (Healthy Subjects)
Screening
Baseline
Last Day of 
Treatment 
Period or 
Early 
Termination
Follow-up 
Safety Phone 
Call
Study Visit Number
1
2
2+24 hr
2+48 hr
2+72 hr
2+96 hr
2+168 hr
(Study Day)
(Day -42 up to 
Day -1)
(Day 1)
(Day2) 
(Day 3)
(Day 4)
(Day 5)
(Day 8)
(Day 22±2)
Confinement a
X
X
X
X
X
X
X
Informed consent
X
Inclusion/exclusion 
criteria
X
Xb
Demographics
X
Medical history
X
Medication history
X
Concomitant medications
X
Xb
X
X
Vital signs, weight, and 
BMI
X
Xb
X
X
X
X
X
Height
X
PTE/AE assessment
X
Xb
X
X
X
X
X
X
12-lead ECG
X
X
X
Physical examination 
without nervous system
X
Physical examination with 
nervous system
X
Xc
C-SSRS
X
Xc
X
Randomization
X
Administer study drug
X


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Table H-6
Schedule of Study Procedures, Sentinel Cohort (Healthy Subjects)
Screening
Baseline
Last Day of 
Treatment 
Period or 
Early 
Termination
Follow-up 
Safety Phone 
Call
Study Visit Number
1
2
2+24 hr
2+48 hr
2+72 hr
2+96 hr
2+168 hr
(Study Day)
(Day -42 up to 
Day -1)
(Day 1)
(Day2) 
(Day 3)
(Day 4)
(Day 5)
(Day 8)
(Day 22±2)
Clinical laboratory 
evaluations, including 
4β-hydroxycholesterol and 
cholesterol d
X
Xc
X
Urine drug and alcohol 
screen
X
Xc
X
Serum pregnancy test 
(hCG) e
X
Xc
X
HBsAg and anti-HCV
X
Plasma samples for 
TAK-071 PK d,f
X
X
X
X
X
X
AE: adverse event; anti-HCV: antibody to hepatitis C virus; BMI: body mass index; C-SSRS: Columbia Suicide Severity Rating Scale; ECG: electrocardiogram; HBsAg: hepatitis B 
surface antigen; hCG: human chorionic gonadotropin; PK: pharmacokinetic; PTE: pretreatment event.
a Confinement to the study site after screening is optional. Confinement from 0 to 48 hr is required. Confinement, or lodging outside the unit, is optional after 48 hr.
b If subject is confined on Day -1, test should be performed on Day -1 as well as Day 1. Weight and BMI do not need to be repeated.
c If subject is confined on Day -1, test may be performed on Day -1 instead of Day 1.
d See Table H.8 for timing of samples.
e Pregnancy test is administered when applicable based on subject sex. For Visit 2 (Day 1), a dipstick urine pregnancy test may be used instead of serum pregnancy test.
f Additional samples can be collected as needed.


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H.6.1 Screening
H.6.2 Baseline/Randomization
Procedures to be completed at baseline are listed in Table H-6.
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized. The randomization system for healthy subjects
will be described in a study manual. The procedure for documenting randomization failures is 
provided in Section 9.1.23.
H.6.3 Treatment Period
Subjects will be administered a single oral dose of TAK-071 under observation in the clinic. PK 
sampling and other procedures will be performed over the subsequent 48 hours according to Table 
H-6. and Table H-8.
H.6.4 Final Visit or Early Termination
The final visit will occur on Day 8 (or early termination).
Procedures to be completed at this visit are listed in Table H-6.
For all subjects receiving study drug, the investigator must complete the End of Study eCRF page.
H.6.5 Follow-up
The follow-up phone call occurs 14 days after the final visit or early termination.
H.6.6 Poststudy Care
Study drug will not be available on 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.
H.7
Cholesterol Determination
A plasma sample will be taken and may be analyzed to determine the levels of 
4β-hydroxycholesterol and cholesterol, and to calculate their ratio.
H.8
Sampling and Blood Volumes
For the sentinel cohort, the maximum volume of blood at any single visit is approximately 41 mL 
and the maximum total volume of blood for the study is approximately 72 mL.
The schedule of samples in the sentinel cohort is shown in Table H-8.


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Table H-8
Schedule of Samples, Sentinel Cohort (Healthy Subjects)
Screening
Baseline
Last Day of 
Treatment 
Period or 
Early 
Termination
Study Visit Number
1
2
2+24 hr
2+48 hr
2+72 hr
2+96 hr
2+168 hr
(Study Day)
(Day -42 up to 
Day -1)
(Day 1)
(Day2)
(Day 3)
(Day 4)
(Day 5)
(Day 8)
Clinical laboratory samples
X
X
X
Plasma sample for 
TAK-071 PK a
Predose; 0.5, 1, 
2, 3, 4, 6, 8, 10, 
12, and 14 
hours following 
the dose 
24 hours after 
dose
48 hours after 
dose
72 hours after 
dose
96 hours after 
dose
168 hours after 
dose
PK: pharmacokinetics.
a Additional samples can be collected as needed.
X denotes a single sample at any time during the visit.
H.9
Statistics
The sample size for an initial sentinel cohort will be approximately 10 subjects initially (with potential replacement of dropouts at 
sponsor’s discretion) at designated sites. Additional (including, potentially older) subjects may be enrolled after analysis of the resulting 
data from subjects aged 56 to 75 years, inclusive. This sample is not based on statistical power considerations and considered to be 
sufficient for evaluation of safety, tolerability, and PK modeling to define a safe dose for people 65 years and older.


 
  
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d681190250
TAK-071-2002 Protocol Amendment 4 07-09-2021
Clinical Pharmacology Approval
14-Sep-2021 15:36 UTC
Clinical Approval
14-Sep-2021 16:09 UTC
Biostatistics Approval
14-Sep-2021 21:01 UTC
Clinical Approval
15-Sep-2021 12:52 UTC

SAP_001.pdf: 
NCT Number: NCT04334317
Title: A Randomized, Double-blind, Placebo-Controlled, 2-Period Crossover, 
Phase 2 Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of Oral TAK-071 in Parkinson Disease Patients with Cognitive 
Impairment and an Elevated Risk of Falls
Study Number: TAK-071-2002
Document Version and Date: Final, 03 March 2023
Certain information within this document has been redacted (ie, specific content is masked 
irreversibly from view) to protect either personally identifiable information or company 
confidential information. 
Statistical Analysis Plan


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-071-2002
A Randomized, Double-blind, Placebo-Controlled, 2-Period Crossover, Phase 2 Study to 
Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of 
Oral TAK-071 in Parkinson Disease Patients with Cognitive Impairment and an Elevated
Risk of Falls
TAK-071 for Falls and Cognition in Parkinson Disease
PHASE 2
Version: Final
Date: 3 March 2023
Prepared by:
, Ph.D. 
, Statistics, TAKEDA
Based on:
Protocol Version: Amendment 04
Protocol Date: 7 September 2021
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda.


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CONFIDENTIAL
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
2.0
TABLE OF CONTENTS.................................................................................................2
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................6
4.1
Sentinel Cohort (Healthy subjects).............................................................................6
4.1.1
Primary Objectives ............................................................................................6
4.1.2
Secondary Objectives ........................................................................................6
4.2
Main Cohort (Parkinson’s Disease (PD) patients) ......................................................6
4.2.1
Primary Objectives ............................................................................................6
4.2.2
Secondary Objectives ........................................................................................6
4.2.3
Additional/Exploratory Objectives.....................................................................6
4.3
Study Design .............................................................................................................7
4.3.1
Sentinel Cohort (Healthy Subjects) ....................................................................7
4.3.2
Main Cohort (PD Subjects)................................................................................8
5.0
ANALYSIS ENDPOINTS...............................................................................................9
5.1
Sentinel Cohort..........................................................................................................9
5.1.1
Primary Endpoints .............................................................................................9
5.1.2
Secondary Endpoints .........................................................................................9
5.2
Main Cohort ............................................................................................................10
5.2.1
Primary Endpoints ...........................................................................................10
5.2.2
Secondary Endpoints .......................................................................................10
5.2.3
Exploratory Endpoints .....................................................................................10
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................11
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................12
7.1
General Principles....................................................................................................12
7.2
Definition of Study Days and Study Visit Windows.................................................12
7.2.1
Conventions for Missing Adverse Event Dates ................................................14
7.2.2
Conventions for Missing Concomitant Medication Dates.................................15
7.2.3
Conventions for Missing PK Data....................................................................16
7.2.4
Conventions for Missing Efficacy Data............................................................16
7.3
Analysis Sets ...........................................................................................................16
7.4
Disposition of Subjects ............................................................................................17
7.5
Demographic and Other Baseline Characteristics.....................................................17
7.6
Medical History and Concurrent Medical Conditions...............................................18


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7.7
Prior and Concomitant Medications .........................................................................18
7.8
Study Drug Exposure and Compliance.....................................................................18
7.9
Efficacy Analysis (Main cohort) ..............................................................................19
7.9.1
Primary objective: Stride Time Variability Analysis ........................................19
7.9.2
Cognition Analysis ..........................................................................................20
7.9.3
Fall Data Analysis ...........................................................................................21
7.9.4
MDS-UPDRS and Other Gait Parameters Analysis..........................................22
7.10
Epworth Sleepiness Scale (ESS) Total Score Analysis .............................................23
7.11
PGI and CGI Analysis .............................................................................................23
7.12
Exploratory Pharmacodynamic Analysis..................................................................24
7.13
Pharmacokinetic Analysis........................................................................................24
7.13.1
Plasma Concentration ......................................................................................24
7.13.2
Plasma Pharmacokinetic Parameters................................................................25
7.14
Safety Analysis........................................................................................................26
7.14.1
Adverse Events................................................................................................26
7.14.2
Clinical Laboratory Evaluations.......................................................................27
7.14.3
Vital Signs.......................................................................................................28
7.14.4
12-Lead ECGs.................................................................................................28
7.14.5
Other Observations ..........................................................................................29
7.15
PK/Pharmacodynamic and PK/Safety Analysis........................................................29
7.16
Unblinded Data Reviews and Interim Analysis ........................................................29
7.16.1
Unblinded Data Reviews .................................................................................29
7.16.2
Interim Analysis ..............................................................................................29
7.17
Changes from the Analysis Specified in the Protocol ...............................................29
8.0
REFERENCES..............................................................................................................30
LIST OF IN-TEXT TABLES
Table 7.a
Visit (Days/Hours) for Scheduled Visits/Samples of Healthy Subjects from 
Sentinel Cohort ..................................................................................................13
Table 7.b
Visit Windows (Days) for Scheduled Visits of PD Subjects During the 
Treatment Period 1.............................................................................................13
Table 7.c
Visit Windows (Days) for Scheduled Visits of PD Subjects During the 
Treatment Period 2.............................................................................................14
Table 7.d
Plasma PK Parameters Definition.......................................................................26


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LIST OF IN-TEXT FIGURES
Figure 4.a
Schematic of Study Design for Subjects in the Sentinel Cohort (Healthy 
Subjects)..............................................................................................................8
Figure 4.b
Schematic of Study Design (Main Cohort)...........................................................9
LIST OF APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values .................31
Appendix B
Criteria for Markedly Abnormal Values for Vital Signs......................................32
Appendix C
Criteria for Markedly Abnormal Values for Electrocardiograms.........................33


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3.0
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AUC 
area under the concentration-time curve
AUC24
area under the concentration-time curve from time 0 to 24 hours
AUCinf
area under the concentration-time curve from time 0 to infinity
AUClast
area under the concentration-time curve from time 0 to time of the last quantifiable concentration
AUCτ
area under the concentration-time curve during a dosing interval
BMI
body mass index
BP
blood pressure
CGI-I
Clinician Global Impression of Improvement
CGI-S
Clinician Global Impression of Severity
CI
confidence interval
Cmax
maximum observed plasma concentration
COVID-19
coronavirus disease 2019
CRF
case report form
C-SSRS
Columbia - Suicide Severity Rating Scale
Ctrough
trough plasma concentration at steady state (observed concentration at the end of a dosing interval)
CYP
cytochrome P-450
DAMP
Data Access Management Plan
DBP
Diastolic blood pressure
ECG
Electrocardiogram
eCRF
Electronic case report form
ESS
Epworth Sleepiness Scale
FDA
Food and Drug Administration
HR
Heart rate
IA
interim analysis
LLN
lower limit of normal
LLOQ
lower limit of quantification
MAV
markedly abnormal value
MedDRA
Medical Dictionary for Regulatory Activities
PD
Parkinson’s Disease
PGI-I
Patient Global Impression of Improvement
PGI-S
Patient Global Impression of Severity
PK
pharmacokinetic(s)
SBP
Systolic blood pressure
TEAE
treatment-emergent adverse event
t1/2 z
terminal disposition phase half-life
tmax
time to reach Cmax
ULN
upper limit of normal


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4.0
OBJECTIVES
4.1
Sentinel Cohort (Healthy subjects)
4.1.1
Primary Objectives
The primary objective for healthy subjects is to evaluate the pharmacokinetics (PK) of TAK-071 
in healthy subjects older than 55 years. 
4.1.2
Secondary Objectives
The secondary objective for healthy subjects is to evaluate the safety and tolerability of TAK-
071 in healthy subjects older than 55 years.
4.2
Main Cohort (Parkinson’s Disease (PD) patients)
4.2.1
Primary Objectives
The primary objectives are:

To evaluate the efficacy of TAK-071 versus placebo on gait dysfunction, as measured by 
stride time variability during a 2-minute walk test, with and without cognitive loading.

To evaluate the safety and tolerability of TAK-071 in subjects with PD.
4.2.2
Secondary Objectives
The secondary objectives are:

To evaluate the efficacy of TAK-071 versus placebo on cognition globally, as determined by 
a global cognition score including attention, executive functioning, and memory.

To evaluate the PK of TAK-071 in subjects with PD.
4.2.3
Additional/Exploratory Objectives
The exploratory/additional objectives are:

To evaluate the efficacy of TAK-071 versus placebo on 
–
specific cognitive test scores that measure domains including attention, executive 
functioning, and memory;
–
fall frequency as assessed using a caregiver–reported falls diary;
–
functional mobility, as measured by time to complete the Timed Up and Go test (TUG);
–
parameters measuring postural sway with eyes open or closed;
–
gait parameters during a 2-minute, 10m walk test in the presence and absence of 
cognitive loading


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–
gait parameters during a cued 180-degree turns test;
–
speech production measured via in-clinic and at-home;
–
step-count as measured by a wearable pendant sensor in the home;
–
fall frequency as assessed using a wearable pendant sensor in the home;
–
subjective daytime sleepiness as assessed by the Epworth Sleepiness Scale (ESS);
–
global improvement, as measured by the Clinical Global Impression-Improvement 
(CGI-I), Clinical Global Impression-Severity (CGI-S), Patient Global Impression-
Improvement (PGI-I), and Patient Global Impression-Severity (PGI-S);
–
motor functioning, as measured by MDS-UPDRS Part 3 and on other aspects of PD by 
MDS-UPDRS Parts 1, 2, and 4.

To evaluate the relationship between specific blood-based biomarkers including neuronally 
derived exosomal M1 receptor and synaptic marker messenger ribonucleic acid (mRNA) 
expression with clinical scales of cognition, gait, balance, and MDS-UPDRS subscales as 
well as treatment response.

To evaluate genomic predictors of treatment response and adverse effects to TAK-071.

To evaluate the ratio of plasma 4-beta-hydroxycholesterol to cholesterol and the relationship 
to plasma TAK-071 area under the concentration-time curve (AUC).
4.3
Study Design
4.3.1
Sentinel Cohort (Healthy Subjects)
An initial sentinel cohort of up to approximately 10 healthy subjects of either sex, aged 56 to 75 
years, inclusive, will be enrolled at designated site(s), in parallel with enrollment of PD patients 
in the main cohort. Healthy subjects will be randomized 3:1 to TAK-071 versus placebo. After 
analysis of data from these subjects, additional subjects may be enrolled, potentially including 
subjects over age 75. Enrollment of the sentinel cohort will conclude when sufficient data are 
available to characterize the PK in older subjects, as determined by the sponsor.
Healthy subjects will be selected on the basis of safety considerations. Of particular importance 
is exclusion on the basis of seizure risk factors, medical disease, and hepatic or renal impairment 
that may influence the PK of TAK-071. 
Assessments for healthy subjects will be limited to safety, tolerability, rich PK sampling, and 
samples for DNA (optional) and biomarkers. 
After the PK, safety, and physiologically based PK modeling data from the sentinel cohort have 
been assessed, a decision will be made about the dose for the remaining subjects with PD to be 
enrolled. If older subjects are expected to remain below the exposure caps, they will also be 
enrolled. The maximum subject age and dose may be modified after analysis of data from the 
sentinel cohort (≤7.5 or ≤5 mg QD, potentially depending on age). Figure 4.a shows a schematic 
of the sentinel cohort (healthy subjects).


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Figure 4.a
Schematic of Study Design for Subjects in the Sentinel Cohort (Healthy 
Subjects)
4.3.2
Main Cohort (PD Subjects)
This is a phase 2, randomized, double-blind, placebo-controlled, 2-period, 2-treatment crossover 
study to evaluate the efficacy, safety, tolerability, PK, and pharmacodynamics of TAK-071 when 
administered orally QD in subjects with PD and evidence of cognitive impairment who are at
risk for falls.
Approximately 64 male and female subjects, aged 40 to ≤65 years (with potential to expand to 
older subjects after analysis of data from the sentinel cohort), inclusive, will be enrolled at up to 
25 sites in the United States.
The study will consist of a ≤6-week screening period, two 6-week double-blind treatment periods 
separated by a ≥3-week washout period, at-home assessments during the third week of each 
6-week treatment period, and a safety follow-up call approximately 14 days after the last dose of 
study drug.
At the screening visit (Visit 1), subjects who provide informed consent will proceed with 
screening procedures. Subjects who meet a current diagnosis of PD, as defined by Movement 
Disorders Society (MDS) clinical diagnostic criteria for PD, will then be given additional 
assessments as specified in the schedule of study procedures (Appendix A of the study protocol).
On Day 1, subjects who continue to meet inclusion and none of the exclusion criteria will be 
randomized 1:1 to treatment with TAK-071 or placebo.
Subjects will receive TAK-071 or placebo QD from Day 1 through Day 42 of each period. Clinic 
visits include Day 1 and Weeks 6, 9, and 15. Clinical assessments, blood collections, and 
laboratory tests will be conducted at specific time points per the schedule of study procedures 
(Appendix A).
A safety follow-up call will be conducted on Day 21, Day 84, and 14 days after completion of 
the last period.
The end of the study will be the date of the last visit of the last subject for safety follow-up, 
i.e., the safety follow-up call.
Rand
PBO
TAK-071
Follow-up
Screening
Single dose PK
and safety evaluation
≤6 weeks
48 hours
10 ± 4 days


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A schematic of the study design is included as Figure 4.b. A detailed schedule of study 
procedures is provided in Appendix A of the study protocol.
Figure 4.b
Schematic of Study Design (Main Cohort)
PBO: placebo; Rand: randomization.
5.0
ANALYSIS ENDPOINTS
5.1
Sentinel Cohort
5.1.1
Primary Endpoints
The primary endpoints for healthy subjects are the following PK parameters for TAK-071:

Cmax. 

tmax.

AUC24.

AUClast.

AUCinf.
5.1.2
Secondary Endpoints
The safety endpoints for healthy subjects are:

AEs.

Clinical laboratory evaluations.

Electrocardiograms (ECGs).

Physical examinations.


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
Suicidal ideation and behavior as measured by the C-SSRS.
5.2
Main Cohort
5.2.1
Primary Endpoints
The primary efficacy endpoint for subjects with PD is the average of left and right foot stride 
time variability (SD) during a 2-minute walk on a 10-meter walkway, either with or without 
cognitive load, after 6-week treatment with either placebo or TAK-071.
The safety endpoints for subjects with PD are:

AEs.

Clinical laboratory evaluations.

Electrocardiograms (ECGs).

Physical examinations.

Suicidal ideation and behavior as measured by the Columbia-Suicide Severity Rating Scale 
(C-SSRS).
5.2.2
Secondary Endpoints
The secondary efficacy endpoint for subjects with PD is the change from baseline in a global 
cognition score consisting of attention (SAT, Symbol Digit Modalities Test [SDMT]), executive 
function (Cogstate Groton Maze Learning Test, Cogstate One Back Test), and episodic memory 
(Cogstate International Shopping List Test (Immediate recall and delayed recall), Cogstate One 
Card Learning Test) after 6-week treatment with placebo or TAK-071.
The PK endpoints for subjects with PD are:

Ctrough of TAK-071 in subjects with PD (Day 42 of Period 1 and Period 2 only).

Cmax and AUClast of TAK-071 in subjects with PD.

tmax.
5.2.3
Exploratory Endpoints
The exploratory pharmacodynamic endpoints for subjects with PD are:

Change from baseline on cognitive performance on individual cognitive test scores(SAT, 
SDMT, Groton Maze Learning Test, Cogstate One-Back Test, Cogstate International 
Shopping List Test, Cogstate One Card Learning Test) after 6 weeks of treatment with TAK-
071 orplacebo.

Change from baseline on cognitive performance on domain cognitive scores:  attention 
(SAT, SDMT), executive function (Cogstate Groton Maze Learning Test, Cogstate One Back 


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Test), and episodic memory (Cogstate International Shopping List Test (Immediate recall and 
delayed recall), Cogstate One Card Learning Test)  after 6 weeks of treatment with TAK-071 
or placebo.

Average number of falls and  near-falls per month measured by a falls diary during 6-week 
treatment with TAK-071 or placebo.

Change from baseline in the completion time of the TUG after 6-week treatment with 
TAK-071 or placebo (average of 3 trials).

Change from baseline in the parameters measuring postural sway with eyes open and eyes 
closed during a 30-second balance test after 6-week treatment with TAK-071 or placebo.

Change from baseline in step time variability and double support time during a 2-minute 
walk after 6-week treatment with TAK-071 or placebo.

Change from baseline in self-directed turns during a 2-minute walk test after 6-week 
treatment with TAK-071 or placebo.

Change from baseline in cued 180 degree turns after 6-week treatment with TAK-071 or
placebo.

Change from baseline in number of falls measured by a wearable pendant sensor during 
6-week treatment with TAK-071 or placebo.

Change from baseline on the ESS total score after 6-week treatment with TAK-071 or
placebo.

Values of CGI-I and PGI-I after 6-week treatment with TAK-071 or placebo.

Change from baseline on MDS-UPDRS Part 3 scores (including individual motor 
assessments in Parts 3.1-3.18) and on MDS-UPDRS Parts 1, 2, and 4 scores after 6-week 
treatment with TAK-071 or placebo.
6.0
DETERMINATION OF SAMPLE SIZE
Sentinel Cohort:
The sample size for an initial sentinel cohort will be approximately 10 subjects initially (with 
potential replacement for dropouts at sponsor’s discretion) at designated sites. Additional 
(including, potentially older) subjects may be enrolled after analysis of the resulting data from 
subjects aged 56 to 75 years, inclusive. This sample size is not based on statistical power 
considerations and considered to be sufficient for evaluation of safety, tolerability, and PK 
modeling to define safe dose for people 65 years and older. 


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Main Cohort:
A sample size of 44 completers will be sufficient to detect a statistically significant (α = 0.05, 
1-sided, 80% power) decrease in stride time variability in 2-minute walk either with or without 
cognitive load for TAK-071 versus placebo. We expect to detect an effect size of at least 0.32 
(Cohen d) in the reduction of stride time variability, 33% higher than what was observed in
Henderson et al. (2016) [2]. Assuming the within-subject correlation of 0.65 [3], the true effect 
size for the two-period cross-over design is 0.382. The sample size calculation is done with 
nQuery v9.2 (Statsols, San Diego, CA, USA). 
It is expected that approximately 64 subjects will be randomized to ensure at least 44 completers, 
assuming a 31% drop-out rate. 
Given the proposed study sample size and 80% power, a detectable operational effect size [4] for 
the global cognition score (α = 0.1, 1-sided) will be at least 0.324. For all primary and secondary 
outcomes, the within-subject correlation was assumed to be 0.65 [3].
7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
Unless otherwise described, general principles, definitions, and summaries described in Section 
7.1 to 7.8 will be applied to each part of the study.
Randomized subjects are the subjects who are enrolled and received a randomization number.
All study-related raw data, including derived data, will be presented in data listings. 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 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. When presenting summary statistics by treatment groups, the treatment groups 
include placebo and TAK-071. 
All p-values will be rounded to 3 decimal points (e.g., 0.123) and two-sided. 
Unless otherwise stated, baseline value is defined as the last observed value before the first dose 
of study medication. In addition, period 2 baseline assessments need to be at least 19 days after 
the end of period 1 treatment (main cohort only). 
All data analyses and figures will be generated using SAS System® Version 9.4 or higher and 
PK analysis will be done using Phoenix® WinNonlin® software version 8.0 or higher (Certara, 
Princeton, NJ, USA).
7.2
Definition of Study Days and Study Visit Windows
For main cohort subjects, study day will be calculated relative to the date of the first dose of the 
study drug for each period. For sentinel cohort subjects, study day will be calculated relative to 
the date of the first dose of the study drug. Study days prior to the first dose of study drug will be 


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calculated as: {date of assessment/event – date of first dose of study drug of the subject}. Study 
days on or after the first dose of study drug will be calculated as: {date of assessment/event –
date of first dose of study drug of the subject + 1}.
The study visit schedules are presented in Table 7.a for the Sentinel Cohort, Table 7.b and Table 
7.c for the Main Cohort. 
For main cohort subjects, a visit window for week 6 visit (day 42 visit for period 1 or day 105 
visit for period 2) will be a visit occurred between study day 23 to 63 within that period, but no 
later than 3 days after the treatment end date of that period. 
The value used in analysis for by-visit summaries is the value within the specified window that is 
the closest to the scheduled study day. If two observations are equidistant from the scheduled 
visit date, the observation with a later date will be used. 
If the date of first dose of double-blind study drug collected in the eCRF is missing, then for 
summary purposes the day after the first dispense date will be used as an estimate for the date of 
first dose. However, if all dispensed study drug is returned, then the subject is assumed to have 
not taken any study drug, and the first dose date will not be imputed.
If the date of last double-blind study drug dose collected in the eCRF is missing, then the latest
of the following dates will be used for the last dose date for analysis and summary purposes: date 
of last visit (recorded in the eCRF)and the last double-blind study drug dispense date (following 
the last drug return date) + 42 days (i.e., the longest double-blind study drug dispensing interval).
Table 7.a
Visit (Days/Hours) for Scheduled Visits/Samples of Healthy Subjects from 
Sentinel Cohort
Screening
Baseline
Last Day of 
Treatment 
Period or 
Early 
Termination
Study Day
Day -42 up to 
Day -1
Day 1
Day 2
(Day 2+24 hr)
Day 3
(Day 2+48 hr)
Day 4
(Day 2+72 hr)
Day 5
(Day 2+96 hr)
Day 8
(Day 2 +68 hr)
Table 7.b
Visit Windows (Days) for Scheduled Visits of PD Subjects During the 
Treatment Period 1
Screening
6-Week Double-blind Treatment Period 
(Period 1)
Washout
Baseline
At-home 
Assessment
Last Day of 
Treatment Period 
or Early 
Termination
Study Day
Day -42 up 
to Day -1
Day 1
Day 21 ±2
Day 42 ±2
Day 43 to Day 63a
a Washout is ≥3 weeks.


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Table 7.c
Visit Windows (Days) for Scheduled Visits of PD Subjects During the 
Treatment Period 2
6-Week Double-blind Treatment Period 
(Period 2)
Follow-up 
Safety Phone 
Call
Baseline
At-home 
Assessment
Last Day of 
Treatment Period 
or Early 
Termination
(Week 17)
Study Day
Day 64 ±2
Day 84 ±2
Day 105 ±2
Day 119
For all efficacy and safety data, data that are obtained more than 3 days after the last dose of 
study medication (start date – last dose date >3) will be listed but excluded from summaries and 
analyses. Adverse events that start more than 22 days after the last dose of study medication for 
sentinel cohort subjects or AEs that start more than 22 days after the last dose of the study 
medication for each period of the main cohort subjects (start date – last dose date >22) will be 
listed but excluded from the summaries and analyses.
7.2.1
Conventions for Missing Adverse Event Dates
Adverse events with start dates that are completely or partially missing will be imputed as 
follows:

If month and year are known but day is missing.
–
If month and year are the same as month and year of first dose date, then impute to first 
dose date;
–
If month and year are not the same as of the first dose, impute first day of the month.

If year is known but day and month are missing.
–
If year is same as year of 1st dose date, then 1st dose date will be used instead.
–
If year is different than year of 1st dose date, then 1st of January of the year will be used. 

If year and day are known but month is missing.
–
If year and day are the same as year and day of first dose date, then impute to first dose 
month;
–
If year is the same but the day is different from the first dose date then if day is after the 
first dose date impute first dose month, otherwise, impute month next after the first dose 
month.
–
If year is different, then impute January as a month.

If year, month, and day are unknown then impute date of the first dose.


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Imputing missing AE start date is mandatory. After the imputation, all imputed dates are checked 
against the start dates to ensure the stop date does not occur before start date. 
Adverse events with stop dates that are completely or partially missing will be imputed as 
follows:

If “ongoing” is checked, no imputation is necessary.

If month and year are known but day is missing, the last day of the month will be imputed.

If year is known, but day and month are missing.
–
If YYYY ≤year of last dose, then 31st of December will be imputed.
–
If YYYY > year of last dose, then the imputed end date should be set to the earliest of the 
(treatment follow up period date, 31DECYYYY, date of death).

If all are missing, no imputation is necessary. The event will be considered “ongoing.” 
If an AE is ongoing, AE stop date could be missing. Otherwise, AE stop date could be imputed 
per above rules. If a subject dies during the study and AE stop date is missing, then the death 
date will be used for AE stop date. After the imputation, all the imputed stop dates are compared 
with the start dates to ensure the stop date does not occur before the start date. If the imputed 
stop date occurs prior to the start date, then the imputed stop date will be the same as the start 
date. 
The imputed dates will not be populated on the data listing, they are used for derivation purpose 
only. The actual and incomplete date will be on the data listing.
7.2.2
Conventions for Missing Concomitant Medication Dates
Concomitant medications with start date that are completely or partially missing will be analyzed 
as follows:

If month and year are known, but day is missing, then impute day to first of the month.

If year is known, but day and month are missing, then 1st of January of the year will be 
imputed.

If year and day are known, but month is missing, then January will be imputed.
Concomitant medications with stop dates that are completely or partially missing will be 
analyzed as follows:

If “ongoing” is checked, no imputation is necessary.

If month and year are known but day is missing, the last day of the month will be imputed.

If year is known, but day and month are missing then 31st of December will be imputed.

If year and day are known, but month is missing then December will be imputed.


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
If all are missing, no imputation is necessary. Concomitant medication will be considered as
“ongoing”.
If a concomitant medication is ongoing, the stop date could be missing. Otherwise, concomitant 
medications stop date could be imputed per above rules. If a subject dies during the study and the 
concomitant medication stop date is missing, then the death date will be used for the stop date. 
After the imputation, all the imputed stop dates are compared with the start dates to ensure the 
stop date does not occur before the start date. If the imputed stop date occurs prior to the start 
date, then the imputed stop date will be the same as the start date.
The imputed dates will not be populated on the data listing, they are used for derivation purpose 
only. The actual and incomplete date will be on the data listing.
7.2.3
Conventions for Missing PK Data
Plasma concentrations that are below the limit of quantification (BLQ) will be treated as zero in 
the summarization of concentration values and derivation of PK parameters, with the exception 
of BLQ values observed between 2 quantifiable concentrations which will be set to missing. 
Missing concentrations will be excluded from summaries and PK parameter calculations and will 
be treated as excluded with a corresponding footnote to explain the reason. These values will be 
flagged in the data listings and deviations from this convention may be considered on a case-by-
case basis as deemed appropriate.
7.2.4
Conventions for Missing Efficacy Data
The pharmacodynamic analyses will be performed according to ITT principle. The subjects will 
be analyzed according to the treatment that they are randomized to. To evaluate the impact of 
missing data, last observation carried forward (LOCF) imputation will be performed for selected 
endpoints in the Main Cohort only.
7.3
Analysis Sets
Safety Set
The safety set will consist of all subjects who are randomized and receive at least 1 dose of study 
drug. Subjects in this analysis set will be used for demographic, baseline characteristics, and 
safety summaries. In summaries and analysis using the Safety Set, subjects will be analyzed by 
the treatment which they received.
PK Set
The PK analysis set will consist of all subjects who receive at least 1 dose of TAK-071 and have 
at least 1 measurable plasma concentration. If any subjects are found to be noncompliant in 
dosing schedule or with incomplete data, a decision will be made on a case-by-case basis as to 
their inclusion in the analysis but will be presented in the subject listings. In summaries and 
analysis using the PK Set, subjects will be analyzed by the treatment which they received.


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Pharmacodynamic Set (Main Cohort only)
The Pharmacodynamic analysis set will consist of all subjects who receive at least 1 dose of 
study drug and have at least 1 evaluable Pharmacodynamic endpoint. In summaries and analysis 
using the Pharmacodynamic Set, subjects will be analyzed by the treatment to which they are 
randomized.
7.4
Disposition of Subjects
All summaries in this section will be performed for Sentinel and Main cohorts respectively.
Disposition of all screened subjects will be tabulated (count and percent); there will be no 
inferential analysis of subject disposition data.

All subjects who signed informed consent form.

All subjects who were randomized.

All subjects who were not randomized.
The primary reasons for subjects who were not randomized will be summarized.
Disposition of randomized subjects will be tabulated as below by corresponding treatment 
groups and overall: 

All subjects who randomized but did not receive any study drug.

All subjects who received at least one dose of study drug (Main cohort only).

Subjects who completed the study drug.

Subjects who prematurely discontinued study drug (Main cohort only).

Subjects who completed all study visits.

Subjects who prematurely discontinued study visits.
Primary reasons for discontinuation of study drug/visits, as entered on the electronic case report 
form (eCRF), will be tabulated. The primary reasons for premature discontinuation of study 
drug/study visit will be presented for each subject in listings. The primary reason for premature 
discontinuation of study drug is applicable to the main cohort only. 
Significant protocol deviations will be listed using the Safety Set by corresponding treatment 
groups and overall. 
7.5
Demographic and Other Baseline Characteristics
All summaries in this section will be performed for Sentinel and Main cohorts respectively.
Demographics of the screening failures collected on the eCRF will be summarized. 
For subjects in the Safety Set, demographics and other baseline characteristics will be 
summarized by treatment groups (Sentinel cohort) or by treatment sequence (Main cohort) and 
overall. Descriptive statistics will be used to summarize data for continuous variables like age 


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and weight (number of subjects [N], mean, median, SD, minimum, and maximum) and for 
categorical variables like sex, ethnicity, and race. Baseline disease characteristic table and listing 
are applicable to the main cohort subjects only. 
All individual demographic and baseline characteristics will be listed by treatment (Sentinel 
cohort) or by treatment sequences (Main cohort), study center and subject number. The 
demographic data listing will include subject identifier, treatment sequence, age at date of 
informed consent, sex, race, height, baseline weight and baseline BMI and other demographic 
and baseline information collected in the eCRF.
7.6
Medical History and Concurrent Medical Conditions
Medical history includes any significant conditions or diseases relevant to the disease under 
study that stopped at or prior to signing of informed consent. Concurrent medical conditions are 
those significant ongoing conditions or diseases present at signing of informed consent. Medical 
history and concurrent medical conditions will be coded using the Medical Dictionary for Drug 
Regulatory Activities (MedDRA, version 23 or higher) coding system.
All medical history and concurrent medical condition data will be listed by subject for the 
sentinel and main cohorts separately. The listing will contain subject identifier, treatment, system 
organ class (SOC), preferred term (PT), whether there was any medical history or concurrent 
condition, and, if yes, a detail of the medical history or concurrent condition.
7.7
Prior and Concomitant Medications
Medication history information obtained includes any medication stopped at or within 28 days
prior to signing of informed consent. Medications used from signing of informed consent
through the end of study will be considered as concomitant medications.
No summary statistics for prior and concomitant medications will be provided. All medication 
history and concomitant medications data will be listed by subject. Study part and/or cohorts will 
be included in the listing.
7.8
Study Drug Exposure and Compliance
All summaries in this section will be performed for the main cohort only.
The date and time of each dose for each subject will be reported in the data listing. Listings and 
summary statistics for TAK-071 plasma concentrations and pharmacokinetic parameters will 
also be provided. 
The summary of study drug exposure and compliance will be based on the Safety Set. Duration 
of exposure to study medication for each subject is defined as (date of last dose – date of first 
dose +1). The date of the first dose and date of the last dose in each treatment period for the main 
cohort is determined by the corresponding in-clinic visit dates. If the date of last dose is missing, 
the last dose date will be estimated as the later date between the last drug dispense date plus the 
number of days in the dosing interval  and the last study visit day for analysis and summary 
purposes.


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Treatment duration (days) will be summarized using descriptive statistics (n, mean, SD, median, 
minimum, and maximum) for each treatment (placebo or TAK-071).
Percent of study drug compliance at each period will be calculated in two ways: 
1) Compliance by tablet counts as {(number of tablets dispensed – number of tablets 
returned)/(date of last dose – date of first dose +1)} *100%. If the number of returned 
tablets is missing, then 100% compliance will be assigned for that treatment period. 
2) Compliance by days as the number of days when the drug was taken (as reported by 
subject or caregiver in the medication diary)/ total number of days in which the 
compliance was reported in the medication diary between the date of the first dose and 
the date of last dose, inclusive in that treatment period*100%.
For each treatment(Placebo or TAK-071), study medication compliance will be summarized as 
the number of subjects and the frequency in each compliance category (<50%, 50 to 70%, and 
≥70%) for both options above. Study medication compliance summarized as a continuous 
variable using descriptive statistics (n, mean, SD, median, minimum, and maximum) for each 
treatment group. 
All study drug administration and accountability data will be listed by subject ID, age/gender, 
period, treatment, first and last dose dates, medication identification number, date dispensed and 
returned, number of tablets dispensed and returned, and compliance percentages by tablet counts, 
number of days in which compliance was reported in the diary (diary compliance) and 
compliance percentages by days.
7.9
Efficacy Analysis (Main cohort)
The efficacy analysis will be based on the Pharmacodynamic Set. For all efficacy analyses, 
baseline value is defined as the last observed value at or before the date that the first dose of 
study medication was taken for each treatment period. In addition, period 2 baseline assessments 
need to occur at least 19 days after the end of period 1 treatment. Separately, a flag will be 
derived to indicate whether a baseline assessment occurred at the same day of the first dose but 
after the actual treatment start time. 
7.9.1
Primary objective: Stride Time Variability Analysis
The primary objective is to evaluate the efficacy of TAK-071 versus placebo on gait dysfunction, 
as measured by stride time variability during a 2-minute walk test.
We will calculate stride time variability as the average of the right and left leg’s stride time 
variability (measured as SD) and referred to as STV. 
STV values from 2-minute walk without cognitive load will be analyzed using a linear mixed 
effect model of the log-transformed STV for each period, with treatment, period, and log-
transformed baseline STV as predictors. The inference is on the ratio of the geometric mean STV
of TAK-071 period to the geometric mean STV of placebo period, adjusted for period and log-
transformed baseline STV. 


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Similar analysis will be done for the STV values from 2-minute walk with cognitive load. 
The following schematic code is an example of SAS code for STV assessment: 
proc mixed data=data;
   class Period Treatment (ref ="Placebo") Subjid;
   model LogSTV = Period Treatment LogBaseSTV / ddfm=KR solution;
   repeated Period/ subject=Subjid type=un;
   lsmeans Treatment / diff cl exp; 
run;
The SAS procedure above assumes an unstructured covariance matrix that may cause a problem 
with model convergency. In a case the procedure does not converge, we would use a compound 
symmetry (cs) structure. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom.
We will present the adjusted Least Squares Means (LSMs) and the associated SEs for log STV in 
TAK-071 and Placebo for 2-minute walks. The adjusted difference between the expected means 
for log(TAK-071)-log(Placebo) will be exponentiated to provide estimates of the ratio of 
adjusted geometric means and will be presented with corresponding two-sided 95% CIs for the 
ratios and p-values. 
To address the potential bias due to missing data, we will run sensitivity analyses using the 
LOCF option mentioned in Section 7.2.4, using the most recent assessment performed prior to 
week 6 within the same period. The models will be the same one as described above using the 
observed data supplemented with the imputed values. 
7.9.2
Cognition Analysis
The secondary outcome is a change from baseline in a global cognition score consisting of 
attention (SAT, Symbol Digit Modalities Test [SDMT]), executive function (Cogstate Groton 
Maze Learning Test, Cogstate One Back Test), and memory (Cogstate International Shopping 
List Test(immediate recall and delayed recall), Cogstate One Card Learning Test) after 6-week 
treatment with TAK-071 compared with placebo. Please refer to the Protocol Amendment 3 
Section 9.1.8.2 or Cogstate and Operation manuals for additional details on these cognitive tests. 
The change from baseline in the global cognition score will be analyzed using a linear mixed 
effect model, with treatment, period and baseline global cognition score modeled as fixed 
effects and  subject as the random effect. The inference is on the difference between the mean 
change from baseline on global cognition score from the TAK-071 period and the placebo 
period, adjusted for period and baseline global score. 
The following schematic code is an example of SAS code for overall cognition analysis: 


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proc mixed data=data;
class Period Treatment (ref ="Placebo") Subjid;
model CFB(GlobalScore) = Period Treatment Base / ddfm=KR solution;
repeated Period/ sub=Subjid type=un;
lsmeans Treatment / diff cl; 
run;
The adjusted means (Least Squares Means) and their two-sided 95% confidence intervals (CIs) 
and difference between the expected means for TAK-071-Placebo with corresponding two-sided 
95% CI and p-value will be estimated for the global cognition score. 
Similar analysis will be done for each individual cognitive test scores as well as each of the three 
domain(attention, executive function, and memory) scores. 
To address the potential bias due to missing data, we will run sensitivity analyses for the week 6 
global cognition score using the LOCF option mentioned in Section 7.2.4. The LOCF will be 
applied to each missing individual test score in order to calculate the imputed global cognition 
score, using the most recent assessment performed prior to week 6 within the same period. The 
models will be the same one as described above using the observed data supplemented with the 
imputed values. 
7.9.3
Fall Data Analysis
Subjects will complete a daily ePRO diary to record falls and near falls. 
Monthly fall rate (MFR) for each treatment period based on study schedule will be calculated as 
below:
 	
  = 
       !!" #!$ #$   "! %!#
   !!" #!$ #$ !  %!#
& ∗30.4375
If a diary for a given day reports ≥0 fall, the day will be counted as a non-missing diary day. If a 
diary for a given day does not report any information about fall (including 0), the day will be 
counted as a missing diary day for the fall. 
MFR will be summarized by treatment period. PD set will be used.
Monthly near fall rate will be calculated similarly as MFR. 
Monthly fall/near fall rate derived from the wearable device will be calculated similarly as:
 	
 *+,* = 
         !!" #$   "! %!#
   !!" #$ !  %!#
& ∗30.4375


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A generalized estimating equation negative binomial regression model will be used to evaluate 
the drug effect on the monthly fall/near fall rate from either diary or wearable device. The 
response variable will be the number of falls recorded in the placebo and TAK-071 period. The 
model will include treatment and period. The log(number of days) will be used as an offset 
variable. An unstructured variance-covariance structure will be used initially in these models. 
Other variance-covariance structures will be evaluated if there are convergence issues with the 
model. The estimated incident rate ratio (IRR) of MFR comparing treatment period to placebo 
period, and the associated 95% CIs, and p-values will be estimated from the model. 
The following schematic code is an example of SAS code for monthly fall rate analysis: 
proc genmod data=data;
class subjid treatment(ref="Placebo") period;
model number_of_fall = treatment period / dist=negbin link=log offset=log(number of day); 
repeated subject = subjid(period) / Type=UN;
lsmeans treatment /diff cl exp;
run;
7.9.4
MDS-UPDRS and Other Gait Parameters Analysis
From 2-minute walk test with and without cognitive load we will analyze 

Step Time Variability 

Stride length variability

Double support time 

Foot strike angle

Range of motion (G/T-Coronal, G/T Sagittal, G/T Transverse, Arm)

Swing velocity

Turn velocity
In addition, we will consider 

MDS-UPDRS Part III sum scores (including individual motor assessments in Parts 3.1-
3.18) impact of dyskinesia, and the Hoehn and Yahr scale 

MDS-UPDRS Parts I, II, and IV sum scores 

Completion time of the TUG 

Postural sway with eyes open and eyes closed during a 30-second balance test, measured 
by average frequency dispersion, mean velocity, average Acc-RMS Sway, average sway 
area, average ang-sway area. 
The detailed description of these tests can be found in the Protocol Amendment 3 Section 
9.1.8.1. The total scores from MDS-UPDRS Part I, Part II, Part III, Part IV as well as the 


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combined total scores from Part I-III will be analyzed. If there are missing item scores in any of 
the MRS-UPDRS Part, the part summary score is not calculated. All analyses will be done using 
linear mixed models with random effect for subject, fixed effects for treatment, period, and with 
baseline value as covariates, similarly to what was described in section 7.9.1. 
7.10
Epworth Sleepiness Scale (ESS) Total Score Analysis
ESS [5] will be measured at baseline and last day of treatment period or early termination (Days 
1, 42, 64 and 105), and the total scores will be derived and summarized for each visit. Change 
from baseline in the ESS total scores to the end of each period will be derived and summarized. 
ESS data will be presented in the listing. Summary statistics by treatment will be provided for 
observed ESS total score at baseline and post dose days, as well as for the change from baseline. 
In addition, number, and percent of subjects with a total ESS score <10 will be summarized at 
each visit by treatment groups. Shift tables will be presented.
Similar to the analysis of the primary efficacy endpoint, linear mixed effect model will be used 
to evaluate the effect of TAK-071 on the change from baseline in the ESS total score. Baseline 
total ESS score will be included as the covariate in the model. Treatment, period will be included 
as fixed effect and subject as a random effect. The least squares mean of change from baseline in 
total ESS score for each treatment and the associated SE and 95% CI will be calculated for TAK-
071 and placebo, along with difference between TAK-071 and placebo and associated SEs, 95% 
CIs, and p-values.
7.11
PGI and CGI Analysis 
The CGI scales consist of 2 subscales: the CGI-Severity (CGI-S) and the CGI-Improvement 
(CGI-I). The CGI-S assesses the clinician’s impression of the subject’s current clinical condition. 
Both the CGI-I and CGI-S will be rated with respect to stability (gait, balance, falls) and 
cognition in separate assessments. The clinician should use his/her total clinical experience with 
this subject population and rate the current severity of the subject’s illness on a 7-point scale 
ranging from 1) “Normal, not at all ill” to 7) “Among the most extremely ill patients”. This 
rating is based on observed and reported symptoms, behavior, and function in the past 7 days and 
should reflect the average severity level across the 7 days. The CGI-I assesses the subject’s 
improvement (or worsening) on a 7-point scale ranging from 1) Very much improved since the 
initiation of treatment to 7) Very much worse since the initiation of treatment. Each time the 
subject is seen after treatment has been initiated, the clinician compares the subject’s overall 
clinical condition to the 1-week period just before the initiation of medication use (baseline). The 
CGI-S score obtained at the baseline visit (Day 1/Day 64) serves as a basis for making this 
assessment. In all cases, the assessment should be made independent of whether the clinician 
believes the improvement is drug-related or not.
Patient-reported global impression of severity and improvement (PGI-S and PGI-I, respectively) 
will be also assessed. PGI-I will be rated on a 7-point scale and PGI-S will be rated on a 6-point 
scale. Both the PGI-I and PGI-S will be rated with respect to stability (gait, balance, falls) and 
cognition in separate assessments.


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Summary statistics for CGI-S, PGI-S, CGI-I and PGI-I will be provided by treatment at baseline 
and end of period.. 
For the linear model for analysis of the change from baseline for the CGI score, CGI-S will be 
used as the baseline and CGI-I will be the measure of the change from baseline. The CGI-S 
responses will be mapped to 1 to 7, starting with 1 = Normal and continuing in order. The CGI-I 
responses will be mapped to two categories: “Improved” and “Not improved”. Responses of 
“Very much improved” and “Much improved” will be mapped to “Improved”; all other non-
missing responses will be mapped to “Not Improved”. In this case, the summary of observed 
values and change from baseline for the CGI-I scales will include the number and percent of 
subjects “Improved” or “Not Improved” at each time point. A GEE logistic regression model 
will be used to analyze the two-category CGI-I score. The model will include treatment, and 
period and baseline CGI-S as covariates. The odds ratio of improvement for active versus 
placebo will be extracted, as well as two-sided 95% CIs, and p-values.
The analysis for PGI-S/PGI-I will follow the same approach described above for CGI-S/CGI-I. 
7.12
Exploratory Pharmacodynamic Analysis 
Plasma biomarkers including neuronally derived exosomal M1 receptor mRNA, amyloid, tau, 
neurofilament light chain (NfL), biomarkers of synaptic integrity, and potentially additional 
blood-based biomarkers, DNA samples and data from wearable digital devices and speech 
performance will be exploratory in nature and will help in the design of future studies. In 
addition, we are going to explore the relationship of pharmacodynamic endpoints to disease 
characteristics, subgroup and mediation analyses. These analyses are not related to the main 
study objectives concerning the safety, tolerability and PK, will not be available during the 
dosing periods of the study, will not be used for clinical decision making during the study, and 
will not be included in the Clinical Study Report. Thus, analysis of these data will be described 
and performed independently of this document by Takeda or its designee. 
7.13
Pharmacokinetic Analysis
7.13.1
Plasma Concentration
Blood samples for the determination of plasma concentrations of TAK-071 will be collected at 
the following time points for PK assessment:
Sentinel Cohort:
Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 14 hours postdose on Day 1; 24 hours postdose 
(Day 2); 48 hours postdose (Day 3); 72 hours postdose (Day 4); 96 hours postdose (Day 5) and 
168 hours postdose (Day 8).
Main Cohort:
Day 1 (Period 1): Predose and 1 and 2 hours postdose
Day 42 (Period 1): Predose and 1, 2, and 3 hours postdose


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Day 64 (Day 1 Period 2): Predose and 1 and 2 hours postdose
Day 105 (Day 42 Period 2): Predose and 1, 2, and 3 hours postdose
TAK-071 plasma concentrations will be tabulated and summarized at each scheduled time point 
using descriptive statistics (including number of observations (n), mean, median, SD, percent 
coefficient of variation [%CV], minimum, and maximum) for each dose level (if needed), and 
separately for each cohort (Sentinel and Main Study). Actual sampling times postdose will be 
considered to be deviations where the actual sample collection time deviated from nominal 
collection time by more than ±5 minutes up to 4 hours postdose, ±15 minutes between 6 and 96 
hours, ±1 day on Day 8, ±2 days between Days 42 and 64, and ±3 days on Day 105. Samples
collected outside these windows will be flagged in data listings and excluded from summaries 
and mean figures.
Individual subject plasma concentration data and actual sampling times will be listed separately 
for each cohort (Sentinel and Main). 
7.13.2
Plasma Pharmacokinetic Parameters
The plasma PK parameters of TAK-071 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. The following PK parameters will be 
calculated if feasible using non-compartmental analysis using Phoenix WinNonLin (version 8.0
or higher (Certara, Princeton, NJ, USA)): AUC24 (sentinel cohort only), AUClast, AUCτ (sentinel 
cohort only), AUCinf (sentinel cohort only), Cmax, Ctrough (main cohort only), tmax, and 
t1/2z(sentinel cohort only). Additional PK parameters may be calculated if necessary.
The plasma PK parameter estimates will be tabulated and summarized by using descriptive 
statistics (n, mean, median, SD, %CV, minimum, and maximum) for each dose level (if needed), 
and separately for each cohort (Sentinel and Main). In addition, geometric means and geometric 
%CVs will be calculated for Cmax, AUCs and Ctrough. Individual PK parameters will be presented 
in a data listing for each subject, separately for each cohort (Sentinel and Main).
The individual plasma concentration of TAK-071 will be plotted by actual time on linear and 
semi-logarithmic scales, separately for each cohort (Sentinel and Main). Mean (±SD) plasma 
concentrations will be plotted by scheduled time for each day (as applicable) on linear and semi-
logarithmic scales, separately for each cohort (Sentinel and Main).
All PK summaries and analyses will be based on the PK set by dose levels (if needed) and within 
each cohort (Sentinel and Main). 
Actual sampling times, rather than scheduled sampling times, will be used in all computations 
involving sampling times. 


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The following PK parameters will be calculated from plasma concentrations of TAK-071, as data 
permit:
Table 7.d
Plasma PK Parameters Definition
Symbol/Term
Definition
Plasma
AUCτ
Area under the plasma concentration-time curve during a dosing interval (168 
h), calculated using the linear trapezoidal rule. (Sentinel only)
AUC24
Area under the concentration-time curve from time 0 to time 24 hours, 
calculated using the linear trapezoidal rule. (Sentinel only)
AUClast
Area under the plasma concentration-time curve from time 0 to time of the last 
quantifiable concentration, calculated using the linear trapezoidal rule.
AUCinf
Area under the concentration-time curve from time 0 to infinity, calculated as 
[AUClast + Clast / λz], where Clast is the last observed quantifiable concentration, 
calculated using the linear trapezoidal rule. (Sentinel only)
Cmax
Maximum observed concentration
Ctrough
Trough plasma concentration at steady state (observed concentration at the end 
of a dosing interval) (Main only; Day 42 of Periods 1 and 2 only)
t1/2z
Terminal disposition phase half-life (Sentinel only)
tmax
Time to reach Cmax
Additional PK parameters and the relationship of the ratio of plasma 4-beta-
hydroxycholesterol/cholesterol with plasma TAK-071 AUC may be analyzed. Details will be 
documented in the clinical pharmacology analysis plan (CPAP).
For the main cohort of PD subjects, a population PK approach will be used to derive the PK 
parameters and the population PK analysis will be reported separately.
7.14
Safety Analysis
Summaries of safety data will be presented by Cohort (Sentinel and PD subjects) and treatment 
group. 
7.14.1
Adverse Events
All AEs will be coded by system organ class (SOC) and preferred term (PT) using MedDRA.
The Treatment-Emergent Adverse Events (TEAE) are defined as those AEs that occurred after 
the start of the treatment and up to 22 days after the end of treatment (for each period for the 
Main cohort subjects). TEAE summary tables will include numbers and percentages of subjects 
experiencing at least one TEAE by SOC and PT and will be tabulated by treatment. The TEAEs 
will also be summarized for all subjects in the overview assessment. The following is a list of 
TEAE summary tables to be generated: 

Overview of Treatment-Emergent Adverse Events.


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
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term. 

Treatment-Emergent Adverse Events by Preferred Term.

Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term. 

Most Frequent (≥2 subjects or ≥5% based on total number of safety set subjects in any 
treatment group, whichever larger) Treatment-Emergent Adverse Events by Preferred Term.

Most Frequent (≥2 subjects or ≥5% based on total number of safety set subjects in any 
treatment group, whichever larger) Non-Serious Treatment-Emergent 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. 

Intensity of Drug-Related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term. 
In addition, data listings will be provided for all AEs including: TEAEs, TEAEs leading to death, 
TEAEs leading to study drug discontinuation, and SAEs.
7.14.2
Clinical Laboratory Evaluations
Clinical safety laboratory tests include clinical chemistry, hematology, and urinalysis. A list of 
all the clinical laboratory evaluations can be found in Protocol Section 9.1.12.
Descriptive statistics (N, mean, SD, median, minimum, and maximum) of clinical laboratory 
variables will be summarized for baseline and post-dose values, as well as change from baseline 
to post dose values by study visits and treatment. Only the scheduled measurements will be 
included in the summary. No statistical tests will be performed.
Individual results for clinical laboratory tests will be evaluated against the Takeda predefined 
laboratory markedly abnormal values (MAV) criteria (Appendix A) using the result and criteria 
in SI units. All subjects with at least 1 post-dose laboratory result that meets the MAV criteria 
will be presented in a data listing.
The number and percentage of subjects with at least one post-dose markedly abnormal laboratory 
test result will also be summarized by treatment. Subjects who meet the MAV criteria will be 
mapped to their respective qualifying laboratory result. All pre- and post-dose clinical lab MAV 
results, including scheduled and unscheduled measurements, will be included in the MAV 
summaries.


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Listings of all clinical safety laboratory data will be provided in the listings and will be presented 
in both SI and conventional units (and CV units, if available). Laboratory data outside of the 
normal reference range will be indicated in the listings. 
7.14.3
Vital Signs 
Vital sign measurements include blood pressure (SBP and DBP), pulse, respiratory rate, and 
body temperature.
SBP, DBP and pulse will be summarized (N, mean, SD, median, minimum, and maximum) for 
baseline, post-dose, and change from baseline (or change from time-matched baseline to post-
dose, if appropriate) by treatment. Only the scheduled measurements will be included in the 
summary. 
Respiratory rate and temperature will be summarized for baseline, post-dose, and change from 
baseline at each time point by treatment. Only the scheduled measurements will be included in 
the summary. 
All individual vital signs that meet Takeda’s predefined criteria for MAVs (Appendix B) will be 
listed. The number and percentage of subjects with at least one post-dose markedly abnormal 
vital sign measurement will be summarized by treatment. Subjects who meet the MAV criteria 
will be mapped to their respective qualifying vital sign result. All pre- and post-dose MAV vital 
signs, including both scheduled and unscheduled measurements, will be included in the MAV 
summaries. Listings of all vital signs data will be provided in the listings, and vital sign MAVs 
will be flagged. 
7.14.4
12-Lead ECGs
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the 
investigational site) will manually interpret the ECG using one of the following categories: 
within normal limits, abnormal but not clinically significant, or abnormal and clinically 
significant.
The following parameters will be calculated automatically by the ECG machine: heart rate, PR 
interval, RR interval, QT interval, QRS interval, and QT interval with Fridericia correction 
method (QTcF) and QTcB.
Descriptive statistics of the continuous ECG parameters will be summarized for baseline, 
post-dose, and change from baseline at each post-dose time point by treatment and time. Only 
the ECGs collected at the scheduled visits or time points will be included in the summary. No 
statistical tests will be performed for the observed ECG parameters. 
All individual ECGs that meet Takeda’s predefined criteria for MAVs (Appendix C) will be 
listed. The number and percentage of subjects with at least one post-dose markedly abnormal 
ECG measurement will be summarized by treatment. Subjects who meet the MAV criteria will 
be mapped to their respective qualifying ECG result. All pre- and post-dose MAV ECG 
parameters, including both scheduled and unscheduled measurements, will be included in the 
MAV summaries.


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Individual subject ECGs will be presented in a data listing. 
7.14.5
Other Observations 
Physical examination findings and C-SSRS data results will be presented in the data listings. C-
SSRS listings will include data from “at screening” questionnaire for the screening visit and 
“since last visit” questionnaire for any post-screening visits. 
7.15
PK/Pharmacodynamic and PK/Safety Analysis
The relationships between TAK-071 plasma concentrations and selected Pharmacodynamic and 
safety measures will be explored graphically as data permit. 
A scatterplot of TAK-071 plasma concentration (x-axis) versus the observed post treatment STV 
from a 2-minute walk with and without cognitive load (y-axis) will be produced. TAK-071
plasma concentrations for placebo data will be included in the plot with a concentration of 0. 
Only measurements from time points common to both STV and PK assessments will be used. 
Data from all doses of TAK-071 (if they vary) will be displayed together in the plot. A similar 
scatterplot of TAK-071 plasma concentration (x-axis) versus change from baseline in HR, SBP 
and DBP will be produced. TAK-071 plasma concentrations for placebo data will be included in 
the plot with a concentration of 0. Only measurements from time points common to both vital 
signs and PK assessments will be used. Data from all doses of TAK-071 will be displayed 
together in the plot. 
In addition, graphical description of the relationship between PK parameters (CL/F, AUC, Cmax 
and t1/2z) and subjects characteristics such as age, sex, liver function (such as AST, ALT, 
albumin, and bilirubin) and kidney function (estimated GFR) will be presented. 
7.16
Unblinded Data Reviews and Interim Analysis
7.16.1
Unblinded Data Reviews
Unblinded data safety review of the Sentinel cohort will be performed by Takeda team and the 
process is described in detail in the Data Access Management Plan (DAMP). 
7.16.2
Interim Analysis
Not applicable.
7.17
Changes from the Analysis Specified in the Protocol
1. The variable “sequence” is deleted from the list of linear mixed effect model covariates. 
2. Cognitive test is analyzed for each test separately, as well as by separate models for the 
domain scores and the global cognitive score. 
3. The analysis of the fall rate is analyzed using generalized estimating equations with a 
negative binomial distribution. 
4. All P-values are reported as 2-sided.


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8.0
REFERENCES
1. A Randomized, Double-blind, Placebo-Controlled, 2-Period Crossover, Phase 2 Study to
Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of
Oral TAK-071 in Parkinson Disease Patients With Cognitive Impairment and an Elevated
Risk of Falls Takeda Development Center, Ltd., Protocol Amendment 03, TAK-071-2002, 
dated 19 January, 2021.
2. Henderson EJ, Lord SR, Brodie MA, Gaunt DM, Lawrence AD, Close JC, et al. 
Rivastigmine for gait stability in patients with Parkinson's disease (ReSPonD): a randomized, 
double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 2016;15(3):249-58.
3. Chung KA, Lobb BM, Nutt JG, Horak FB. Effects of a central cholinesterase inhibitor on 
reducing falls in Parkinson disease. Neurology. 2010 Oct 5;75(14):1263-9.
4. Dallow NS, Leonov SL, Roger JH. Practical usage of O'Brien's OLS and GLS statistics in 
clinical trials. Pharm Stat 2008;7(1):53-68.
5. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. 
Sleep 1991;14(6):540-5.
6. Ratitch, B., Lipkovich, I. & O'Kelly, M. 2013. Combining Analysis Results from Multiply 
Imputed Categorical Data - PharmaSUG Paper SP03.


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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
--
>1.5x ULN
SI
--
>1.5x ULN
Albumin
Conventional 
<2.5 g/dL
--
SI 
<25 g/L
--
Total protein
Both
<0.8x LLN
>1.2x ULN
Creatinine
Conventional 
--
>1.5x ULN 
SI
>1.5x ULN 
Blood urea nitrogen
Conventional 
>40 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
>5.3 mEq/L
SI
<3.0 mmol/L
>5.3 mmol/L
CPK
Both
--
>3x ULN
Glucose
Conventional
<50 mg/dL
>300 mg/dL
SI
<2.8 mmol/L
>19.4 mmol/L
Calcium
Conventional
<7.7 mg/dL
>11.1 mg/dL
SI
<1.92 mmol/L
>2.77 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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Appendix B
Criteria for Markedly Abnormal Values for Vital Signs
Parameter
Unit
Lower Criteria 
Upper Criteria
Pulse
bpm
<40 
>115
Systolic blood pressure
mm Hg
<90 
≥160 
Diastolic blood pressure
mm Hg
<50 
≥100
Systolic blood pressure change
mm Hg
>20, >30 
Diastolic blood pressure change
mm Hg 
>20, >30
Body temperature
oC
>38.5 
Respiratory Rate
Breath/min
>21


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Statistical Analysis Plan{Final} 
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CONFIDENTIAL
Appendix C
Criteria for Markedly Abnormal Values for Electrocardiograms
Parameter
Lower Criteria 
Upper Criteria
Heart rate
<40 beats per minute
>115 beats per minute
PR
≤80 milliseconds
≥200 milliseconds
QTcF Interval
≤300 milliseconds
>500 milliseconds OR 
≥30 milliseconds change from baseline and >450 
milliseconds
QRS
≤80 milliseconds
≥180 milliseconds