Clinical trial NCT02769065
Conditions: Alzheimer Disease Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2016-05-05; Completion date: 2017-06-08
Enrollment: 179 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to assess the safety, tolerability, and pharmacokinetic (PK) of TAK-071 when administered as single rising dose (SRD) and multiple rising dose (MRD) orally in healthy participants and participants with mild cognitive impairment (MCI) or mild Alzheimer disease (AD).

Detailed description:
TAK-071 was being tested to find a safe and well-tolerated dose in healthy participants (non-Japanese and Japanese) and participants with MCI or mild AD (non-Japanese).

The study enrolled 179 participants. The study consisted of 4 parts: Single-rising dose (SRD) part (Cohorts 1-6, and 18-22), multiple-rising dose (MRD) part (Cohorts 7-15), Cohort 16 with 2-arm parallel design, and Cohort 17 relative bioavailability and food effect 3 period crossover design.

Participants in each cohort were randomized to receive treatment with TAK-071 or matching placebo using drug-in-capsule (DIC) in the morning following a minimum fast of 8 hours. In Cohort 16, participants were assigned to 1 of 2 possible treatments, TAK-071 or matching placebo. In Cohort 17, participants were assigned to 1 of 3 treatment sequences (ABC, BCA, or CAB) with treatment A being fasted state and capsule formulation, treatment B being fasted state and tablet formulation, and treatment C being fed state and tablet formulation. In Cohorts 20-22, participants were administered as a single dose of TAK-071 or placebo on Day 1, and a single dose of donepezil or placebo approximately 24 hours later on Day 2.

This multi-center trial was conducted in United States. The overall time to participate in this study was approximately 41 days. Participants made multiple visits to the clinic and were also contacted for the follow-up through the telephone.

Arms: arm 1: TAK-071 placebo-matching capsules, orally, once on Day 1 to non-Japanese healthy participants in the single-rising dose (SRD) period. arm 2: TAK-071 1 mg, capsule, orally, once on Day 1 to non-Japanese healthy participants. arm 3: TAK-071 3 mg capsule, orally, once on Day 1 to non-Japanese healthy participants. Dose of TAK-071 was based on the 24-hour post-dose safety, tolerability and pharmacokinetic (PK) data from cohort 1. arm 4: TAK-071 9 mg capsule, orally, once on Day 1 to non-Japanese healthy participants. Dose of TAK-071 was based on 24-hour safety, tolerability, and preliminary plasma PK and 12-hour CSF PK data. arm 5: TAK-071 20 mg capsule, orally, once on Day 1 to non-Japanese healthy participants. Dose of TAK-071 was based on the 24-hour post-dose safety and tolerability data from previous cohort. arm 6: TAK-071 40 mg capsule, orally, once on Day 1 to non-Japanese healthy participants. Dose of TAK-071 will be based on 24-hour safety, tolerability, and preliminary plasma PK data from Cohort 4. arm 7: TAK-071 80 mg capsules, orally, once on Day 1 to non-Japanese healthy participants. Dose of TAK-071 was based on 24-hour safety, tolerability, and preliminary plasma PK data from Cohort 5 arm 8: TAK-071 placebo-matching capsule, orally, once on Day 1 to non-Japanese healthy participants in the multiple-rising dose (MRD) period. arm 9: TAK-071 3 mg capsules, orally, once daily from Day 1 up to Day 21 to non-Japanese healthy participants. Dose of TAK-071 was based on 24-hour safety and tolerability from Cohort 4 and the 24-hour preliminary plasma PK and 12-hour CSF PK data from Cohort 3. arm 10: TAK-071 9 mg capsules, orally, once daily from Day 1 up to Day 21 to non-Japanese healthy participants. Dose of TAK-071 was based on safety, tolerability and available PK data arising from the ongoing SRD part and previous MRD cohort. arm 11: TAK-071 15 mg capsule, orally, once on Day 1, followed by a washout period of 7 days, then TAK-071 once daily for 21 days to non-Japanese healthy participants. Dose of TAK-071 will be based on safety, tolerability and available PK data arising from the ongoing SRD part and previous MRD cohort. arm 12: TAK-071 placebo-matching capsule, orally, once daily along with donepezil 5 mg, tablets, orally, once daily from Day 1 up to Day 21 to non-Japanese healthy participants who were pre-treated with donepezil 5 mg, tablet, once daily for 3 weeks prior to administration of TAK-071. arm 13: TAK-071 3 mg capsules, orally, once daily along with donepezil 5 mg, tablets, orally, once daily from Day 1 up to Day 21 to non-Japanese healthy participants who were pre-treated with donepezil 5 mg, tablet, once daily for 3 weeks prior to administration of TAK-071. Dose of TAK-071 was same as the dose used in MRD Cohort 7. arm 14: TAK-071 9 mg capsules, orally, once daily along with donepezil 5 mg, tablets, orally, once daily from Day 1 up to Day 21 to non-Japanese healthy participants who were pre-treated with donepezil 5 mg, tablet, once daily for 3 weeks prior to administration of TAK-071. Dose of TAK-071 was same as the dose used in MRD Cohort 8. arm 15: TAK-071 15 mg capsule, orally, once daily along with donepezil 5 mg, tablets, orally, once daily from Day 1 up to Day 21 to non-Japanese healthy participants who were pre-treated with donepezil 5 mg, tablet, once daily for 3 weeks prior to administration of TAK-071. Dose of TAK-071 was same as the dose used in MRD Cohort 9. arm 16: TAK-071 placebo-matching capsule, orally, once on Day 1 to Japanese healthy participants. arm 17: TAK-071 3 mg capsule, orally, once on Day 1, followed by a washout period of 7 days, then TAK-071 once daily for 21 days to Japanese healthy participants. Dose of TAK-071 was same as the dose used in MRD Cohort 7. arm 18: TAK-071 9 mg capsule or matching placebo, orally, once on Day 1, followed by a washout period of 7 days, then TAK-071 once daily for 21 days to Japanese healthy participants. Dose of TAK-071 was same as the dose used in MRD Cohort 8. arm 19: TAK-071 15 mg capsule, orally, once on Day 1, followed by a washout period of 7 days, then TAK-071 once daily for 21 days to Japanese healthy participants. Dose of TAK-071 was same as the dose used in MRD Cohort 9. arm 20: None arm 21: A: TAK-071 10 mg capsule, orally once on Day 1 in the fasted state in Period 1, followed by B: TAK-071 10 mg tablet, orally, once on Day 1 in the fasted state in Period 2, followed by C: TAK-071 10 mg tablet, orally, once on Day 1 in the fed state in Period 3 in non-Japanese healthy participants. There was a 21-day washout after each period. arm 22: B: TAK-071 10 mg tablet, orally, once on Day 1 in the fasted state in Period 1, followed by C: TAK-071 10 mg tablet, orally, once on Day 1 in the Fed state in Period 2, followed by A: TAK-071 10 mg capsule, orally once on Day 1 in the fasted state Period 3 in non-Japanese healthy participants. There was a 21-day washout after each period. arm 23: C: TAK-071 10 mg tablet, orally, once on Day 1 in the fed state in Period 1, followed by A: TAK-071 10 mg capsule, orally once on Day 1 in the fasted state in Period 2, followed by B: TAK-20 10 mg tablet, orally, once on Day 1 in the fasted state in Period 3 in non-Japanese healthy participants. There was a 21-day washout after each period. arm 24: TAK-071 120 mg capsule, orally, once on Day 1 to non-Japanese healthy participants. Dose of TAK-071 was based on 24-hour safety, tolerability, and preliminary plasma PK data from Cohort 6. arm 25: TAK-071 160 mg capsule, orally, once on Day 1 to non-Japanese healthy participants. Dose of TAK-071 was based on 24-hour safety, tolerability, and preliminary plasma PK data from Cohort 18. arm 26: TAK-071 placebo-matching capsule, orally, once on Day 1 followed by donepezil placebo-matching tablet, orally on Day 2 to non-Japanese healthy participants. arm 27: TAK-071 placebo-matching capsule, orally, once on Day 1 followed by donepezil 10 mg tablet, orally, on Day 2 to non-Japanese healthy participants. arm 28: TAK-071 40 mg capsule, orally, once on Day 1 followed by donepezil 10 mg, tablets, orally, once on Day 2 to non-Japanese healthy participants. Dose of TAK-071 was based on 24-hour safety, tolerability, and preliminary plasma PK data from Cohort 19. arm 29: TAK-071 60 mg capsule, orally, once on Day 1 followed by donepezil 10 mg, tablets, orally, once on Day 2 to non-Japanese healthy participants. Dose of TAK-071 was based on 24-hour safety and tolerability data from Cohort 20. arm 30: TAK-071 80 mg capsule, orally, once on Day 1, followed by donepezil 10 mg, tablets, orally, once on Day 2 to non-Japanese healthy participants. Dose of TAK-071 was based on 24-hour safety and tolerability data from Cohort 21.
Interventions: intervention 1: TAK-071 intervention 2: Donepezil intervention 3: TAK-071 Placebo intervention 4: Donepezil Placebo
Intervention descriptions: intervention 1: TAK-071 capsules intervention 2: Donepezil over-encapsulated tablet intervention 3: TAK-071 placebo-matching capsules intervention 4: Donepezil placebo-matching over-encapsulated tablet

Protocol documents:
Prot_000.pdf: 
This may include, but is not limited to, redaction of the following: 


•
Title: A Phase 1 Safety, Tolerability, and Pharmacokinetic Study of Escalating Single and Multiple 
Oral Doses of TAK-071 in Healthy Subjects and Subjects With Mild Cognitive Impairment/Mild 
Alzheimer Disease and Relative Bioavailability and Food Effect of TAK-071 in Healthy Subjects
NCT Number: NCT02769065
Protocol Approve Date: 15 May 2017
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, 
or to otherwise protect the integrity of the clinical study.


TITLE PAGE
PROTOCOL AMENDMENT
A Phase 1 Safety, Tolerability, and Pharmacokinetic Study of Escalating Single and 
Multiple Oral Doses of TAK-071 in Healthy Subjects and Subjects With Mild Cognitive 
Impairment/Mild Alzheimer Disease and Relative Bioavailability and Food Effect of 
TAK-071 in Healthy Subjects
Phase 1 Single and Multiple Rising Dose Study of TAK-071 in Healthy Subjects and 
Subjects With Mild Cognitive Impairment/Mild Alzheimer Disease and Relative 
Bioavailability and Food Effect of TAK-071 in Healthy Subjects
Sponsor:
Takeda Development Center Americas, Inc.
One Takeda Parkway
Deerfield, IL 60015
USA
Study Number:
TAK-071-1001
IND Number:
128,849
EudraCT Number:
Not applicable
Compound:
TAK-071 
Date:
15 May 2017
Version/Amendment 
Number:
Amendment No. 05
Amendment History:
Date
Amendment Number
Region
24 March 2016
Initial version
Global
31 May 2016
01
Global
19 August 2016
02
Global
21 October 2016
03
Global
15 February 2017
04
Global
15 May 2017
05
Global
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.


TAK-071
Study No. TAK-071-1001
Page 2 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided to each site.
Contact Type / Role
Contact
Serious adverse event and pregnancy reporting
Pharmacovigilance
Takeda Development Center Americas, Inc. (TDC Americas)
Medical Monitor
(medical advice on protocol and compound)
Responsible Medical Officer (carries overall 
responsibility for the conduct of the study)
TDC Americas
One Takeda Parkway
Deerfield, IL 60015
USA
PPD


TAK-071
Study No. TAK-071-1001
Page 3 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
1.2
Approval
REPRESENTATIVES OF TAKEDA
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonisation E6 Good Clinical Practice Consolidated
Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical
trial disclosure laws, and regulations.
SIGNATURES
Electronic signatures of the following responsible Takeda medical officer and other signatories are 
located on the last page of this document.
PPD


TAK-071
Study No. TAK-071-1001
Page 4 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and any 
other product information provided by the sponsor. I agree to conduct this study in accordance 
with the requirements of this protocol and also to protect the rights, safety, privacy, and well-being 
of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B - Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State)
Location of Facility (Country)


TAK-071
Study No. TAK-071-1001
Page 5 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
1.3
Protocol Amendment No. 05 Summary of Changes 
Rationale for Amendment 05
This document describes the changes in reference to the protocol incorporating Amendment 
No. 05. The primary reason for this amendment is to update the study design to include an interim 
analysis of the single-rising dose (SRD) and multiple-rising dose (MRD) data, revise Cohort 16 
inclusion criteria and screening period length, add optional run-in period for Cohort 16, and add 
flexible language to allow for additional SRD cohorts for TAK-071 coadministered with donepezil 
(10 mg). Personnel changes, inconsistencies, and minor grammatical, editorial, and formatting 
changes are included for clarification purposes only.
For specific description of text changes and where the changes are located, see Appendix G. 
Changes in Amendment 05
1. An additional SRD cohort (Cohort 22) has been added to the study and the approximate total 
number of subjects to be enrolled has been increased accordingly.
2. Allowing flexibility for enrollment in Cohort 16.
3. The inclusion criteria and screening period length for Cohort 16 have been revised. An 
optional run-in period of 49 days was added for Cohort 16.
4. An interim analysis of the SRD and MRD cohort data has been included.
5. To add no food effect statement for Cohort 16.
6. The sponsor signatories for this protocol have been updated.


TAK-071
Study No. TAK-071-1001
Page 6 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment No. 05 Summary of Changes ...................................................5
2.0
STUDY SUMMARY ....................................................................................................13
3.0
STUDY REFERENCE INFORMATION ......................................................................19
3.1
Study-Related Responsibilities.................................................................................19
3.2
Principal Investigator...............................................................................................19
3.3
List of Abbreviations ...............................................................................................20
3.4
Corporate Identification...........................................................................................22
4.0
INTRODUCTION.........................................................................................................23
4.1
Background .............................................................................................................23
4.2
Rationale for the Proposed Study.............................................................................24
4.3
Benefit/Risk Profile .................................................................................................25
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................27
5.1
Objectives................................................................................................................27
5.1.1
Primary Objectives......................................................................................27
5.1.2
Secondary Objectives..................................................................................27
5.1.3
Exploratory/Additional Objectives ..............................................................27
5.2
Endpoints.................................................................................................................28
5.2.1
Primary Endpoints.......................................................................................28
5.2.1.1
Safety.....................................................................................................28
5.2.1.2
PK..........................................................................................................28
5.2.2
Secondary Endpoints...................................................................................28
5.2.3
Exploratory/Additional Endpoints...............................................................29
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................31
6.1
Study Design ...........................................................................................................31
6.1.1
SRD Part (Cohorts 1 to 6 and 18 to 22) .......................................................36
6.1.2
MRD Part (Cohorts 7 to 15) ........................................................................37
6.1.2.1
Non-Japanese Subjects (Cohorts 7 to 9)..................................................37
6.1.2.2
Non-Japanese Subjects Pretreated With Donepezil (Cohorts 10 to 12)....38
6.1.2.3
Japanese Subjects (Cohorts 13 to 15)......................................................38
6.1.3
Subjects With MCI or Mild AD (Cohort 16) ...............................................39
6.1.4
Relative BA and FE Cohort (Cohort 17)......................................................39


TAK-071
Study No. TAK-071-1001
Page 7 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
6.1.5
Dose Escalation...........................................................................................40
6.2
Justification for Study Design, Dose, and Endpoints ................................................41
6.2.1
Study Design...............................................................................................41
6.2.2
Dose Selection ............................................................................................42
6.2.2.1
TAK-071 Starting Dose (Cohort 1).........................................................42
6.2.2.2
Dose Escalations and Maximum TAK-071 Dose to be Administered......43
6.2.2.3
Dose selection for the Food Effect/Relative BA Cohort 17 .....................46
6.2.2.4
Donepezil Dose Selection.......................................................................47
6.2.3
Endpoints....................................................................................................48
6.3
Premature Termination or Suspension of Study or Investigational Site.....................49
6.3.1
Criteria for Premature Termination or Suspension of the Study...................49
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites ..50
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s).........................................................50
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............51
7.1
Inclusion Criteria .....................................................................................................51
7.2
Exclusion Criteria ....................................................................................................52
7.2.1
Additional Exclusion Criteria for Cohorts With CSF Collection..................54
7.2.2
Additional Exclusion Criteria for Cohorts 18 to 22......................................55
7.3
Excluded Medications, Dietary Products, Procedures, and Treatments.....................55
7.4
Diet, Fluid, and Activity Control..............................................................................56
7.4.1
Fasting Cohorts (1 to 15 and 17 to 22).........................................................57
7.4.2
Cohort 16....................................................................................................58
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................58
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................59
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................60
8.1
Study Medication and Materials...............................................................................60
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling..............................60
8.1.1.1
Investigational Drug ...............................................................................60
8.1.1.2
Companion Medication ..........................................................................61
8.1.1.3
Sponsor-Supplied Drug ..........................................................................61
8.1.2
Storage........................................................................................................61
8.1.3
Dose and Regimen ......................................................................................61
8.1.4
Overdose.....................................................................................................62
8.2
Investigational Drug Assignment and Dispensing Procedures ..................................63
8.3
Randomization Code Creation and Storage..............................................................63


TAK-071
Study No. TAK-071-1001
Page 8 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
8.4
Investigational Drug Blind Maintenance ..................................................................64
8.5
Unblinding Procedure..............................................................................................64
8.5.1
Sponsor PD Unblinding ..............................................................................64
8.5.2
Sponsor Interim Analysis Unblinding..........................................................64
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................64
9.0
STUDY PLAN ..............................................................................................................66
9.1
Study Procedures.....................................................................................................66
9.1.1
Informed Consent Procedure.......................................................................66
9.1.1.1
Pharmacogenomics Informed Consent Procedure ...................................66
9.1.2
Demographics, Medical History, and Medication History Procedure...........66
9.1.3
Physical Examination Procedure .................................................................67
9.1.3.1
Funduscopy (Cohorts With CSF Sampling Only)....................................67
9.1.4
Weight, Height, and BMI............................................................................67
9.1.5
MMSE ........................................................................................................68
9.1.6
Vital Sign Procedure ...................................................................................68
9.1.7
Documentation of Concomitant Medications...............................................69
9.1.8
Documentation of Concurrent Medical Conditions......................................69
9.1.9
Procedures for Clinical Laboratory Samples................................................69
9.1.10
Contraception and Pregnancy Avoidance Procedure....................................71
9.1.11
Pregnancy ...................................................................................................72
9.1.12
ECG Procedure ...........................................................................................73
9.1.12.1
Screening and Safety ECGs....................................................................73
9.1.12.2
Holter.....................................................................................................73
9.1.13
Bowel Function...........................................................................................74
9.1.14
PGx Sample Collection ...............................................................................75
9.1.15
PK Sample Collection.................................................................................76
9.1.15.1
Collection of Blood for PK Sampling .....................................................76
9.1.15.2
Collection of Urine for PK Sampling......................................................79
9.1.15.3
Collection of CSF for PK Sampling........................................................80
9.1.15.4
Bioanalytical Methods............................................................................80
9.1.16
PK Parameters.............................................................................................80
9.1.17
PD Assessments..........................................................................................82
9.1.17.1
.....................................................................................................82
9.1.17.2
...............................................................................................83
9.1.18
PD Parameters.............................................................................................84
CCI
CCI


TAK-071
Study No. TAK-071-1001
Page 9 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
9.1.19
Documentation of Screen Failure ................................................................85
9.1.20
Documentation of Randomization ...............................................................85
9.1.21
Assessment of Suicidal Ideation and Behavior ............................................86
9.2
Monitoring Subject Treatment Compliance..............................................................86
9.3
Schedule of Observations and Procedures................................................................86
9.3.1
Screening ....................................................................................................86
9.3.2
Study Randomization..................................................................................86
9.3.3
Treatment Phase/Washout Phase .................................................................86
9.3.4
Final Visit ...................................................................................................87
9.3.5
Early Termination .......................................................................................87
9.3.6
Follow-up Visit/Telephone Call ..................................................................87
9.4
Biological Sample Retention and Destruction ..........................................................87
9.5
Blood Volume .........................................................................................................88
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................95
10.1
Definitions...............................................................................................................95
10.1.1
PTEs...........................................................................................................95
10.1.2
AEs.............................................................................................................95
10.1.3
Additional Points to Consider for PTEs and AEs.........................................95
10.1.4
SAEs...........................................................................................................97
10.1.5
Severity of PTEs and AEs ...........................................................................98
10.1.6
Causality of AEs .........................................................................................98
10.1.7
Relationship to Study Procedures................................................................98
10.1.8
Start Date....................................................................................................99
10.1.9
Stop Date ....................................................................................................99
10.1.10
Frequency ...................................................................................................99
10.1.11
Action Concerning Study Drug ...................................................................99
10.1.12
Outcome .....................................................................................................99
10.2
Procedures.............................................................................................................100
10.2.1
Collection and Reporting of AEs...............................................................100
10.2.1.1
PTE and AE Collection Period .............................................................100
10.2.1.2
PTE and AE Reporting .........................................................................100
10.2.2
Collection and Reporting of SAEs.............................................................101
10.2.3
Reporting of Abnormal Liver Function Tests ............................................101
10.3
Follow-up of SAEs ................................................................................................102
10.3.1
Safety Reporting to Investigators, IRBs, and Regulatory Authorities.........102


TAK-071
Study No. TAK-071-1001
Page 10 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
11.0
STUDY-SPECIFIC COMMITTEES ...........................................................................103
12.0
DATA HANDLING AND RECORDKEEPING..........................................................104
12.1
CRFs (Electronic and Paper)..................................................................................104
12.2
Record Retention ...................................................................................................104
13.0
STATISTICAL METHODS........................................................................................106
13.1
Statistical and Analytical Plans ..............................................................................106
13.1.1
Analysis Sets.............................................................................................106
13.1.2
Analysis of Demographics and Other Baseline Characteristics ..................106
13.1.3
PK Analysis ..............................................................................................107
13.1.4
PD Analysis ..............................................................................................108
13.1.5
Safety Analysis .........................................................................................109
13.1.5.1
AEs ......................................................................................................109
13.1.5.2
Clinical Laboratory Evaluation.............................................................109
13.1.5.3
Vital Signs............................................................................................109
13.1.5.4
ECGs....................................................................................................109
13.1.5.5
Bowel Function ....................................................................................109
13.2
Interim Analysis and Criteria for Early Termination ..............................................110
13.2.1
Interim Analysis of Cohorts 1 to 15 and 17 to 22 Data ..............................110
13.2.2
Interim Analysis of PD Data .....................................................................110
13.2.2.1
Pupillometry Data.................................................................................110
13.2.2.2
...........................................................................................110
13.3
Determination of Sample Size................................................................................110
14.0
QUALITY CONTROL AND QUALITY ASSURANCE.............................................112
14.1
Study-Site Monitoring Visits .................................................................................112
14.2
Protocol Deviations................................................................................................112
14.3
Quality Assurance Audits and Regulatory Agency Inspections ..............................113
15.0
ETHICAL ASPECTS OF THE STUDY......................................................................114
15.1
IRB Approval ........................................................................................................114
15.2
Subject Information, Informed Consent, and Subject Authorization .......................114
15.3
Subject Confidentiality ..........................................................................................116
15.4
Publication, Disclosure, and Clinical Trial Registration Policy...............................116
15.4.1
Publication and Disclosure........................................................................116
15.4.2
Clinical Trial Registration.........................................................................117
15.4.3
Clinical Trial Results Disclosure ...............................................................117
15.5
Insurance and Compensation for Injury..................................................................117
CCI


TAK-071
Study No. TAK-071-1001
Page 11 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
16.0
REFERENCES............................................................................................................118
LIST OF IN-TEXT TABLES
Table 6.a
Overview of Treatment Cohorts.........................................................................33
Table 6.b
Sequence Groups and Regimen Assignment for Cohort 17.................................40
Table 6.c
Exposure to TAK-071 at the NOAEL in Rats and Monkeys (28-day GLP data) 
at Steady-State and Human Predicted Mean Exposure After a Single 1 mg 
TAK-071 Dose...................................................................................................43
Table 7.a
Prohibited Medications and Dietary Products.....................................................56
Table 7.b
Content of a Standard, High-Fat Breakfast .........................................................58
Table 8.a
Composition of TAK-071 for DIC and Matching Placebo ..................................60
Table 8.b
Composition of Over-Encapsulated Donepezil and Matching Placebo................61
Table 9.a
Clinical Laboratory Tests...................................................................................70
Table 9.b
Timing of Holter ECG Monitoring.....................................................................74
Table 9.c
Collection of Blood Samples for PK Analysis for Cohorts 1 to 6, 18, and 19......77
Table 9.d
Collection of Blood Samples for PK Analysis for Cohorts 7 and 8 .....................77
Table 9.e
Collection of Blood Samples for PK Analysis for Cohorts 9 and 13 to 15...........77
Table 9.f
Collection of Blood Samples for PK Analysis for Cohorts 10 to 12....................78
Table 9.g
Collection of Blood Sample for PK Analysis of Cohort 16.................................78
Table 9.h
Collection of Blood Sample for PK Analysis of Cohort 17.................................78
Table 9.i
Collection of Blood Sample for PK Analysis of Cohorts 20 to 22.......................78
Table 9.j
Collection of Urine Samples for PK Analysis for Cohorts 1 to 6, 18 and 19 .......79
Table 9.k
Collection of Urine Samples for PK Analysis for Cohorts 7 and 8......................79
Table 9.l
Collection of Urine Samples for PK Analysis for Cohorts 9 and 13 to 15...........79
Table 9.m
Collection of Urine Samples for PK Analysis for Cohort 16...............................79
Table 9.n
Collection of 
..........................................................................................82
Table 9.o
Collection of Safety 
................................................................................83
Table 9.p
Pupillometry Collection .....................................................................................84
Table 9.q
Approximate Blood Volume for Cohorts 1 to 6, 18, and 19................................88
Table 9.r
Approximate Blood Volume for Cohorts 7 and 8................................................89
Table 9.s
Approximate Blood Volume for Cohorts 9 and 13 to 15 (Japanese)....................90
Table 9.t
Approximate Blood Volume for Cohorts 10 to 12 ..............................................91
Table 9.u
Approximate Blood Volume for Cohort 16 ........................................................92
Table 9.v
Approximate Blood Volume for Cohort 17 ........................................................93
Table 9.w
Approximate Blood Volume for Cohorts 20 to 22 ..............................................93
CCI
CCI


TAK-071
Study No. TAK-071-1001
Page 12 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Table 10.a
Takeda Medically Significant AE List................................................................98
Table 14.a
Windows for PK Blood Sample Collection ......................................................113
LIST OF IN-TEXT FIGURES
Figure 6.a
Flow of Treatment Cohorts ................................................................................34
Figure 6.b
Schematic of Study Design for SRD Cohorts 1 to 6 and 18 to 22........................34
Figure 6.c
Schematic of Study Design for MRD Cohorts 7 and 8........................................35
Figure 6.d
Schematic of Study Design for MRD Cohorts 9 and 13 to 15.............................35
Figure 6.e
Schematic of Study Design for MRD Cohorts 10 to 12.......................................35
Figure 6.f
Schematic of Study Design for Cohort 16...........................................................35
Figure 6.g
Schematic Study Design for Cohort 17...............................................................36
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures..........................................................................120
Appendix B
Responsibilities of the Investigator...................................................................138
Appendix C
Elements of the Subject Informed Consent.......................................................140
Appendix D
Investigator Consent to Use of Personal Information........................................143
Appendix E
Collection, Storage, and Shipment of Bioanalytical Samples............................144
Appendix F
Moderate and Strong CYP3A4, 2D6, or 2C9 Inducers/Inhibitors......................148
Appendix G
Detailed Description of Amendments to Text...................................................149


TAK-071
Study No. TAK-071-1001
Page 13 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc.
Compound:
TAK-071
Title of Protocol: A Phase 1 Safety, Tolerability, and 
Pharmacokinetic Study of Escalating Single and Multiple 
Oral Doses of TAK-071 in Healthy Subjects and Subjects 
With Mild Cognitive Impairment/Mild Alzheimer Disease 
and Relative Bioavailability and Food Effect of TAK-071 in 
Healthy Subjects
IND No.:
128,849
EudraCT No.:
Not applicable
Study Number: TAK-071-1001
Phase: 1
Study Design:
This is a first-in-human, phase 1, safety, tolerability, and pharmacokinetic (PK) study of escalating single and multiple 
oral doses of TAK-071 in healthy adult (non-Japanese and Japanese) male and female subjects and subjects with mild 
cognitive impairment (MCI) or mild Alzheimer disease (AD) (non-Japanese). In addition, the relative bioavailability 
of a tablet formulation (test) vs the reference drug-in-capsule (DIC) formulation as well as the effect of food on the PK 
of the tablet formulation will be investigated in healthy subjects.
The first time TAK-071 is dosed to humans will be a single oral dose administered in Cohort 1 of the single-rising dose 
(SRD) part of this study. Additional cohorts (Cohorts 2 to 6, 18, and 19) will be used to study escalating single-dose 
levels.
Higher or lower dose cohort(s) may be added in the SRD part of the study to fully understand safety and tolerability of 
TAK-071. The SRD part of the study will consist of a randomized, double-blind, placebo-controlled, parallel-group 
ascending dose design with 8 subjects per cohort. 
SRD cohorts (Cohorts 20 to 22) will explore the safety and tolerability of single doses of TAK-071 (80, 60, and 40 mg, 
respectively; however, actual doses administered will be determined from emerging data) when coadministered with 
donepezil (10 mg) in healthy subjects. These cohorts will consist of a randomized, double-blind, placebo-controlled, 
parallel-group ascending dose design with 12 subjects per cohort. These cohorts will establish a high well-tolerated 
dose of TAK-071 when coadministered with donepezil for the scopolamine challenge proof-of-mechanism (PoM) 
study.
Cohorts 7 to 15 will be used in the multiple-rising dose (MRD) part of this study. The MRD part of the study will thus 
consist of a randomized, double-blind, placebo-controlled, 9-cohort, parallel-group multiple ascending dose design 
with 8 subjects per cohort in Cohorts 7 to 12 and 6 subjects in Cohorts 13 to 15. Additional MRD cohorts (TAK-071 
and/or TAK-071+donepezil) may be added to fully understand safety and tolerability of TAK-071. Selected MRD 
cohorts (Cohorts 10 to 12) will be pretreated for 3 weeks with daily oral doses of donepezil (5 mg once daily [QD]), 
followed by continued daily oral donepezil dosing during the TAK-071 treatment period. 
Cohort 16 will include up to 8 subjects (minimum of 6) with MCI or mild AD on stable donepezil treatment or who 
consent to a donepezil run-in period of 5 mg dose for 28 days and titrate up to 10 mg for at least 21 days. Subjects with 
previous MCI/AD diagnosis who have been treated with 5 mg for at least 28 days prior to Screening may consent to a 
donepezil run-in period of 10 mg for at least 21 days. This cohort will be conducted in a placebo-controlled, 
2-sequence, 2-period, 2-way crossover design.
Cohort 17 will include up to 12 subjects. This cohort will be conducted in an open-label 3-period, 3-sequence, 3-way 
crossover design. Cohorts 1 to 12 and 16 to 21 will include non-Japanese subjects. Cohorts 13 to 15 will include 
Japanese subjects.
Subjects in each cohort (Cohorts 1 to 16, 18, and 19) will be randomized to receive treatment with TAK-071 or 
matching placebo using DIC in the morning following a minimum fast of 8 hours. In Cohorts 1 to 12, 18, and 19, 
placebo treatments will be assigned in a 3:1 ratio (within each cohort of 8 subjects, 6 will receive active treatment and 
2 will receive placebo). 
Subjects in Cohorts 20 and 22 will be assigned in a 1:1:2 ratio to receive treatments (within each cohort of 12 subjects, 


TAK-071
Study No. TAK-071-1001
Page 14 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
3 will receive TAK-071 placebo+donepezil placebo, 3 subjects will receive TAK-071 placebo+donepezil, and 6 
subjects will receive TAK-071+donepezil).
In Cohorts 13 to 15, placebo treatments will be assigned in a 5:1 ratio (within each cohort of 6 subjects, 5 will receive 
active treatment and 1 will receive placebo. In Cohort 16, subjects will be assigned to 1 of 2 possible treatment 
sequences (AB or BA), with Treatment A being TAK-071 and Treatment B being matching placebo. In Cohort 17, 
subjects will be assigned to 1 of 3 possible treatments as Regimen Sequences ABC, BCA, and CAB, where, Regimen 
A=Fasted State and Capsule Formulation (10 mg in DIC formulation), Regimen B=Fasted State and Tablet 
Formulation (10 mg tablet formulation), and Regimen C=Fed State and Tablet Formulation (10 mg tablet 
formulation). 
The safety of TAK-071 alone or in combination with donepezil or with/without food will be assessed through adverse 
events (AEs), clinical laboratory results, physical examination findings, electrocardiogram (ECG) findings, bowel 
function, vital signs, and suicidal assessments. Continuous 12-lead Holter ECG monitoring will also be performed on 
selected study cohorts.
The safety and tolerability of donepezil alone will be evaluated during the donepezil dosing phase (before TAK-071 is 
given in Cohorts 10 to 12) during the 3-week pretreatment period, and the safety and tolerability of donepezil in 
combination with TAK-071 (Cohorts 20 to 22) will be evaluated by assessing AEs, clinical laboratory results, physical 
examination findings, ECG findings, bowel function, and vital signs. 
In addition to safety monitoring, TAK-071 plasma and urine PK profiles will be generated and PK parameters derived. 
It is planned that cerebrospinal fluid (CSF) samples for PK analysis will be obtained in Cohort 3 (following a single 
dose) and Cohort 9 (at steady-state). Pharmacodynamic measures will include the determination of pupil size and 
quantitative electroencephalography (EEG).
Approximately 186 subjects are expected to be randomized in this study.
End of study is defined as the date of last visit of the last subject for last clinical assessment.
Primary Objectives:

To characterize the safety, tolerability, and plasma PK profile of TAK-071 when administered as single and 
multiple QD oral doses at escalating dose levels in healthy subjects (non-Japanese).

To characterize the safety, tolerability, and plasma PK profile of TAK-071 when administered as single and 
multiple QD oral doses at escalating dose levels in healthy subjects (non-Japanese) in the presence of steady-state 
exposure of donepezil QD. 

To characterize the safety, tolerability, and plasma PK profile of TAK-071 when administered as single and 
multiple QD oral doses at escalating dose levels in healthy Japanese subjects.

To characterize safety, tolerability, and plasma PK profile of 10 mg donepezil when administered as a single dose, 
and to compare it to combination of 10 mg donepezil plus TAK-071.

To characterize the safety, tolerability, and plasma PK profile of TAK-071 when administered as multiple QD 
oral doses to subjects with MCI or mild AD (non-Japanese) receiving donepezil treatment for a minimum of 3 
months.
Secondary Objectives:

To assess safety of 120 mg or higher single dose of TAK-071 measured by EEG.

To evaluate the urinary clearance of TAK-071 following single and multiple oral doses.

To evaluate the brain penetration of TAK-071 as measured in CSF following single and multiple dosing.

To evaluate the dose proportionality and any time dependency in TAK-071 plasma PK.

To evaluate the effect of multiple daily doses of TAK-071 on donepezil steady-state PK.

To evaluate the relative bioavailability (BA) of TAK-071 10 mg administered as tablet formulation compared 
with TAK-071 10 mg administered as DIC formulation.

To evaluate potential effect of food on the TAK-071 plasma PK following a single oral dose of 10 mg tablet 
formulation.


TAK-071
Study No. TAK-071-1001
Page 15 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Subject Population: 
Cohorts 1 to 12, 17, and 18 to 22: Healthy non-Japanese subjects aged 18 to 55 years, inclusive.
Cohorts 13 to 15: Healthy Japanese subjects aged 20 to 55 years, inclusive.
Cohort 16: Subjects aged 55 to 90 years, inclusive, with MCI or mild AD.
Number of Subjects:
Cohorts 1 to 12, 18, and 19: 8 (6 TAK-071, 2 placebo) 
Cohorts 13 to 15: 6 (5 TAK-071, 1 placebo)
Cohort 16: 8 (minimum of 6 completers) (TAK-071 and 
placebo)
Cohort 17: 12
Cohorts 20 to 22: 12 (6 TAK-071+donepezil, 3 donepezil, 3 
placebo)
Estimated total: 186 randomized
Number of Sites:
Estimated total: 1 site in the United States
Dose Levels:
TAK-071
SRD Cohorts (1 to 6, 18, and 19): first dose 1 mg TAK-071 
QD, subsequent dose levels to be determined by emerging 
safety, tolerability, and PK data in preceding cohorts.
SRD+donepezil Cohorts (20 to 22): 80, 60, and 40 mg (the 
actual dose will be determined based on emerging data).
MRD Cohorts 7 to 15 and Cohort 16: doses to be 
determined by emerging safety, tolerability, and PK data in 
preceding SRD/MRD cohorts.
Note: There will be a TAK-071 exposure/dose cap, so that 
subjects do not exceed the observed average plasma 
exposures at the lowest steady-state 
no-observed-adverse-effect level (NOAEL) achieved in 
4-week toxicology studies.
Food effect cohort (Cohort 17): 10 mg administered as a 
tablet or DIC. Higher or lower dose may be selected based 
on emerging PK data from previous cohorts.
Donepezil
Cohorts 10 to 12: donepezil 5 mg QD in the morning.
Cohort 16: donepezil 10 mg (or titrated to 10 mg in run-in 
period) QD in the evening (bedtime).
Cohorts 20 to 22: donepezil 10 mg as a single dose.
Route of Administration:
Oral
Duration of Treatment:
SRD Cohorts 1 to 6, 18 and 19: 1 day TAK-071
SRD+donepezil Cohorts 20 to 22: 2 days (TAK-071 on Day 
1 and donepezil on Day 2).
MRD Cohorts 7 to 8: 21 days TAK-071
MRD Cohorts 9 and 13 to 15: 1 day TAK-071, followed by 
a 7-day washout period and 21 days of TAK-071 dosing
MRD Cohorts 10 to 12: 21 days of pretreatment with 
donepezil followed by 21 days of dosing with TAK-071 and 
donepezil.
Cohort 16: 21 days TAK-071 (Treatment A) followed by 21 
days of washout and 21 days of matching placebo 
Period of Evaluation:
SRD Cohorts 1 to 6, 18 and 19: approximately 40 days.
SRD+donepezil Cohorts 20 to 22: approximately 40 
days.
MRD Cohorts 7 and 8: approximately 60 days.
MRD Cohorts 9 and 13 to 15: approximately 57 days.
MRD Cohorts 10 to 12: approximately 76 days.
MRD Cohort 16: approximately 130 days.
Food effect Cohort 17: approximately 82 days.


TAK-071
Study No. TAK-071-1001
Page 16 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
(Treatment B), or vice versa. A donepezil run-in period of 
49 days, prior to starting Treatment A, may be included if 
the subject is diagnosed at Screening. 
Cohort 17: 1 day TAK-071 (single dose as DIC, tablet under 
fasting, or tablet under fed condition) in each of 3 periods 
with 21-day washout after Periods 1 and 2. 
Main Criteria for Inclusion:

The subject is a man or woman who weighs at least 50 kg and has a body mass index (BMI) from 18.0 to 
30.0 kg/m2, inclusive, at Screening.

For Cohorts 13 to 15 only: First-generation Japanese, defined as having been born in Japan of Japanese parents 
and Japanese grandparents and living no more than 10 years outside of Japan, with no significant change in 
lifestyle, including diet, while living outside of Japan.

Cohort 16 only: Subjects with a documented previous diagnosis of MCI or mild AD, with a Mini Mental State 
Examination score of 18 to 30, inclusive, and no biomarker data to contradict this diagnosis. Retrospectively, 
subjects will have met a diagnosis of probable AD based on the National Institute of Neurological Disorders and 
Stroke Alzheimer’s Disease and Related Disorders Association criteria or MCI diagnosis based on criteria such as 
subjective cognitive complaint, evidence of impairment in 1 or more cognitive domain, preservation of functions, 
and absence of dementia. Subjects must be receiving ongoing donepezil therapy (10 mg) for a minimum of 21 
days or who consent to take donepezil dose titrated up to 10 mg as run-in treatment for at least 21 days.
Main Criteria for Exclusion:

The subject has clinically significant (Cohorts 1 to 15, and 17 to 22) or uncontrolled (Cohort 16) neurologic, 
cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal (GI), urologic, immunologic, endocrine, or 
psychiatric disease or other abnormality (other than the disease being studied), which may impact the ability of 
the subject to participate or potentially confound the study results.

A subject with a history of type 1 diabetes (Cohorts 1 to 22) or type 2 diabetes (Cohorts 1 to 15 and 17 to 22 or 
subject with hemoglobin A1c >6.5% at Screening. Note: subjects with controlled (hemoglobin A1c <7.0% at 
Screening) type 2 diabetes in Cohort 16 may participate in the study.

The subject has a risk of suicide or suicidal ideation with intent and plan according to the investigator’s clinical 
judgment (affirmative answer to questions 4 and 5 of the ideation section of the Columbia-Suicide Severity 
Rating Scale) or has made a suicide attempt in the previous 6 months.

Cohort 16 only: Any significant neurologic disease (other than suspected incipient or mild AD), such as 
Parkinson disease, stroke, transient ischemic attack, multi-infarct dementia, Huntington disease, head trauma with 
clinically significant cognitive sequelae, or chronic central nervous system infection.

The subject has current or recent (within 6 months) GI disease that would be expected to influence the absorption 
of drugs (ie, a history of malabsorption, any surgical intervention known to impact absorption [eg, bariatric 
surgery or bowel resection], esophageal reflux, peptic ulcer disease, erosive esophagitis, or frequent [more than 
once per week] occurrence of heartburn).
Main Criteria for Evaluation and Analyses:
The primary safety endpoints are as follows:

Percentage of subjects who have at least 1 treatment-emergent adverse event (TEAE).

Percentage of subjects who meet the Takeda markedly abnormal value (MAV) criteria at least once postdose for 
the following:
–
Clinical laboratory parameters. 
–
Vital sign measurements. 
–
ECG parameters. 
The primary PK parameters of TAK-071 in plasma following a single dose (Day 1) and at steady-state (after the final 


TAK-071
Study No. TAK-071-1001
Page 17 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
dose following multiple dosing) are as follows:

Time of first occurrence of Cmax (tmax). 

Maximum observed plasma concentration (Cmax). 

Area under the plasma concentration-time curve from time 0 to 24 hours (AUC24).

Area under the plasma concentration-time curve from time 0 to infinity (AUC∞) (single dose only [Day 1]).
The secondary endpoints are as follows:
Plasma and urine PK parameters of TAK-071 following a single dose (Day 1) and at steady-state (after the final dose 
following multiple dosing), including but not limited to the following: 

Area under the plasma concentration-time curve from time 0 to time t (AUCt).

Terminal disposition phase half-life (t1/2z), as permitted by the data (single dose only [Day 1]).

Apparent clearance after extravascular administration (CL/F).

Apparent volume of distribution during the terminal disposition phase after extravascular administration (Vz/F).

Accumulation ratio based on AUCτ (Rac(AUC)).

Accumulation ratio based on Cmax (Rac(Cmax)).

Amount of drug excreted in urine from time 0 to time t (Aet).

Fraction of administered dose of drug excreted in urine from time 0 to time t (fe,t).

Renal clearance (CLR).
CSF PK of TAK-071 planned for the single-dose Cohort 3 and at steady-state in Cohort 9 (after the final dose 
following multiple dosing), including but not limited to the following: 

Maximum observed concentration in CSF (CSF Cmax).

Area under the CSF concentration-time curve from time 0 to 12 hours (CSF AUC12) (Cohort 3 only [Day 1]).

Area under the CSF concentration-time curve from time 0 to 36 hours (CSF AUC36) (Cohort 9 only [Day 28]). 

The ratio of CSF AUC12 to the plasma AUC12 (CSF AUC12:plasma AUC12) (Cohort 3 only [Day 1]).

The ratio of CSF AUC36 to the plasma AUC36 (CSF AUC36:plasma AUC36) (Cohort 9 only [Day 28]).
Plasma steady-state PK parameters of donepezil (Cohorts 10 to 12) on the last donepezil pretreatment day and after 21 
daily doses of TAK-071, including but not limited to the following: 

tmax.

Cmax.

AUC24.

Ratio of geometric mean steady-state AUC24 and Cmax for donepezil after 21 daily doses of TAK-071 in reference 
to donepezil alone and the associated 90% confidence intervals (CIs).
Statistical Considerations:
PK Analysis
Plasma and CSF concentrations of TAK-071 and plasma concentrations of donepezil, where appropriate, will be 
summarized by dose or regimen over each scheduled sampling time using descriptive statistics. Individual plasma 
concentration data vs time will be presented in a data listing.
Plasma PK parameters and CSF PK parameters, where applicable, will be summarized separately for SRD, MRD, 
presence/absence of donepezil, and for Japanese subjects. 
Dose proportionality for the SRD and MRD parts (separately) will be assessed using the empirical power law model. 
This analysis will be carried out to assess the degree of dose proportionality based on the dose-proportionality 
exponent (β) for the model, for both Cmax and AUC∞on Day 1 and Cmax and AUC24 at steady-state.
Dose linearity will be examined in the event that dose proportionality cannot be established by using a simple linear 


TAK-071
Study No. TAK-071-1001
Page 18 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
regression on the exposure parameter.
Trough plasma concentrations measured in the MRD part will be summarized to assess steady-state. The time to 
steady-state will be assessed by fitting trough concentration values to a nonlinear mixed effects model in order to 
predict the time to achieve 90% of the steady-state trough concentrations separately for each dose.
Time dependency will be investigated in selected MRD cohorts. The time invariance of TAK-071 will be assessed by 
comparing AUC24 for the last day of dosing to the AUC∞for Day 1 using analysis of variance with a random effect for 
subject and a ﬁxed effect for day.
The effect of TAK-071 on the natural log-transformed steady-state Cmax and AUC24 of donepezil will be assessed 
with a linear mixed-effects model; point estimates for geometric means and geometric mean ratios with 90% CIs will 
be determined.
The concentration and cumulative amount of TAK-071 excreted in urine will be summarized by dose over each 
scheduled collection interval and for selected time intervals, ie, 0 to 96 hours postdose, using descriptive statistics for 
the SRD and MRD parts.
The relative BA of the tablet formulation compared to the reference DIC formulation and the effect of food on the 
plasma PK of TAK-071 will be assessed using an analysis of variance (ANOVA) on the natural logarithms of Cmax 
and AUC∞, with factors for sequence, subject nested within sequence, period, and regimen. The factor of subject 
nested within sequence will be random effect and others are fixed effects.
Safety Analysis
AEs will be presented in listings, and TEAEs will be summarized in tables. Individual results of laboratory tests 
(hematology, chemistry, and urinalysis), vital signs, ECG parameters, and Bristol Stool Form scale scores will be 
listed. Baseline, postdose and change from Baseline to postdose laboratory data, vital signs, ECG parameters, and 
Bristol Stool Form scale scores will be summarized as well as percentage of subjects who meet Takeda MAV criteria. 
Where applicable, within each part, for the non-Japanese and Japanese SRD and MRD cohorts separately, safety data 
will be summarized by placebo, each TAK-071 dose level, TAK-071 overall, and overall total. Placebo data will be 
pooled across cohorts for SRD and MRD parts separately.
Sample Size Justification: The sample sizes chosen for the SRD (8 subjects in Cohorts 1 to 6, 18, and 19, and 12 
subjects in Cohorts 20 to 22) and MRD parts are considered to be sufficient for evaluation of safety, tolerability, and 
PK of each cohort but are not based on statistical power considerations. A sample size of 12 subjects (4 per sequence) 
was chosen for the 3-period, 3-sequence, crossover design in Cohort 17. The sample size is considered sufficient to 
assess the bioavailability of TAK-071 from the tablet relative to the capsule and to assess the effect of food on the 
bioavailability of TAK-071 from the tablet. This sample size was not based on statistical power considerations. 


TAK-071
Study No. TAK-071-1001
Page 19 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator
PPD


TAK-071
Study No. TAK-071-1001
Page 20 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
3.3
List of Abbreviations
λz
terminal disposition phase rate constant
ACh
acetylcholine
AChE
acetylcholinesterase
AChEI
acetylcholinesterase inhibitor
AD
Alzheimer disease
AE
adverse event
Aet
amount of drug excreted in urine from time 0 to time t.
ALT
alanine aminotransferase
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC12
area under the plasma concentration-time curve from time 0 to 12 hours
AUC24
area under the plasma concentration-time curve from time 0 to 24 hours
AUC36
area under the plasma concentration-time curve from time 0 to 36 hours
AUC∞
area under the plasma concentration-time curve from time 0 to infinity
AUCτ
area under the plasma concentration-time curve during a dosing interval
AUClast
area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration
AUCt
area under the plasma concentration-time curve from time 0 to time t
AUEC12
area under the effect concentration-time curve from time 0 to 12 hours 
BA
bioavailability
BMI
body mass index
bpm
beats per minute
BSF
Bristol Stool Form
CFR
Code of Federal Regulations
ChAT
choline acetyltransferase
CI
confidence interval
CL/F
apparent clearance after extravascular administration, calculated using the observed value of the 
last quantifiable concentration
CL/Fss
apparent clearance after extravascular administration, at steady state, calculated using AUCτ
CLR
renal clearance
Cmax
maximum observed concentration
CNS
central nervous system
CSF
cerebrospinal fluid
CSF AUC12
Area under the CSF concentration-time curve from 0 to 12 hours
CSF AUC36
Area under the CSF concentration-time curve from 0 to 36 hours
CSF Cmax
Maximum observed CSF concentration
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P-450


TAK-071
Study No. TAK-071-1001
Page 21 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
DIC
drug-in-capsule
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF 
electronic case report form
EDC
electronic data capture
EEG
electroencephalography
Emax
maximum observed effect
FDA
Food and Drug Administration
FE
food effect
fe
fraction of administered dose of drug excreted in urine
fe,t
fraction of administered dose of drug excreted in urine from time 0 to time t
FIH
first-in-human
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
GLP
Good Laboratory Practice
hCG
human chorionic gonadotropin
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
ICF
informed consent form
ICH
International Conference on Harmonisation
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
K2EDTA
potassium ethylenediamine tetra-acetic acid
LFT
liver function test
M1R
muscarinic acetylcholine receptor 1
MAV
markedly abnormal value
MCI
mild cognitive impairment
MedDRA
Medical Dictionary for Regulatory Activities
MMSE
Mini-Mental State Examination
MRD
multiple-rising dose
MRSD
maximum recommended starting dose
MTD
maximum tolerated dose
NOAEL
no-observed-adverse-effect level
OTC
over-the-counter
PAM
positive allosteric modulator
PD
pharmacodynamic
PGx
pharmacogenomics
PK
pharmacokinetic(s)
PoM
proof-of-mechanism


TAK-071
Study No. TAK-071-1001
Page 22 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
PT
prothrombin time
PTE
pretreatment event
QD
once daily
qEEG
quantitative electroencephalography
Rac(AUC)
accumulation ratio based on AUCτ
Rac(Cmax)
accumulation ratio based on Cmax
RCF
relative centrifugal force
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SOC
system organ class
SOP
standard operating procedure
SRD
single-rising dose
SUSAR
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
t1/2z
terminal disposition phase half-life
TK
toxicokinetic
tmax
time of first occurrence of Cmax
ULN
upper limit of normal
Vz/F
apparent volume of distribution during the terminal disposition phase after extravascular 
administration, calculated using the observed value of the last quantifiable concentration
3.4
Corporate Identification
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable


TAK-071
Study No. TAK-071-1001
Page 23 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
4.0
INTRODUCTION
4.1
Background
Treatment of Alzheimer disease (AD) is a significant healthcare challenge [1-3], with over 
46 million people living with AD or a related dementia worldwide. This number is estimated to 
increase to 131.5 million by 2050 [4]. Of those patients diagnosed with AD, more than two-thirds 
will likely be categorized as having mild or moderate disease [2]. Dementia-related diseases also 
have a huge economic impact. Today, the total estimated worldwide cost of dementia is US 
$818 billion, and it will become a trillion dollar disease by 2018 [4].
Impairment of cholinergic neuronal functions leads to cognitive disturbances and memory loss, the 
hallmark symptoms of AD [5,6]. A reduction in cholinergic neurotransmission has been observed 
in very early stages of AD and is also considered to be associated with the cognitive decline 
associated with dementia with Lewy bodies and Parkinson disease [7]. Postmortem studies of 
patients with AD have confirmed significant losses in the number of basal forebrain cholinergic 
neurons and cortical efferents and reductions in the activity of choline acetyltransferase (ChAT) 
activity, the enzyme that converts choline to acetylcholine (ACh) in presynaptic nerve terminals. 
Reductions in ChAT activity were significant in the medial frontal cortex, inferior parietal cortex, 
and hippocampus and were consistent with clinical symptoms [8]. 
Inhibition of acetylcholinesterase (AChE), the enzyme responsible for the breakdown of ACh, 
represents the current standard of care for AD. This therapeutic strategy results in the generalized 
preservation of endogenous ACh and aims to compensate for its disease-related decline. These 
treatments have only modest effects in the treatment of AD [9]. The combination of AChE 
inhibitors (AChEIs) with the N-methyl-D-aspartate antagonist memantine has a weak effect in the 
treatment of mild to moderate AD [10] with transient clinical benefit.
From a safety and tolerability perspective, AChEIs, such as donepezil, galantamine, and 
rivastigmine, increase the concentration of ACh at the synaptic cleft, thus nonselectively 
increasing ACh concentration in all subtypes of ACh muscarinic receptors (M1-M5R), leading to 
manifestation of various mechanism-related side effects, most commonly diarrhea. Therefore, 
given the paucity of treatment options as well as the tolerability profile of current standard of care,
there exists an unmet medical need for a new more selective treatment for patients with AD with 
an improved efficacy and safety profile.
TAK-071 is a novel muscarinic acetylcholine receptor 1 (M1R) positive allosteric modulator 
(PAM). M1R PAMs do not bind to the orthosteric ACh-binding site but instead act at a distinct site 
to potentiate activation of the receptor by its natural ligand, ACh. M1R is predominantly expressed 
in brain regions related to cognition, learning, and memory, such as the frontal cortex, 
hippocampus, and limbic area. Based on the expression pattern of M1R and its role in cognitive 
function, the selective stimulation of this receptor would be expected to result in an amelioration of 
cognitive deficits, with little or no worsening of the previously cited cholinergic-related side 
effects. Indeed, in a nonclinical in vivo pharmacology study in rats, 0.3 mg/kg TAK-071 
ameliorated scopolamine-induced cognitive deficits using a novel object recognition paradigm.


TAK-071
Study No. TAK-071-1001
Page 24 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
TAK-071 is characterized by a high systemic bioavailability in rats and monkeys, with absolute 
bioavailability values of 65% and 72%, respectively. It is also a low plasma clearance compound 
with a low to moderate volume of distribution and brain tissue distribution in rat and monkey (total 
brain tissue to plasma concentration partition coefficient in these 2 species of 0.12 and 0.42, 
respectively). The terminal disposition phase half-life (t1/2z) values after oral administration were 
5 and 8 hours in rats and monkeys, respectively.
TAK-071 has high permeability and is not a substrate of P-glycoprotein or breast cancer resistance 
protein, which are highly expressed in the blood-brain barrier. In vitro plasma protein binding in 
mice, rats, monkeys, and humans is high (≥98.9%) and concentration independent across species 
(0.1 to 10 µg/mL). TAK-071 is mainly metabolized by cytochrome P-450 (CYP) 3A4 and, to a 
lesser extent, by CYP2D6 and/or CYP2C9. No human-specific metabolites have been identified. 
TAK-071 had little or no direct or time-dependent inhibitory effects on CYP1A2, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. TAK-071 did not induce CYP1A2, but 
it is probably a weak inducer of CYP2B6 or CYP3A4 in vitro. Therefore, the risk of 
CYP-mediated drug-drug interaction between TAK-071 and donepezil is predicted to be low in 
humans.
TAK-071 was studied for potential toxicity in Good Laboratory Practice (GLP)-compliant repeat 
dosing studies in rats and monkeys for up to 28 days in duration. TAK-071 was also examined for 
genotoxicity in vitro and in vivo, and for phototoxicity in vitro. A toxicokinetic (TK) study was
conducted in nonpregnant female rabbits to assess the tolerability and TK profile in this species 
after dosing with TAK-071 to support future embryo-fetal toxicity studies in this species. In the 
28-day rat toxicity study, no animals died and no test article-related abnormalities were noted in 
body weight, food consumption, ophthalmoscopy, urinalysis parameters, hematology or clinical 
chemistry parameters, gross necropsy, organ weights, or histopathology. In clinical signs, loose 
stool was noted at 30 mg/kg/day and at 100 mg/kg/day; however, it was not considered to be 
toxicologically relevant because almost all findings were seen after the first dosing only. In the 
28-day monkey toxicity study, no test article-related changes were noted in clinical signs, body 
weight, food consumption, electrocardiogram (ECG) parameters, body temperature, 
ophthalmoscopy, urinalysis parameters, hematology and clinical chemistry parameters, gross 
necropsy, organ weights, or histopathology.
Overall, the existing body of evidence suggests that TAK-071 has the potential to be of significant 
clinical benefit in neurodegenerative disorders associated with cognitive decline related to an 
impairment of ACh neurons, including AD and/or dementia with Lewy bodies. It has been shown 
to have adequate nonclinical pharmacologic, pharmacokinetic (PK), and toxicologic properties, 
supporting the initiation of clinical investigation. 
For full details on all the relevant nonclinical studies, please refer to the Investigator Brochure.
4.2
Rationale for the Proposed Study
A broad program of nonclinical studies has already been performed to explore the pharmacology, 
PK, and toxicological potential of TAK-071 in animals and in vitro. Those studies indicate that 
TAK-071 is a selective and specific M1R PAM, with good oral bioavailability and PK properties 


TAK-071
Study No. TAK-071-1001
Page 25 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
as well as a toxicological profile that is not anticipated to present an unacceptable risk to humans at 
the proposed clinical doses.
The activation of M1R is expected to achieve significant cognitive improvement without 
cholinomimetic-related side effects, including diarrhea, which is seen with donepezil and other 
cholinesterase inhibitors, and thus has the potential to be a treatment with an improved side effect 
profile for dementia with Lewy bodies and AD.
This is the first study involving dosing of TAK-071 to humans. Therefore, the main aim of this 
multipart single-rising dose (SRD) and multiple-rising dose (MRD) study is to explore the safety 
and tolerability of single and multiple doses of TAK-071 in healthy (non-Japanese) subjects. After 
confirmation of the acceptable safety and tolerability of TAK-071 alone, a subsequent aim of this 
study is to explore the safety and tolerability in combination with donepezil in healthy subjects 
(non-Japanese) because this is the gold standard treatment for AD, one of the key target 
populations of later phase TAK-071 clinical studies.
Healthy Japanese subjects will be included to investigate any ethnic differences in the safety, 
tolerability, and/or PK of TAK-071. This part of the study is anticipated to enable Japanese 
subjects to be recruited into global phase 2 and 3 clinical studies.
Following confirmation of the acceptable safety and tolerability of TAK-071 both alone and in 
combination with donepezil in healthy subjects, subjects with mild cognitive impairment (MCI) or 
mild AD (non-Japanese) will also be exposed to combination treatment with the main objective of 
obtaining early safety and tolerability data in the target population.
This study is intended to explore the safety and tolerability of single and multiple TAK-071 doses, 
some of which may exceed doses anticipated to be therapeutically effective. However, it should be 
noted that the study is not intended to determine the maximum tolerated dose (MTD).
In addition to the battery of tests and assessments to characterize the safety and tolerability profile 
of the compound, the study also includes PK assessments of TAK-071 in plasma and cerebrospinal 
fluid (CSF) and of donepezil in plasma. Pharmacodynamic (PD) assessments include the 
evaluation of the quantitative electroencephalography (qEEG) profile and pupil size 
measurements after TAK-071 administration in the presence and absence of donepezil for selected 
cohorts. These assessments will characterize the PK/PD properties of TAK-071 in humans, 
provide evidence of brain penetration, and probe peripheral and central cholinergic system 
responses.
4.3
Benefit/Risk Profile
There is no expected clinical benefit for subjects entering this study. The risks of participation are 
primarily those associated with adverse reactions to the study drug. There may also be some 
discomfort from collection of blood samples and other study procedures.
This is the first study involving dosing of TAK-071 to humans. While extensive clinical safety and 
efficacy data are available from other cholinomimetic agents, such as donepezil, there are 
currently no safety data from clinical studies in the public domain for other M1R PAMs. Therefore, 
data from nonclinical studies with TAK-071, together with clinical data from other 


TAK-071
Study No. TAK-071-1001
Page 26 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
cholinomimetics, such as donepezil, are the only available guide to potential adverse reactions, 
which typically include side effects as a predictable consequence of its pharmacological 
properties, ie, diarrhea, nausea, and vomiting [11].
Based on allometric scaling of nonclinical PK data, predicated exposure in humans at the proposed 
starting dose of 1 mg is substantially below the corresponding exposure at the lowest 
no-observed-adverse-effect level (NOAEL) in toxicology (>50-fold; see Section 6.2.2.1). This 
dose is also lower than the human equivalent dose used in the rat safety pharmacology studies at 
which increased spontaneous activity was observed (3-fold) and is the lowest anticipated dose that 
may exert pharmacological effects on cognition. 
A PK exposure cap has been instituted because the NOAEL is also the highest dose tested in the 
28-day GLP toxicology studies; therefore, it is unknown if adverse events (AEs) at higher untested 
doses might have been reversible and/or monitorable. For this reason, stopping rules will be 
implemented to ensure that the maximum human exposure remains appropriately below the 
corresponding average exposure observed at the NOAEL in the most sensitive nonclinical species.
There is no anticipated additional risk from a potential PK interaction for cohorts coadministered 
TAK-071 and donepezil. Indeed, currently available in vitro data indicate that the risk of PK 
interaction between these 2 compounds is low. From a PD interaction point of view, it is 
anticipated that these 2 compounds might have synergistic effects. For this reason, in the healthy 
subject combination treatment cohorts, there will be 3 TAK-071 dose escalation steps, after each 
of which there will be a review of the safety/tolerability and available PK data. Subjects with MCI 
or mild AD on stable donepezil will only be dosed after review of the safety/tolerability and 
available PK of the combination treatment cohorts in healthy subjects.
Overall, based on the substantial exposure safety margin for the initial clinical dose and all the 
available preclinical pharmacology, toxicology, drug metabolism, and PK data, TAK-071 alone or 
in combination with donepezil is not anticipated to present unacceptable risks to healthy 
(non-Japanese or Japanese) subjects or to subjects with MCI or mild AD at the proposed doses and 
dose regimens. This study is not designed to allow the assessment of the therapeutic potential for 
this compound, and it is not expected that this study will result in any therapeutic benefit for the 
included study populations. However, data generated from this study should enable the 
investigation of TAK-071 in subsequent clinical proof-of-mechanism (PoM) and efficacy studies 
of longer duration in the relevant subject populations (ie, phase 2).


TAK-071
Study No. TAK-071-1001
Page 27 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objectives
!
To characterize the safety, tolerability, and plasma PK profile of TAK-071 when administered 
as single and multiple once daily (QD) oral doses at escalating dose levels in healthy subjects 
(non-Japanese).
!
To characterize the safety, tolerability, and plasma PK profile of TAK-071 when administered 
as single and multiple QD oral doses at escalating dose levels in healthy subjects 
(non-Japanese) in the presence of steady-state exposure of donepezil QD.
!
To characterize the safety, tolerability, and plasma PK profile of TAK-071 when administered 
as single and multiple QD oral doses at escalating dose levels in healthy Japanese subjects.
!
To characterize safety, tolerability, and plasma PK profile of 10 mg donepezil when 
administered as a single dose, and to compare it to combination of 10 mg donepezil+TAK-071.
!
To characterize the safety, tolerability, and plasma PK profile of TAK-071 when administered 
as multiple QD oral doses to subjects with MCI or mild AD (non-Japanese) receiving 
donepezil treatment for a minimum of 3 months.
5.1.2
Secondary Objectives
!
To assess safety of 120 mg or higher single dose of TAK-071 measured by 
electroencephalography (EEG). 
!
To evaluate the urinary clearance of TAK-071 following single and multiple oral doses.
!
To evaluate the brain penetration of TAK-071 as measured in CSF following single and 
multiple dosing.
!
To evaluate the dose proportionality and any time dependency in TAK-071 plasma PK.
!
To evaluate the effect of multiple daily doses of TAK-071 on donepezil steady-state PK.
!
To evaluate the relative bioavailability (BA) of TAK-071 10 mg administered as tablet 
formulation compared with TAK-071 10 mg administered as drug-in-capsule (DIC) 
formulation.
!
To evaluate potential effect of food on the TAK-071 plasma PK following a single oral dose of 
10 mg tablet formulation.
5.1.3
Exploratory/Additional Objectives
!
CCI


TAK-071
Study No. TAK-071-1001
Page 28 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
!
!
!
!
5.2
Endpoints
5.2.1
Primary Endpoints
5.2.1.1
Safety 
!
Percentage of subjects who have at least 1 treatment-emergent adverse event (TEAE).
!
Percentage of subjects who meet the Takeda markedly abnormal value (MAV) criteria at least 
once postdose for the following:
–
Clinical laboratory parameters. 
–
Vital sign measurements. 
–
ECG parameters. 
5.2.1.2
PK
PK parameters of TAK-071 in plasma following a single dose (Day 1) and at steady-state (after the 
final dose following multiple dosing):
!
Time of first occurrence of Cmax (tmax). 
!
Maximum observed plasma concentration (Cmax). 
!
Area under the plasma concentration-time curve from time 0 to 24 hours (AUC24). 
!
Area under the plasma concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration (AUC∞) (single dose only [Day 1]).
5.2.2
Secondary Endpoints
Plasma and urine PK parameters of TAK-071 following a single dose (Day 1) and at steady-state 
(after the final dose following multiple dosing), including but not limited to the following: 
!
Area under the plasma concentration-time curve from time 0 to time t (AUCt).
!
t1/2z, as permitted by the data (single dose only [Day 1]).
!
Apparent clearance after extravascular administration (CL/F).
CCI


TAK-071
Study No. TAK-071-1001
Page 29 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
!
Apparent volume of distribution during the terminal disposition phase after extravascular 
administration (Vz/F).
!
Accumulation ratio based on AUCτ (Rac(AUC)).
!
Accumulation ratio based on Cmax (Rac(Cmax)).
!
Amount of drug excreted in urine from time 0 to time t (Aet).
!
Fraction of administered dose of drug excreted in urine from time 0 to time t (fe,t).
!
Renal clearance (CLR).
CSF PK parameters of TAK-071 planned for the single-dose Cohort 3 and at steady-state in 
Cohort 9 (after the final dose following multiple dosing), including but not limited to the 
following: 
!
CSF Cmax.
!
Area under the CSF concentration-time curve from time 0 to 12 hours (CSF AUC12) (Cohort 3 
only [Day 1]).
!
Area under the CSF concentration-time curve from time 0 to 36 hours (CSF AUC36) (Cohort 9 
only [Day 28]). 
!
The ratio of CSF AUC12 to the plasma AUC12 (CSF AUC12:plasma AUC12) (Cohort 3 only 
[Day 1]).
!
The ratio of CSF AUC36 to the plasma AUC36 (CSF AUC36:plasma AUC36) (Cohort 9 only 
[Day 28]).
Plasma steady-state PK parameters of donepezil (Cohorts 10 to 12) on the last donepezil 
pretreatment day and after 21 daily doses of TAK-071, including but not limited to the following: 
!
tmax.
!
Cmax.
!
AUC24.
!
Ratio of geometric mean steady-state AUC24 and Cmax for donepezil after 21 daily doses of 
TAK-071 in reference to donepezil alone and the associated 90% confidence intervals (CIs).
5.2.3
Exploratory/Additional Endpoints
CCI


TAK-071
Study No. TAK-071-1001
Page 30 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
CCI


TAK-071
Study No. TAK-071-1001
Page 31 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a first-in-human (FIH), phase 1, safety, tolerability, and PK study of escalating single and 
multiple oral doses of TAK-071 in healthy adult (non-Japanese and Japanese) male and female 
subjects and subjects with MCI or mild AD (non-Japanese). In addition, the relative bioavailability 
of a tablet formulation (test) vs the DIC formulation as well as the effect of food on the PK of the 
tablet formulation will be assessed in healthy subjects.
The first time TAK-071 is dosed to humans will be a single oral dose administered in Cohort 1 of 
the SRD part of this study. Additional cohorts (Cohorts 2 to 6, 18, and 19) will be used to study 
escalating single-dose levels.
Higher or lower dose cohort(s) may be added in the SRD part of the study to fully understand 
safety and tolerability of TAK-071. The SRD part of the study will consist of a randomized, 
double-blind, placebo-controlled, parallel-group ascending dose design with 8 subjects per cohort. 
SRD cohorts (Cohorts 20 to 22) will explore the safety and tolerability of single doses of TAK-071 
(80, 60 and 40 mg, respectively; however, actual doses administered will be determined from 
emerging data) when coadministered with donepezil (10 mg) in healthy subjects. These cohorts 
will consist of a randomized, double-blind, placebo-controlled, parallel-group ascending dose 
design with 12 subjects per cohort. These cohorts will establish a high well-tolerated dose of 
TAK-071 when coadministered with donepezil for the scopolamine challenge PoM study. Higher 
or lower dose cohort(s) may be added in the SRD part of the study to fully understand safety and 
tolerability of TAK-071 when coadministered with donepezil.
Cohorts 7 to 15 will be used in the MRD part of this study. The MRD will thus consist of a 
randomized, double-blind, placebo-controlled, 9-cohort, parallel-group multiple ascending dose 
design with 8 subjects in Cohorts 7 to 12 and 6 subjects in Cohorts 13 to 15. Additional MRD 
cohorts (TAK-071 and/or TAK-071+donepezil) may be added to fully understand safety and 
tolerability of TAK-071.
Selected MRD cohorts (Cohorts 10 to 12) will be pretreated for 3 weeks with daily oral doses of 
donepezil (5 mg QD), followed by continued daily oral donepezil dosing during the TAK-071 
treatment period. 
Cohort 16 will include up to 8 subjects (minimum of 6) with MCI or mild AD on stable donepezil 
treatment or who consent to a donepezil run-in period of 5 mg dose for 28 days and titrate up to 
10 mg for at least 21 days. Subjects with previous MCI/AD diagnosis who have been treated with 
5 mg for at least 28 days prior to Screening may consent to a donepezil run-in period of 10 mg for 
at least 21 days. This cohort will be conducted as a placebo-controlled, 2-sequence, 2-period, 
2-way crossover design. 
Cohort 17 will include up to 12 subjects. This cohort will be conducted in an open-label, 3-period, 
3-sequence, 3-way crossover design.


TAK-071
Study No. TAK-071-1001
Page 32 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Cohorts 1 to 12, and 16 to 22 will include non-Japanese subjects. Cohorts 13 to 15 will include 
Japanese subjects. 
Subjects in each cohort (Cohorts 1 to 16, 18, and 19) will be randomized to receive treatment with 
TAK-071 or matching placebo using DIC in the morning following a minimum fast of 8 hours. In 
Cohorts 1 to 12, 18, and 19, placebo treatments will be assigned in a 3:1 ratio (within each cohort 
of 8 subjects, 6 will receive active treatment and 2 will receive placebo). 
Subjects in Cohorts 20 to 22 will be assigned in a 1:1:2 ratio to receive treatments (within each 
cohort of 12 subjects, 3 will receive TAK-071 placebo+donepezil placebo, 3 subjects will receive 
TAK-071 placebo+donepezil, and 6 subjects will receive TAK-071+donepezil).
In Cohorts 13 to 15, placebo treatments will be assigned in a 5:1 ratio (within each cohort of 
6 subjects, 5 will receive active treatment and 1 will receive placebo. In Cohort 16, subjects will be 
assigned to 1 of 2 possible treatment sequences (AB or BA), with Treatment A being TAK-071 
and Treatment B being matching placebo. In Cohort 17, subjects will be assigned to 1 of 3 possible 
treatments as Regimen Sequences ABC, BCA, and CAB, where, Regimen A=Fasted State and 
Capsule Formulation (10 mg DIC formulation), Regimen B=Fasted State and Tablet Formulation 
(10 mg tablet formulation), and Regimen C=Fed State and Tablet Formulation (10 mg tablet 
formulation). 
The safety of TAK-071 alone or in combination with donepezil will be assessed through AEs, 
clinical laboratory results, physical examination findings, ECG findings, bowel function, vital 
signs, and suicidal assessments. Continuous 12-lead Holter ECG monitoring will also be 
performed on selected study cohorts. 
The safety and tolerability of donepezil alone will be evaluated during the donepezil dosing phase 
(before TAK-071 is given in Cohorts 10 to 12) during the 3-week pretreatment period, and the 
safety and tolerability of donepezil in combination with TAK-071 (Cohorts 20 to 22) will be 
evaluated by assessing AEs, clinical laboratory results, physical examination findings, ECG 
findings, bowel function, and vital signs.
In addition to safety monitoring, TAK-071 plasma and urine PK profiles will be generated and PK 
parameters derived. It is planned that CSF samples for PK analysis will be obtained in Cohort 3 
(following a single dose) and Cohort 9 (at steady-state). 
 
.
Approximately 186 subjects are expected to be randomized in this study.
End of study is defined as the date of last visit of the last subject for last clinical assessment.
The treatment groups and cohorts are outlined in Table 6.a.
CCI
CCI


TAK-071
Study No. TAK-071-1001
Page 33 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Table 6.a
Overview of Treatment Cohorts
Group
Cohort
Age
(years)
Type
Regimen
Number of Subjects 
per Cohort
Total
TAK-071
Placebo
SRD (a)
1 to 6, 18, 
and 19
18-55
HV
Single
6
2
64
SRD + 
donepezil post 
TAK-071 
treatment (a, b)
20 to 22
18-55
HV
Single
6
3 (+3 
donepezil)
36
MRD (a)
7, 8
18-55
HV
1 dose QD for 21 days
6
2
16
MRD (a)
9
18-55
HV
1 single dose, 7-day 
washout, 1 dose QD for 
21 days
6
2
8
MRD + 
donepezil 
pretreatment (a, 
c)
10 to 12
18-55
HV
1 dose QD for 21 days
6
2
24
MRD
13 to 15
20-55
jHV
1 single dose, 7-day 
washout, 1 dose QD for 
21 days
5
1
18
Subjects with 
MCI or mild AD 
(a)
16
55-90
MCI or mild 
AD (d)
21 days TAK-071 QD 
(Treatment A) or 21 days of 
matching placebo 
(Treatment B). Subjects will 
be randomized to 2 
sequences (AB or BA), with 
21 days washout between 
treatment sequences.
NA
NA
up to 8 
(minimum 
of 6)
Relative BA and 
FE (e)
17
18-55
HV
Single dose in each of 3 
periods with washout period 
of 21 days after Periods 1 
and 2
12
NA
12
Total:
186
jHV=Japanese healthy volunteers, FE=food effect, HV=healthy volunteers, NA=not applicable.
(a) Non-Japanese subjects.
(b) Donepezil (10 mg) will be given as a single dose as an over-encapsulated oral tablet, 24 hours post TAK-071 dose. 
(c) Donepezil (5 mg QD) will be given as an oral tablet daily for 3 weeks prior to dosing and during the TAK-071 
dosing interval.
(d) Subjects with MCI or mild AD (non-Japanese) who have been stable on 10 mg donepezil treatment for at least 21 
days or who consent to donepezil run-in period. 
(e) Healthy subjects. Subjects will be randomized to receive TAK-071 as a DIC formulation and a tablet formulation 
under fasted condition, and as a tablet formulation under fed conditions.
The flow of planned cohorts is provided in Figure 6.a.


TAK-071
Study No. TAK-071-1001
Page 34 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Figure 6.a
Flow of Treatment Cohorts
SRD:
1
2
3
4
5
6
18
19
SRD + Donepezil: 
20
21
22
MRD:
7
8
9
MRD + Donepezil:
predose donepezil
10
predose donepezil
11
predose donepezil
12
MRD Japanese:
13
14
15
Subjects with MCI or mild AD:
stable on donepezil therapy or donepezil-run-in
16
relative BA and food-effect
17
Schematic of study design are included as Figure 6.b for Cohorts 1 to 6 and 18 to 22, Figure 6.c for 
Cohorts 7 and 8, Figure 6.d for Cohorts 9 and 13 to 15, Figure 6.e for Cohorts 10 to 12, Figure 6.f
for Cohort 16, and Figure 6.g for Cohort 17. Schedules of Study Procedures are listed in 
Appendix A.
Figure 6.b
Schematic of Study Design for SRD Cohorts 1 to 6 and 18 to 22
Pretreatment Period 
Treatment Period (a)
Final Visit
PK Follow-Up
Follow-Up
Screening
Check-in
Single Dose/PK
PK
Check-out/PK
PK
Follow-up 
Telephone 
Call
Days -28 to -2
Day -1
Day 1
Days 2-4
Day 5
Day 8
Day 12 (±2)
Confinement 
(a) Subjects in Cohorts 20 to 22 will receive donepezil 10 mg or placebo as a single dose approximately 24 hours after 
the TAK-071 or placebo dose.


TAK-071
Study No. TAK-071-1001
Page 35 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Figure 6.c
Schematic of Study Design for MRD Cohorts 7 and 8
Pretreatment Period
Treatment Period
Final Visit
Follow-Up
Screening
Check-in
Multiple Dosing/PK
PK
Check-out/PK
Follow-up 
Telephone Call
Days -28 to -2
Day -1
Days 1 to 21
Day 22
Day 23
Day 32 (±2)
Confinement 
Figure 6.d
Schematic of Study Design for MRD Cohorts 9 and 13 to 15
Pretreatment Period
Treatment Period
Final Visit
Follow-Up
Screening
Check-in
Single 
Dose/PK
PK
Washout
Multiple 
Dosing/PK
PK
Check-out 
/PK
Follow-up 
Telephone Call
Days 
-28 to -2
Day -1
Day 1
Days 
2 to 5
Days 2 to 7
Days 
8 to 28
Day 29
Day 30
Day 39 (±2)
Confinement 
Figure 6.e
Schematic of Study Design for MRD Cohorts 10 to 12
Pretreatment Period
Treatment Period
Final 
Visit
Follow-Up
Screening Check-in
Donepezil Pretreatment/
PK
TAK-071 and 
Donepezil Multiple 
Dosing/PK
PK
Check-out
/PK
Follow-up 
Telephone 
Call
Days 
-44 to -23
Day -22
Days 
-21 to -19
Days 
-18 to -11
Days 
-10 to -1
Days 1 to 21
Day 22
Day 23
Day 32 (±2)
Confinement
Outpatient
Confinement 
Figure 6.f
Schematic of Study Design for Cohort 16
Pretreatment Period (a)
Treatment Period 1:
TAK-071 or Placebo
Washout 21 days
Treatment Period 2:
TAK-071 or Placebo
Final 
Visit
Follow-Up
Screening
Donepezil 
run-in
Check-in
Multiple 
Dosing/PK
PK
Check-in
Multiple 
Dosing/PK
Check-out
/PK
Follow-up 
Telephone 
Call
Days -60
to -2
Days -49 to 
-1
Day -1
Days 1 to 21 Day 22
Day 41
Days 
42 to 62
Day 63
Day 73 (±2)
Intermittent Confinement 
Confinement on Days -1 to 2, 11, 20 to 22, 41 to 43, 52, and 61 
to 63 
(a) Subjects with MCI or mild AD on stable donepezil (10 mg) treatment or who consent to a donepezil run-in period 
of 5 mg dose for 28 days and titrate up to 10 mg for at least 21 days. Subjects with previous MCI/AD diagnosis who 
have been treated with 5 mg for at least 28 days prior to Screening may consent to a donepezil run-in period of 10 mg 
for at least 21 days.


TAK-071
Study No. TAK-071-1001
Page 36 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Figure 6.g
Schematic Study Design for Cohort 17
Pretreatment Period
Treatment Periods 1, 2, and 3 (a)
Final Visit
Follow-Up
Screening Check-in Single Dose/PK
PK
Follow-up 
Telephone 
Call
Days 
-28 to -2
Day -1
Day 1
Days 2 to 5 and 8
Day 8 
Period 3
Day 12 (±2) 
Period 3 
Washout (b)
Days 2 to 21 of Periods 1 and 2 only
Intermittent Confinement 
Confinement on Days -1 to 4 and outpatient PK visit on Day 8
(a) Visit Day count shown as relative to Day 1 of each treatment period.
(b) The total washout period will be 21 days from the time of dosing.
For Cohorts 7 to 8 and 10 to 12, the dosing duration and for Cohorts 9 and 13 to 16, the dosing 
and/or washout duration may be adjusted if PK data from the SRD part indicate that a different 
period may be more appropriate (ie, 5 times the observed t1/2z). For Cohort 17, washout period may 
be adjusted if PK data from previous cohorts warrants so.
The planned duration of dosing in all MRD cohorts will be of 21 days. If warranted based on 
emerging PK data (ie, based on the observed range of t1/2z values) and assuming acceptable safety 
and tolerability in preceding cohorts, the duration of TAK-071 dosing may be reduced to at a 
minimum of 14 days or extended for up to a maximum of 28 days.
6.1.1
SRD Part (Cohorts 1 to 6 and 18 to 22)
The SRD part of the study is a randomized, double-blind, placebo-controlled, parallel-group, 
ascending dose design involving single-dose escalation through 7 (or more, if needed) cohorts. 
Subjects will be confined throughout the Treatment Period (from Day -1 to Day 5), with a 
follow-up assessment on Day 12 (±2) days. Based on emerging preliminary PK data following 
Cohort 1, an additional visit for PK collection will be done on Day 8. For Cohorts 1 to 6, 18, and 
19, healthy subjects will be randomly assigned to TAK-071 or matching placebo in a 3:1 ratio. 
For Cohorts 20 to 22, healthy subjects will be randomly assigned to TAK-071+donepezil, 
donepezil, and placebo in a 2:1:1 ratio so that after completion of each cohort, 6 subjects had 
received TAK-071+donepezil, 3 subjects had received donepezil+TAK-071 placebo, and 3 
subjects had received donepezil placebo+TAK-071 placebo.
Sentinel dosing will be used for Cohort 1 (1 subject to receive TAK-071 and 1 subject to receive 
placebo) to provide safety and tolerability evaluations prior to administering TAK-071 to the 
remainder of subjects within the cohort. After reviewing 24-hour postdose safety and tolerability 
data from the sentinel group, the remaining 6 subjects of the cohort may be dosed provided that the 
AE profile of TAK-071 in the first 2 subjects is considered acceptable. For subsequent cohorts (2, 
4 to 6, 18, and 19), the intent is to stagger dosing between the first 2 subjects (1 TAK-071 and 
1 placebo) and subsequent subjects dosed, starting no earlier than the median tmax observed in 


TAK-071
Study No. TAK-071-1001
Page 37 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
earlier cohorts (providing that there are no issues arising in the previous cohort). Depending on the 
observed length of tmax, this could involve dosing the next day. 
Sentinel dosing will be used for Cohorts 20 to 22 (1 subject to receive donepezil 
placebo+TAK-071 placebo, 1 subject to receive donepezil+TAK-071 placebo, and 1 subject to 
receive donepezil+TAK-071). After reviewing 24-hour postdose safety and tolerability data from 
the sentinel group, the remaining 9 subjects of the cohort may be dosed provided that the AE 
profile of TAK-071 in the first 3 subjects is considered acceptable.
For Cohort 3, subjects will be staggered across multiple days to facilitate CSF collection.
For Cohort 3, CSF samples will be obtained at 5 selected time points after the dose on Day 1 via an 
indwelling cannula to provide an indication of brain penetration for TAK-071 and the 
concentration relative to circulating plasma concentrations. If measured CSF concentrations are 
deemed to be low, ie, most time points are below the limit of quantification of the assay, TAK-071 
CSF concentrations may also be determined in subsequent SRD cohorts until acceptable 
concentrations are attained. 
.
6.1.2
MRD Part (Cohorts 7 to 15)
Each of the healthy subject MRD cohorts, including TAK-071 alone in non-Japanese subjects 
(Cohorts 7 to 9), TAK-071 in combination with donepezil in non-Japanese subjects (Cohorts 10 to 
12), and TAK-071 alone in Japanese subjects (Cohorts 13 to 15), will be a randomized, 
double-blind, placebo-controlled, 9-cohort, parallel-group, multiple ascending dose design with 
8 subjects per cohort (6 active and 2 placebo) for Cohorts 7 to 12 and 6 subjects per cohort 
(5 active and 1 placebo) for Cohort 13 to 15.
Dosing will be staggered in Cohorts 7 and 8 and 10 to 11 between the first 2 subjects (1 TAK-071 
and 1 placebo) and subsequent subjects dosed, starting no earlier than the median tmax. Depending 
on the observed length of tmax, this could involve dosing the next day. For Cohort 9, subjects will 
be staggered across multiple days to facilitate CSF collection. 
 
 Japanese Cohorts 13 to 15 will not 
require staggering since doses will be equal or lower than those in the corresponding non-Japanese 
Cohorts 7 to 9, thus effectively acting as front runner groups.
Additional MRD cohorts may be added to fully understand safety and tolerability of TAK-071.
6.1.2.1
Non-Japanese Subjects (Cohorts 7 to 9)
Dose escalation will progress through 3 cohorts. Subjects will be confined during the Treatment 
Period from Day -1 to Day 22 (Cohorts 7 and 8) or Day 29 (Cohort 9). 
For Cohorts 7 and 8, healthy subjects will be randomized to receive multiple doses (21 oral doses 
QD) of TAK-071 or matching placebo in a 3:1 ratio.
For Cohort 9, TAK-071 or placebo will be administered as a single oral dose, followed by a 7-day 
washout period and then daily dosing for 21 days or matching placebo in a 3:1 ratio. The 7-day 
CCI
CCI


TAK-071
Study No. TAK-071-1001
Page 38 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
washout period in Cohort 9 is intended to provide sufficient time to characterize the TAK-071 
terminal disposition phase, but it is not expected to result in complete disappearance of TAK-071 
from plasma prior to starting repeat dosing on Day 8. Nonetheless, Day 8 trough concentrations are 
expected to be very low (ie, <5% steady state Cmax). 
For Cohort 9, the potential for time dependency in PK will be evaluated. CSF samples will also be 
obtained at 5 selected time points after the dose on Day 28 via an indwelling cannula to provide an 
indication of brain penetration and the concentration relative to circulating plasma concentrations 
at steady-state of TAK-071.
 
6.1.2.2
Non-Japanese Subjects Pretreated With Donepezil (Cohorts 10 to 12)
Cohorts 10 to 12 will be conducted in a double-blind manner with respect to TAK-071 but not for 
donepezil. Therefore, healthy subjects will be randomized to receive 21 QD oral doses of either 
TAK-071 or matching placebo in a 3:1 ratio. In addition, subjects will be pretreated for 3 weeks 
with daily oral doses of donepezil (5 mg), followed by continued daily oral donepezil QD dosing 
during the 21-day TAK-071 treatment period. Subjects will be confined from Day -22 to Day -19. 
Subjects will be discharged from the clinic on Day -19 and will continue donepezil dosing at home 
on Days -18 to -11. Subjects will return to clinic on Day -10 and remain confined until the Study 
Exit visit (Day 23) or Early Termination. During outpatient dosing (Days -18 to -11), subjects will 
be contacted by study site by telephone call every day to ensure treatment compliance.
Additional MRD cohorts may be added to fully understand safety and tolerability of TAK-071 in 
subjects pretreated with donepezil. 
6.1.2.3
Japanese Subjects (Cohorts 13 to 15)
The MRD part in Japanese subjects will involve dose escalation through 3 cohorts. Subjects will 
be confined throughout the Treatment Period from Day -1 to Day 29. Healthy Japanese subjects 
will be randomized to receive a single dose of TAK-071 or matching placebo in a 5:1 ratio, 
followed by a 7-day washout period and multiple doses (21 oral doses QD) of TAK-071 or 
placebo. The 7-day washout period in Cohorts 13 to 15 is intended to provide sufficient time to 
characterize the TAK-071 terminal disposition phase, but it is not expected to result in complete 
disappearance of TAK-071 from plasma prior to starting repeat dosing on Day 8. Nonetheless, 
Day 8 trough concentrations are expected to be very low (ie, <5% steady state Cmax).
PK parameters will include a determination of time to steady-state, potential for accumulation, and 
time dependency in PK. In addition, data will be compared with data generated in non-Japanese 
subjects to determine if there are any ethnic differences in human PK.
CCI
CCI


TAK-071
Study No. TAK-071-1001
Page 39 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
6.1.3
Subjects With MCI or Mild AD (Cohort 16)
Cohort 16 will have a placebo-controlled, randomized, 2-sequence, 2-period, crossover study 
design to investigate the safety, tolerability, and PK in 1 of the intended target populations for 
TAK-071 treatment (subjects with MCI or mild AD). Up to 8 subjects (minimum of 6) previously 
diagnosed with MCI or mild AD and receiving ongoing donepezil (10 mg) therapy or who consent 
to a donepezil run-in period of 5 mg dose for 28 days and titrate up to 10 mg for at least 21 days. 
Subjects with previous MCI/AD diagnosis who have been treated with 5 mg for at least 28 days 
prior to Screening may consent to a donepezil run-in period of 10 mg for at least 21 days will be 
enrolled in Cohort 16. Subjects will continue with their donepezil therapy during the TAK-071 
Treatment Period. 
Subjects will be randomized to 1 of 2 possible treatment sequences (AB or BA) before the first 
dose of study drug. In each period, subjects will receive 1 of 2 possible treatments as follows: 
!
Treatment A: TAK-071 QD for 21 days, or 
!
Treatment B: matching placebo QD for 21 days.
There will be a washout period of at least 21 days between the treatment sequences. The washout 
and/or dosing duration may be adjusted with additional day(s) if PK data from the SRD/MRD 
parts indicate that a longer washout may be more appropriate (ie, 5 times the observed t1/2z).
.
6.1.4
Relative BA and FE Cohort (Cohort 17)
Cohort 17 will be administered in 3 single-dose regimens in a 3-way crossover design to 12 male 
and female subjects using 10 mg oral dose treatments. Subjects will receive a TAK-071 10 mg 
single oral regimen on Day 1 of each period. TAK-071 tablet or DIC will be administered with 
240 mL of water.
Regimen A – Fasted State and Capsule Formulation (10 mg in DIC formulation) 
Subjects will be fasted overnight for at least 8 hours. Treatment will be administered orally with 
240 mL of water. No food should be allowed for at least 4 hours postdose. Water can be allowed 
after 2 hours postdose. 
Regimen B – Fasted State and Tablet Formulation (10 mg [2× 5 mg] tablet formulation) 
Subjects will be fasted overnight for at least 8 hours. Treatment will be administered orally with 
240 mL of water. No food should be allowed for at least 4 hours postdose. Water can be allowed as 
desired after 2 hours postdose.
Regimen C – Fed State and Tablet Formulation (10 mg [2× 5 mg] tablet formulation)
Subjects will be fasted overnight for at least 8 hours. After this time, subjects should start the 
standard high fat meal (~50% fats) 30 minutes prior to administration of the drug product. Study 
subjects should eat this meal in 25 minutes or less. Drug product should be dosed 30 minutes after 
CCI


TAK-071
Study No. TAK-071-1001
Page 40 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
the start of the meal with 240 mL of water. No food should be allowed for at least 4 hours postdose. 
Water can be allowed as desired after 2 hours postdose. 
Four subjects will be randomly assigned to 1 of 3 sequence groups and receive the regimens in the 
order shown in Table 6.b.
Table 6.b
Sequence Groups and Regimen Assignment for Cohort 17
Sequence Group
Number of Subjects
Period 1 Day 1
Period 2 Day 1
Period 3 Day 1
1
4
A
B
C
2
4
B
C
A
3
4
C
A
B
Regimen A: Fasted State and Capsule Formulation (10 mg in DIC formulation). 
Regimen B: Fasted State and Tablet Formulation (10 mg tablet formulation).
Regimen C: Fed State and Tablet Formulation (10 mg tablet formulation).
6.1.5
Dose Escalation
All decisions concerning dose escalation will be made by the Takeda clinical science 
representative and the principal investigator.
Additionally, the Takeda clinical science physician and the principal investigator may jointly 
decide to not escalate the dose for a particular cohort but rather administer the same or a lower dose 
level to the next cohort.
After dosing in Cohort 2, there will be a minimum period of 4 days between each dose escalation 
to allow for review of safety and tolerability data and any available PK data. For Cohorts 1, 3, 4, 5, 
and 6, dose escalation to the next cohort will also be conditional to a review of preliminary 24-hour 
PK data after the last administered dose. For Cohort 3, it is planned that preliminary 12-hour CSF 
PK data will also be required prior to dose escalation. For further details on dose escalation 
justification and requirements, see Section 6.2.2.2. In the event that higher dose SRD cohorts are 
required, dose escalation to the next cohort will also be conditional to a review of preliminary 
24-hour PK data after the last administered dose from the preceding cohort.
For each dose level administered/completed cohort, the principal investigator and Takeda clinical 
science physician will carefully review the available blinded 24-hour safety, tolerability, and 
available PK data and determine whether dosing should stop or continue (and, if continue, at what 
dose, including whether to repeat the previous dose), whether to review PK data on the last 
administered dose in additional cohorts, and whether the blind should be broken to identify 
whether the subjects received TAK-071 or placebo.
All AEs reported during the Treatment Period, both within and across cohorts will be evaluated to 
assess the need for subject and/or study termination in accordance with the prespecified criteria for 
discontinuation/termination (Section 6.3.1).
Following assessment of the AE data and predefined criteria for study termination, dose escalation 
may be interrupted/stopped and the blind broken for further analysis. Based on review of 


TAK-071
Study No. TAK-071-1001
Page 41 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
unblinded data, Takeda in consultation with the principal investigator will decide if and how it is 
appropriate for the study to proceed.
If agreement regarding a dose escalation decision cannot be reached between the principal 
investigator and Takeda, the study will be stopped.
Other criteria to consider discontinuation of cohort entry are as follows.
1. If a serious adverse event (SAE) whose relationship to the study drug cannot be denied is 
observed.
2. At the onset of an AE for which relationship to the study drug cannot be denied and for which 
it is considered difficult to give medications continuously.
6.2
Justification for Study Design, Dose, and Endpoints
6.2.1
Study Design
This phase 1 study is randomized, double blind, and placebo controlled to avoid subjective bias in 
the assessment of safety and tolerability and pharmacological effects of the study drug. Placebo 
will be administered as a control in order to establish the frequency or magnitude of changes in 
clinical endpoints that may occur in the absence of active treatment.
The study will be initiated as an SRD (Cohorts 1 to 6, 18, and 19) so that each enrolled subject will 
only receive a single exposure to study drug to minimize the potential for adverse effects from 
repeated drug exposure. The SRD TAK-071+donepezil cohorts (Cohorts 20 to 22) will establish a 
high well-tolerated dose of TAK-071 when coadministered with donepezil, and will help to 
determine the dose in the scopolamine PoM study.
Cohorts 18 and 19 (and additional cohorts, if needed) with dose(s) of 120 mg or higher dose are to 
explore the safety and tolerability of TAK-071 in single dose(s) of at least 120 mg, with a special 
focus on safety EEG.
 
 
Optional cohorts have been included to allow the opportunity to explore higher exposures in the 
event that neither the NOAEL plasma exposure threshold nor the MTD are attained. Identifying a 
single TAK-071 dose that, while remaining appropriately below the 28-Day monkey NOAEL 
threshold, provides a high plasma exposure that is deemed to be of importance for the purposes of 
an upcoming PoM scopolamine challenge study (TAK-071-1002) in healthy subjects. This is 
because a high TAK-071 dose is expected to maximize the potential for observing a significant 
reversal of scopolamine-induced cognitive impairment.
The MRD (Cohorts 7 to 9) will allow for the characterization of the safety/tolerability and PK of 
repeated TAK-071 daily exposures over a limited duration of time, as well as the characterization 
of any time dependency in the PK in Cohort 9 (the highest dose). Subjects in the first MRD cohort 
(Cohorts 7) will only be dosed after confirmation of acceptable safety and tolerability and 
evaluation of the 24-hour plasma PK and 12-hour CSF PK data from Cohort 3. The 
CCI


TAK-071
Study No. TAK-071-1001
Page 42 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
safety/tolerability and PK of repeated TAK-071 doses in combination with donepezil will be 
investigated in MRD Cohorts 10 to 12 in healthy subjects.
Japanese subjects have been included in this study in order to facilitate study in this ethnic group as 
part of phase 2 studies (Cohorts 13 to 15). Consequently, it is important to assess the safety, 
tolerability, and PK in this population at the earliest opportunity.
Clinical trials with cholinomimetic drugs show differential tolerability in healthy young adults and 
the target population of patients with AD [12]. Therefore, the strategy in this study is to include an 
MCI/mild AD cohort (Cohort 16) to act as a bridge to determine the safety and tolerability of 
TAK-071 in combination with a cholinesterase inhibitor in the target population (subjects with 
MCI or mild AD). This cohort, together with the experience of the combined TAK-071 and 
donepezil treatment in healthy subjects, will help guide selection of appropriate doses for 
later-stage efficacy studies [13].
A preliminary assessment of the effect of food and a tablet formulation on TAK-071 PK is 
included (Cohort 17) to expedite the further development of TAK-071. A crossover design is 
planned to enable each subject to provide their own control reference point (fasted DIC/tablet 
delivery). Subjects will be randomly assigned to 1 of 3 sequence groups to avoid bias. A 21-day 
washout interval between treatments is planned to ensure that there is no drug carryover effect. 
Discontinued or withdrawn subjects may be replaced to ensure that a minimum of 10 subjects 
complete all 3 regimens.
A total of up to 186 subjects are required for this design, and numbers required per cohort are 
deemed to be the lowest required for satisfying the overall aims of the study.
6.2.2
Dose Selection
6.2.2.1
TAK-071 Starting Dose (Cohort 1)
The starting dose for this FIH study was determined taking into consideration the results of the 
definitive 4-week repeat-dose toxicity studies in rats and monkeys, the results from the safety 
pharmacology studies in rats and human PK predictions (based on allometric scaling) together 
with the observed minimal effective dose and exposure in animal models.
In the rat, the NOAELs were 100 and 30 mg/kg/day in males and females, respectively, with 
associated Day 28 average exposures of 105,000 and 146,000 ng∙hr/mL, respectively. Based on 
body surface area, 30 mg/kg/day in the rat equates to 180 mg/m2, with a human dose equivalent of 
4.8 mg/kg/day×60 kg=288 mg/day.
In the monkey, the NOAEL in both sexes was 10 mg/kg/day, with associated Day 28 mean 
exposures of 48,000 and 49,100 ng∙hr/mL in males and females, respectively. Based on body 
surface area, 10 mg/kg/day equates to 120 mg/m2, with a human dose equivalent of 
3.2 mg/kg/day×60 kg=192 mg/day.
Given the lower NOAEL and associated exposures in monkeys, the FIH dose will be based on this 
species rather than the rat. Therefore, considering the regulatory guidelines for setting the 
maximum recommended starting dose (MRSD) based on the Food and Drug Administration 


TAK-071
Study No. TAK-071-1001
Page 43 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
(FDA) Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical 
Trials for Therapeutics in Adult Healthy Volunteers [14] and the imposition of a 10-fold safety 
margin, the MRSD for this FIH study is 19.2 mg/day. 
In safety pharmacology studies in rats, doses ≥10 mg/kg were associated with increases in activity, 
with no effects observed at 3 mg/kg. Based on allometric scaling of the 3 mg/kg dose, the human 
equivalent dose would be approximately 29 mg, and imposing a 10-fold margin would result in a 
human equivalent dose of 2.9 mg/day. 
Additionally, nonclinical studies (data on file) have also suggested (based on efficacy in animal 
models and allometric scaling) that the human minimum effective dose could be in the range of 
1 to 10 mg. As shown in Table 6.c, the human plasma exposure for TAK-071 at the lowest 
anticipated minimum effective dose of 1 mg, obtained based on allometric scaling and monkey PK 
data, is predicted to be substantially below the corresponding exposure at the lowest NOAEL level 
in the most sensitive species (>50-fold). 
Table 6.c
Exposure to TAK-071 at the NOAEL in Rats and Monkeys (28-day GLP data) 
at Steady-State and Human Predicted Mean Exposure After a Single 1 mg 
TAK-071 Dose
Nonclinical Toxicity Study
NOAEL
(mg/kg/day)
Cmax
(ng/mL)
AUC24
(ng·hr/mL)
28-day GLP repeat-dose rat
100/30
7220/8940
105,000/146,000
28-day GLP repeat-dose monkey
10
3320/3190
48,000/49,100
Human Predicted 1 mg TAK-071
NA
37.7
951 (a)
Note: Results reported as male/female.
NA=not applicable.
(a) Predicted human AUC∞.
Overall, a TAK-071 dose of 1 mg is an appropriate starting dose for this FIH study because of the 
following:

It is significantly lower (19-fold) than the regulatory requirements for an MRSD based on the 
NOAEL from the monkey 4-week repeat-dose toxicity study [15].

It has an ample predicted exposure-based safety margin (50-fold).

It is lower (3-fold) than the estimated human equivalent dose base on safety pharmacology 
studies.

It is the lowest dose anticipated to have a potential for cognitive improvement effects in 
humans.
6.2.2.2
Dose Escalations and Maximum TAK-071 Dose to be Administered
The study is intended to explore the safety and tolerability of single and multiple TAK-071 doses, 
some of which may exceed doses anticipated to be therapeutically effective. However, it should be 
noted that the study is not intended to determine the MTD.


TAK-071
Study No. TAK-071-1001
Page 44 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
For Cohort 2, the actual choice of the subsequent dose level will occur after a review of the blinded 
24-hour safety, tolerability, and PK data from Cohort 1. Dose escalation to this cohort will be 
limited to an escalated dose that is expected to give no greater than an average approximately 
3-fold increase in either Cmax or AUC24 based on experience in the preceding cohort. In the event 
that the majority of plasma concentrations of TAK-071 are below the limit of detection, or 
exposures are significantly lower than predicted based on animal data, the dose will be escalated 
up to 5-fold with respect to the starting dose, if safety and tolerability of the initial dose are found 
to be acceptable.
The dose escalation decision after dosing in Cohort 2 will be based primarily on a review of the 
blinded 24-hour safety and tolerability data. PK data (0 to 24 hours postdose) will be generated 
after each cohort (but not available prior to the next cohort) and will not inform dose escalation 
decisions for these cohorts unless emerging information from the preceding cohorts indicates that 
PK data are needed between cohorts. 
Dose escalation decisions following dosing in Cohort 3 will be based on a review of the blinded 
24-hour safety, tolerability, and preliminary plasma PK and 12-hour CSF PK data.
For Cohorts 5, 6, 18, and 19, the actual choice of dose level will occur after a review of the blinded 
24-hour safety, tolerability, and preliminary plasma PK data from Cohorts 4, 5, and 6, 
respectively. Based on extrapolation, using a power-law model, of currently available preliminary 
plasma PK parameters (Cmax and AUC24), the planned dose (120 mg) in Cohort 18 is not expected 
to result in individual subjects exceeding the lowest average NOAEL plasma exposure achieved in 
4-week GLP animal toxicology studies. 
For any additional cohorts, the actual choice of dose level will occur after a review of the blinded 
24-hour safety, tolerability, and preliminary plasma PK data from the preceding cohort. The dose 
used will not be expected to exceed the lowest NOAEL plasma exposure achieved in 4-week GLP 
animal toxicology studies.
It is planned that Cohort 2 plasma samples (post-24 hours) will be analyzed separately and will not 
comprise part of the dose escalation PK datasets.
For illustration purposes, and based on human PK predictions using animal data, the planned dose 
escalation in the SRD is as follows: 1, 3, 9, 20, 40, and 50 mg. However, based on emerging safety 
and PK data from Cohort 1 through 6, 18, and 19, doses of 80, 60, and 40 mg are planned for 
Cohorts 20 to 22 to understand safety and tolerability of TAK-071+donepezil (10 mg). The 
TAK-071 plasma exposure following an 80 mg TAK-071 + 10 mg donepezil dose is predicted to 
be approximately equivalent to 15 mg TAK-071 + 5 mg donepezil in chronic administration in the 
MRD study, and this dose was well-tolerated in Cohort 12. A dose of 160 mg TAK-071 + 10 mg 
donepezil will provide an approximate 1.5-fold increase in TAK-071 exposure compared to the 
80 mg TAK-071 + 10 mg donepezil dose. The dose selected for Cohort 21 will be not higher than 
160 mg and will be based on the safety data from TAK-071 120 mg dose. 
It is planned that the MRD cohorts will start no sooner than after all subjects in the SRD Cohort 4 
have been dosed. The starting dose of the MRD cohorts will then be decided following a review of 
the blinded 24-hour safety (AEs, vital signs, ECG, clinical laboratory results) and tolerability from 


TAK-071
Study No. TAK-071-1001
Page 45 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Cohort 4 and the 24-hour preliminary plasma PK and 12-hour CSF PK data from Cohort 3. Under 
no circumstances will the starting dose for MRD Cohort 7 exceed that of the immediately 
preceding cohort for which blinded 24-hour safety and tolerability data have been evaluated and 
deemed to be acceptable. For example, safety and tolerability data from Cohort 4 would enable a 
maximum starting MRD dose analogous to Cohort 3. In the unlikely event that CSF concentrations 
are found to be low, ie, the majority of time points are below the limit of quantification, the MRD 
start may be postponed until a single dose that provides acceptable CSF concentrations is 
identified. 
For subsequent MRD cohorts, doses will be selected after review of the blinded safety, tolerability, 
and available PK data arising from the ongoing SRD part and previous MRD cohort. Selected 
doses will include exposures that have the potential to be in the range required for therapeutic 
efficacy and can be chosen to provide either higher or lower exposure. Higher exposure can be 
greater than approximately 3-fold increments in exposure compared with the previous MRD 
cohort provided that overall, these do not exceed the highest dose administered in the SRD at that 
time and/or the NOAEL exposure (either after the first dose or upon attainment of steady-state).
Safety pharmacology studies in monkeys are in progress to examine the effects of donepezil and 
TAK-071 when dosed alone and in combination on the central nervous system (CNS), and on 
cardiovascular and respiratory function; the PK of the compounds will also be determined. The 
data from this study will be used for guiding TAK-071 dose selection and for determining the 
TAK-071 exposure caps for Cohorts 10 to 12 and 16.
The starting TAK-071 dose for MRD Cohort 10 will be that used in MRD Cohort 7, if supported 
by the preliminary safety and tolerability data. Cohort 10 will start no sooner than after the last 
dose in MRD Cohort 8 has been given and after the 24-hour postdose blinded safety, tolerability, 
and available PK data have been evaluated. It is intended that in Cohorts 10 to 12, the same doses 
will be used as for Cohorts 7 to 9 and, in particular, that the dose for
 
 
 However, if warranted after review of the blinded safety, tolerability, and available 
PK data arising from the ongoing MRD part and previous SRD cohorts, planned doses might be 
altered. In that event, TAK-071 doses would then be selected to include exposures in the range 
believed to be required for therapeutic efficacy in combination with donepezil and could be chosen 
to provide either higher or lower exposure but under no circumstances would exceed the highest 
TAK-071 dose administered in MRD Cohorts 7 to 9.
Cohort 13 can start after the last dose of Cohort 7 has been completed, providing there are no 
safety concerns arising from Cohort 7 following evaluation of the 24-hour postdose blinded safety, 
tolerability, and available PK data. The oral doses of TAK-071 for Cohorts 13 to 15 will be those 
used for Cohorts 7 to 9, respectively. This will facilitate a direct comparison of exposure in 
Japanese and non-Japanese subjects. If TAK-071 is not tolerated at a particular dose level in 
Japanese subjects, alternative doses may be selected for Cohorts 13 to 15. However, under no 
circumstances will doses in Japanese subjects exceed those of Cohorts 7 to 9.
Cohort 16, consisting of subjects with MCI or mild AD, may start after Cohorts 10 to 12 have been 
completed and their preliminary safety, tolerability, and available PK data have been evaluated. 
CCI


TAK-071
Study No. TAK-071-1001
Page 46 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
The selected TAK-071 doses in subjects with MCI or mild AD will not exceed the highest
TAK-071 dose tested in the healthy subject donepezil combination treatment Cohorts 10 to 12. 
The TAK-071 dosing frequency in the healthy subject MRD Cohorts 7 to 15 and patient Cohort 16 
will be QD. The dosing duration in all MRD cohorts is planned to be 21 days, as it is expected that 
the majority subjects will attain steady state prior to the last dosing day. If warranted based on 
emerging PK data from the SRD (ie, several subjects present t1/2z >140 hours) with acceptable 
safety and tolerability in preceding cohorts, the duration of TAK-071 dosing may be extended for 
up to a maximum of 28 days. The maximal duration of dosing in the MRD cohorts of 28 days has 
been set based on the FDA ‘Guidance for Industry - M3(R2) Nonclinical Safety Studies for the 
Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals’ and the 
available 28-day GLP toxicology studies. Under no circumstances a subject will receive 
>28 TAK-071 doses in total through the course of their participation in this study. If the majority 
of subjects present with shorter t1/2z values (ie, <65 hours), TAK-071 dosing duration may be 
shortened to a minimum of 14 days. 
Cohort 17, the relative BA and food effect cohorts, a 10 mg single dose will be administered as a 
DIC or a tablet formulation under fasted condition and tablet formulation in fed state. A dose of 
10 mg has been selected because, based on nonclinical and ongoing clinical data, this is the highest 
anticipated dose likely to be used in future clinical studies.
The endpoints outlined in Section 6.2.3 are those which will allow an appropriate assessment of 
safety, tolerability, and PK of TAK-071, effect of food on the PK of TAK-71 and relative BA for a 
tablet versus DIC formulation. 
Enrolled participants who withdraw from the study for reasons other than safety may be replaced 
to ensure adequate numbers of evaluable subjects. The decision to replace a withdrawn subject will 
be made at the discretion of Takeda and the investigator.
6.2.2.3
Dose selection for the Food Effect/Relative BA Cohort 17
Based on nonclinical and preliminary clinical data, the doses for chronic treatment likely to be 
effective in the clinic are anticipated to be in the range of 3 to 10 mg QD. Tablets of 1 and 5 mg 
have been developed because it is thought these strengths will provide the flexibility to cover doses 
within the cited effective range in future clinical studies. The planned dose for the BA/FE 
Cohort 17 will therefore be 10 mg, administered as either a single 10 mg DIC formulation 
(Reference) or as 2 x 5 mg tablet formulation (Test) with or without a high-fat high-calorie meal. 
The choice of 10 mg has been made for practical reasons and because it is expected to have the 
greatest potential (as compared to lower doses) for a food effect. A higher or lower dose may be 
tested for Cohort 17 if warranted based on emerging preclinical or clinical data; however, under no 
circumstances will the selected TAK-071 dose exceed 20 mg, thus ensuring there is an 
approximately 10-fold safety margin with respect to single dose exposures in humans versus those 
observed at the NOAEL in the 28-Day GLP monkeys toxicology study. An approximately 10-fold 
safety margin is thought to be ample enough to provide exposure coverage in the event of an 
increase in plasma TAK-071 concentrations due to either a formulation and/or food effect.


TAK-071
Study No. TAK-071-1001
Page 47 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
6.2.2.4
Donepezil Dose Selection
Donepezil is a marketed drug and has been widely used in the human population at a 5 mg oral 
dose, which is the lowest dose level used in the treatment of AD. In addition, nonclinical studies 
show that TAK-071 has the potential to be efficacious in a scopolamine-induced cognitive deficit 
model in the presence of low/suboptimal donepezil doses due to synergistic effects. TAK-071 will 
likely be used as add-on therapy in subsequent clinical studies; consequently, it is relevant to study 
the lower standard dose of donepezil. Due to the plasma half-life of donepezil (>70 hours), it is 
necessary to pretreat subjects with donepezil for 3 weeks to ensure that steady-state concentrations 
have been reached prior to dosing with TAK-071. Although donepezil is available at higher 
strengths (10 and 23 mg), there is an increased incidence of side effects, including nausea, 
vomiting, and diarrhea, at these dose levels. Consequently, it is not suitable to provide a loading 
dose to facilitate reaching the desired plasma concentrations in a shorter time interval.
A dose of 5 mg QD has been selected for the healthy subject cohorts (10 to 12) because the target 
population of patients with AD is known to better tolerate cholinomimetic treatments as compared 
with healthy young adults [12]; thus, a dose of 5 mg is thought to be appropriate for the purposes of 
an initial evaluation of the safety, tolerability, and PK of the donepezil plus TAK-071 
combination. Because PK sampling for donepezil plasma concentrations will be performed in 
these cohorts, for practical purposes and to avoid PK sampling overnight, donepezil dosing will 
occur in the morning simultaneously with TAK-071. This will also provide an opportunity to 
evaluate the potential for a drug-drug interaction of TAK-071 on donepezil while at steady-state. 
For this reason, the exact dosing time of donepezil relative to TAK-071 will be selected so as to 
ensure that both drugs attain their peak concentrations at approximately the same time to maximize 
the potential for interaction. Donepezil is reported to have a tmax of 3 to 4 hours, and preliminary 
TAK-071 PK data from SRD Cohorts 1 to 4 indicates that maximum, or near maximum, plasma 
concentrations are attained approximately 4 hours postdose; thus, donepezil should be dosed 
approximately 1 hour after TAK-071; however, the definitive dosing time of donepezil relative to 
TAK-071 will be confirmed following evaluation of all preliminary PK data from the SRD part of 
the FIH study.
According to the donepezil (Aricept) product label, the recommended starting dosage of donepezil 
is 5 mg administered once per day in the evening, just prior to retiring. The maximum 
recommended dosage in patients with mild-to-moderate AD is 10 mg per day. A dose of 10 mg 
should not be administered until patients have been on a daily dose of 5 mg for 4 to 6 weeks. 
Because the majority of patients with mild AD are prescribed donepezil 10 mg QD, 10 mg has 
been selected as the donepezil dose for Cohort 16. To minimize variability, subjects who are 
regularly taking this dose in the evening, as recommended in the product labeling [11], will be 
recruited into the study. This will also provide safety and tolerability data for the combination 
treatment in the intended target population under realistic dosing regimen conditions and will also 
provide data at a higher donepezil dose than that tested in the preceding healthy subject cohorts.
Donepezil has been previously administered to healthy subjects in the context of multiple phase 1 
clinical trials, indicating that single doses of 10 mg are safe and well tolerated in this population 
[19-22]. In particular, donepezil doses of both 5 and 10 mg have been employed in published 


TAK-071
Study No. TAK-071-1001
Page 48 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
[21,22] and unpublished (Study ROF-ALZ_102) scopolamine challenge studies. The higher 
10 mg dose is therefore expected to maximize the chances of a successful positive control in 
Cohorts 20 to 22.
6.2.3
Endpoints
The SRD/MRD cohorts (Cohorts 1 to 15, and 18 to 22) will be conducted in healthy subjects to 
collect safety and tolerability information that will not be biased by any comorbidity and other 
intrinsic/extrinsic factors. The safety and tolerability will then be investigated in subjects with 
MCI or mild AD (Cohort 16) at doses with an acceptable safety profile in the healthy subject 
cohorts. The safety endpoints include AEs, vital signs, weight, ECG findings, and laboratory test 
results. In addition, bowel function will be assessed (eg, BSF scale) to further investigate the 
potential cholinomimetic effects on the gastrointestinal (GI) tract.
The plasma concentration of TAK-071 will be examined to characterize the PK of TAK-071 
following single and multiple doses. Determination of TAK-071 PK in this study will also enable 
the evaluation of the effect of ethnicity on PK as well as exploration of the comparability of PK 
between the target population (patients with AD) and healthy subjects.
Currently available in vitro data indicate there is a low potential for PK drug-drug interaction of 
TAK-071 on donepezil via CYP enzymes. The determination of donepezil plasma concentrations 
will enable the investigation of any effect of TAK-071 on donepezil PK via any other unaccounted 
for mechanisms prior to dosing subjects with MCI or mild AD. The effect of donepezil on 
TAK-071 PK will also be explored.
The investigation of CSF concentrations of TAK-071 is intended to establish some understanding 
of the approximate level of brain penetration relative to plasma for TAK-071 itself, which will be 
helpful for guiding dose selection within the present study and for the interpretation of future 
studies.
The M3 receptor, rather than M1, is the most abundant postjunctional receptor and is thought to be 
the most important muscarinic receptor subtype for mediating pupil contraction. Because 
TAK-071 selectively modulates M1 activity, changes in pupil size following TAK-071 treatment 
are not expected [16]. However, this evaluation will allow confirmation of the lack of engagement 
with other muscarinic receptors in a clinical setting.
 
CCI


TAK-071
Study No. TAK-071-1001
Page 49 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
6.3
Premature Termination or Suspension of Study or Investigational Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a change in the known risk/benefit profile for the product, such that the risk is no 
longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.

Study-specific criteria for terminating the study (eg, study meets predefined rule for futility or 
benefit, study meets predefined stopping rules within or between cohorts per Section 6.1.5).
1. Dose escalation will be stopped if it is predicted that further dose escalation will not result 
in a further increase in plasma exposure (ie, an exposure ceiling is reached).
2. Dose escalation will be stopped at a dose level (ie, 1 escalation step) below the dose that is 
predicted to give a TAK-071 AUC or Cmax that exceeds that of the 28-day monkey 
toxicology study NOAEL.
3. Two or more subjects in any single cohort or across more than 1 cohort experience any of 
the Takeda Medically Significant List events (as outlined in Table 10.a).*
4. Two or more subjects in any single cohort or across more than 1 cohort experience alanine 
aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevations >5× upper 
limit of normal (ULN) in the absence of a concomitant bilirubin increase [see point 
5 below].*
5. One or more subjects in any single cohort or across more than 1 cohort 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”).
6. Two or more subjects in any single cohort or across more than 1 cohort 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%).*
* Please note that the study may be terminated early prior to full attainment of these criteria 
(eg, if just 1 subject experiences 1 of these events) if warranted by safety data from the 
other subjects dosed in the study to date.
7. Two or more subjects in any single dose cohort show a shift in safety EEG electroclinical 
assessment from rating (grading) 0 to 2, or any of the subjects shows clinical signs of 
clinically manifest convulsive or non-convulsive seizure activity.


TAK-071
Study No. TAK-071-1001
Page 50 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)
In the event that the sponsor, an institutional review board (IRB), or regulatory authority elects to 
terminate or suspend the study or the participation of an investigational site, a study-specific 
procedure for early termination or suspension will be provided by the sponsor; the procedure will 
be followed by applicable investigational sites during the course of termination or study 
suspension.


TAK-071
Study No. TAK-071-1001
Page 51 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to randomization. For Cohorts 
10 to 12, check-in occurs on Day -22 for all eligibility criteria.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study:
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative signs and dates 
a written informed consent form (ICF) and any required privacy authorization prior to the 
initiation of any study procedures including requesting that a subject fast for any laboratory 
evaluations.
3. The subject is a healthy man or woman. Subjects should be aged 18 to 55 years, inclusive 
(nonelderly at the time of informed consent and first study drug dose) for Cohorts 1 to 12, and 
17 to 22; 20 to 55 years, inclusive, for Cohorts 13 to 15; and 55 to 90 years, inclusive, for 
Cohort 16.
4. The subject weighs at least 50 kg and has a body mass index (BMI) from 18.0 to 30.0 kg/m2, 
inclusive, at Screening. 
5. For Cohorts 13 to 15 only: First-generation Japanese, defined as having been born in Japan of 
Japanese parents and Japanese grandparents and living no more than 10 years outside of Japan, 
with no significant change in lifestyle, including diet, while living outside of Japan.
6. Cohort 16 only: 
a) Subjects with a documented previous diagnosis of MCI or mild AD or current diagnosis of 
AD criteria met at Screening Visit.
b) Mini Mental State Examination (MMSE) score of 18 to 30, inclusive for subjects with 
existing diagnosis of MCI or mild AD or 18 to 26 inclusive for subjects diagnosed with 
mild AD at Screening and no biomarker data to contradict this diagnosis. 
c) Retrospectively, or at Screening Visit, subjects will have met a diagnosis of probable AD 
based on the National Institute of Neurological Disorders and Stroke Alzheimer’s Disease 
and Related Disorders Association criteria [17] or retrospective clinical diagnosis of MCI 
based on criteria such as subjective cognitive complaint, evidence of impairment in 1 or 
more cognitive domain, preservation of functions, and absence of dementia [18]. (Note: 
treatment can be initiated ONLY based on Mild AD Diagnosis at Screening Visit.)
d) Subjects must be receiving ongoing donepezil therapy (10 mg) in the evening for a 
minimum of 21 days prior to Check-in (Day -1). 
7. A female subject with no childbearing potential, defined as subjects who have been surgically 
sterilized (hysterectomy, bilateral oophorectomy, or tubal ligation) or who are postmenopausal 


TAK-071
Study No. TAK-071-1001
Page 52 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
(defined as continuous amenorrhea of at least 2 years and follicle-stimulating hormone [FSH] 
>40 IU/L).
8. A male subject who is nonsterilized* and sexually active with a female partner of childbearing 
potential* agrees to use adequate contraception* from signing of informed consent throughout 
the duration of the study and for 30 days after last dose. 
*Definitions and acceptable methods of contraception are defined in 
Section 9.1.10 Contraception and Pregnancy Avoidance Procedure and reporting 
responsibilities are defined in Section 9.1.11 Pregnancy.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1. The subject has received any investigational compound within 30 days prior to the first dose of 
study drug.
2. 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) or may consent under duress.
3. If female, the subject is of childbearing potential (eg, premenopausal, not sterilized).
4. The subject has clinically significant (Cohorts 1 to 15 and 17 to 22) or uncontrolled (Cohort 
16) neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, GI, urologic, 
immunologic, endocrine, or psychiatric disease or other abnormality (other than the disease 
being studied), which may impact the ability of the subject to participate or potentially 
confound the study results.
5. A subject with a history of type 1 diabetes (Cohorts 1 to 22) or type 2 diabetes (Cohorts 1 to 15 
and 17 to 22) or subject with hemoglobin A1c >6.5% at Screening. Note: subjects with 
controlled (hemoglobin A1c <7.0% at Screening) type 2 diabetes in Cohort 16 may participate 
in the study. 
6. A subject with evidence or history of a significant hepatic disorder that may either compromise 
subject safety or interfere with the safety and/or outcome evaluation of the study drug. Subjects 
with acute hepatitis (including but not limited to hepatitis B or hepatitis C) or subjects with the 
following results will be excluded:
a) Total bilirubin >1.5× ULN or
b) ALT or AST >2× ULN and total bilirubin >1.3 mg/dL.
7. A subject with a creatinine clearance <60 mL/min (as determined by the Cockcroft-Gault 
formula), confirmed on repeat testing.
8. The subject has a known hypersensitivity to any component of the formulation of TAK-071 or 
placebo. For Cohorts 10 to 12, 16, and 20 to 22, subject has a known hypersensitivity to any 
component of the formulation of donepezil.


TAK-071
Study No. TAK-071-1001
Page 53 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
9. The subject has a sustained supine blood pressure outside the ranges of 90 to 140 mm Hg for 
systolic and 60 to 90 mm Hg for diastolic, confirmed on repeat testing within a maximum of 30 
minutes, at Screening or Check-in. 
10. The subject has a sustained resting vital signs heart rate outside the range 50 to 100 beats per 
minute (bpm), confirmed on repeat testing within a maximum of 30 minutes, at Screening or 
Check-in.
11. The subject has a history of hereditary short QT syndrome.
12. The subject has a Fridericia-corrected QT interval >450 ms or PR interval outside the range 
120 to 220 ms, confirmed on repeat testing within a maximum of 30 minutes, at Screening or 
Check-in.
13. The subject has a positive urine drug result for drugs of abuse (defined as any illicit drug use) at 
Screening or Check-in.
14. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse within 1 year prior to the Screening Visit; or regularly drinks more than 21 units of 
alcohol per week in men (or more than 4 units per day) and 14 units in women (or more than 
3 units per day); or is unwilling to agree to abstain from alcohol and drugs throughout the 
study. One unit is equivalent to a half pint of beer, 1 measure of spirits, or 1 glass of wine. 
15. There is any finding in the subject’s medical history, physical examination, or safety 
laboratory tests giving reasonable suspicion of a disease that would contraindicate taking 
TAK-071 (or donepezil for Cohorts 10 to 12, 16, and 20 to 22) or a similar drug in the same 
class or that might interfere with the conduct of the study.
16. The subject has a risk of suicide or suicidal ideation with intent and plan according to the 
investigator’s clinical judgment (affirmative answer to questions 4 and 5 of the ideation section 
of the Columbia-Suicide Severity Rating Scale [C-SSRS]) or has made a suicide attempt in the 
previous 6 months.
17. The subject has taken any excluded medication, supplements, or food products during the time 
periods listed in the Excluded Medications and Dietary Products table (listed in Section 7.3).
18. The subject has evidence of current cardiovascular, CNS, GI condition, seizure, or any other 
neurological condition that increases the risk of seizure.
19. Cohort 16 only: Any significant neurologic disease (other than suspected incipient or mild 
AD), such as Parkinson disease, stroke, transient ischemic attack, multi-infarct dementia, 
Huntington disease, head trauma with clinically significant cognitive sequelae, or chronic CNS 
infection, per investigator discretion.
20. Cohorts 9, 10 to 12, and 18 to 22 only: Subjects with a history of eye diseases/ocular pathology 
(eg, eye injury, cataract surgery, glaucoma).
21. The subject has current or recent (within 6 months) GI disease that would be expected to 
influence the absorption of drugs (ie, a history of malabsorption, any surgical intervention 
known to impact absorption [eg, bariatric surgery or bowel resection], esophageal reflux, 


TAK-071
Study No. TAK-071-1001
Page 54 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
peptic ulcer disease, erosive esophagitis, or frequent [more than once per week] occurrence of 
heartburn).
22. The subject has a history of cancer, except basal cell carcinoma that has been in remission for 
at least 5 years prior to Check-in.
23. A subject with a known history of human immunodeficiency virus infection at Screening.
24. The subject has used nicotine-containing products (including but not limited to cigarettes, 
pipes, cigars, electronic cigarettes, chewing tobacco, nicotine patch, or nicotine gum) within 
28 days prior to Check-in or has a positive cotinine test at Screening or Check-in.
25. The subject has poor peripheral venous access.
26. The subject has donated or lost 450 mL or more of his or her blood volume (including 
plasmapheresis) or had a transfusion of any blood product within 45 days prior to the first dose 
of study drug.
27. The subject has a clinically significant abnormal ECG at Screening or Check-in. Entry of any 
subject with an abnormal (not clinically significant) ECG must be approved, justified, and 
documented by signature of the principal investigator or medically qualified investigator.
28. The subject has abnormal Screening or Check-in laboratory values that suggest a clinically 
significant underlying disease, confirmed on repeat testing.
7.2.1
Additional Exclusion Criteria for Cohorts With CSF Collection
1. The subject has had CSF collection performed within 30 days prior to Check-in.
2. The subject has a known hypersensitivity to the anesthetic or its derivatives used during CSF 
collection or any medication used to prepare the area of lumbar puncture.
3. The subject has significant vertebral deformities (scoliosis or kyphosis) that, in the opinion of 
the investigator, may interfere with the lumbar puncture procedure.
4. The subject has a history of clinically significant back pain and/or injury in the opinion of the 
investigator.
5. The subject has local infection at the puncture site.
6. The subject has thrombocytopenia or other suspected bleeding tendencies noted before the 
procedure.
7. The subject has developed signs and symptoms of spinal radiculopathy, including lower 
extremity pain and paresthesias.
8. The subject has any focal neurological deficit that might suggest an increase in intracranial 
pressure.
9. The subject has any abnormal findings on ophthalmological assessment/funduscopy 
suggestive of raised intracranial pressure (ie, optic disc swelling/edema; or [uncontrolled] 
hypertensive retinopathy).


TAK-071
Study No. TAK-071-1001
Page 55 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
10. The subject suffers regularly from moderate-to-severe headaches requiring analgesics.
7.2.2
Additional Exclusion Criteria for Cohorts 18 to 22
1. Subjects with lifetime history of seizures, including but not limited to childhood febrile 
seizure. 
2. Subjects with EEG abnormality at Screening of Category 2, exclusionary criteria defined in the 
EEG manual. Categories: 0 (within normal limits), 1 (mildly abnormal, not exclusionary) 
and 2 (abnormal, exclusionary).
7.3
Excluded Medications, Dietary Products, Procedures, and Treatments
Use of the agents in Table 7.a (prescription or nonprescription) is prohibited from the time points 
specified until completion of all study activities.


TAK-071
Study No. TAK-071-1001
Page 56 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Table 7.a
Prohibited Medications and Dietary Products
28 Days Prior to Check-in
7 Days Prior to Check-in
72 Hours Prior to Check-in
Cohorts 1 to 15, 17 to 22 (and higher 
dose cohort, if needed): Prescription 
medications (other than donepezil, 
where applicable)
OTC medications (a)
Products containing caffeine or 
xanthine
Nutraceuticals (eg, St. John’s wort, 
ginseng, kava kava, ginkgo biloba, 
Chinese herbs, and melatonin)
Vitamin supplements
Poppy seeds
Immunization/vaccines
Foods or beverages containing 
grapefruit or Seville-type (sour) 
oranges and marmalade, apple, orange, 
pineapple, vegetables from the mustard 
green family (eg, kale, broccoli, 
watercress, collard greens, kohlrabi, 
Brussels sprouts, mustard), and 
charbroiled meats
Nicotine-containing products
Alcohol-containing products
Cohorts 1 to 15: Intake of known OTC 
inhibitors/inducers of CYPs 3A4/5, 2C9, 
2C19, 2D6, 1A2, 2B6, 2E1, and 2A6
Cohort 16: Intake of known OTC or 
prescription drugs that are moderate or 
strong inhibitors of CYP3A4 (eg, azole 
antifungals), 2D6 (eg, fluoxetine), or 2C9 
(b) (c)
Intake of the following drug classes: 
anti-emetics; antidiarrhetics, 
anticholinergics, cholinergic agonists and 
laxatives
Intake of the following drug classes: 
antacids and proton pump inhibitors.
OTC=over-the-counter. 
(a) Occasional use of acetaminophen/paracetamol (1 g/day) or other medication as approved by Takeda on a 
case-by-case basis is allowed but is prohibited on dosing and sample collection days. Prohibition and approval on a 
case-by-case basis may both be acceptable terms.
(b) In Cohort 16, Takeda may review and approve concomitant medications on a case-by-case basis.
(c) For a list of moderate/strong CYP3A4, 2D6, or 2C9 inducers/inhibitors [19-21], see Appendix F.
Subjects must be instructed not to take any medications including OTC products, without first 
consulting with the investigator.
7.4
Diet, Fluid, and Activity Control 
Subjects will be confined to the clinic for the duration of each Treatment Period. During 
confinement, subjects will be given 3 meals and an evening snack, each containing approximately 
30% fat (relative to the total calories). The meals served on the day of dosing should be similar in 
composition and caloric content for each cohort in the study. The study menu should be recorded 
and submitted to the study file with a copy provided to the sponsor prior to the start of the study.


TAK-071
Study No. TAK-071-1001
Page 57 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
If a blood draw or any study procedure coincides with a meal, the blood draw will take precedence
followed by the study procedure and then the meal. 
7.4.1
Fasting Cohorts (1 to 15 and 17 to 22)
TAK-071 and placebo will be administered with approximately 240 mL of water after a fast of at 
least 8 hours. Subjects will continue to fast for an additional 4 hours after dosing. If a subject is 
unable to continue fasting for 4 hours postdose, a light snack may be provided no earlier than 
2 hour postdose on nonintense PK collection days. Subjects may consume water ad libitum with 
the exception of 1 hour before and 1 hour after drug administration. 
While subjects should aim to swallow all the study drug medication in quick succession with 
approximately 240 mL of water, if the combined total number of capsules/tablets required for 
delivering the dose for a cohort (ie, Cohort 6) exceeds 2 dosage units, subjects will be allowed to 
have a small amount of additional water (up to approximately 120 mL) to complete the study drug 
administration, and the administered approximate total volume should be recorded in the 
electronic case report form (eCRF).
For Cohorts 20 to 22, on Day 1, TAK-071 administration, diet, fluid, and activity control will be 
same as above. On Day 2, donepezil will be administered with approximately 240 mL of water 
after a fast of at least 8 hours. A low-fat, low-calorie breakfast, defined as <300 calories and <20% 
fat content, will be given at approximately 1.5 hours after donepezil administration. Subjects may 
consume water ad libitum with the exception of 1 hour before and 1 hour after drug administration. 
The study menu should be recorded and submitted to the study file. The start and end time of meals 
and percentage of meals consumed on Day 1 and Day 2 will be recorded in the eCRF.
Subjects will remain upright (seated, standing, or ambulatory) for 4 hours following the dose 
administration, except as necessitated by the occurrence of an AE or study procedures (eg, 
obtaining 12-lead ECG). Subjects will refrain from strenuous and/or unaccustomed exercise 
throughout the entire course of the study.
For cohorts with CSF sampling, subjects need to remain recumbent due to CSF sampling.
For relative BA of tablet formulation (compared to DIC) and the FE cohort (Cohort 17), TAK-071 
will be administered as DIC and tablet formulations in a cross-over design as 3 regimens 
(Regimens A, B, and C). For all 3 regimens study drug will be administered after an overnight fast 
of at least 8 hours on each dosing day. Subjects randomized to Regimens A and B will remain 
fasted prior to dosing; however, subjects assigned to Regimen C should start the standard high fat 
meal (~ 50% fats) 30 minutes prior to administration of the drug product and finish the meal within 
25 minutes. On dosing days, the source documentation and the eCRF will record whether the 
subjects consumed 100% of their breakfast (or the approximate percentage of the meal consumed: 
0%, 25%, 50%, or 75%) during the fed regimen (Regimen C). Subjects in all 3 regimens will fast 
for an additional 4 hours after dosing. Water will be allowed ad libitum after 2 hours postdose.
Subjects in Regimen C, randomized to receive drug administration with food, will consume a 
high-fat (approximately 50% of the total caloric content of the meal), high-calorie (approximately 
1000 calories) breakfast beginning 30 minutes prior to study drug administration, consume the 


TAK-071
Study No. TAK-071-1001
Page 58 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
meal within 25 minutes and receive study drug 30 minutes after the start of the meal. Subjects will 
then fast from food until approximately 4 hours postdose at which time a standard lunch will be 
served. Water will be allowed ad libitum after 2 hours postdose. The content of a sample high-fat 
breakfast is listed in Table 7.b.
Table 7.b
Content of a Standard, High-Fat Breakfast
2 fried or scrambled eggs
2 strips bacon
2 slices of toast with 2 pats of butter
4 oz (113 g) hash browns (fried potato)
240 mL whole milk
7.4.2
Cohort 16
Based on the preliminary results from cohort 17, food did not appear to affect the systemic 
exposure to TAK-071. Therefore, TAK-071 and donepezil can be given with or without food. 
However, on the days of blood draws for clinical laboratory tests, TAK-071 and placebo will be 
administered with approximately 240 mL of water after a fast of at least 8 hours.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of a subject from the study or study drug 
should be recorded in the eCRF using the following categories. For screen failure subjects, refer to 
Section 9.1.19.
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 medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/Baseline status, see Section 9.1.9), if any 1 of the following circumstances occur at 
any time during study drug treatment:
–
ALT or AST >8×ULN.
–
ALT or AST >5×ULN and persists for more than 2 weeks.
–
ALT or AST >3×ULN in conjunction with elevated total bilirubin >2×ULN or 
INR>1.5.
–
ALT or AST >3×ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).


TAK-071
Study No. TAK-071-1001
Page 59 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
2. Significant protocol deviation. The discovery postrandomization that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued participation 
poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic, and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented.
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. Withdrawal due to an AE 
should not be recorded in the “voluntary withdrawal” category.
5. Study termination. The sponsor, IRB, or regulatory agency terminates the study.
6. If, in spite of preventive measures, the PK exposure (Cmax and AUC24 for steady-state) in an 
individual unexpectedly exceeds, or is predicted to exceed upon repeat dosing, the 
corresponding average steady-state exposure at the NOAEL in the 28-day monkey toxicology 
study.
7. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
Early Termination Visit. 
Enrolled participants who withdraw from the study for reasons other than safety may be replaced 
to ensure adequate numbers of evaluable subjects. The decision to replace a withdrawn subject will 
be made at the discretion of Takeda and the investigator.


TAK-071
Study No. TAK-071-1001
Page 60 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication 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 clinical trial material.
8.1
Study Medication and Materials
Study drug refers to TAK-071, matching placebo, and donepezil. TAK-071 drug substance will be 
compounded into a hard capsule (DIC) or formulated as a tablet, which will be labeled in a blinded 
fashion with third-party dispensing. Donepezil will be packed and labeled in an unblinded fashion 
at the study site. An unblinded pharmacist will manage and prepare doses as needed throughout the 
study.
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term study drug refers to all or any of the drugs defined below.
8.1.1.1
Investigational Drug
TAK-071 Drug Substance 
TAK-071 drug substance will be manufactured by Ube Industries Limited, Yamaguchi, Japan and 
supplied to the clinical site and then compounded into a hard capsule.
TAK-071 DIC and Matching Placebo
The TAK-071 DIC will be prepared at the clinical site by feeding TAK-071 drug substance into a 
hard gelatin capsule (color: Swedish orange opaque). The range of TAK-071 drug substance 
loaded will be 1 to 30 mg per capsule. Compounding and blinding instructions will be provided to 
the clinical site using the compounding worksheet or a similar document. The matching placebo 
will be an empty capsule and will also be prepared at the site.
The composition of the TAK-071 DIC and matching placebo can be found in Table 8.a.
Table 8.a
Composition of TAK-071 for DIC and Matching Placebo
Components 
TAK-071 DIC
Matching Placebo
TAK-071
1 to 30 mg
0 mg
Hard gelatin capsule (Size: 00, Color: Swedish orange opaque)
TAK-071 Tablet
The TAK-071 tablet will be available in 2 strengths (1 and 5 mg). In addition to TAK-071, the 
inactive constituents of the tablet formulation include mannitol, microcrystalline cellulose, 
hydroxypropyl cellulose, sodium starch glycolate type A, magnesium stearate, hypromellose 
2910, titanium dioxide, ferric oxide red, and ferric oxide yellow.


TAK-071
Study No. TAK-071-1001
Page 61 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
8.1.1.2
Companion Medication
Donepezil is delivered orally as a 5 mg oral tablet QD in Cohorts 10 to 12 and a 10 mg (or 5 mg 
followed by 10 mg in run-in period) oral tablet QD in Cohort 16. In Cohorts 20 to 22, donepezil 10 
mg tablet manufactured by Eisai Inc. will be over-encapsulated, labeled in a blinded fashion with 
third-party dispensing, and delivered as an oral capsule. The composition of the over-encapsulated 
donepezil and matching placebo is provided in Table 8.b.
Table 8.b
Composition of Over-Encapsulated Donepezil and Matching Placebo
Components 
Aricept OE
Matching Placebo
Donepezil 10 mg tablet, United States Pharmacopeia
1 tablet
-
Microcrystalline cellulose, National Formulary
Approximately 100 mg
Approximately 150 mg
Hard gelatin capsule (Size: AA, Color: Swedish orange opaque)
OE=over-encapsulated.
8.1.1.3
Sponsor-Supplied Drug
TAK-071 drug substance is manufactured by Ube Industries Limited, Yamaguchi, Japan and 
supplied to the clinical site by Takeda Development Center Americas, Inc. (TDC Americas).
TAK-071 tablets are manufactured by Takeda Pharmaceutical Company Limited, Osaka, Japan 
and supplied to the clinical site.
Either branded Aricept or generic donepezil (5 and 10 mg tablets) will be selected based on study 
design and sourced locally by the clinical site. For Cohorts 20 to 22, however, branded Aricept will 
be selected and over-encapsulated since stability data in the over-encapsulated condition is 
available only for branded Aricept.
8.1.2
Storage
Based upon the recent stability study data, the recommended storage conditions for the TAK-071 
DIC and tablets are 20°C to 25°C (68°F to 77°F) with temporary excursions permitted 15°C to 
30°C (59°F to 86°F). Any excursions from the labeled storage conditions must be reported to 
Takeda immediately. Donepezil tablet must be stored according to the commercial label. 
Over-encapsulated donepezil must be stored according to the label.
All clinical trial material must be kept in an appropriate, limited-access, secure place until it is used 
or returned to the sponsor or designee for destruction.
All study drug must be stored under the conditions specified on the label and remain in the original 
container until dispensed. A daily temperature log of the drug storage area must be maintained 
every working day.
8.1.3
Dose and Regimen
The investigator or investigator’s designee will instruct the subject on dosing procedures. All 
dosing will occur while subjects are in the clinic under the supervision of the principal investigator 


TAK-071
Study No. TAK-071-1001
Page 62 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
or designee (except Days -18 to -11 during Cohorts 10 to 12 where the subject will self-administer 
donepezil and Days 3 to 10, 12 to 19, 43 to 50, and 52 to 59 during Cohort 16 where the subject 
will self-administer TAK-071 or placebo each morning at home). The doses taken in the clinic will 
be administered to the subjects by the investigator or investigator’s designee. The exact time of 
dose will be recorded in the source documents and on the appropriate eCRF.
The planned initial dose of TAK-071 or matching placebo for Cohort 1 is 1 mg. TAK-071 is dosed 
on the morning of Day 1 after fasting for at least 8 hours. Cohorts 2 through 6, 18, and 19 will 
escalate through the SRD levels and Cohorts 7 through 9 through the MRD dose levels. 
Additionally, Cohorts 10 to 12 will be pretreated for 3 weeks with 5 mg donepezil orally 
continuing through Day 21. In healthy subjects in Cohorts 10 to 12, donepezil will be administered 
in the morning, shortly before or after TAK-071; the precise relative timing will be confirmed once 
TAK-071 PK data are available. Cohorts 9 and 13 through 15 will have 1 dose of TAK-071 on 
Day 1 followed by a 7-day washout period before administration of 21 daily doses of TAK-071. 
Subjects in Cohorts 20 to 22 will be administered as a single dose of TAK-071 or placebo on 
Day 1, and a single dose of donepezil or placebo approximately 24 hours later on Day 2. 
In Cohort 16, subjects with MCI or mild AD who are stable on donepezil will be randomized to 
1 of 2 possible treatment sequences consisting of 2 periods and 2 treatments, alternating in a 
crossover fashion. In each period, subjects will receive 1 of the following treatments: TAK-071 
QD for 21 days (Treatment A) or 21 days of matching placebo (Treatment B). Background 10 mg 
QD donepezil treatment will be administered in the evening just before bedtime.
In Cohort 17 (Relative BA and FE), TAK-071 DIC or tablet will be administered as a single dose 
(Regimen A, B, and C) in a cross-over design over 3 periods, with a 21-day washout after each 
treatment. The planned dose is 10 mg in each of the 3 periods. Diet assigned to each regimen is 
described in Section 7.4.
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study subject, at a dose above that which is assigned to that individual subject according 
to the study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on AE CRF(s) according to Section 10.0, PTEs and AEs.
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2, Collection and Reporting of SAEs.
In the event of drug overdose, the subject should be treated symptomatically.


TAK-071
Study No. TAK-071-1001
Page 63 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
8.2
Investigational Drug Assignment and Dispensing Procedures
Subjects will be assigned, in the order in which they are randomized into the study, to receive their 
treatment according to the randomization schedule allocated to the site. The Randomization 
Sequence Number will be entered onto the eCRF.
For each dosing cohort in SRD, MRD, and BA/FE parts, randomized subjects will be assigned a 
5-digit randomization number in the order which they are enrolled. Randomization sequence 
numbers will be XYY01 to XYY08 (Cohorts 7 to 12) or XYY06 (Cohorts 13 to 15), where X 
refers to SRD (Part 1) or MRD (Part 2) and Y refers to cohort number.
For example:

Subjects in SRD Cohort 1 will have randomization sequence numbers 10101 to 10108, and 
subjects in SRD Cohort 2 will have numbers 10201 to 10208.

Subjects in MRD Cohort 7 will have randomization sequence numbers 20701 to 20708, and 
subjects in MRD Cohort 11 will have numbers 21101 to 21108. 

Subjects in MRD Cohort 13 will have randomization sequence numbers 21301 to 21306.

Subjects in BA/FE Cohort 17 will have randomization sequence numbers 21701 to 21712. 

Subjects in Cohort 20 will have randomization sequence numbers 12001 to 12012.
If a subject needs to be replaced, the replacement subject will receive the same treatment or 
treatment sequence of the subject being replaced. The replacement randomization number will be 
50 larger than the randomization number of the subject who is being replaced. For example, 
randomization number 10251 will be used for the subject who replaces the subject who had 
randomization number 10201, using the same treatment or treatment sequence in Cohort 2. 
This 5-digit number will be used by the clinical site to facilitate the prelabeling of PK samples and 
will be the only subject identifier used on all PK and/or PD sample collections. It should also be 
contained on the PK transport vials shipped to the bioanalytical laboratory and will be used by the 
laboratory to report the subject data results. This 5-digit number should only be used for the 
purposes described in this section. It does not replace the 3-digit subject number that is assigned at 
the time the informed consent is obtained and used for all other procedures to identify the subjects 
throughout the study.
Study drugs will be dispensed in the clinic under the supervision of the investigator or designee.
8.3
Randomization Code Creation and Storage
Randomization personnel of the sponsor or designee will generate the randomization schedule and 
will provide it to the site pharmacist prior to the start of this study. A revised randomization 
schedule for Cohorts 13 to 15 will be provided to the site pharmacist. All randomization 
information will be stored in a secured area, accessible only by authorized personnel.


TAK-071
Study No. TAK-071-1001
Page 64 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
8.4
Investigational Drug Blind Maintenance
The investigational drug blind is maintained through a randomization schedule held by the 
dispensing pharmacist. The site-designated study personnel will maintain the investigational drug 
blind information.
8.5
Unblinding Procedure
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. All study 
assessments and causality should be performed, if possible, prior to unblinding. In the event of a 
medical emergency, if possible, the medical monitor should be contacted before the 
investigational drug blind is broken to discuss the need for unblinding.
The sponsor must be notified as soon as possible if the investigational 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, investigational drug must be stopped immediately and the 
subject withdrawn from the study.
No change should be made to any assessment of the subject after unblinding.
8.5.1
Sponsor PD Unblinding
A Takeda representative outside the main study team will receive the randomization schedule to 
analyze the PD data for interim analysis. This team member will not be involved in the conduct of 
the study or interpretation of any safety or PK data.
8.5.2
Sponsor Interim Analysis Unblinding
The main Takeda study team will be unblinded to Cohorts 1 to 15 and 17 to 22 data during the 
interim analysis and Cohort 16 will remain blinded.
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 or before being destroyed at the site following local site procedures with sponsor 
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. To document appropriate use 
of sponsor-supplied drug (TAK-071 drug substance, DIC, and donepezil), the investigator or 
designee must maintain records of all sponsor-supplied drug delivery to the site, site inventory, 
dispensation and use by each subject, and return to the sponsor or designee, or destruction at the 
site following local procedures with sponsor approval.
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct and that 


TAK-071
Study No. TAK-071-1001
Page 65 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
the medication is in good condition. If the quantity and conditions are acceptable, the investigator 
or designee should acknowledge the receipt of the shipment by signing the bottom half of the 
packing list and faxing per instructions provided on the form. If there are any discrepancies 
between the packing list and the actual product received, Takeda must be contacted to resolve the 
issue. The packing list should be filed in the investigator’s essential document file.
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
(TAK-071 drug substance, DIC, and donepezil) received and dispensed during his or her entire 
participation in the study. Proper drug accountability includes, but is not limited to, the following:

Continuously monitoring expiration dates if expiry date is provided to the investigator or 
designee. 

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the drug lot 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, otherwise uninvolved with study conduct, will review the randomization 
schedule and subject dosing log prior to Day 1 dosing and following dosing to ensure all 
subjects received the correct dose of study drug.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The investigator or designee must record the current inventory of all sponsor-supplied drugs 
(TAK-071 drug substance, DIC, and donepezil) on a sponsor-approved drug accountability log. 
The following information will be recorded at a minimum: protocol number and title, name of 
investigator, site identifier and number, description of sponsor-supplied drugs, expiry date, and 
amount dispensed (including initials, seal, or signature of the person dispensing the drug). The log 
should include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
All study drug not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug accountability log.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 
drugs are returned to the sponsor or its designee for destruction. The investigator or designee will 
retain a copy of the documentation regarding sponsor-supplied drug accountability, return, and/or 
destruction, and originals will be sent to the sponsor or designee.
The investigator will be notified of any expiry date or retest date extension of sponsor-supplied 
drug during the study conduct. On expiry date notification from the sponsor or designee, the site 
must complete all instructions outlined in the notification, including segregation of expired 
sponsor-supplied drug for return to the sponsor or its designee for destruction.


TAK-071
Study No. TAK-071-1001
Page 66 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
Schedule of Study Procedures is located in Appendix A.
The timing of planned procedures for assessment of safety procedures (eg, vital signs, ECG, safety 
laboratory tests) currently outlined in the protocol may be modified during the study based on 
newly available safety, tolerability, PK, or PD data (eg, to obtain data closer to the time of peak 
plasma concentrations). These changes may increase the number of study procedures for a given 
subject during his/her participation in the entire study. 
If additional days of dosing or confinement are required based on emerging data, the following at a 
minimum would be collected daily; AE assessment, concomitant medication assessment, vital 
signs, Bristol stool scale, and ECG.
If additional safety laboratory or PK samples are obtained, the total blood volume should not 
exceed a total blood volume of 550 mL.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study and before any 
protocol-directed procedures are performed, including requesting that a subject fast for laboratory 
evaluations.
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is obtained; this subject number will be used throughout the study.
9.1.1.1
Pharmacogenomics Informed Consent Procedure
Pharmacogenomics (PGx) informed consent is a component of the overall study informed consent. 
The requirements are described in Section 15.2.
PGx sample collection is mandatory.
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, caffeine consumption, alcohol use, reproductive status 
(including last menstrual period), 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 stopped at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.8).


TAK-071
Study No. TAK-071-1001
Page 67 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
For subjects in Cohort 16, the following medical history will be collected: diagnosis, date of 
diagnosis, MMSE score, date of onset of donepezil treatment, and dose and timing of 
administration of donepezil (evening [bedtime] required).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 28 days prior to signing of informed consent.
9.1.3
Physical Examination Procedure
A physical examination will consist of the following body systems: (1) eyes (see more details in 
Section 9.1.3.1); (2) ears, nose, throat; (3) cardiovascular system; (4) respiratory system; (5) GI 
system; (6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; 
(10) lymph nodes; and (11) other.
Any abnormal finding on a pretreatment physical examination assessment must be assessed as not 
clinically significant or clinically significant by the investigator and recorded in the source 
document and eCRF. All clinically significant findings/changes will be recorded as a PTE or 
concurrent medical condition in the source document and on the appropriate eCRF described in 
Section 10.0 or Section 9.1.8. 
On subsequent examinations, any abnormal change from the pretreatment physical examination 
assessment occurring immediately prior to the start of the investigational drug must be assessed as 
not clinically significant or clinically significant by the investigator and recorded in the source 
document and eCRF. Any clinically significant change or new diagnosis as a result of a clinically 
significant change, as determined by the investigator, will be recorded as an AE in source 
documentation and on the PTE/AE eCRF described in Section 10.0. 
9.1.3.1
Funduscopy (Cohorts With CSF Sampling Only)
A Baseline ophthalmological assessment of the retina (funduscopy) will be performed at 
Screening for subjects enrolled in cohorts for CSF sampling. Funduscopy will be performed by a 
trained person (optometrist, ophthalmologist, or neurologist) after dilatation of the pupil in both 
eyes by administration of tropicamide 0.5% eye drop. After pupil dilatation, subjects will be 
advised to wear sunglasses for the next 4 to 6 hours and avoid operating a car.
9.1.4
Weight, Height, and BMI
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The Takeda standard for collecting height is centimeters without decimal places and for 
weight it is kilograms with 1 decimal place. 
BMI should be derived as follows: 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.


TAK-071
Study No. TAK-071-1001
Page 68 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
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. However, if the BMI is used to satisfy the entry criteria, then this 
determination must be made after rounding.
9.1.5
MMSE
The MMSE is an 11-question tool that tests 5 areas of cognitive function: orientation, registration, 
attention and calculation, recall, and language. The maximum score is 30, with lower scores 
indicating more cognitive impairment [22]. The MMSE will be administered at Screening to 
subjects in Cohort 16 only by trained site personnel.
9.1.6
Vital Sign Procedure
In subjects who are not undergoing CSF collection (Cohorts 2, 4 to 8, and 10 to 22), vital signs will 
include body temperature (oral), respiratory rate, and orthostatic blood pressure and pulse (bpm). 
In subjects who have completed enrollment for Cohort 1 at the time of this amendment and in 
subjects who are undergoing CSF collection (Cohorts 3 and 9), vital signs include body 
temperature (oral), respiratory rate, supine blood pressure (resting more than 5 minutes), and pulse 
(bpm). 
Vital signs should be collected daily, predose and upon morning rising on days during 
confinement. In addition, vital signs should be collected in Cohorts 3 and 9 at approximately 5 
hour postdose on Day 1 and Day 8 (Cohort 9 only). Vital signs may be repeated. All measurements 
will be recorded on the source documents and in the eCRF. 
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 the scheduled blood draw.
For BA/FE Cohort 17, for the fed regimen, if vital signs coincide with a meal, vital signs will take 
precedence followed by the meal.
For Cohorts 2, 4 to 8, and 10 to 22, orthostatic blood pressure and pulse will be measured at 
predose and at 2, 4, 6, 8, and 12 hours postdose in the first 24 hours after the initial dose of 
TAK-071 (Day 1) and then afterwards on days while subjects are in the phase 1 unit. Orthostatic 
blood pressure will be measured as follows [23]: 
1. Have the patient lie down for 5 minutes. 
2. Measure blood pressure and pulse rate. 
3. Have the patient stand. 
4. Repeat blood pressure and pulse rate measurements after standing 1 and 3 minutes. 
A drop in bp of ≥20 mm Hg, or in diastolic bp of ≥10 mm Hg, or experiencing lightheadedness or 
dizziness is considered abnormal [23].


TAK-071
Study No. TAK-071-1001
Page 69 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
9.1.7
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 OTC. Concomitant medication is not provided by 
Takeda. 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 Follow-up Call/Visit), and 
all medication including vitamin supplements, OTC medications, and oral herbal preparations, 
must be recorded in the eCRF. Documentation will include generic medication name, dose, unit, 
frequency, route of administration, start and end dates, and reason for use.
9.1.8
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, ECG, or physical 
examination abnormalities noted at the Screening/Baseline examination. The condition (ie, 
diagnosis) should be described.
9.1.9
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. Laboratory 
samples will be taken following a minimum 8-hour overnight fast on the days stipulated in the 
Schedule of Study Procedures (Appendix A).
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).
Table 9.a lists the tests that will be obtained for each laboratory specimen.


TAK-071
Study No. TAK-071-1001
Page 70 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Red blood cells
White blood cells with 
differential (absolute counts)
Hemoglobin
Hematocrit
Platelets
ALT
Albumin
Alkaline phosphatase
AST
Total bilirubin
Direct bilirubin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
-Glutamyl transferase
Potassium
Sodium
Glucose
Chloride
Bicarbonate
Calcium
Lactate dehydrogenase
Glutamate dehydrogenase
pH
Specific gravity
Protein
Glucose
Blood 
Nitrite
Microscopic analysis (only 
if positive dipstick results): 
white blood cells, red blood 
cells, epithelial cells, casts
Coagulation
PT/INR
aPTT
Diagnostic Screening:
Serum
Urine/Blood
Hemoglobin A1c
Creatinine clearance (a)
HBsAg and anti-HCV
Female subjects: serum hCG (b)
Drug screen for amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, opiates, alcohol, 
and cotinine (c).
Female subjects, if postmenopausal and not surgically 
sterile: FSH (d)
aPTT=activated partial thromboplastin time, HBsAg=hepatitis B surface antigen, hCG=human chorionic 
gonadotropin, HCV=hepatitis C virus, PT=prothrombin time.
(a) Calculated using the Cockcroft-Gault formula.
(b) Serum hCG pregnancy test will be done at Screening, Check-in, Final Visit/Early Termination and at the 
Follow-up Visit if the subject is brought back to the clinic for re-evaluation (Cohorts 1 to 15 only). For Cohort 17 
(BA/FE) additional serum hCG pregnancy tests will be done in each period at check-in.
(c) To be performed at Screening and as indicated in the Schedule of Assessments.
(d) FSH level will be obtained for female subjects at Screening if they are postmenopausal (ie, continuous amenorrhea 
of at least 2 years) and not surgically sterile. The result must be >40 IU/L for the subject to be enrolled.
The local laboratory will perform laboratory tests for hematology, coagulation, 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, γ-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.


TAK-071
Study No. TAK-071-1001
Page 71 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
If the 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
Reporting of Abnormal Liver Function Tests for reporting requirements).
Please refer to Section 7.5 for discontinuation criteria and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests in relation to ALT or AST >3×ULN in 
conjunction with total bilirubin >2×ULN.
Laboratory reports must be signed and dated by the principal investigator or subinvestigator 
indicating that the report has been reviewed and any abnormalities have been assessed for clinical 
significance. Any abnormalities identified prior to first dose will require clear and complete 
documentation in the source documents as to the investigator’s assessment of not clinically 
significant before proceeding with enrollment/randomization.
All clinically significant laboratory abnormalities must be recorded as a PTE/AE in the subject’s 
source documents and on the appropriate eCRF. A clinically significant laboratory abnormality 
that has been verified by retesting will be followed until the abnormality returns to an acceptable 
level or a satisfactory explanation has been obtained.
The investigator will maintain a copy of the laboratory accreditation and the reference ranges for 
the laboratory used.
9.1.10 Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for 30 days after last 
dose of study drug, nonsterilized** male subjects who are sexually active with a female partner of 
childbearing potential* must use barrier contraception (eg, condom with spermicidal cream or 
jelly).
*Females 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 2 years and an 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 a consent form stating that they 
understand the requirements for avoidance of pregnancy during the course of the study and for 
30 days after the last dose of study drug.


TAK-071
Study No. TAK-071-1001
Page 72 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. 
In this study, where medications and devices containing hormones are excluded, the only 
acceptable methods of contraception are as follows:
Barrier methods (each time the subject has 
intercourse):
Intrauterine devices (IUDs):

Male condom PLUS spermicide.

Cap (plus spermicidal cream or jelly) PLUS male 
condom and spermicide.

Diaphragm (plus spermicidal cream or jelly) 
PLUS male condom and spermicide.

Copper T PLUS condom or spermicide.
During the course of the study, regular serum hCG pregnancy tests will be performed for female 
subjects (Cohorts 1 to 15 and 17 to 22) and subjects will receive continued guidance with respect 
to the avoidance of pregnancy as part of the study procedures (Appendix A). In addition to a 
negative serum hCG pregnancy test at Screening, female subjects must have a negative serum hCG 
pregnancy test at Check-in prior to receiving any dose of study medication.
9.1.11 Pregnancy
Women of childbearing potential will not be included in this study.
However, if any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug immediately discontinued. In addition, any pregnancies in the partner of a 
male subject during the study or for 30 days after the last dose should be recorded following 
authorization from the subject’s partner.
If the pregnancy occurs during administration of active study drug, eg, within 30 days of the last 
dose of active study drug, the pregnancy should be reported immediately, using a pregnancy 
notification form, to the contact listed in Section 1.0.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
Subjects randomized to placebo need not be followed. 
If the female 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 the female partner of a male subject became pregnant and provide details of 
treatment the subject received (blinded or unblinded, as applicable).
All reported pregnancies will be followed up to final outcome using the pregnancy form. The 
outcome, including any premature termination, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted.


TAK-071
Study No. TAK-071-1001
Page 73 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
9.1.12 ECG Procedure
The investigator will review all vital signs and 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. 
Holter recordings will be stored by Takeda and will be sent to a central ECG analysis laboratory 
for retrospective expert review and estimation of ECG intervals at an appropriate time for the 
TAK-071 program during or after completion of the present study.
9.1.12.1 Screening and Safety ECGs
A standard 12-lead ECG will be recorded as indicated in the Schedules of Assessments 
(Appendix A). The investigator (or a qualified observer at the investigational 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 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, QT interval with Bazett correction, and T and U 
wave morphology.
All stationary 12-lead ECG machines will be supplied by the site. Subjects should be in a supine 
position following 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.
9.1.12.2 Holter
To help ensure high-quality data recording, prior to electrode placement, the anatomical sites must 
be prepared to allow for proper skin/electrode interface. Any hair on the electrode sites must be 
shaven. Any oils, lotions, or dead skin should be removed from the electrode sites using an 
abrasive, alcohol prep pad designed for this purpose. An indelible skin marker must be used to 
mark the exact electrode placement site so that the electrode positions will remain constant 
throughout each treatment period. The electrodes should always be attached to the Holter 
connecting cable prior to skin placement.
All Holter recordings will be obtained on 1000 sps flash cards using a 12-lead Holter recorder. The 
flash cards will be couriered to the central cardiac core laboratory. Alternatively, Holter recordings 
will be digitally transmitted to the central cardiac core laboratory, as appropriate.


TAK-071
Study No. TAK-071-1001
Page 74 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Each 12-lead Holter ECG acquisition window will be approximately 10 minutes in duration, from 
which cardiac data analysis laboratory will extract 10-second ECGs in triplicate. This window will 
be preceded by 10 minutes of quiet supine rest. The timing of continuous 12-lead Holter ECG
monitoring is provided in Table 9.b. 
Table 9.b
Timing of Holter ECG Monitoring
Cohort
Scheduled Time
2, 4, 6, 18, 19 2 hours predose until 48 hours postdose
7 to 8
2 hours predose until 24 hours postdose on Day 1 and 1 hour predose until 48 hours postdose on Day 21
9
2 hours predose until 48 hours postdose on Day 1 and 1 hour predose until 48 hours postdose on Day 28
ECG extraction time points (triplicates) will occur at 1.5, 1, and 0.5 hours predose on Day 1 
(Cohorts 2, 4, 6 to 9, and 18 to 19) for estimation of Baseline and immediately prior (within 15 
minutes) to the predose PK blood draw on the last TAK-071 dosing day (Cohorts 7 to 9). In 
addition, postdose triplicate ECG extractions will occur immediately prior (within 15 minutes) to 
each PK blood draw, starting with the 0.5 postdose collection (see Section 9.1.15 for PK sampling 
time points). 
Triplicate parameter estimates will be derived from the ECG traces at each nominal time point, 
including heart rate, RR interval, PR interval, QT interval, QRS interval, QT interval with 
Fridericia correction, QT interval with Bazett correction, and T and U wave morphology, as 
appropriate. Other time points may also be retrospectively assessed if clinical observations or 
findings require further investigation.
Subjects will be supervised while remaining at rest, quiet, awake, and in a supine position from at 
least 10 minutes prior to the beginning of each ECG extraction time point and will remain quiet, 
awake, motionless, and supine for at least 10 minutes after the beginning of each ECG extraction 
time point.
ECGs derived from Holter monitoring are not intended to be analyzed for real-time safety 
monitoring but will be used for future retrospective ECG analyses, unless an earlier analysis is 
warranted by emerging safety information.
9.1.13 Bowel Function
Subjects will be provided with a bowel function diary card during Screening to record their 
Baseline bowel function using the BSF scale for stool consistency rating.
From Check-in through Final Visit, subjects will use the bowel function diary card to assess the 
time of each bowel movement during the dosing period (and until Check-out/Final Visit), stool 
consistency (pictorial BSF score), and completeness of evacuation for an exploratory comparison 
of the clinical effects of TAK-071.
Stool frequency is defined as the number of episodes of defecation recorded per day in the bowel 
function card; stool consistency is defined by the 7-point pictorial BSF scale, which ranges from 
unformed/watery to hard pellets; ease of passage is defined by the 7-point adjectival scale, which 


TAK-071
Study No. TAK-071-1001
Page 75 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
ranges from incontinence to requiring manual disimpaction; and sense of complete evacuation is 
defined by a yes-or-no answer to the question “Did you feel like you completely emptied your 
bowels?” [24].
9.1.14 PGx Sample Collection
PGx sample collection is mandatory.
Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) form 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 how the drug is broken down or how the drug affects the 
body. This is called a “PGx research study.” Specific purposes of this study include the following:

Identifying genetic reasons why certain people respond differently to TAK-071

Finding out more information about the mechanism of action of TAK-071.

Generating information needed for research, development, and regulatory approval of tests to 
predict response to TAK-071.

Identifying variations in genes related to the biological target of TAK-071.
This information may be used, for example, to develop a better understanding of the safety and 
efficacy of TAK-071 and other study drugs and for improving the efficiency, design, and study 
methods of future research studies.
Since PGx is an evolving science, many genes and their functions are not yet fully understood. 
Future data may suggest a role of these genes in drug response, which may lead to additional 
hypothesis-generating exploratory research and diagnostic development on stored samples.
DNA Collection (SRD Cohorts 1 to 6 and 18 to 22, MRD Cohorts 7 to 9 and 13 to 16
One 6-mL whole blood sample for DNA isolation will be collected before dosing on Day 1 from 
each subject in the study into plastic potassium ethylenediamine tetraacetic acid (K2EDTA) 
spray-coated tubes and stored under frozen conditions.
DNA Collection (MRD Cohorts 10 to 12)
One 6-mL whole blood sample for DNA isolation will be collected before dosing on Day -21 from 
each subject in the study into plastic K2EDTA spray-coated tubes and stored under frozen 
conditions.
If necessary and feasible, a second aliquot of blood may be taken if isolation of DNA from the first 
sample was not successful or possible.
RNA Collection (SRD Cohorts 1 to 6 and 18 to 22)
Two whole blood samples (2.5 mL per sample) will be collected predose on Day 1, 12 hours 
postdose on Days 1 and 5 for RNA analysis from each subject in the study into a PAXgene tube.


TAK-071
Study No. TAK-071-1001
Page 76 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
RNA Collection (MRD Cohorts 7 and 8)
Two whole blood samples (2.5 mL per sample) will be collected predose on Day 1 and 12 hours 
postdose on Days 1 and 21 for RNA analysis from each subject in the study into a PAXgene tube. 
RNA Collection (MRD Cohorts 9 and 13 to 15)
Two whole blood samples (2.5 mL per sample) will be collected predose on Day 1, predose on 
Day 8, and 12 hours postdose on Day 28 for RNA analysis from each subject in the study into a 
PAXgene tube. 
RNA Collection (MRD Cohorts 10 to 12)
Two whole blood samples (2.5 mL per sample) will be collected predose donepezil on Day -21, 
predose TAK-071 on Day 1, and 12 hours postdose on Day 21 for RNA analysis from each subject 
in the study into a PAXgene tube. 
RNA Collection (Cohort 16)
Two whole blood samples (2.5 mL per sample) will be collected predose on Days 1 and 42 and 
12 hours postdose on Days 21 and 62 for RNA analysis from each subject in the study into a 
PAXgene tube.
Each PGx sample should be identifiable on the requisition form with an 8-digit subject 
identification number (the 5-digit site number plus the 3-digit subject number).
The samples will be stored for no longer than 15 years after completion of the TAK-071 study 
and/or until the drug development of TAK-071 is no longer actively pursued by Takeda or its 
collaborators. No samples will be stored for longer than permitted by the applicable law and 
samples will be destroyed upon notification from Takeda. 
Detailed instructions for the handling and shipping of samples will be provided in the Laboratory 
Manual.
No DNA or RNA samples will be collected in Cohort 17.
9.1.15 PK Sample Collection
9.1.15.1 Collection of Blood for PK Sampling
Blood samples (one 3-mL sample per scheduled time) for PK analysis of plasma TAK-071 will be 
collected into chilled vacutainers containing anticoagulant K2EDTA according to the schedule in 
Appendix A. Blood samples (one 4-mL sample per scheduled time for Cohorts 10 to 12 and 20 to 
21) for PK analysis of plasma donepezil will be collected into chilled vacutainers containing 
anticoagulant sodium heparin according to the schedule in Appendix A. Instructions for sample 
processing and shipment are provided in Appendix E.
Serial blood samples for determination of TAK-071 (and donepezil, where stated) will be 
collected according to Table 9.c for Cohorts 1 to 6, 18, and 19; Table 9.d for Cohorts 7 and 8; 
Table 9.e for Cohorts 9 and 13 to 15; Table 9.f for Cohorts 10 to 12; Table 9.g for Cohort 16, and 
Table 9.h for Cohort 17, and Table 9.i for Cohorts 20 to 22. 


TAK-071
Study No. TAK-071-1001
Page 77 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Table 9.c
Collection of Blood Samples for PK Analysis for Cohorts 1 to 6, 18, and 19
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Plasma
1
Cohorts 1 to 6: Predose (within 30 minutes before dosing) and 
0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 24, 48, 72, 96, and 168 
hours postdose
Cohort 18 and 19: Predose (within 30 minutes before dosing) 
and 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 32, 40, 48, 56, 64, 72, 96, and 
168 hours postdose
Table 9.d
Collection of Blood Samples for PK Analysis for Cohorts 7 and 8
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Plasma
1
Predose (within 30 minutes before dosing) and 0.25, 0.5, 1, 1.5, 
2, 3, 4, 6, 8, 10, 12, 14, and 24 hours postdose 
TAK-071
Plasma
8, 14, 19, and 
20
Predose (within 30 minutes before dosing)
TAK-071
Plasma
21
Predose (within 30 minutes before dosing) and 0.25, 0.5, 1, 1.5, 
2, 3, 4, 6, 8, 10, 12, 14, and 24 hours postdose
Table 9.e
Collection of Blood Samples for PK Analysis for Cohorts 9 and 13 to 15
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Plasma
1
Predose (within 30 minutes before dosing) and 0.25, 0.5, 1, 1.5, 
2, 3, 4, 6, 8, 10, 12, 14, 24, 48, 72, and 96 hours postdose 
TAK-071
Plasma
8
Predose (within 30 minutes before dosing) and 0.25, 0.5, 1, 1.5, 
2, 3, 4, 6, 8, 10, 12, 14, and 24 hours postdose 
TAK-071
Plasma
15, 20, 26, 
and 27
Predose (within 30 minutes before dosing of TAK-071)
TAK-071
Plasma
28
Predose (within 30 minutes before dosing) and 0.25, 0.5, 1, 1.5, 
2, 3, 4, 6, 8, 10, 12, 14, and 24 hours postdose. For Cohort 9 
only, an additional sample at 36 hours postdose 


TAK-071
Study No. TAK-071-1001
Page 78 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Table 9.f
Collection of Blood Samples for PK Analysis for Cohorts 10 to 12
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Plasma
1
Predose (within 30 minutes before dosing) and 0.25, 0.5, 1, 1.5, 
2, 3, 4, 6, 8, 10, 12, 14, and 24 hours postdose of TAK-071
TAK-071
Plasma
8, 14, 19, and 
20
Predose (within 30 minutes before dosing of TAK-071)
TAK-071
Plasma
21
Predose (within 30 minutes before dosing) and 0.25, 0.5, 1, 1.5, 
2, 3, 4, 6, 8, 10, 12, 14, and 24 hours postdose of TAK-071
Donepezil 
Plasma
-7, -3, and -2
Predose (within 30 minutes before dosing of donepezil)
Donepezil
Plasma
-1
Predose (within 30 minutes before dosing) and 1, 2, 3, 4, 6, 8, 
10, 12, 14, and 24 hours postdose of donepezil
Donepezil
Plasma
8, 14, and 20
Predose (within 30 minutes before dosing of donepezil)
Donepezil
Plasma
21
Predose (within 30 minutes before dosing) and 1, 2, 3, 4, 6, 8, 
10, 12, 14, and 24 hours postdose of donepezil
Table 9.g
Collection of Blood Sample for PK Analysis of Cohort 16
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Plasma
1, 21, 42, and 62
Predose (within 30 minutes before dosing) and 0.5, 1, 2, 4, 6, 8, 
10, 12, and 24 hours postdose of TAK-071
Donepezil
Plasma
1, 21, 42, and 62 
Predose (within 30 minutes before dosing of donepezil)
Table 9.h
Collection of Blood Sample for PK Analysis of Cohort 17
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Plasma
1 (each of 3 
periods)
Predose (within 30 minutes before dosing) and 0. 5, 1, 2, 3, 4, 6, 
8, 10, 12, 16, 24, 32, 40, 48, 72, 96, and 168 hours postdose
Table 9.i
Collection of Blood Sample for PK Analysis of Cohorts 20 to 22
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Plasma
1
Predose (within 30 minutes before dosing) and 2, 4, 8, 12, 16, 
24, 25, 26, 27, 28, 30, 32, 36, 40, 48, 56, 64, 72, 96, and 168 
hours post TAK-071 dose
Donepezil
Plasma
2 
Predose (within 30 minutes before donepezil dosing) and 1, 2, 3, 
4, 6, 8, 12, 16, 24, 32, 40, 48, 72, 144 hours post donepezil dose
The actual time of sample collection will be recorded on the source document and eCRF.
Sampling time points may be adjusted based on the preliminary emerging PK data collected from 
prior cohort(s), but the total number of samples collected per subject should not exceed the 
planned number.


TAK-071
Study No. TAK-071-1001
Page 79 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Placebo samples will not be analyzed by the bioanalytical laboratory except 2 samples per subject 
receiving placebo, 1 predose and the other around the expected time at which Cmax occurred (as 
emerging from the actual measurement of the samples of the first dose group) to ensure from a 
safety perspective that no additional subjects could have been on active treatment.
9.1.15.2 Collection of Urine for PK Sampling
Serial urine samples for determination of TAK-071 will be collected according to Table 9.j for 
Cohorts 1 to 6 and 18 (and higher dose cohorts, if needed), Table 9.k for Cohorts 7 and 8, Table 9.l
for Cohorts 9 and 13 to 15, and Table 9.m for Cohort 16.
Table 9.j
Collection of Urine Samples for PK Analysis for Cohorts 1 to 6, 18 and 19
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Urine
1
Predose urine void within approximately 1 hour of dosing and (0 to 
6), (6 to 12), (12 to 24), (24 to 48), (48 to 72), and (72 to 96) hours 
postdose
Table 9.k
Collection of Urine Samples for PK Analysis for Cohorts 7 and 8
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Urine
1
Predose urine void within approximately 1 hour of dosing and (0 to 
6), (6 to 12), and (12 to 24) hours postdose
TAK-071
Urine
21
(0 to 6), (6 to 12), and (12 to 24) hours after the last dose
Note: Subjects should void urine prior to dosing on Day 21.
Table 9.l
Collection of Urine Samples for PK Analysis for Cohorts 9 and 13 to 15
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Urine
1
Predose urine void within approximately 1 hour of dosing and (0 to 
6), (6 to 12), (12 to 24), (24 to 48), (48 to 72), and (72 to 96) hours 
postdose
TAK-071
Urine
28
(0 to 6), (6 to 12), and (12 to 24) hours postdose
Note: Subjects should void urine prior to dosing on Day 28.
Table 9.m
Collection of Urine Samples for PK Analysis for Cohort 16
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Urine
1 and 42
Predose urine void within approximately 1 hour of dosing and (0 to 
6), (6 to 12), and (12 to 24) hours postdose
TAK-071
Urine
21 and 62
(0 to 6), (6 to 12), and (12 to 24) hours postdose
Note: Subjects should void urine prior to dosing on Days 21 and 61.
Urine samples will not be collected from Cohorts 10 to 12, 17 and 20 to 22.
The timing of the urine collection intervals may be adjusted based on the preliminary emerging PK 
data collected from prior cohort(s).


TAK-071
Study No. TAK-071-1001
Page 80 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Instructions for PK sample processing and shipment are provided in Appendix E.
Urine samples for subjects randomized to placebo will not be analyzed.
9.1.15.3 Collection of CSF for PK Sampling
It is planned that CSF samples (1.25 mL per sample) for determination of TAK-071 will be 
collected predose (within 30 minutes before dosing) and at 0.5, 2, 4, 6, and 12 hours postdose in 
Cohort 3 and predose (within 30 minutes before dosing) and at 4, 8, 12, 24, and 36 hours post last 
dose in Cohort 9.
The procedure will be performed by an experienced anesthetist using local anesthetic (used to 
numb the skin and tissues) injected into the skin and disc space between the lumbar vertebrae to 
prevent discomfort during the procedure. An indwelling spinal catheter will be inserted into the 
subarachnoid space at the level of the L2 to L3 or L3 to L4 intervertebral space by trained 
personnel at the site. The procedure will be performed under sterile conditions, and the subject will 
be closely observed and monitored during the CSF collection.
Instructions for CSF collection and lumbar x-ray are provided in the Study Manual.
If measured concentrations in Cohort 3 are excessively low, ie, most time points are below the 
limit of quantification of the assay, TAK-071 CSF concentrations may also be determined in 
subsequent SRD cohorts until a dose deemed to provide adequate brain penetration is identified 
(eg, a dose that provides CSF concentrations analogous to the efficacious free [estimated] plasma 
concentrations observed in preclinical animal models). A different criterion might be applied.
CSF sampling time points may be adjusted based on the preliminary emerging PK data; the total 
number of CSF samples collected per subject will not exceed the planned number.
9.1.15.4 Bioanalytical Methods
Plasma, urine, and CSF concentrations of TAK-071 will be measured by high-performance liquid 
chromatography with tandem mass spectrometry.
Part of the archival plasma and urine samples will be sent to Drug Metabolism and 
Pharmacokinetics Research Laboratories at Shonan Research Center for potential analysis of 
unknown metabolite characterization, if appropriate.
9.1.16 PK Parameters 
The plasma PK parameters of TAK-071 will be determined from the plasma concentration-time 
profiles for all evaluable subjects according to standard noncompartmental analysis methods. 
Actual sampling times, rather than scheduled sampling times, will be used in all computations 
involving sampling times. The following PK parameters will be calculated: 


TAK-071
Study No. TAK-071-1001
Page 81 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Symbol/Term
Definition
Plasma
AUC∞
Area under the plasma concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration
AUClast
Area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration
AUC24
Area under the plasma concentration-time curve from time 0 to time 24 hours
AUCt
Area under the plasma concentration-time curve from time 0 to time t
Cmax
Maximum observed concentration.
CL/F
Apparent clearance after extravascular administration, calculated using the observed value of the 
last quantifiable concentration
CL/Fss
Apparent clearance after extravascular administration, at steady state, calculated using AUCτ
λz
Terminal disposition phase rate constant
Rac(AUC)
Accumulation ratio based on AUCτ
Rac(Cmax)
Accumulation ratio based on Cmax
t1/2z
Terminal disposition phase half-life
tmax
Time of first occurrence of Cmax
Vz/F
Apparent volume of distribution during the terminal disposition phase after extravascular 
administration, calculated using the observed value of the last quantifiable concentration
For Cohort 17 the key PK parameters Cmax, tmax, and AUC∞will be determined. 
In general, if AUC∞cannot be accurately estimated in a sufficient number of subjects, AUClast will 
be used for statistical analysis instead. Additional plasma PK parameters may be derived and/or 
reported as appropriate.
The urine PK parameters of TAK-071 will be determined from the concentration-time profiles for 
all evaluable subjects according to standard noncompartmental analysis methods. Scheduled 
sampling times will be used in all computations involving urine collection times. The following 
urine PK parameters of TAK-071 will be estimated:
Urine
Aet
Amount of drug excreted in urine from time 0 to time t
fe,t
Fraction of administered dose of drug excreted in urine from time 0 to time t
CLR
Renal clearance
Additional urine PK parameters may be derived and/or reported as appropriate.
The CSF PK parameters of TAK-071 (planned for Cohorts 3 and 9) will be determined from the 
CSF concentration-time profiles for all evaluable subjects according to standard 
noncompartmental analysis methods. Actual sampling times, rather than scheduled sampling 
times, will be used in all computations involving sampling times. The following PK parameters 
will be calculated: CSF Cmax following a single dose (Day 1) and at steady-state (after final dose 
following multiple dosing), CSF AUC12 following a single dose (Day 1) and CSF AUC36 at 


TAK-071
Study No. TAK-071-1001
Page 82 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
steady-state (after final dose following multiple dosing), and the ratio of CSF AUC12 to the plasma 
AUC12 (CSF AUC12:plasma AUC12) following a single dose (Cohort 3) and the ratio of CSF 
AUC36 to the plasma AUC36 (CSF AUC36:plasma AUC36) at steady-state (Cohort 9). In the event 
that CSF sampling time points are adjusted in Cohort 9 following review of PK data from previous 
cohorts, ie, continuous sampling is extended to 48 hours postdose and then the corresponding 
AUC for the investigated time interval (ie, AUC48) will be used instead of AUC36. Additional CSF 
PK parameters may be derived and/or reported as appropriate.
The plasma PK parameters of donepezil will be determined from the concentration-time profiles 
for all evaluable subjects according to standard noncompartmental analysis methods. Actual 
sampling times, rather than scheduled sampling times, will be used in all computations involving 
sampling times. The following PK parameters will be calculated: tmax, Cmax, and AUC24. In 
addition, the ratio of geometric mean AUC24 and Cmax for donepezil after 21 daily doses of 
TAK-071 in reference to donepezil alone and the associated 90% CIs will be estimated. Additional 
donepezil plasma PK parameters may be derived and/or reported as appropriate.
In addition to the above, other PK analysis methodologies may be employed to further characterize 
the PK behavior of TAK-071 in healthy subjects, including conventional compartmental analyses 
and nonlinear mixed-effect modeling using TAK-071 pooled data across studies.
9.1.17 PD Assessments
9.1.17.1
qEEGs will be collected for subjects in Cohorts 9, 12, and 18 to 22. 
CCI
CCI


TAK-071
Study No. TAK-071-1001
Page 83 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
9.1.17.2
CCI
CCI
CCI
CCI


TAK-071
Study No. TAK-071-1001
Page 84 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
9.1.18 PD Parameters
CCI
CCI


TAK-071
Study No. TAK-071-1001
Page 85 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
The PD parameters will include the following:
Symbol/Term
AUEC12
Area under the effect concentration-time curve from time 0 to 12 hours; calculated as the area 
under the effect concentration-time curve that is above the Baseline minus the area that is below the 
Baseline and above the effect concentration-time curve (net area). 
Emax
Maximum observed effect, taken directly from change from Baseline data. 
Time to Emax
Time from dosing to occurrence of Emax, taken directly from the change from Baseline data.
Additional PD parameters may be calculated and/or reported, as appropriate.
9.1.19 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent. If the subject is found to be 
not eligible at this visit, the investigator should complete the eCRF screen failure form.
The primary reason for screen failure is recorded in the eCRF using the following categories:

PTE/AE.

Failure to meet inclusion criteria or did meet exclusion criteria (specify reason).

Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal (specify reason).

Study termination.

Other (specify reason).
Subject numbers assigned to subjects who fail screening should not be reused. If a subject fails 
screening, but is later successfully rescreened, the data for the subject will be entered as if these 
were 2 separate subjects. Therefore, the data should be entered as follows:
1. The screen failure data should be entered as a screen failure subject.
2. Rescreened subjects should be assigned a new subject number and treated as a stand-alone 
subject.
9.1.20 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 a subject is found to be ineligible for randomization, the investigator should record the primary 
reason for failure on the applicable eCRF.


TAK-071
Study No. TAK-071-1001
Page 86 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
9.1.21 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.
9.2
Monitoring Subject Treatment Compliance
Study medication will be administered while subjects are under observation in the clinical research 
unit. Following administration of the study drug, appropriate mouth and/or hand checks will be 
performed to ensure that the dose is swallowed and noted in the source document. The date and 
time of each dose will be recorded in the source documents and on the eCRFs. An inventory of the 
study drug supplies dispensed will be performed by the site pharmacist or authorized study 
designee and recorded onto the Drug Accountability Log in the subject’s source document records 
or equivalent. The exact dose time of consecutive subjects may be staggered to facilitate logistics 
at the site.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s).
9.3.1
Screening
Subjects in Cohorts 1 to 9, 13 to 15, and 17 to 22 will be screened within 28 days prior to 
randomization, subjects in Cohorts 10 to 12 will be screened within 44 days prior to 
randomization, and Cohort 16 will be screened within 60 days prior to randomization in 
accordance with predefined inclusion and exclusion criteria as described in Section 7.0. See 
Section 9.1.19 for procedures for documenting screening failures.
9.3.2
Study Randomization
Study randomization will take place on Day 1 for Cohorts 1 to 9, 13 to 15, and 17 to 22. Study 
randomization will take place on Day -21 for Cohorts 10 to 12.
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized as described in Section 8.2. Subjects will be 
administered the first dose of study drug in the unit under the supervision of the investigator or 
designee, as described in Section 8.2. The procedure for documenting Screening failures is 
provided in Section 9.1.19.
9.3.3
Treatment Phase/Washout Phase
For Cohorts 1 to 6 and 18 to 22, the Treatment Phase will consist of a single dose of study drug (for 
Cohorts 20 to 22 donepezil will be administered approximately 24 hours after the TAK-071 dose). 
For Cohorts 7, 8, and 10 to 12, the Treatment Phase will consist of 21 QD doses of study drug. For 


TAK-071
Study No. TAK-071-1001
Page 87 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Cohorts 9 and 13 to 15, the Treatment Phase will consist of a single dose of study drug, followed 
by a washout period of 7 days and 21 QD doses of study drug. 
For Cohorts 9 and 13 to 15, the washout and/or dosing duration may be adjusted with additional 
day(s) if PK data from the SRD part indicate that a longer duration may be more appropriate.
For Cohort 16 the treatment duration will consist of 21 QD doses of Treatment A (TAK-071) or B 
(placebo) in Period 1, a 21-day washout, and then 21 daily doses of Treatment A or B in Period 2. 
Treatment assignments will be switched between Period 1 and 2. A donepezil run-in period of 49 
days, prior to starting Treatment A, may be included if the subject is diagnosed at Screening.
For Cohort 17, the treatment duration will consist of a single dose of study drug in each of 3 
periods. Washout period of 21 days will follow Periods 1 and 2.
The washout and/or dosing duration may be adjusted with additional day(s) if PK data from the 
SRD part indicate that a longer washout may be more appropriate.
9.3.4
Final Visit
Subjects will be released from the clinic on Day 5 for Cohorts 1 to 6 and 18 to 22; Day 23 for 
Cohorts 7, 8, and 10 to 12; Day 30 for Cohorts 9 and 13 to 15; Day 63 for Cohort 16, and Day 8 of 
Period 3 for Cohort 17.
For all subjects receiving study drug, the investigator must complete the End of Study eCRF page.
9.3.5
Early Termination
The reason for discontinuation must be documented in the source document and eCRF. 
PK samples should be collected at the Early Termination Visit, if possible and relatively close to a 
protocol-specified time point. The site may seek guidance. For example, collect samples if early 
withdrawal is due to an AE and/or if several hours elapsed since last blood draw.
For all subjects receiving study drug, the investigator must complete the End of Study eCRF page.
9.3.6
Follow-up Visit/Telephone Call
The Follow-up Visit will occur by phone on Day 12 (±2 days) for Cohorts 1 to 6 and 18 to 22; 
Day 32 (±2 days) for Cohorts 7, 8, and 10 to 12; Day 39 (±2 days) for Cohorts 9 and 13 to 15; 
Day 73 (±2 days) for Cohort 16; and Day 12 (±2 days) of Period 3 for Cohort 17 and will be 
considered the subject’s last visit unless abnormal clinically significant findings are observed at 
discharge. If abnormal clinically significant findings are observed, subjects must visit the clinic for 
re-evaluation per investigator’s discretion. If no abnormal clinically significant findings are 
observed, follow-up will occur via a telephone call.
9.4
Biological Sample Retention and Destruction
In this study, specimens for genome/gene analysis will be collected as described in Section 9.1.14. 
The genetic material will be preserved and retained at Covance for up to but not longer than 
15 years or as required by applicable law. The sponsor has put into place a system to protect the 


TAK-071
Study No. TAK-071-1001
Page 88 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
subjects’ personal information to ensure optimal confidentiality and defined standard processes for 
sample and data collection, storage, analysis, and destruction.
The samples will be sent to a central laboratory that processes the blood sample and serves as a 
secure storage facility. The samples will be initially stored at Covance Central Laboratory 
Services. The sponsor and researchers working with the sponsor will have access to the samples 
collected and any test results. All samples collected during the study will be stored securely with 
limited access, and the sponsor will require anyone who works with the samples to agree to hold 
the research information and any results in confidence.
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; the samples are stripped of all personal identifying information, but a key linking 
the samples to clinical analysis data exists. 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 PGx sample for DNA and RNA analysis can withdraw 
their consent and request disposal of a stored sample at any time prior to analysis. The investigator 
must notify the sponsor of consent withdrawal.
9.5
Blood Volume
Total blood sampling volume for an individual subject is shown in Table 9.q for Cohorts 1 to 6, 18, 
and 19; Table 9.r for Cohorts 7 and 8; Table 9.s for Cohorts 9 and 13 to 15; Table 9.t for Cohorts 10 
to 12; Table 9.u for Cohort 16, and Table 9.v for Cohort 17, and Table 9.w for Cohorts 20 to 22.
Table 9.q
Approximate Blood Volume for Cohorts 1 to 6, 18, and 19
Sample Type
Sample 
Volume 
(mL)
Number of Samples
Total 
Volume 
(mL)
Screening
Day 
-1
Day 
1 (a)
Day 
2
Day 
3
Day 
4
Final 
Visit
Day 5
PK 
Follow-Up 
Day 8
Clinical laboratory tests
20 
1
1
1
1
1
1
1
1
160
Serology tests
8.5
1
0
0
0
0
0
0
0
8.5
PGx DNA sample collection
6 
0
0
1
0
0
0
0
0
6
PGx RNA sample collection
2.5 
0
0
4
0
0
0
2
0
15
PK blood collection (b)
3
0
0
13
1
1
1
1
1
54
Total Approximate Blood Sampling Volume
243.5
(a) TAK-071 dose.
(b) For Cohorts 18 and 19, PK blood samples were as follows: Day 1: 9, Day 2: 3, Day 3: 1: Day 4: 1, Day 5:1, and 
Day 8:1 (Total volume 54 mL).


TAK-071
Study No. TAK-071-1001
Page 89 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Table 9.r
Approximate Blood Volume for Cohorts 7 and 8
Sample Type
Sample 
Volume (mL)
Number of Samples
Total 
Volume 
(mL)
Screening
Day -1
Day 
1 (a)
Day 
2
Days
4-5
Days
8-20
Day 21 
(b)
Day 22
Final Visit 
Day 23
Clinical laboratory tests
20 
1
1
1
1
1 (c)
3 (d)
1
1
1
220
Serology tests
8.5
1
0
0
0
0
0
0
0
0
8.5
PGx DNA sample collection
6 
0
0
1
0
0
0
0
0
0
6
PGx RNA sample collection
2.5 
0
0
4
0
0
0
2
0
0
15
PK blood collection
3
0
0
13
1
0
4 (e)
13
1
0
96
Total Approximate Blood Sampling Volume
345.5
(a) First dose of multiple daily TAK-071.
(b) Last dose of multiple daily TAK-071.
(c) Blood sample on Day 5.
(d) Blood samples on Days 8, 14, and 20.
(e) Blood samples on Days 8, 14, 19, and 20.


TAK-071
Study No. TAK-071-1001
Page 90 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Table 9.s
Approximate Blood Volume for Cohorts 9 and 13 to 15 (Japanese)
Sample Type
Sample
Volume 
(mL)
Number of Samples
Total Volume 
(mL)
Screening
Day -1
Day 1 
(a)
Day 2
Days 3-7
Day 8 
(b)
Days 
9-17
Days 
18-27
Day 28 
(c)
Day 29
Final Visit 
Day 30
Clinical laboratory tests
20 
1
1
1
1
1 (d)
1
3 (e)
2 (f)
1
1
1
280
Serology test
8.5
1
0
0
0
0
0
0
0
0
0
0
8.5
PGx DNA sample 
collection
6 
0
0
1
0
0
0
0
0
0
0
0
6
PGx RNA sample 
collection
2.5 
0
0
2
0
0
2
0
0
2
0
0
15
PK blood collection
3
0
0
13
1
3 (g)
13
3 (h)
3 (i)
13
2 (j)
0
147
Total Approximate Blood Sampling Volume
456.5
Note: There is a 7-day washout between the single dose of TAK-071 and the first dose of multiple-dose TAK-071.
(a) First single dose of TAK-071.
(b) First dose of multiple daily TAK-071.
(c) Last dose of multiple daily TAK-071.
(d) Blood sample on Day 3.
(e) Blood sample on Days 9, 10, and 15.
(f) Blood samples on Days 20 and 27. 
(g) Blood samples on Days 3, 4, and 5.
(h) Blood sample on Day 15.
(i) Blood sample on Days 20, 26, and 27.
(j) Blood sample at 24 hours post last dose for all 3 cohorts and an additional sample for only Cohort 9 at 36 hours post last dose.


TAK-071
Study No. TAK-071-1001
Page 91 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Table 9.t
Approximate Blood Volume for Cohorts 10 to 12
Sample Type
Sample 
Volume 
(mL)
Number of Samples
Total 
Volume 
(mL)
Screening
Day
-22
Day 
-21 
(a)
Days 
-10 to 
-2
Day 
-1
Day 
1 (b)
Day 
2
Days
3-8
Day 11
Days 
12-20
Day 
21 (c)
Day 
22
Final Visit 
Day 23
Clinical laboratory 
tests
20 
1
1
1
1 (d)
1
1
1
2 (e)
1
2
1
0
1
280
Serology test
8.5
1
0
0
0
0
0
0
0
0
0
0
0
0
8.5
PGx DNA sample 
collection
6 
0
0
1
0
0
0
0
0
0
0
0
0
0
6
PGx RNA sample 
collection
2.5 
0
0
2
0
0
2
0
0
0
0
2
0
0
15
PK blood collection 
for TAK-071
3
0
0
0
0
0
13
1
1(f)
0
3 (g)
13
1
0
96
PK blood collection 
for donepezil
4
0
0
0
3 (h)
10
1
0
1(f)
0
2 (g)
10
1
0
112
Total Approximate Blood Sampling Volume
517.5
(a) First dose of donepezil.
(b) First dose of multiple daily TAK-071.
(c) Last dose of multiple daily TAK-071.
(d) A blood sample for clinical laboratory tests will be collected on Day -10.
(e) Blood samples on Days 5, 8.
(f) Blood sample will be collected on Day 8.
(g) Blood samples will be collected on Days 14, 19 (TAK-071 only), and 20.
(h) Blood samples will be collected for PK analysis of donepezil on Days -7, -3, and -2.


TAK-071
Study No. TAK-071-1001
Page 92 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Table 9.u
Approximate Blood Volume for Cohort 16
Sample Type
Sample
Volume 
(mL)
Number of Samples
Total 
Volume 
(mL)
Screening
Day 
-1
Day 
1 (a)
Day 
2
Day 
11
Day 
20
Day 
21 (b)
Day
22
Day 
41
Day 
42 (c)
Day 
43
Day 
52
Day 
61
Day 
62 (d)
Final Visit 
Day 63
Clinical laboratory tests
20
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
300
Serology test
8.5
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
8.5
PGx DNA sample 
collection
6
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
6
PGx RNA sample 
collection
2.5
0
0
2
0
0
0
2
0
0
2
0
0
0
2
0
20
PK blood collection 
TAK-071
3
0
0
9
1
0
0
9
1
0
9
1
0
0
9
1
120
PK blood collection 
donepezil
4
0
0
1
0
0
0
1
0
0
1
0
0
0
1
0
16
Total Approximate Blood Sampling Volume
470.5
(a) First dose of study drug in Period 1.
(b) Last dose of study drug in Period 1.
(c) First dose of study drug in Period 2.
(d) Last dose of study drug in Period 2.


TAK-071
Study No. TAK-071-1001
Page 93 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Table 9.v
Approximate Blood Volume for Cohort 17
Sample Type
Sample
Volume 
(mL)
Number of Samples
Total 
Volume 
(mL)
Screening
Day 
-1
Day 
1 (a)
Days 
2 to 5
Day 8
Day 
-1
Day 
1 (b)
Days 
2 to 5
Day 8
Day 
-1
Day 
1 (c)
Days 
2 to 5
Final Visit 
Day 8
Period 1
Period 2
Period 3
Clinical laboratory tests 
20
1
1
1
2 (d)
1
1
1
2 (d)
1
1
1
2 (d)
1
320
Serology test
8.5
1
0
0
0
0
0
0
0
0
0
0
0
0
8.5
PK blood collection 
TAK-071
3
0
0
11
6 (e)
1
0
11
6 (e)
1
0
11
6 (e)
1
162
Total Approximate Blood Sampling Volume
490.5
(a) Single dose of study drug in Period 1.
(b) Single dose of study drug in Period 2.
(c) Single dose of study drug in Period 3.
(d) Days 2 and 5.
(e) Three samples on Day 2 and 1 sample each on Days 3, 4, and 5.
Table 9.w
Approximate Blood Volume for Cohorts 20 to 22
Sample Type
Sample Volume 
(mL)
Number of Samples
Total Volume 
(mL)
Screening
Day -1
Day 1 
(a)
Day 2 Day 3 Day 4
Final Visit
Day 5
PK Follow-Up 
Day 8
Clinical laboratory tests
20 
1
1
1
1
1
1
1
1
160
Serology tests
8.5
1
0
0
0
0
0
0
0
8.5
PGx DNA sample collection
6 
0
0
1
0
0
0
0
0
6
PGx RNA sample collection
2.5 
0
0
4
0
0
0
2
0
15
PK blood collection TAK-071
3
0
0
6
9
3
1
1
1
63
PK blood collection donepezil
4
0
0
0
9
3
1
1
1
60
Total Approximate Blood Sampling Volume
312.5
(a) TAK-071 dose only. Donepezil will be administered approximately 24 hours after the TAK-071 dose.


TAK-071
Study No. TAK-071-1001
Page 94 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
The maximum volume of blood at any single day is approximately 75 mL for Cohorts 1 to 8, and 
18 to 22; 70 mL for Cohorts 9 and 13 to 15; 80 mL for Cohorts 10 to 12; 61 mL for Cohort 16; 
53 mL for Cohort 17. 
The approximate total volume of blood for the study is 243.5 mL for Cohorts 1 to 6, 18, and 19; 
345.5 mL for Cohorts 7 and 8; 453.5 mL for Cohorts 9 and 13 to 15; 517.5 mL for Cohorts 10 to
12; 470.5 mL for Cohort 16; 490.5 mL for Cohort 17; and 312.5 mL for Cohorts 20 to 22.
Direct venipuncture is the preferred method of blood collection; however, a catheter with a single 
saline flush may be used. If a catheter with a normal saline flush is used, the total blood volume 
does not include discarded blood from predraws (assuming minimally the catheter dead volume 
plus 1 mL of blood is discarded each time a sample is collected from a catheter). If a catheter is 
used, the total blood volume taken during the study must not exceed 550 mL for healthy subjects 
and 480 mL for subjects with MCI or mild AD.


TAK-071
Study No. TAK-071-1001
Page 95 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1 PTEs
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to study drug (TAK-071) administration 
or increase in dose/start of donepezil prior to TAK-071 dose; 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 finding), 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 underlying disease should not be considered PTEs or AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study drug or a concomitant medication.

Be considered unfavorable by the investigator for any reason. 

PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters 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 re-test and/or continued monitoring of an abnormal value are not considered an 


TAK-071
Study No. TAK-071-1001
Page 96 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
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 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 condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after starting administration of 
the study drug, the worsening or complication should be recorded appropriately as an AE. 
Investigators should ensure that the AE term recorded captures the change in the condition (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 severity of AEs/serious PTEs:

If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 


TAK-071
Study No. TAK-071-1001
Page 97 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
worsening of the condition should be captured appropriately 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 an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of 
the eCRF.
10.1.4 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is 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).


TAK-071
Study No. TAK-071-1001
Page 98 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Table 10.a
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Torsade de pointes/ventricular fibrillation/ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizure
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome Confirmed or suspected transmission of infectious agent by a 
medicinal product
Neuroleptic malignant syndrome/malignant hyperthermia
Spontaneous abortion/stillbirth and fetal death
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 Severity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.6 Causality of AEs
The relationship of each AE to study drug(s) will be assessed using the following categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs 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 drugs, 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.


TAK-071
Study No. TAK-071-1001
Page 99 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
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 physician.
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 for reasons other than the event, dosing with study 
drug was already stopped before the onset of the AE.
10.1.12
Outcome

Recovered/resolved – subject returned to first assessment status with respect to the AE/PTE.

Recovering/resolving – the intensity is lowered by one 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.


TAK-071
Study No. TAK-071-1001
Page 100 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 PTE and AE Collection Period
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study drug (TAK-071) 
(Day 1 for Cohorts 1 to 9, 13 to 15, and 17 to 22; Day -21 for Cohorts 10 to 12; and Day 1 [if on 
stable 10 mg dose at Screening] or Day -21 [if donepezil dose increased to 10 mg in subjects 
already on donepezil 5 mg], or Day -49 [if donepezil initiated as 5 mg dose]) or until screen failure. 
For subjects who discontinue prior to study drug administration, PTEs are collected until the 
subject discontinues study participation.
Collection of AEs will commence from the time that the subject is first administered study drug 
(Day 1 for Cohorts 1 to 9, 13 to 15, and 17 to 22; Day -21 for Cohorts 10 to 12; and Day 1, Day -21, 
or Day -49 as the case may be [see above]). Routine collection of AEs will continue until the 
Follow-up Telephone Call/Visit (Day 12 for Cohorts 1 to 6 and 18 to 21, Day 32 for Cohorts 7 to 8 
and 10 to 12, Day 39 for Cohorts 9 and 13 to 15, Day 72 for Cohort 16, and Day 28 for Cohort 17).
For subjects in Cohort 16 who receive donepezil during the run-in period, they will be followed-up 
for PTEs/AEs via weekly phone calls during the run-in period.
10.2.1.2 PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or there is a satisfactory explanation for the change. 
Nonserious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study drug or 
not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or until there is a satisfactory explanation for the 
changes observed. All PTEs and AEs will be documented in the PTE/AE page of the eCRF, 
whether or not the investigator concludes that the event is related to the drug treatment. The 
following information will be documented for each event:
1. Event term.
2. Start and stop date and time.
3. Frequency.
4. Severity.


TAK-071
Study No. TAK-071-1001
Page 101 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
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 and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
A Takeda SAE form (eCRF SAE form in electronic data capture [EDC]) must be completed, in 
English and signed by the investigator immediately or within 24 hours of first onset or notification 
of the event. A paper SAE form should only be used if EDC is not available. The information 
should be completed as fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study drug(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.0.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of serious PTEs will follow the procedure described for SAEs.
10.2.3 Reporting of Abnormal Liver Function Tests
If a subject is noted to have ALT or AST elevated >3×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3×ULN and total bilirubin >2×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 


TAK-071
Study No. TAK-071-1001
Page 102 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
tests as described in Section 9.1.9 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Takeda SAE form (as per Section 10.2.2).
10.3
Follow-up of SAEs
If information that is 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 1.1. 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 1.1, 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, as 
applicable, in accordance with national regulations in the countries where the study is conducted. 
Relative to the first awareness of the event by/or further provision to the sponsor or sponsor’s 
designee, SUSARs will be submitted to the regulatory authorities as expedited report within 7 days 
for fatal and life-threatening events and 15 days for other serious events, unless otherwise required 
by national regulations. The sponsor will also prepare an expedited report for other safety issues 
where these might materially alter the current benefit-risk assessment of an investigational 
medicinal product or that would be sufficient to consider changes in the investigational medicinal 
products administration or in the overall conduct of the study. The investigational site also will 
forward a copy of all expedited reports to his or her IRB in accordance with national regulations.


TAK-071
Study No. TAK-071-1001
Page 103 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
11.0
STUDY-SPECIFIC COMMITTEES
No independent data safety monitoring board/data monitoring committee is required for this study.
The Takeda clinical science representative and the principal investigator will review the safety and 
tolerability data and available PK data (if applicable) for each cohort prior to dosing any additional 
cohort. The decision for the next subsequent dose must be agreed by the Takeda clinical science 
lead and the principal investigator. If any one person has concerns regarding subsequent dosing 
then this acts as veto and the decision not to proceed with an additional cohort escalated to Takeda 
management.


TAK-071
Study No. TAK-071-1001
Page 104 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization 
Drug Dictionary.
12.1
CRFs (Electronic and Paper)
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative 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 to 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.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date 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 clinical 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 study monitors. 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.
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 ICFs, subject authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copy of eCRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from regulatory 


TAK-071
Study No. TAK-071-1001
Page 105 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
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, International Conference on Harmonisation (ICH) E6 
Section 4.9.5 requires the investigator to retain essential documents specified in ICH E6 
(Section 8) until at least 2 years after the last approval of a marketing application for a specified 
drug indication being investigated or, if an application is not approved, until at least 2 years after 
the investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
Section 4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the Clinical Study Site Agreement 
between the investigator and sponsor.
Refer to the phase 1 Site Specifications document 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.


TAK-071
Study No. TAK-071-1001
Page 106 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of a subject’s 
treatment assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives.
13.1.1 Analysis Sets
Safety Set
The safety analysis set will consist of all subjects who are enrolled and received 1 dose of study 
drug. Subjects in this analysis set will be used for demographic, Baseline characteristics, and 
safety summaries.
PK Set
The PK set will consist of all subjects who receive study drug and have at least 1 measurable 
plasma concentration or amount of drug in the urine.
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 the data will 
be presented in the subject listings.
PD Set
The PD set will consist of all subjects who receive study drug and have at least 1 postdose PD 
measurement.
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.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
For each part of the study, descriptive statistics (N, mean, SD, median, minimum, and maximum) 
will be generated for continuous demographic variables and Baseline characteristics variables 
(age, height, weight, and BMI) for the pooled placebo group, each TAK-071 dose level, TAK-071 
overall, and overall total, as applicable (ie, by sequence and overall only for the cross-over 
portions of the study, cohorts 16 and 17). For each part, the number and percentage of subjects in 
each class of the categorical demographic variables and Baseline characteristics variables (sex, 
ethnicity, and race) will be tabulated for the pooled placebo group, each TAK-071 dose level, 
TAK-071 overall, and overall total. Placebo data will be pooled across the cohorts within each 
part.
For each part, demographic variables of screen failure subjects and reasons for screen failures will 
be summarized overall for subjects who are screened but not enrolled in the study. Individual 
demographic characteristics, date of informed consent, and reason for screen failure will be listed.


TAK-071
Study No. TAK-071-1001
Page 107 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
13.1.3 PK Analysis
Plasma and CSF concentrations of TAK-071 and donepezil, where appropriate, will be 
summarized by dose or regimen over each scheduled sampling time using descriptive statistics 
(including arithmetic mean, SD, median, minimum and maximum, geometric mean, and percent 
coefficient of variation of the geometric mean). Individual plasma concentration data vs time will 
be presented in a data listing, along with graphical plots of individual and mean plasma 
concentration vs time profiles by treatment.
Plasma PK parameters and CSF PK parameters, where applicable, will be summarized separately 
for SRD, MRD, presence/absence of donepezil, and for subjects with MCI or mild AD and 
Japanese subjects. Descriptive statistics (including arithmetic mean, SD, median, minimum and 
maximum, geometric mean, and percent coefficient of variation of the geometric mean) will be 
used as appropriate.
Dose proportionality for the SRD and MRD parts (separately) will be assessed using the empirical 
power law model [25]. This analysis will be carried out to assess the degree of dose proportionality 
based on the dose proportionality exponent (β) for the model for both Cmax and AUC∞on Day 1 
and for Cmax and AUC24 at steady-state.
Dose linearity will be examined in the event that dose proportionality cannot be established by 
using a simple linear regression on the exposure parameter.
Trough plasma concentrations measured in the MRD part will be summarized to assess 
steady-state. The time to steady-state will be assessed by fitting trough concentration values to a 
nonlinear mixed effects model in order to predict the time to achieve 90% of the steady-state 
trough concentrations separately for each dose.
Time dependency will be investigated in selected MRD cohorts. The time invariance of TAK-071 
will be assessed by comparing AUC24 for the last day of dosing to the AUC∞for Day 1 using 
analysis of variance with a random effect for subject and a ﬁxed effect for day. If AUC∞cannot be 
robustly estimated in a sufficient number of subjects, then the AUClast will be used instead in 
statistical analyses.
In Cohorts 10 to 12, a linear mixed model will be used to evaluate the effect of TAK-071 on the 
steady-state PK parameters (Cmax and AUC24) of donepezil:
yijk=μ + τj + πk + si +εijk (i=1, …N; j=A, B, C; k=1, 2, 3),
where μ is a general mean of a logarithmically transformed primary variable, si is the random 
effect of subject i, πk is the fixed effect of period k, τj is the fixed effect of treatment j, εijk is the 
random error of the observation yijk, and N is the number of subjects included in the analysis.
The model will be used to estimate 90% CIs together with their corresponding geometric mean 
ratios for the PK parameters obtained from the comparisons between the treatments. The 
comparison of interest is TAK-071 plus donepezil vs donepezil alone.
Other exploratory comparisons, including the PK of Japanese subjects or subjects with MCI or 
mild AD vs healthy subjects and the effect of donepezil on the PK of TAK-071, will be performed 


TAK-071
Study No. TAK-071-1001
Page 108 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
by using side-by-side tabular summaries of exposure-related PK parameters and by graphical 
comparisons of concentration-time profiles, as appropriate.
For the BA/FE cohort, PK parameters of TAK-071 will be summarized by regimen. A mixed 
effects analysis of variance (ANOVA) will be performed on natural logarithms of TAK-071 Cmax
and AUCs with sequence, period, and regimen as fixed effects and subject nested within sequence 
as a random effect. Within the framework of ANOVA, comparisons will be performed for tablet 
versus capsule and for fed versus fasting dosing condition to assess the relative bioavailability of 
TAK-071. 
The ratios and the 90% CIs for the central values of each test regimen relative to the reference 
regimen will be provided. Wilcoxon signed-rank test will be used to compare tmax between the test 
and reference regimens.
The concentration and cumulative amounts of TAK-071 excreted in urine will be summarized by 
dose over each scheduled collection interval and for selected time intervals, ie, 0 to 96 hours 
postdose, using descriptive statistics for SRD and MRD. Individual urine TAK-071 data vs time 
will be presented in a data listing, along with plots of individual and mean cumulative amounts 
excreted in urine vs time profiles will be produced.
A more detailed description of the analyses will be presented in the SAP.
13.1.4 PD Analysis
For PD variables at each assessment time point, corresponding changes from Baseline and derived 
PD parameters (eg, Emax and AUEC12) will be listed by subject and summarized using descriptive 
summary statistics (including arithmetic mean, SD, median, minimum and maximum, geometric 
mean, and percent coefficient of variation of the geometric mean) as appropriate. Graphical plots 
of individual and mean absolute and change from Baseline vs time profiles will also be produced 
for each treatment group, along with plots showing derived parameters by dose. 
 (Cohorts 9, 12, and 18 to 22 [and 
higher dose SRD cohorts, if needed]) with respect to the steady-state presence of TAK-071 alone 
(Day 27, Cohort 9), the steady-state presence of donepezil alone (Day -2, Cohort 12), and the 
steady-state presence of donepezil and TAK-071 (Day 20, Cohort 12). Baseline is defined as the 
predose time point prior to donepezil or TAK-071 dosing, as appropriate.
Change from Baseline in pupil size diameter will be estimated (Cohorts 9, 10 to 12, 16, and 18 to 
22 [and higher dose SRD cohorts, if needed]) with respect to the steady-state presence of TAK-071 
alone (Day 27, Cohort 9), the steady-state presence of donepezil alone (Day -2, Cohorts 10 to 12), 
and the steady-state presence of donepezil and TAK-071 (Day 27, Cohorts 10 to 12 or Day 20 or 
40, Cohort 16). Baseline is defined as the predose time point prior to donepezil or TAK-071 
dosing, as appropriate.
Mixed model analysis using the same analysis of variance model as described in Section 13.1.3
section might be used to evaluate differences in the change from Baseline AUEC12 and Emax
parameters between the TAK-071 treatments and placebo.
CCI


TAK-071
Study No. TAK-071-1001
Page 109 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Additional details will be provided in the SAP.
13.1.5 Safety Analysis
All safety data will be presented in listings. Where applicable, within each part, for the 
non-Japanese and Japanese SRD and MRD cohorts separately, safety data will be summarized by 
placebo, each TAK-071 dose level, TAK-071 overall, and overall total, as applicable (ie, by 
sequence and overall only for the cross-over portions of the study, cohorts 16 and 17). Placebo data 
will be pooled across cohorts for the SRD and MRD parts separately.
13.1.5.1 AEs
All AEs will be coded by system organ class (SOC) and preferred term using MedDRA. TEAEs 
with onset occurring within 30 days (onset date – last date of dose +1≤30) after study drug 
administration will be listed and included in the summary tables. TEAEs will be summarized by 
SOC and preferred term. The following summary tables will be included in the report: summary of 
TEAEs and drug-related AEs, relationship of AEs to study drug (related vs not-related), severity of 
AEs, and related AEs. AEs leading to study drug discontinuation and SAEs will be listed. Data 
listings will be provided for all AEs, including PTEs, TEAEs, AEs leading to study drug 
discontinuation, and SAEs.
13.1.5.2 Clinical Laboratory Evaluation
Individual results of laboratory tests from hematology, chemistry, and urinalysis that meet 
Takeda’s MAV criteria to be defined in the SAP will be listed and summarized. Baseline, 
postdose, and change from Baseline to postdose laboratory data will be summarized. All clinical 
laboratory data will be listed.
13.1.5.3 Vital Signs
Individual results of vital signs that meet Takeda’s MAV criteria to be defined in the SAP will be 
listed and summarized. Observed values and changes from Baseline in vital sign measurements 
(systolic and diastolic blood pressure, heart and respiratory rate, and oral temperature) will be 
summarized. All vital signs data will be provided in the data listings.
13.1.5.4 ECGs
Individual results of ECG parameters that meet Takeda’s MAV criteria to be defined in the SAP 
will be listed and summarized. Observed values and changes from Baseline in ECG parameters 
will be summarized. All ECG data will be provided in the data listings.
Shift tables will be generated for the investigator’s ECG interpretations. All ECG data will be 
provided in the data listings.
13.1.5.5 Bowel Function
Data describing stool frequency, time to first stool after dosing, stool consistency, and ease of 
passage will be assessed using descriptive statistics as appropriate. In addition, diary components 


TAK-071
Study No. TAK-071-1001
Page 110 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
(ie, the daily stool counts and BSF scores) will be examined graphically by subjects and by dose 
group to assess the time course of drug effect over time.
Descriptive statistics by visit will be presented for the percentage of subjects with BSF scale scores 
≥6 vs <6 post Baseline compared with BSF scale scores ≥6 vs <6 at Baseline and for the 
percentage of subjects with a change from Baseline in BSF scale score of ≥2.
13.2
Interim Analysis and Criteria for Early Termination
Section 6.1.5 describes the blinded safety and available PK review that will take place after 
completion of each cohort and prior to the next dose escalation stage in the study.
13.2.1 Interim Analysis of Cohorts 1 to 15 and 17 to 22 Data
Interim analysis of all data (except Cohort 16) will be completed to enable the planning of phase 2 
studies, while Cohort 16 enrollment is ongoing. The interim analysis will be initiated once all SRD 
and MRD cohorts have completed the study. 
The main Takeda study team will be unblinded to the data in order to provide interim results to 
support phase 2 protocol development. 
13.2.2 Interim Analysis of PD Data
 A Takeda representative, outside 
of the main Takeda study team, will analyze unblinded data and provide summary results by 
treatment group to the main study team. 
13.2.2.1 Pupillometry Data
For Cohorts 18 and 19, an unblinded interim analysis will be performed for pupillometry data to 
obtain information about target engagement measured by changes in dilatation and contraction 
velocity, initial and final diameter of the pupil, and P75 from Baseline to postdose. 
Pupillometry data for Cohort 9, 12, 20, and 22 may be analyzed to further explore the PD 
interaction of TAK-071 and donepezil. 
13.2.2.2
 
13.3
Determination of Sample Size
The sample sizes chosen for the SRD and MRD parts are considered to be sufficient for evaluation 
of safety, tolerability, and PK of each cohort but are not based on statistical power considerations. 
CCI
CCI
CCI


TAK-071
Study No. TAK-071-1001
Page 111 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
A sample size of 12 subjects (4 per sequence) was chosen for the 3-period, 3-sequence, crossover 
design in Cohort 17. The sample size is considered sufficient to assess the bioavailability of 
TAK-071 from the tablet relative to the capsule and to assess the effect of food on the 
bioavailability of TAK-071 from the tablet. This sample size was not based on statistical power 
considerations.
Enrolled participants who withdraw from the study for reasons other than safety may be replaced 
to ensure adequate numbers of evaluable subjects. The decision to replace a withdrawn subject will 
be made at the discretion of Takeda and the investigator.
In addition, in the event of a nonsafety-related critical procedure study interpretation (ie, CSF 
collection) where a subject is not withdrawn and remains in the study for the completion of all 
other assessments, that subject may be replaced on a case-by-case basis to ensure evaluability of 
that particular endpoint (ie, CSF, PK).


TAK-071
Study No. TAK-071-1001
Page 112 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee 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 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 ICFs), and eCRFs and 
associated source documents. It is important that the investigator and other study personnel are 
available during the monitoring visits and that sufficient time is devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB, 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 the 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.
Every attempt will be made to collect each PK blood sample at the designated time point, and the 
actual time of each blood sample will be recorded on the source document and eCRF. Table 14.a
defines the windows allowed for sample collections. 
However, blood samples not collected within the interval specified for the scheduled sample time 
should be documented as deviations in the site source document.


TAK-071
Study No. TAK-071-1001
Page 113 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Table 14.a
Windows for PK Blood Sample Collection
Minutes/Hours
Nominal Sampling Time
no more than 30 minutes predose
0 hour
±5 minutes
immediately postdose to ≤6 hours
±10 minutes
>6 hours to 12 hours postdose
±15 minutes
>12 hours to 24 hours
±30 minutes
>24 to ≤96 hours
±24 hours
>96 hours
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 and institution guarantee access for quality assurance auditors to all 
study documents as described in Section 14.1.


TAK-071
Study No. TAK-071-1001
Page 114 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB Approval
IRBs must be constituted according to the applicable state and federal/local requirements of each 
participating region. The sponsor or designee will require documentation noting all names and 
titles of members who make up the respective IRB. If any member of the IRB has direct 
participation in this study, written notification regarding his or her abstinence from voting must 
also be obtained. Those Americas sites unwilling to provide names and titles of all members due to 
privacy and conflict of interest concerns should instead provide a Federal Wide Assurance 
Number or comparable number assigned by the 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 or study specific screening activity). The IRB 
approval must refer to the study by exact protocol title, number, and version date; identify versions 
of other documents (eg, ICF) reviewed; and state the approval date. The sponsor will notify site 
once the sponsor has confirmed the adequacy of site regulatory documentation and, when 
applicable, the sponsor has received permission from competent authority to begin the study. Until 
the site receives notification no protocol activities, including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the ICF, 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 


TAK-071
Study No. TAK-071-1001
Page 115 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
applicable laws and regulations. The ICF, 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 ICF 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 ICF 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 ICF and if 
applicable, the subject authorization form. The ICF, subject authorization form (if applicable), and 
subject information sheet (if applicable) must be approved by both the IRB and the sponsor prior to 
use.
The ICF, 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 ICF, 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 ICF and subject authorization form (if applicable) must be signed and dated by 
the subject, or the subject’s legally acceptable representative, at the time of consent and prior to the 
subject entering into the study. The subject or the subject’s legally acceptable representative 
should be instructed to sign using their legal names, not nicknames, using blue or black ballpoint 
ink. The investigator must also sign and date the ICF and subject authorization (if applicable) at 
the time of consent and prior to the subject entering into the study; however, the sponsor may allow 
a designee of the investigator to sign to the extent permitted by applicable law.
Once signed, the original ICF, 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 ICF, the signed subject authorization form (if applicable), and subject information sheet (if 
applicable) shall be given to the subject.
All revised ICFs 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 ICF.


TAK-071
Study No. TAK-071-1001
Page 116 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Subjects who consented and provided a PGx sample for DNA and RNA analysis can withdraw 
their consent and request disposal of a stored sample at any time prior to analysis. The sponsor 
must be notified 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 study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs to review the subject’s original medical records (source data or documents), 
including, but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and autopsy 
reports. Access to a subject’s original medical records requires the specific authorization of the 
subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.


TAK-071
Study No. TAK-071-1001
Page 117 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
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 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov 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 trial 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 Takeda providing this 
information to callers must provide Takeda 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 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 clinical study subjects. 
Refer to the Clinical 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.


TAK-071
Study No. TAK-071-1001
Page 118 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
16.0
REFERENCES
1. Wimo A. Clinical and economic outcomes--friend or foe? Int Psychogeriatr 
2007;19(3):497-507.
2. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US 
population: prevalence estimates using the 2000 census. Arch Neurol 2003;60(8):1119-22.
3. Alzheimer's Disease International. Policy Brief for Heads of Government: The Global Impact 
of Dementia 2013-2050. Published December 2013.
4. Prince M, Wilmo A, Guerchet M, Ali G-C, Wu Y-T, Prina M, et al. World Alzheimer Report 
2015. The Global Impact of Dementia: An Analysis of Prevalence, Incidence, Cost, and 
Trends. 2015.
5. Davies P, Maloney AJ. Selective loss of central cholinergic neurons in Alzheimer's disease. 
Lancet 1976;2(8000):1403.
6. Auld DS, Kornecook TJ, Bastianetto S, Quirion R. Alzheimer's disease and the basal forebrain 
cholinergic system: relations to beta-amyloid peptides, cognition, and treatment strategies. 
Prog Neurobiol 2002;68(3):209-45.
7. Bohnen NI, Kaufer DI, Hendrickson R, Ivanco LS, Lopresti BJ, Constantine GM, et al. 
Cognitive correlates of cortical cholinergic denervation in Parkinson's disease and 
parkinsonian dementia. J Neurol 2006;253(2):242-7.
8. Pappas BA, Bayley PJ, Bui BK, Hansen LA, Thal LJ. Choline acetyltransferase activity and 
cognitive domain scores of Alzheimer's patients. Neurobiol Aging 2000;21(1):11-7.
9. Rockwood K. Size of the treatment effect on cognition of cholinesterase inhibition in 
Alzheimer's disease. J Neurol Neurosurg Psychiatry 2004;75(5):677-85.
10. Schneider LS, Dagerman KS, Higgins JP, McShane R. Lack of evidence for the efficacy of 
memantine in mild Alzheimer disease. Arch Neurol 2011;68(8):991-8.
11. Aricept (donepezil hydrochloride) 5 mg and 10 mg film coated tablets. Summary of Product 
Characteristics. Hatfield, United Kingdom: Eisai Ltd., Revised 18 February 2013.
12. Cutler NR, Sramek JJ, Seifert RD, Sawin SF. The target population in phase I trials of 
acetylcholinesterase inhibitors in dementia: the role of the "bridging study". In: Corain B, Iqbal 
K, Nicolini M, Winblad B, Wisniewski H, Zatta P, editors. Alzheimer's Disease: Advances in 
Clinical and Basic Research. Sussex, England.: John Wiley & Sons, Ltd.; 1993, p. 559-62.
13. Cutler NR, Sramek JJ, Murphy MF, Nash RJ. Implications of the study population in the early 
evaluation of anticholinesterase inhibitors for Alzheimer's disease. Ann Pharmacother 
1992;26(9):1118-22.
14. Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials 
for Therapeutics in Adult Healthy Volunteers. US Dept of Health and Human Services, Food 
and Drug Administration, Center for Drug Evaluation and Research. 06 July 2005. Publication 
No. 5541.


TAK-071
Study No. TAK-071-1001
Page 119 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
15. Guideline on Strategies to Identify and Mitigate Risks for First-In-Human Clinical Trials With 
Investigational Medicinal Products. Committee for Medicinal Products for Human Use, 
European Medicines Agency. 19 July 2007. Publication No. EMEA/CHMP/SWP/28367/07.
16. Anticholinergic medications and cognition in older adults. Doctoral Dissertation. Pittsburgh, 
PA: University of Pittsburgh.
17. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of 
Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of 
Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 
1984;34(7):939-44.
18. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive 
impairment: clinical characterization and outcome. Arch Neurol 1999;56(3):303-8.
19. Polasek TM, Lin FP, Miners JO, Doogue MP. Perpetrators of pharmacokinetic drug-drug 
interactions arising from altered cytochrome P450 activity: a criteria-based assessment. Br J 
Clin Pharmacol 2011;71(5):727-36.
20. Indiana University Department of Medicine. P450 Drug Interaction Table. Indiana University, 
Division of Clinical Pharmacology. Updated 25 January 2012. Accessed 03 April 2013. 
Available at: http://medicine.iupui.edu/clinpharm/ddis/table.aspx.
21. FDA. Drug development and drug interactions: table of substrates, inhibitors and inducers. 
U.S. Food and Drug Administration. Updated 27 October 2014. Accessed 04 June 2015. 
Available at: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractio
nslabeling/ucm093664.htm.
22. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading 
the cognitive state of patients for the clinician. J Psychiatr Res 1975;12(3):189-98.
23. CDC. Measuring Orthostatic Blood Pressure. Centers for Disease Control and Prevention, 
National Center for Injury Prevention and Control. Accessed 27 May 2016. Available at: 
http://www.cdc.gov/steadi/pdf/measuring_orthostatic_blood_pressure-a.pdf.
24. O'Donnell LJ, Virjee J, Heaton KW. Detection of pseudodiarrhoea by simple clinical 
assessment of intestinal transit rate. BMJ 1990;300(6722):439-40.
25. Gough K, Hutchison M, Keene O, Byrom B, Ellis S, Lacey L, et al. Assessment of dose 
proportionality: report from the statisticians in the pharmaceutical industry/pharmacokinetics 
UK joint working party. Drug Inform J 1995;29:1039-48.


TAK-071
Study No. TAK-071-1001
Page 120 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Appendix A
Schedule of Study Procedures
SRD Cohorts 1 to 6, 18, and 19 
Screening
Days
-28 to -2
Check-in
Day -1
Day 1
Day 2
Day 3
Day 4
Final 
Visit
Day 5
PK 
Follow-U
p Day 8
ET 
(a)
Follow-up 
Day 12 (±2)
(b)
Informed consent 
X
Inclusion/exclusion criteria
X
X
Demographics and medical 
history
X
Medication history and 
concurrent medical 
conditions
X
Physical examination
X
X
X
X
(X)
Vital signs (c) 
X
X
X
X
X
X
X
X
(X)
Height, weight, and BMI 
(d)
X
X
X
X
Concomitant medications 
(e)
X
X
X
X
X
X
X
X
X
X
Clinical laboratory 
evaluations (f)
X
X
X
X
X
X
X
X
X
(X)
Serum hCG (g)
X
X
X
X
(X)
FSH (h)
X
12-lead ECG (i)
X
X
X
X
X
X
X
X
(X)
Continuous 12-lead Holter 
ECG (j)
X
X
X
Urine drug and alcohol 
screen
X
X
HBsAg and anti-HCV
X
Hemoglobin A1c
X
Creatinine clearance
X
Confinement
X
X
X
X
X
PGx DNA collection (k)
X
PGx RNA collection (k)
X
X
Footnotes are on last table page.


TAK-071
Study No. TAK-071-1001
Page 121 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
SRD Cohorts 1 to 6, 18 and 19 (continued)
Screening
Days
-28 to -2
Check-in
Day -1
Day 1
Day 2
Day 3
Day 4
Final 
Visit
Day 5
PK 
Follow-Up 
Day 8
ET 
(a)
Follow-up 
Day 12 (±2)
(b)
PK blood collection (l)
X
X
X
X
X
X
X
PK urine collection (m)
X
X
X
X
X
CSF (n)
X
Lumbar x-ray (n)
X
Funduscopy (o)
X
TAK-071 dosing (p)
X
PTE assessment (q)
X
X
X
AE assessment (r)
X
X
X
X
X
X
X
X
Bowel function (s)
X
X
X
X
X
X
X
X
C-SSRS (t)
X
X
X
X
(X)
Pupillometry (v)
X
X
X
Footnotes are on the following page.
CCI


TAK-071
Study No. TAK-071-1001
Page 122 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
ET=Early Termination Visit, HBsAg=hepatitis B surface antigen, HCV=hepatitis C virus.
(a) A PK blood sample should be collected at the Early Termination Visit, if possible.
(b) Follow-up will occur by telephone on Day 12 (±2) unless abnormal clinically significant findings are observed upon discharge. 
In these cases, subjects must then be brought back to the clinic for re-evaluation per investigator’s discretion.
(c) Vital signs (oral temperature, respiration, pulse, and blood pressure) will be obtained as indicated. In Cohort 3, vital signs will be 
collected at approximately 5 hours postdose. In addition, orthostatic blood pressure will be measured in all cohorts except Cohort 3, 
at predose and at 2, 4, 6, 8, and 12 hours postdose in the first 24 hours after the initial dose of TAK-071 and then daily afterwards 
while subjects are confined in the phase 1 unit as detailed in Section 9.1.6.
(d) Height and BMI will be collected at Screening only. 
(e) All ongoing medications will be recorded from Screening and throughout the study. 
(f) Blood and urine samples for clinical laboratory tests (hematology, coagulation, serum chemistry, urinalysis) will be collected as 
indicated. On Day 1, the urine sample for urinalysis will be taken predose (within 2 hours prior to dosing) and the blood sample will 
be taken 1 hour postdose. On subsequent days, blood and urine samples will be taken upon rising in the morning under fasted 
condition. Laboratory sample collection on Day 8 does not require fasting conditions.
(g) During the course of the study, regular serum hCG pregnancy tests will be performed for female subjects and subjects will 
receive continued guidance with respect to the avoidance of pregnancy as part of the study procedures. In addition to a negative 
serum hCG pregnancy test at Screening, female subjects must have a negative serum hCG pregnancy test at Check-in prior to 
receiving the first dose of study drug.
(h) FSH concentration will be obtained from postmenopausal women (defined as continuous amenorrhea of at least 2 years and not 
surgically sterile). 
(i) A standard 12-lead ECG will be recorded at Screening, Check-in (Day -1), Day 1 (predose [within 60 minutes prior to dosing], 
and at 0.5, 1, 2, 4, and 8 hours postdose), and Days 2 through 5 (upon morning rising) or ET. Single ECGs will be taken at all visits.
(j) Continuous 12-lead Holter ECG monitoring will be conducted from 2 hours predose until 48 hours postdose in Cohorts 2, 4, 6, 
18, and 19 only.
(k) Blood samples for PGx analysis will be collected as follows: 6 mL for DNA on Day 1; 2×2.5 mL for RNA analysis on Day 1 
(predose and 12 hours postdose) and Day 5.
(l) Blood samples (up to 3 mL/sample collected into K2EDTA-coated tubes) for plasma measurement of TAK-071 will be collected 
predose (within 30 minutes prior to dosing) and at specified time points outlined in Section 9.1.15.
(m) Urine samples for PK analyses will be collected predose within approximately 1 hour of dosing and at specified intervals 
outlined in Section 9.1.15.
(n) CSF (up to 1.25 mL/sample) will be obtained predose (within 30 minutes before dosing) and at 0.5, 2, 4, 6, and 12 hours post 
dose in Cohort 3 only. If not performed within the last 12 months prior to Screening, a lumbar x-ray will be performed at Screening 
in Cohort 3 subjects to ensure that there are no deformities that could interfere with insertion of an indwelling cannula for the 
subsequent collection of CSF.
(o) Funduscopy will be performed in Cohort 3 only.
(p) DIC will be dispensed for treatment.
(q) PTEs will be collected from signing of informed consent up until dosing on Day 1.
(r) Any event after dosing on Day 1 will be captured as an AE.
(s) Bowel function will be assessed using the BSF scale and daily stool count.
(t) C-SSRS will be determined as indicated. If clinically significant at Final Visit, C-SSRS will also be determined as part of the 
Follow-up Visit. 
(u) 
 
(v) Pupillometry will be performed only in Cohort 18 (and higher dose SRD cohorts, if needed) at check-in (Day -1), predose on 
Day 1, approximately 25 hours postdose (Day 2).
CCI
CCI


TAK-071
Study No. TAK-071-1001
Page 123 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
SRD+Donepezil Cohorts 20 to 22
Screening
Days
-28 to -2
Check-in
Day -1
Day 1
Day 2
Day 3
Day 4
Final 
Visit
Day 5
PK 
Follow-Up 
Day 8
ET 
(a)
Follow-up 
Day 12 (±2)
(b)
Informed consent 
X
Inclusion/exclusion criteria
X
X
Demographics and medical 
history
X
Medication history and 
concurrent medical 
conditions
X
Physical examination
X
X
X
X
(X)
Vital signs (c) 
X
X
X
X
X
X
X
X
(X)
Height, weight, and BMI 
(d)
X
X
X
X
Concomitant medications 
(e)
X
X
X
X
X
X
X
X
X
X
Clinical laboratory 
evaluations (f)
X
X
X
X
X
X
X
X
X
(X)
Serum hCG (g)
X
X
X
X
(X)
FSH (h)
X
12-lead ECG (i)
X
X
X
X
X
X
X
X
(X)
Urine drug and alcohol 
screen
X
X
HBsAg and anti-HCV
X
Hemoglobin A1c
X
Creatinine clearance
X
Confinement
X
X
X
X
X
PGx DNA collection (j)
X
PGx RNA collection (j)
X
X
Footnotes are on last table page.


TAK-071
Study No. TAK-071-1001
Page 124 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
SRD (Pretreated with Donepezil) Cohorts 20 to 22 (continued)
Screening
Days
-28 to -2
Check-in
Day -1
Day 1
Day 2
Day 3
Day 4
Final 
Visit
Day 5
PK 
Follow-Up 
Day 8
ET 
(a)
Follow-up 
Day 12 (±2)
(b)
Donepezil dosing (k)
X
TAK-071 dosing (k)
X
TAK-071 PK blood 
collection (l)
X
X
X
X
X
X
X
Donepezil PK blood 
collection (m)
X
X
X
X
X
X
PTE assessment (n)
X
X
X
AE assessment (o)
X
X
X
X
X
X
X
X
Bowel function (p)
X
X
X
X
X
X
X
X
C-SSRS (q)
X
X
X
X
(X)
Pupillometry (s)
X
X
X
Footnotes are on the following page.
CCI


TAK-071
Study No. TAK-071-1001
Page 125 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
ET=Early Termination Visit, HBsAg=hepatitis B surface antigen, HCV=hepatitis C virus.
(a) A PK blood sample should be collected at the Early Termination Visit, if possible.
(b) Follow-up will occur by telephone on Day 12 (±2) unless abnormal clinically significant findings are observed upon discharge. 
In these cases, subjects must then be brought back to the clinic for re-evaluation per investigator’s discretion.
(c) Vital signs (oral temperature, respiration, pulse, and blood pressure) will be obtained as indicated. In addition, orthostatic blood 
pressure will be measured at predose and at 2, 4, 6, 8, and 12 hours postdose in the first 24 hours after the initial dose of TAK-071 
and then daily afterwards while subjects are confined in the phase 1 unit as detailed in Section 9.1.6.
(d) Height and BMI will be collected at Screening only. 
(e) All ongoing medications will be recorded from Screening and throughout the study. 
(f) Blood and urine samples for clinical laboratory tests (hematology, coagulation, serum chemistry, urinalysis) will be collected as 
indicated. On Day 1, the urine sample for urinalysis will be taken predose (within 2 hours prior to dosing) and the blood sample will 
be taken 1 hour postdose. On subsequent days, blood and urine samples will be taken upon rising in the morning under fasted 
condition.
(g) During the course of the study, regular serum hCG pregnancy tests will be performed for female subjects and subjects will 
receive continued guidance with respect to the avoidance of pregnancy as part of the study procedures. In addition to a negative 
serum hCG pregnancy test at Screening, female subjects must have a negative serum hCG pregnancy test at Check-in prior to 
receiving the first dose of study drug.
(h) FSH concentration will be obtained from postmenopausal women (defined as continuous amenorrhea of at least 2 years and not 
surgically sterile). 
(i) A standard 12-lead ECG will be recorded at Screening, Check-in (Day -1), Day 1 (predose [within 60 minutes prior to dosing], 
and at 0.5, 1, 2, 4, and 8 hours postdose), and Days 2 through 5 (upon morning rising) or ET. Single ECGs will be taken at all visits.
(j) Blood samples for PGx analysis will be collected as follows: 6 mL for DNA on Day 1; 2×2.5 mL for RNA analysis on Day 1 
(predose and 12 hours postdose) and Day 5.
(k) TAK-071 as DIC will be dispensed for treatment. Donepezil 10 mg will be administered approximately 24 hours after TAK-071 
dose.
(l) Blood samples for TAK-071 PK (up to 3 mL/sample collected into K2EDTA-coated tubes) for plasma measurement of TAK-071 
will be collected predose (within 30 minutes prior to dosing) and at specified time points outlined in Section 9.1.15.
(m) Blood samples for donepezil PK (up to 4 mL/sample collected into sodium heparin tubes) for plasma measurement of donepezil 
will be collected predose (within 30 minutes prior to dosing) and at specified time points outlined in Section 9.1.15.
(n) PTEs will be collected from signing of informed consent up until dosing on Day 1.
(o) Any event after dosing on Day 1 will be captured as an AE.
(p) Bowel function will be assessed using the BSF scale and daily stool count.
(q) C-SSRS will be determined as indicated. If clinically significant at Final Visit, C-SSRS will also be determined as part of the 
Follow-up Visit. 
(r)
 
(s) Pupillometry will be performed at check-in on Day -1 (approximately 25 hours predose), Day 1 (1 hour predose), and Day 2 
(approximately 23 hours post TAK-071 dose) and 5 hours post donepezil dose.
CCI
CCI


TAK-071
Study No. TAK-071-1001
Page 126 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
MRD Healthy Volunteer Cohorts 7 and 8
Day(s)
Screening
Days -28 to -2
Check-in
Day -1
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22
Final 
Visit
Day 23
ET 
(a)
Follow-
up Day 
32 (±2) 
(b)
Informed consent 
X
Inclusion/exclusion criteria
X
X
Demographics and medical history
X
Medication history and concurrent medical 
conditions
X
Physical examination
X
X
X
X
(X)
Vital signs (c) 
X
X
X X X X X X X X X X X X X X X X X X X X X X
X
X
(X)
Height, weight and BMI (d)
X
X
X
X
Concomitant medications (e)
X
X
X X X X X X X X X X X X X X X X X X X X X X
X
X
X
Clinical laboratory evaluations (f)
X
X
X X
X
X
X
X X X
X
X
(X)
Serum hCG (g)
X
X
X
X
X
FSH (h)
X
12-lead ECG (i)
X
X
X X X X X X X X X X X X X X X X X X X X X X
X
X
(X)
Continuous 12-lead Holter ECG (j)
X X
X X
X
Urine drug and alcohol screen
X
X
HBsAg and anti-HCV
X
Hemoglobin A1c
X
Creatinine clearance
X
Confinement
X
X X X X X X X X X X X X X X X X X X X X X X
X
TAK-071 dosing (k)
X X X X X X X X X X X X X X X X X X X X X
PGx DNA collection (l)
X
PGx RNA collection (l)
X
X
PK blood collection (m)
X X
X
X
X X X X
X
PK urine collection (n)
X X
X X
PTE assessment (o)
X
X
X
AE assessment (p)
X X X X X X X X X X X X X X X X X X X X X X
X
X
X
Bowel function (q)
X
X
X X X X X X X X X X X X X X X X X X X X X X
X
X
C-SSRS (r)
X
X
X
X
(X)
Footnotes are on the following page.


TAK-071
Study No. TAK-071-1001
Page 127 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
ET=Early Termination Visit, HBsAg=hepatitis B surface antigen, HCV=hepatitis C virus.
(a) A PK blood sample should be collected at the Early Termination Visit if possible. 
(b) Follow-up will occur by telephone on Day 32 (±2) unless abnormal clinically significant findings are observed upon discharge. In these cases, subjects must then be brought back 
to the clinic for re-evaluation per investigator’s discretion. 
(c) Vital signs (oral temperature, respiration, pulse, and blood pressure) will be obtained as indicated. In addition, orthostatic blood pressure will be measured at predose and at 2, 4, 
6, 8, and 12 hours postdose in the first 24 hours after the initial dose of TAK-071 and then daily afterwards while subjects are confined in the phase 1 unit as detailed in Section 9.1.6.
(d) Height and BMI will be collected at Screening only. 
(e) All ongoing medications will be recorded from Screening and throughout the study. 
(f) Blood and urine samples for clinical laboratory tests (hematology, coagulation, serum chemistry, urinalysis) will be collected as indicated. On Day 1, the urine sample for 
urinalysis will be taken predose (within 2 hours prior to dosing) and the blood sample for these tests will be taken 1 hour postdose. On subsequent days, blood and urine samples will 
be taken predose upon rising in the morning under fasted condition. 
(g) During the course of the study, regular serum hCG pregnancy tests will be performed for female subjects and subjects will receive continued guidance with respect to the 
avoidance of pregnancy as part of the study procedures. In addition to a negative serum hCG pregnancy test at Screening, female subjects must have a negative serum hCG pregnancy 
test at Check-in prior to receiving the first dose of study drug.
(h) FSH concentration will be obtained from postmenopausal women (defined as continuous amenorrhea of at least 2 years and not surgically sterile).
(i) A standard 12-lead ECG will be recorded at Screening, Check-in (Day -1), Day 1 (TAK-071 predose [within 60 minutes prior to dosing] and at 0.5, 1, 2, 4, and 8 hours postdose), 
Days 2 through 21 (predose), Days 22 and 23 (upon morning rising) or ET. Single ECGs will be taken at all visits.
(j) Continuous 12-lead Holter ECG monitoring will be conducted from 2 hours predose until 24 hours postdose TAK-071 on Day 1 and from 1 hour predose until 48 hours postdose 
TAK-071 on Day 21.
(k) DIC will be dispensed for treatment 
(l) Blood samples for PGx analysis will be collected as follows: 6 mL for DNA on Day 1; 2×2.5 mL for RNA on Day 1 (predose and 12 hours postdose) and 12 hours postdose on 
Day 21.
(m) Blood samples (3 mL/sample) for plasma measurement of TAK-071will be collected predose (within 30 minutes prior to dosing) and specified time points outlined in 
Section 9.1.15.1.
(n) Urine samples for PK analyses will be collected predose within approximately 1 hour of dosing and specified time points outlined in Section 9.1.15.2.
(o) PTEs will be collected from signing of informed consent up until dosing on Day 1. 
(p) Any event after dosing on Day 1 will be captured as an AE.
(q) Bowel function will be assessed using the BSF scale and daily stool count.
(r) C-SSRS will be determined as indicated. If clinically significant at Final Visit, C-SSRS will also be determined as part of the Follow-up Visit.


TAK-071
Study No. TAK-071-1001
Page 128 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
MRD Healthy Volunteer Cohort 9
Day(s)
Screening
-28 to -2
Check-in
-1
1
2
3
4
5 
6 to 
7
8
9 10
11 to 
14
15
16 to 
19
20
21 to 
26
27 28 29
Final 
Visit
Day 30
ET
(a)
Follow-up 
Day 39±2 (b)
Informed consent 
X
Inclusion/exclusion criteria
X
X
Demographics and medical history
X
Medication history and concurrent medical conditions
X
Physical examination
X
X
X
X
(X)
Vital signs (c) 
X
X
X X X X X
X
X X X
X
X
X
X
X
X X X
X
X
(X)
Height, weight and BMI (d)
X
X
X
X
Concomitant medications (e)
X
X
X X X X X
X
X X X
X
X
X
X
X
X X X
X
X
X
Clinical laboratory evaluations (f)
X
X
X X X
X X X
X
X
X X X
X
X
(X)
Serum hCG (g)
X
X
X
X
(X)
FSH (h)
X
12-lead ECG (i)
X
X
X X X X X
X
X X X
X
X
X
X
X
X X X
X
X
(X)
Continuous 12-lead Holter ECG (j)
X X X
X X
X
Urine drug and alcohol screen
X
X
HBsAg and anti-HCV
X
Hemoglobin A1c
X
Creatinine clearance
X
Confinement
X
X X X X X
X
X X X
X
X
X
X
X
X X X
X
TAK-071 dosing (k)
X
X X X
X
X
X
X
X
X X
PGx DNA collection (l)
X
PGx RNA collection (l)
X
X
X
PK blood collection (m)
X X X X X
X X
X
X
X
X X X
X
PK urine collection (n)
X X X X
X X
CSF (o)
X X
Lumbar x-ray (o)
X
Funduscopy
X
PTE assessment (p)
X
X
X
AE assessment (q)
X X X X X
X
X X X
X
X
X
X
X
X X X
X
X
X
Bowel function (r)
X
X
X X X X X
X
X X X
X
X
X
X
X
X X X
X
X
C-SSRS (s)
X
X
X
X
(X)
Pupil size (t)
X
X
Footnotes are on the following page.
CCI


TAK-071
Study No. TAK-071-1001
Page 129 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
ET=Early Termination Visit, HBsAg=hepatitis B surface antigen, HCV=hepatitis C virus.
(a) A PK blood sample should be collected at the Early Termination Visit if possible. 
(b) Follow-up will occur by telephone on Day 39 (±2) unless abnormal clinically significant findings are observed upon discharge. In these cases, subjects must then be brought back 
to the clinic for re-evaluation per investigator’s discretion. 
(c) Vital signs (oral temperature, respiration, pulse, and blood pressure) will be obtained as indicated. 
(d) Height and BMI will be collected at Screening only. 
(e) All ongoing medications will be recorded from Screening and throughout the study. 
(f) Blood and urine samples for clinical laboratory tests (hematology, coagulation, serum chemistry, urinalysis) will be collected as indicated. On Day 1, the urine sample for 
urinalysis will be taken at predose (within 2 hours prior to dosing) and the blood sample for these tests will be taken 1 hour postdose. On subsequent days, samples will be taken 
predose upon rising in the morning under fasted condition. 
(g) During the course of the study, regular serum hCG pregnancy tests will be performed for female subjects and subjects will receive continued guidance with respect to the 
avoidance of pregnancy as part of the study procedures. In addition to a negative serum hCG pregnancy test at Screening, female subjects must have a negative serum hCG pregnancy 
test at Check-in prior to receiving the first dose of study drug.
(h) FSH concentration will be obtained from postmenopausal women (defined as continuous amenorrhea of at least 2 years and not surgically sterile).
(i) A standard 12-lead ECG will be recorded at Screening, Check-in (Day -1), Days 1 and 8 (TAK-071 predose [within 60 minutes prior to dosing] and at 0.5, 1, 2, 4, and 8 hours 
postdose), and Days 2 to 7 and 9 to 30 upon morning rising, or ET. Single ECGs will be taken at all visits.
(j) Continuous 12-lead Holter ECG monitoring will be conducted 2 hours predose until 48 hours postdose on Day 1 and 1 hour predose until 48 hours postdose on Day 28.
(k) DIC will be dispensed for treatment.
(l) Blood samples for PGx analysis will be collected as follows: 6 mL for DNA on Day 1; 2×2.5 mL for RNA predose TAK-071 on Day 1, predose TAK-071 on Day 8, and 12 hours 
postdose on Day 28.
(m) Blood samples (3 mL/sample into EDTA coated tubes) for plasma measurement of TAK-071 will be collected predose (within 30 minutes prior to dosing) and specified time 
points outlined in Section 9.1.15.1.
(n) Urine samples for PK analyses will be collected predose within approximately 1 hour of dosing and specified time points outlined in Section 9.1.15.2.
(o) CSF (up to 1.25 mL/sample) will be obtained Day 28 at predose (within 30 minutes before dosing) and at 4, 8, 12, 24, and 36 hours post last dose. If not performed within the last 
12 months prior to Screening, a lumbar x-ray will be performed at Screening in to ensure that there are no deformities that could interfere with insertion of an indwelling cannula for 
the subsequent collection of CSF.
(p) PTEs will be collected from signing of informed consent up until dosing on Day 1. 
(q) Any event after dosing on Day 1 will be captured as an AE. 
(r) Bowel function will be assessed using the BSF scale and daily stool count.
(s) C-SSRS will be determined as indicated. If clinically significant at Final Visit, C-SSRS will also be determined as part of the Follow-up Visit. 
(t) Pupil size will be measured at the time points outlined in Section 9.1.17.2.


TAK-071
Study No. TAK-071-1001
Page 130 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
MRD + Donepezil Pretreatment Healthy Volunteer Cohorts 10 to 12
Day
Screening
-44 to -23
Check- in
-22
-21 to 
-19
-18 to 
-11
-10 
to -1 1 2 3 4 5 6
7
8
9 10 11 12 13 14
15 to 
19
20 21 22
Final 
Visit
Day 23
ET 
(a)
Follow-
up 
Day 32
(±2) (b)
Informed consent 
X
Inclusion/exclusion criteria
X
X
Demographics and medical history
X
Medication history and concurrent 
medical conditions
X
Physical examination
X
X
X
X
(X)
Vital signs (c) 
X
X
X
X
X X X X X X X X X X X X X X
X
X X X
X
X
(X)
Height, weight and BMI (d)
X
X
X
X
Concomitant medications (e)
X
X
X
X
X
X X X X X X X X X X X X X X
X
X X X
X
X
X
Clinical laboratory evaluations (f)
X
X
X
X
X X
X
X
X
X
X X
X
X
(X)
Urine drug and alcohol screen
X
X
Serum hCG (g)
X
X
X
X
X
(X)
FSH (h)
X
12-lead ECG (i)
X
X
X
X
X X X X X X X X X X X X X X
X
X X X
X
X
(X)
HBsAg and anti-HCV
X
Hemoglobin A1c
X
Creatinine clearance
X
Confinement
X
X
X
X X X X X X X X X X X X X X
X
X X X
X
TAK-071 dosing (j)
X X X X X X X X X X X X X X
X
X X
Donepezil dosing (k)
X
X
X
X X X X X X X X X X X X X X
X
X X
Subject Call Dosing Reminder (l)
X
PGx DNA collection (m) 
X
PGx RNA collection (m)
X
X
X
PK blood collection (n,o)
X
X X
X
X
X
X X X
X
PTE assessment (q)
X
X
X
AE assessment (r)
X
X
X
X X X X X X X X X X X X X X
X
X X X
X
X
X
Bowel function (s)
X
X
X
X
X
X X X X X X X X X X X X X X
X
X X X
X
X
C-SSRS (t)
X
X
X
X
X
(X)
Pupil size measurement (u)
X
X
X
X
Footnotes are on the following page.
CCI


TAK-071
Study No. TAK-071-1001
Page 131 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
ET=Early Termination Visit, HBsAg=hepatitis B surface antigen, HCV=hepatitis C virus.
(a) A PK blood sample should be collected at the ET Visit if possible. 
(b) Follow-up will occur by telephone on Day 32 (±2) unless abnormal clinically significant findings are observed upon discharge. In these cases, subjects must then be brought back 
to the clinic for re-evaluation per investigator’s discretion.
(c) Vital signs (oral temperature, respiration, pulse, and blood pressure) will be obtained as indicated. In addition, orthostatic blood pressure will be measured at predose and at 2, 4, 
6, 8, and 12 hours postdose in the first 24 hours after the initial dose of TAK-071 and then daily afterwards while subjects are confined in the phase 1 unit as detailed in Section 9.1.6.
(d) Height and BMI will be collected at Screening only. 
(e) All ongoing medications will be recorded from Screening and throughout the study. 
(f) Blood and urine samples for clinical laboratory tests (hematology, coagulation, serum chemistry, urinalysis) will be collected as indicated. On Days -21 to -1, blood and urine 
samples will be collected on Days -21, -10 and -1. On Day 1, the urine sample for urinalysis will be taken at predose (within 2 hours prior to dosing) and the blood sample for these 
tests will be taken 1 hour postdose. On subsequent days, blood and urine samples will be taken predose upon rising in the morning under fasted condition. 
(g) During the course of the study, regular serum hCG pregnancy tests will be performed for female subjects and subjects will receive continued guidance with respect to the 
avoidance of pregnancy as part of the study procedures. In addition to a negative serum hCG pregnancy test at Screening, female subjects must have a negative serum hCG pregnancy 
test at Check-in (Day -10) prior to receiving the first dose of study drug.
(h) FSH concentration will be obtained from postmenopausal women (defined as continuous amenorrhea of at least 2 years and not surgically sterile). 
(i) A standard 12-lead ECG will be recorded at Screening, Check-in (Day -22) (donepezil predose [within 60 minutes prior to dosing]), Day -1, Day 1 (TAK-071 predose [within 60 
minutes prior to dosing] and at 0.5, 1, 2, 4, and 8 hours postdose), Days 2 to 21 (predose), and Days 22 to 23 (upon morning rising) or ET. Single ECGs will be taken at all visits.
(j) DIC will be dispensed for treatment 
(k) Donepezil will be given as an oral daily 5 mg tablet in the morning. Subjects will administer donepezil in the morning at home on Days -18 to -11.
(l) Subjects should be called each outpatient day with a reminder to take their study medication in the morning daily on Days -18 to -11.
(m) Blood samples for PGx analysis will be collected as follows: 6 mL for DNA predose donepezil on Day -21; 2×2.5 mL for RNA predose donepezil on Day -21, predose TAK-071 
on Day 1, and 12 hours postdose on Day 21.
(n) Blood samples (3 mL/sample collected into EDTA-coated tubes) for plasma measurement of TAK-071 will be collected predose (within 30 minutes prior to dosing) and specified 
time points outlined in Section 9.1.15.1.
(o) Blood samples (4 mL/sample collected into sodium heparin tubes) for the measurement of donepezil will be collected predose (within 30 minutes prior to TAK-071 dosing) and 
specified time points outlined in Section 9.1.15.1.
(p)
 
 
(r) Any event after the first dose of donepezil on Day -21 will be captured as an AE. 
(s) Bowel function will be assessed using the BSF scale and daily stool count.
(t) C-SSRS will be determined as indicated. On Days -10 to -1, C-SSRS will be done on Day -1 only. If clinically significant at Final Visit, C-SSRS will also be determined as part of 
the Follow-up Visit. 
(u) Pupil size will be measured at the time points outlined in Section 9.1.17.2.
CCI
CCI


TAK-071
Study No. TAK-071-1001
Page 132 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
MRD Japanese Healthy Volunteer Cohorts 13 to 15
Day(s)
Screening
-28 to -2
Check-in
-1
1
2
3
4
5
6 to 
7
8
9 10
11 to 
14
15
16 to 
19
20
21 to 
26
27 28 29
Final 
Visit
Day 30
ET
(a)
Follow-up 
Day 39±2 
(b)
Informed consent 
X
Inclusion/exclusion criteria
X
X
Demographics and medical history
X
Medication history and concurrent medical 
conditions
X
Physical examination
X
X
X
X
(X)
Vital signs (c) 
X
X
X X X X X
X
X X X
X
X
X
X
X
X
X X
X
X
(X)
Height, weight and BMI (d)
X
X
X
X
Concomitant medications (e)
X
X
X X X X X
X
X X X
X
X
X
X
X
X
X X
X
X
X
Clinical laboratory evaluations (f)
X
X
X X X
X X
X
X 
X
X
X X
X
X
(X)
Serum hCG (g)
X
X
X
X
(X)
FSH (h)
X
12-lead ECG (i)
X
X
X X X X X
X
X X X
X
X
X
X
X
X
X X
X
X
(X)
Urine drug and alcohol screen
X
X
HBsAg and anti-HCV
X
Hemoglobin A1c
X
Creatinine clearance
X
Confinement
X
X X X X X
X
X X X
X
X
X
X
X
X
X X
X
TAK-071 dosing (j)
X
X X X
X
X
X
X
X
X
X
PGx DNA collection (k)
X
PGx RNA collection (k)
X
X
X
PK blood collection (l)
X X X X X
X X
X
X
X
X
X X
X
PK urine collection (m)
X X X X
X X
PTE assessment (n)
X
X
X
AE assessment (o)
X X X X X
X
X X X
X
X
X
X
X
X
X X
X
X
X
Bowel function (p)
X
X
X X X X X
X
X X X
X
X
X
X
X
X
X X
X
X
C-SSRS (q)
X
X
X
X
(X)
Footnotes are on the following page.


TAK-071
Study No. TAK-071-1001
Page 133 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
ET=Early Termination Visit, HBsAg=hepatitis B surface antigen, HCV=hepatitis C virus.
(a) A PK blood sample should be collected at the Early Termination Visit if possible. 
(b) Follow-up will occur by telephone on Day 39 (±2) unless abnormal clinically significant findings are observed upon discharge. In these cases, subjects must then be brought back 
to the clinic for re-evaluation per investigator’s discretion. 
(c) Vital signs (oral temperature, respiration, pulse, and blood pressure) will be obtained as indicated. In addition, orthostatic blood pressure will be measured at predose and at 2, 4, 
6, 8, and 12 hours postdose in the first 24 hours after the initial dose of TAK-071 and then daily afterwards (upon morning rising) while subjects are confined in the phase 1 unit as 
detailed in Section 9.1.6.
(d) Height and BMI will be collected at Screening only. 
(e) All ongoing medications will be recorded from Screening and throughout the study. 
(f) Blood and urine samples for clinical laboratory tests (hematology, coagulation, serum chemistry, urinalysis) will be collected as indicated. On Day 1, the urine sample for 
urinalysis will be taken at predose (within 2 hours prior to dosing) and the blood sample for these tests will be taken 1 hour postdose. On subsequent days, blood and urine samples will 
be taken predose upon rising in the morning under fasted condition. 
(g) During the course of the study, regular serum hCG pregnancy tests will be performed for female subjects and subjects will receive continued guidance with respect to the 
avoidance of pregnancy as part of the study procedures. In addition to a negative serum hCG pregnancy test at Screening, female subjects must have a negative serum hCG pregnancy 
test at Check-in prior to receiving the first dose of study drug.
(h) FSH concentration will be obtained from postmenopausal women (defined as continuous amenorrhea of at least 2 years and not surgically sterile).
(i) A standard 12-lead ECG will be recorded at Screening, Check-in (Day -1), Days 1 and 8 (TAK-071 predose [within 60 minutes prior to dosing] and at 0.5, 1, 2, 4, and 8 hours 
postdose). On the remaining days during confinement 12-lead ECG be recorded (upon morning rising), or ET. Single ECGs will be taken at all visits.
(j) DIC will be dispensed for treatment.
(k) Blood samples for PGx analysis will be collected as follows: 6 mL for DNA on Day 1; 2×2.5 mL for RNA predose TAK-071 on Day 1, predose TAK-071 on Day 8, and 12 hours 
postdose on Day 28.
(l) Blood samples (3 mL/sample into EDTA coated tubes) for plasma measurement of TAK-071 will be collected predose (within 30 minutes prior to dosing) and specified time points 
outlined in Section 9.1.15.1.
(m) Urine samples for PK analyses will be collected predose within approximately 1 hour of dosing and specified time points outlined in Section 9.1.15.2.
(n) PTEs will be collected from signing of informed consent up until dosing on Day 1. 
(o) Any event after dosing on Day 1 will be captured as an AE. 
(p) Bowel function will be assessed using the BSF scale and daily stool count.
(q) C-SSRS will be determined as indicated. If clinically significant at Final Visit, C-SSRS will also be determined as part of the Follow-up Visit. 


TAK-071
Study No. TAK-071-1001
Page 134 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Subjects With MCI or Mild AD Cohort 16
Day
Follow-
up 
Day 
73±2 (c)
Screen
ing
-60 to -2
Run-in Period 
(a)
Check 
-in
-1
1
2
3 to 
10
11
12 
to 
19 20
21
22
23 
to 
40
41 42
43
44 
to 
51
52
53 
to 
60 61
62
Final 
Visit
Day 63
ET
(b)
-49
-21
Informed consent 
X
Inclusion/exclusion criteria
X
X
Demographics and medical history
X
Medication history and concurrent 
medical conditions
X
Physical examination
X
X
X
X
(X)
MMSE
X
Diagnosis of AD/MCI
X
Vital signs (d) 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)
Height, weight and BMI (e)
X
X
X
X
Concomitant medications (f)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical laboratory evaluations (g)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)
FSH (h)
X
12-lead ECG (i)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)
Urine drug and alcohol screen
X
HBsAg and anti-HCV
X
Hemoglobin A1c
X
Creatinine clearance
X
Confinement
X
X
X
X
X
X
X
X
X
X
X
X
X
TAK-071 dosing or placebo (j)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Donepezil dosing (k)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PGx DNA collection (l)
X
PGx RNA collection (l)
X
X
X
X
PK blood collection (m,n)
X
X
X
X
X
X
X
X
X
PK urine collection (o)
X
X
X
X
X
X
X
X
PTE assessment (p)
X
AE assessment (q)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Bowel function (r)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS (s)
X
X
X
X
(X)
Pupil size measured (t)
X
X
X
X
Footnotes are on the following page.


TAK-071
Study No. TAK-071-1001
Page 135 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
ET=Early Termination Visit, HBsAg=hepatitis B surface antigen, HCV=hepatitis C virus.
(a) Only subjects in donepezil run-in period will have these assessments.
(b) A PK blood sample should be collected at the Early Termination Visit if possible. 
(c) Follow-up will occur by telephone on Day 73 (±2) unless abnormal clinically significant findings are observed upon discharge. In these cases, subjects must then be brought back 
to the clinic for re-evaluation per investigator’s discretion. 
(d) Vital signs (oral temperature, respiration, pulse, and blood pressure) will be obtained as indicated. In addition, orthostatic blood pressure will be measured at predose and at 2, 4, 
6, 8, and 12 hours postdose in the first 24 hours after the initial dose of TAK-071 and then afterwards on Days 2, 11, 20 to 22, 41 to 43, 52, and 61 to 63 (upon morning rising or arrival 
for outpatient visit) or ET as detailed in Section 9.1.6.
(e) Height and BMI will be collected at Screening only. 
(f) All ongoing medications will be recorded from Screening and throughout the study. 
(g) Blood and urine samples for clinical laboratory tests (hematology, coagulation, serum chemistry, urinalysis) will be collected as indicated. On Days 1 and 42, the urine sample for 
urinalysis will be taken at predose (within 2 hours prior to dosing) and the blood sample for these tests will be taken 1 hour postdose. On all other days, when the subjects are confined 
at the phase 1 unit, blood and urine samples will be taken predose upon rising in the morning under fasted condition.
(h) FSH concentration will be obtained from postmenopausal women (defined as continuous amenorrhea of at least 2 years and not surgically sterile). The result must be >40 IU/L for 
the subject to be enrolled.
(i) A standard 12-lead ECG will be recorded at Screening, Check-in (Day -1), Days 1, 21, 42, and 62 (TAK-071 predose [within 60 minutes prior to dosing] and at 0.5, 1, 2, 4, and 8 
hours postdose), Days 2, 11, 20 to 22, 41 to 43, 52, and 61 to 63 (upon morning rising or arrival for outpatient visit) or ET. Single ECGs will be taken at all visits.
(j) DIC will be dispensed for treatment.
(k) Subjects must be receiving ongoing donepezil therapy (10 mg) in the evening for a minimum of 21 days prior to Check-in and during the study (if subjects were receiving 5 mg 
dose at Screening, it should be up-titrated to 10 mg on Day -21). Alternatively, subjects may be diagnosed at Screening and start donepezil run-in for 49 days prior to Day -1, and on 
stable 10 mg dose of donepezil 21 days prior to Day -1. Subjects will continue with their donepezil therapy during the TAK-071 Treatment Period.
(l) Blood samples for PGx analysis will be collected as follows: 6 mL for DNA on Day 1; 2×2.5 mL for RNA predose TAK-071 on Days 1 and 42 and 12 hours postdose on Days 21 
and 62.
(m) Blood samples (3 mL/sample into EDTA coated tubes) for plasma measurement of TAK-071 will be collected predose (within 30 minutes prior to dosing) and specified time 
points outlined in Section 9.1.15.1.
(n) Blood samples (4 mL/sample collected into sodium heparin tubes) for the measurement of donepezil will be collected predose (within 30 minutes prior to TAK-071 dosing) and 
specified time points outlined in Section 9.1.15.1.
(o) Urine samples for PK analyses will be collected predose within approximately 1 hour of dosing and specified time points outlined in Section 9.1.15.2.
(p) PTEs will be collected from signing of informed consent up until dosing on Day 1 or prior to the first dose of donepezil during the run-in period. 
(q) Any event after TAK-071 dose on Day 1 or after the first dose of donepezil in newly diagnosed subjects or first day the dose of donepezil is increased in subjects who are receiving 
lower donepezil dose during the run-in period will be captured as an AE. During the run-in period, weekly telephone calls will be made for AE assessment. 
(r) Bowel function will be assessed using the BSF scale and daily stool count.
(s) C-SSRS will be determined as indicated. If clinically significant at Final Visit, C-SSRS will also be determined as part of the Follow-up Visit. 
(t) Pupil size will be measured at the time points outlined in Section 9.1.17.2.


TAK-071
Study No. TAK-071-1001
Page 136 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
BA/FE Cohort 17
Screening
Check
-in
Periods 1, 2, 3
Final 
Visit
Early 
Termination
Follow up
Day
Study Day:
-28 to -2
-1
1
2
3
4
5
8 
(Periods 
1 and 2)
8 
(Period 3)
(a)
12±2 days 
post Period 
3 dosing
(b)
Informed consent
X
Confinement
X
X
X
X
X
X
Inclusion/exclusion criteria 
X
X
Demographics and medical 
history
X
Medication history
X
Physical examination
X
X
X
(X)
Vital signs (c)
X
X
X
X
X
X
X
X
X
X
(X)
Weight, height, and BMI (d)
X
X
X
(X)
Concomitant medications (e)
X
X
X
X
X
X
X
X
X
X
X
Concurrent medical conditions 
X
X
Clinical laboratory tests (f)
X
X
X
X
X
X
X
X
(X)
Hepatitis panel
X
Hemoglobin A1c
X
FSH (g)
X
Pregnancy test (hCG) 
X
X
X
X
(X)
Urine drug screen
X
X
ECG (h)
X
X
X
X
X
X
X
X
X
X
(X)
PK blood collection (i)
X
X
X
X
X
X
X
X
Study Drug Dosing (j)
X
PTE assessment (k)
X
X
X
AE assessment (l)
X
X
X
X
X
X
X
X
X
X
C-SSRS (m)
X
X
X
X
(X)
Footnotes are on the following page.


TAK-071
Study No. TAK-071-1001
Page 137 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
NOTE: Study exit will occur on Day 8 of Period 3 when all scheduled assessments have been completed.
(a) A PK blood sample should be collected at the Early Termination Visit if possible. 
(b) Follow-up will occur by telephone on Day 12±2 of Period 3 unless abnormal clinical significant findings were observed upon 
discharge. In these cases subjects must then be brought back to the clinic for re-evaluation per investigators discretion. 
(c) Vital signs (oral temperature, respiration, pulse, and blood pressure) will be recorded at Screening and in each period at
Check-in (Day -1), Orthostatic vitals should be collected on Day 1 (predose [within 45 minutes prior to dosing] and at 2, 4, 6, 8, and 
12 hours postdose), and Days 2 through 5 (upon rising), Day 8 PK visit, Study Exit ([Day 8 of Period 3] or Early Termination and 
Follow-up Visit (Day 12 [±2]) of Period 3, as appropriate.
(d) Height and BMI will be collected at Screening only and if early terminated. 
(e) Record all ongoing medications from Screening and throughout the study. 
(f) Clinical laboratory tests (hematology, serum chemistry, urinalysis) will be collected at Screening and in each period at Check-in 
(Day -1), on Day 1 urine will be collected predose and blood will be collected 1 hour post dose, upon rising on Days 2 and 5 and, at 
PK visit on Day 8 (Day 8 of Period 3 is the final visit), at Early Termination, if occurs, and Follow-up Visit (Day 12 [±2]) of Period 
3, as appropriate. 
(g) A FSH level will be obtained on postmenopausal women (defined as continuous amenorrhea of at least 2 years and not 
surgically sterile). The result must be >40 IU/L for the subject to be enrolled.
(h) Standard 12-lead ECGs will be recorded at Screening, and in each period at Check-in (Day -1), Day 1 (predose [within 
45 minutes prior to dosing], and at 0.5, 1, 2, 4, and 8 hours postdose), Days 2 through 5 (upon morning rising), and Day 8 of Period 
1 and 2, Study Exit (Day 8 of Period 3) or Early Termination, and Follow-up Visit Day 12 (±2), as appropriate.
(i) Blood samples (~3 mL/sample) for PK analyses will be collected at Predose (within 30 minutes prior to dosing) and at 0.5, 1, 2, 
3, 4, 6, 8, 10, 12, 16, 24, 32, 40, 48, 72, 96, and 168 hours postdose in each period. 
(j) For fasted regimens, there will be an overnight fast with a minimum period of 8 hours prior to dosing and for the fed regimen, 
after an overnight of fast of approximately 8 hours followed by consuming a high-fat meal before dosing. The high-fat meal is to be 
finished within 25 minutes. Dosing commences 30 minutes after the start of the meal.
(k) PTEs will be collected from signing of informed consent up until dosing on Day 1 of Period 1. 
(l) Any event after dosing on Day 1 of Period 1 will be captured as an AE. 
(m) C-SSRS: Columbia-Suicide Severity Rating Scale. The Screening/Baseline C-SSRS will be administered at Screening and the 
Since Last Visit C-SSRS will be administered at Day -1 Period 1, at Study Exit (Day 8 Period 3) or Early Termination, and 
Follow-up Visit [Period 3 Day 12 (±2)] (as appropriate, if clinically significant at Study Exit).


TAK-071
Study No. TAK-071-1001
Page 138 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB that conform to 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
6. Ensure that the IRB will be responsible for initial review, continuing review, and approval of 
the protocol. Promptly report to the IRB 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, 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. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc., and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.


TAK-071
Study No. TAK-071-1001
Page 139 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
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.


TAK-071
Study No. TAK-071-1001
Page 140 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Appendix C
Elements of the Subject Informed Consent 
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that is 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, 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 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 may discontinue 


TAK-071
Study No. TAK-071-1001
Page 141 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
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 PGx 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;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study drug(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
25. All female subjects must be of non-childbearing potential.


TAK-071
Study No. TAK-071-1001
Page 142 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
26. Male subjects must use adequate contraception (as defined in the informed consent) from 
Screening, throughout the duration of the study, and for 30 days after the last dose of study 
drug. 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. 


TAK-071
Study No. TAK-071-1001
Page 143 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs.
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.


TAK-071
Study No. TAK-071-1001
Page 144 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Appendix E
Collection, Storage, and Shipment of Bioanalytical Samples
Instructions for Processing of Plasma Samples for PK Analysis of TAK-071
1. Collect 3 mL of venous blood into a chilled Becton-Dickinson Vacutainer. All TAK-071 blood 
samples should be collected into vacutainers containing K2EDTA.
2. Gently invert the vacutainer several times to mix the additive with the collected blood prior to 
centrifugation and place immediately on ice.
3. Centrifuge the vacutainers for 10 minutes at approximately 1100 to 1300 (relative centrifugal 
force [RCF]) at 4°C. Note: if using a collection device other than Becton-Dickinson, refer to 
manufacturer’s instruction for proper centrifugation force and time.
4. Immediately following centrifugation, gently remove plasma from the packed cells. To ensure 
a more homogeneous sample, all plasma should first be transferred into 1 aliquot. From there, 
split the plasma evenly between the 2 aliquots. A minimum of 0.5 mL needs to be obtained for 
each sample. Labeling may include protocol number (TAK-071-1001), sample matrix (ie, 
plasma) randomization/enrollment number, period, profile day and time, and either “SET 1” 
(for original sample) or “SET 2” (for duplicate sample).
5. Cap the labeled storage tubes and freeze the plasma samples immediately at 
approximately -20°C or lower until shipment to PPD, Middleton, WI. No more than 45-60 
minutes will elapse between blood collection and freezing the plasma sample.
Instructions for Processing of Plasma Samples for PK Analysis of Donepezil
1. Collect 4 mL of venous blood into a chilled Becton-Dickinson Vacutainer. All donepezil blood 
samples should be collected into vacutainers containing sodium heparin.
2. Gently invert the vacutainer several times to mix the additive with the collected blood prior to 
centrifugation and place immediately on ice.
3. Centrifuge the vacutainers for 10 minutes at approximately 1100 to 1300 (RCF) at 4°C. Note: 
if using a collection device other than Becton-Dickinson, refer to manufacturer’s instruction 
for proper centrifugation force and time.
4. Immediately following centrifugation, gently remove plasma from the packed cells. To ensure 
a more homogeneous sample, all plasma should first be transferred into 1 aliquot. From there, 
split the plasma evenly between the 2 aliquots. A minimum of 0.8 mL needs to be obtained for 
each sample. Labeling may include protocol number (TAK-071-1001), sample matrix 
(ie, plasma) randomization/enrollment number, period, profile day and time, and either “SET 
1” (for original sample) or “SET 2” (for duplicate sample).
5. Cap the labeled storage tubes and freeze the plasma samples immediately at 
approximately -20°C or lower until shipment to PPD, Middleton, WI. No more than 
45-60 minutes will elapse between blood collection and freezing the plasma sample.


TAK-071
Study No. TAK-071-1001
Page 145 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Instructions for Processing of Urine Samples for PK Analysis of TAK-071
1. Collect urine into polypropylene containers. During the collection interval, the urine will be 
stored at approximately 4°C. The urine collection will require the use 2% (w/v) Tween80 to 
prevent compound absorption to collection/storage containers.
2. At the end of each void (no more than 30 minutes postvoid), mix the urine, transfer to a 
graduated cylinder, measure and record the volume. For the urine sample in the graduated 
cylinder intended for bioanalysis, measure “X” amount of 2% Tween80 solution (2% Tween80 
by weight in water) into a separate graduated cylinder (where “X” equals 1 part in 10 of the 
urine volume in the cylinder).
3. Pour ¾ of the “X” amount of the 2% Tween80 solution into the graduated cylinder containing 
the subject’s urine. Mix and transfer to the bioanalysis sample jug for the time period.
4. With the remaining 2% Tween80 solution, rinse the original collection jug and combine with 
the sample in the bioanalysis sample jug for the time period.
5. Store the collection jug at approximately 4°C during the collection period. Record the final 
volume of the urine fortified with the 2% Tween80 solution.
6. Mix well and measure the urine volume within 2 hours of the end of the collection period. 
7. Transfer approximately 5.0 mL aliquots of urine in duplicate into appropriate polypropylene 
containers. Container should be filled to approximately 50% of the nominal volume. Labeling 
should include protocol number (TAK-071-1001), 4-digit randomization number, period, 
nominal day and time, and either “SET 1” (for original sample), or “SET 2” (for duplicate 
sample).
8. Freeze the urine samples immediately and store frozen at approximately -80°C or lower. Keep 
samples frozen at approximately -80°C or lower until shipment to PPD. SET 1 samples will be 
shipped first on dry ice, followed by shipment of duplicate SET 2 samples after SET 1 samples 
have been received by the analytical laboratory.


TAK-071
Study No. TAK-071-1001
Page 146 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Instructions for Processing of CSF Samples for PK Analysis of TAK-071
1. Using the peristaltic pump collect approximately 1.25 mL of CSF into a polypropylene tube. 
Note: the tubing may need to be flushed with the appropriate amount of CSF prior to initiation 
of collection of subsequent samples.
2. Immediately after collection, within 5 minutes, volumetrically remove a 1.0 mL aliquot of the 
collected sample to a properly labeled polypropylene cryo tube, the remaining sample after the 
1.0 mL is removed can be discarded. Add 100 µL of 2% Tween 80 solution, cap the tube and 
vortex gently for approximately 2 seconds. Labeling should include protocol number 
(TAK-071-1001), matrix (CSF), 5-digit randomization number, period, nominal day and time.
3. Freeze the CSF samples immediately and store frozen at approximately -80 C or lower until 
shipment to PPD.
Shipping of Plasma, CSF and Urine Samples
The following instructions are recommended unless they differ from the site’s standard operating 
procedures (SOPs) for labeling, packaging, or shipping of PK samples.
1. Biological samples (ie, plasma, urine, or CSF) should be shipped on dry ice to prevent thawing 
during transit. Samples should be shipped only on Monday, Tuesday, or Wednesday, and at 
least 2 days prior to a national holiday, in order to minimize the possibility of samples in transit 
over a weekend or holiday. If duplicate samples are to be shipped, send SET 1 samples and 
await confirmation of arrival before shipping the duplicate SET 2 samples. Please note that 
there are only SET 1 samples for CSF.
2. Before shipping, make sure the sample tubes are tightly sealed. Separate each subject’s 
samples as follows:
3. Separate the duplicate SET 2 samples from the SET 1 samples.
4. Place SET 1 samples for each subject into self-sealing bag (eg, Ziploc) containing additional 
absorbent material.
5. Using a permanent marker, write the 5-digit randomization sequence number, sample matrix 
(ie, plasma, CSF, or urine), number of samples, and “SET 1” on each self-sealing bag.
6. Place the bags of individual subject’s samples into a larger plastic bag so that samples are 
double bagged. Duplicate SET 2 samples should be returned to the freezer for storage. Repeat 
steps 3 through 6 above when preparing duplicate samples for shipment, except self-sealing 
bags should be marked “SET 2.”
7. An inventory of individual samples should accompany each shipment and should include the 
Sponsor’s name (Takeda), study drug (TAK-071), protocol number (TAK-071-1001), 
investigator’s name, sample type (ie, plasma, CSF, or urine), subject 
randomization/enrollment number, period, nominal collection day and time, and intended 
sample storage conditions. When duplicate SET 2 samples are being shipped, make a copy of 
the original SET 1 sample inventory and mark as “SET 2.” Place the inventory paperwork into 
a large self-sealing bag. SET 1 samples will be shipped first on dry ice, followed by shipment 


TAK-071
Study No. TAK-071-1001
Page 147 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
of duplicate SET 2 samples after SET 1 samples have been received by the analytical 
laboratory.
8. For sample packing, utilize dry ice generously (eg, 20-25 pounds per day of transit) to 
safeguard against longer than expected shipping times and delays. Use newspaper or other 
material to insulate the double-bagged samples from direct contact with the dry ice. Place the 
sample bundles into a Styrofoam container (or other suitable container) and fill the excess 
space with dry ice slabs or ice pellets (preferably the latter). Make a note of the estimated 
weight of the dry ice used per shipping container.
9. Place the inventory paperwork (in a large self-sealing bag) on top of the dry ice in the 
Styrofoam container. Place the lid on the Styrofoam container and seal completely with 
strapping tape. Place the Styrofoam container in a cardboard shipping carton and seal securely 
with strapping tape.
10. Mark the outside of shipping carton(s) with a tally number (eg, 1 of 5, 2 of 5).
11. Affix an address label to each shipping carton. Complete the address label with the following 
information:
Plasma, CSF, and Urine Samples for TAK-071
12. Affix a carbon dioxide label on each carton, specifically:
Carbon Dioxide Solid UN-1845
Class 9 PKG GR III
Quantity _____________________
(fill in weight to nearest lb/kg and specify unit of measure used)
13. Affix 2 dry ice symbol labels on opposite sides of the carton. Mark KEEP FROZEN on each 
carton. Specify a return address and contact person on the carton.
14. Obtain the airway bill number and a receipt of shipment from the carrier.
15. After shipping of the TAK-071 samples, please email
at 
to notify him of next day delivery. When calling, provide the 
Name of courier or transport company
Time and date the shipment left the clinical site
Airway bill number
PPD
PPD
PPD


TAK-071
Study No. TAK-071-1001
Page 148 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Appendix F
Moderate and Strong CYP3A4, 2D6, or 2C9 Inducers/Inhibitors
Please note that this is not an exhaustive list. The medication for each subject will have to be 
individually reviewed to identify potential CYP3A, 2D6, or 2C9 strong/moderate inhibitory 
medications or foods. 
CYP450 Isoform
Strong Inhibitors
Moderate Inhibitors
CYP3A4
indinavir
nelfinavir
lopinavir /ritonavir
ritonavir
clarithromycin
erythromycin
itraconazole
ketoconazole
nefazodone
saquinavir
saquinavir/ritonavir
telithromycin
boceprevir
conivaptan
mibefradil
posaconazole
telaprevir
voriconazole
aprepitant
atazanavir
atazanavir/ritonavir
fluconazole
verapamil
diltiazem 
amprenavir 
atazanavir
ciprofloxacin 
darunavir/ritonavir
fosamprenavir
imatinib
cimetidine
cyclosporin
fluvoxamine
posaconazole
CYP2C9
n/a
amiodarone
fluconazole
miconazole
oxandrolone
CYP2D6
Bupropion, fluoxetine,
paroxetine, quinidine
Cinacalcet, duloxetine, sertraline,
terbinafine
Strong Inducers
Moderate Inducers
CYP3A4
avasimibe
phenobarbital
carbamazepine
phenytoin
rifampicin
rifabutin
st. john’s wort
troglitazone
bosentan
efavirenz
etravirine
modafinil
nafcillin
CYP2C9
rifampicin
secobarbital
n/a
CYP2D6
Dexamethasone, rifampin
n/a
NA=not applicable. 
(a) Polasek TM, Lin FP, Miners JO, Doogue MP. Perpetrators of pharmacokinetic drug-drug interactions arising from altered 
cytochrome P450 activity: a criteria-based assessment. Br J Clin Pharmacol 2011;71(5):727-36.
(b) Indiana University Department of Medicine. P450 Drug Interaction Table. Indiana University, Division of Clinical 
Pharmacology. Updated 25 January 2012. Accessed 03 April 2013. Available at: 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx.
(c) FDA. Drug development and drug interactions: table of substrates, inhibitors and inducers. U.S. Food and Drug Administration. 
Updated 27 October 2014. Accessed 04 June 2015. Available at: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm.


TAK-071
Study No. TAK-071-1001
Page 149 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Appendix G
Detailed Description of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment No. 05 are indicated. 
The corresponding text has been revised throughout the protocol.
Change 1: An additional SRD cohort (Cohort 22) has been added to the study and the approximate 
total number of subjects to be enrolled has been increased accordingly.
The primary change occurs in Section 6.1 Study Design:
Initial 
wording:
SRD cohorts (Cohorts 20 and 21) will explore the safety and tolerability of single 
doses of TAK-071 (planned 80 and 160 mg, respectively; however, actual doses 
administered will be determined from emerging data) when coadministered with 
donepezil (10 mg) in healthy subjects. These cohorts will consist of a randomized, 
double-blind, placebo-controlled, parallel-group ascending dose design with 12 
subjects per cohort. These 2 cohorts will establish a high well-tolerated dose of 
TAK-071 when coadministered with donepezil for the scopolamine challenge PoM 
study.
…
Cohort 16 will include up to 8 subjects (minimum of 6) with MCI or mild AD on 
stable donepezil treatment. This cohort will be conducted as a placebo-controlled, 
2-sequence, 2-period, 2-way crossover design.
....
Cohorts 1 to 12, and 16 to 21 will include non-Japanese subjects. Cohorts 13 to 15 
will include Japanese subjects. 
…
Subjects in Cohorts 20 and 21 will be assigned in a 1:1:2 ratio to receive treatments 
(within each cohort of 12 subjects, 3 will receive TAK-071 placebo+donepezil 
placebo, 3 subjects will receive TAK-071 placebo+donepezil, and 6 subjects will 
receive TAK-071+donepezil).
…
The safety and tolerability of donepezil alone will be evaluated during the 
donepezil dosing phase (before TAK-071 is given in Cohorts 10 to 12) during the 
3-week pretreatment period, and the safety and tolerability of donepezil in 
combination with TAK-071 (Cohorts 20 and 21) will be evaluated by assessing 
AEs, clinical laboratory results, physical examination findings, ECG findings, 
bowel function, and vital signs.
…
Approximately 174 subjects are expected to be randomized in this study.


TAK-071
Study No. TAK-071-1001
Page 150 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
…
Schematic of study design are included as Figure 6.b for Cohorts 1 to 6 and 18 to 
21, Figure 6.c for Cohorts 7 and 8, Figure 6.d for Cohorts 9 and 13 to 15, Figure 6.e
for Cohorts 10 to 12, Figure 6.f for Cohort 16, and Figure 6.g for Cohort 17. 
Schedules of Study Procedures are listed in Appendix A
Amended or 
new wording:
SRD cohorts (Cohorts 20 and 21to 22) will explore the safety and tolerability of 
single doses of TAK-071 (planned 80and 160, 60 and 40 mg, respectively; 
however, actual doses administered will be determined from emerging data) when 
coadministered with donepezil (10 mg) in healthy subjects. These cohorts will 
consist of a randomized, double-blind, placebo-controlled, parallel-group 
ascending dose design with 12 subjects per cohort. These 2 cohorts will establish a 
high well-tolerated dose of TAK-071 when coadministered with donepezil for the 
scopolamine challenge PoM study. Higher or lower dose cohort(s) may be 
added in the SRD part of the study to fully understand safety and tolerability 
of TAK-071 when coadministered with donepezil.
....
Cohorts 1 to 12 and 16 to 2122 will include non-Japanese subjects. Cohorts 13 to 
15 will include Japanese subjects. 
…
Subjects in Cohorts 20and 21 to 22 will be assigned in a 1:1:2 ratio to receive 
treatments (within each cohort of 12 subjects, 3 will receive TAK-071 
placebo+donepezil placebo, 3 subjects will receive TAK-071 placebo+donepezil, 
and 6 subjects will receive TAK-071+donepezil).
…
The safety and tolerability of donepezil alone will be evaluated during the 
donepezil dosing phase (before TAK-071 is given in Cohorts 10 to 12) during the 
3-week pretreatment period, and the safety and tolerability of donepezil in 
combination with TAK-071 (Cohorts 20and 21 to 22) will be evaluated by 
assessing AEs, clinical laboratory results, physical examination findings, ECG 
findings, bowel function, and vital signs.
…
Approximately 174186 subjects are expected to be randomized in this study.
…
Schematic of study design are included as Figure 6.b for Cohorts 1 to 6 and 18 to 
2122, Figure 6.c for Cohorts 7 and 8, Figure 6.d for Cohorts 9 and 13 to 15, 
Figure 6.e for Cohorts 10 to 12, Figure 6.f for Cohort 16, and Figure 6.g for Cohort 
17. Schedules of Study Procedures are listed in Appendix A.


TAK-071
Study No. TAK-071-1001
Page 151 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Rationale for Change: 
To further evaluate the safety and tolerability of TAK-071 when coadministered with donepezil.
The following sections also contain this change:
!
Section 2.0 Study Summary.
!
Section 5.2.3 Exploratory/Additional Endpoints.
!
Table 6.a Overview of Treatment Cohorts.
!
Figure 6.a Flow of Treatment Cohorts.
!
Figure 6.b Schematic of Study Design for SRD Cohorts 1 to 6 and 18 to 22.
!
Section 6.1.1 SRD Part (Cohorts 1 to 6 and 18 to 22).
!
Section 6.2.1 Study Design.
!
Section 6.2.2 Dose Selection.
!
Section 6.2.3 Endpoints.
!
Section 7.1 Inclusion Criteria.
!
Section 7.2 Exclusion Criteria.
!
Section 7.2.2 Additional Exclusion Criteria for Cohorts 18 to 22.
!
Table 7.a Prohibited Medications and Dietary Products.
!
Section 7.4 Diet, Fluid, and Activity Control.
!
Section 8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling.
!
Section 8.1.3 Dose and Regimen.
!
Section 9.1.6 Vital Sign Procedure.
!
Section 9.1.10 Contraception and Pregnancy Avoidance Procedure
!
Section 9.1.14 PGx Sample Collection.
!
Section 9.1.15 PK Sample Collection.
!
Table 9.i Collection of Blood Sample for PK Analysis of Cohorts 20 to 22.
!
Section 9.1.17 PD Assessments.
!
Table 9.n Collection of
!
Table 9.o Collection of Safety 
!
Table 9.p Pupillometry Collection.
CCI
CCI


TAK-071
Study No. TAK-071-1001
Page 152 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL

Section 9.3.1 Screening.

Section 9.3.2 Study Randomization.

Section 9.3.3 Treatment Phase/Washout Phase.

Section 9.3.4 Final Visit.

Section 9.3.6 Follow-up Visit/Telephone Call.

Section 9.5 Blood Volume.

Table 9.w Approximate Blood Volume for Cohorts 20 to 22.

Section 10.2.1 Collection and Reporting of AEs.

Section 13.1.4 PD Analysis.

Section 13.2 Interim Analysis and Criteria for Early Termination.

Appendix A Schedule of Study Procedures.
Change 2: Allowing flexibility for enrollment in Cohort 16.
The primary change occurs in Section 6.1.3 Subjects With MCI or Mild AD (Cohort 16):
Initial 
wording:
Cohort 16 will have a placebo-controlled, randomized, 2-sequence, 2-period, 
crossover study design to investigate the safety, tolerability, and PK in 1 of the 
intended target populations for TAK-071 treatment (subjects with MCI or mild 
AD). Up to 8 subjects (minimum of 6) previously diagnosed with MCI or mild AD 
and receiving ongoing donepezil (10 mg) therapy will be enrolled in Cohort 16. 
Subjects will continue with their donepezil therapy during the TAK-071 Treatment 
Period.
Amended or 
new wording:
Cohort 16 will include up to 8 subjects (minimum of 6) with MCI or mild AD on 
stable donepezil treatment or who consent to a donepezil run-in period of 5 mg 
dose for 28 days and titrate up to 10 mg for at least 21 days. Subjects with 
previous MCI/AD diagnosis who have been treated with 5 mg for at least 28 
days prior to Screening may consent to a donepezil run-in period of 10 mg for 
at least 21 days. This cohort will be conducted as a placebo-controlled, 
2-sequence, 2-period, 2-way crossover design.
Rationale for Change: 
To facilitate improved enrollment, added flexibility to include subjects who have previous 
diagnosis, but are on a lower donepezil dose and subjects who are currently diagnosed and are to 
participate in a donepezil step-up dose run-in period for Cohort 16.


TAK-071
Study No. TAK-071-1001
Page 153 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
The following sections also contain this change:

Section 2.0 Study Summary.

Table 6.a Overview of Treatment Cohorts.

Figure 6.a Flow of Treatment Cohorts.

Figure 6.f Schematic of Study Design for Cohort 16

Section 6.1.3 Subjects With MCI or Mild AD (Cohort 16)

Section 6.2.2 Dose Selection.

Section 7.1 Inclusion Criteria.

Section 7.4 Diet, Fluid, and Activity Control.

Section 8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling.

Section 9.3.3 Treatment Phase/Washout Phase.

Appendix A Schedule of Study Procedures.
Change 3: The inclusion criteria and screening period length for Cohort 16 have been revised. An 
optional run-in period of 49 days was added for Cohort 16.
The primary change occurs in 7.1 Inclusion Criteria:
Initial 
wording:
3. The subject is a healthy man or woman. Subjects should be aged 18 to 55 years, 
inclusive (nonelderly at the time of informed consent and first study drug dose) 
for Cohorts 1 to 12, and 17 to 21; 20 to 55 years, inclusive, for Cohorts 13 to 15; 
and 60 to 80 years, inclusive, for Cohort 16.
…
6. Cohort 16 only: 
a) Subjects with a documented previous diagnosis of MCI or mild AD.
b) Mini Mental State Examination (MMSE) score of 20 to 30, inclusive, at 
Screening and no biomarker data to contradict this diagnosis.


TAK-071
Study No. TAK-071-1001
Page 154 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Amended or 
new wording:
3. The subject is a healthy man or woman. Subjects should be aged 18 to 55 years, 
inclusive (nonelderly at the time of informed consent and first study drug dose) 
for Cohorts 1 to 12, and 17 to 2122; 20 to 55 years, inclusive, for Cohorts 13 to 
15; and 6055 to 8090 years, inclusive, for Cohort 16.
…
6. Cohort 16 only: 
a) Subjects with a documented previous diagnosis of MCI or mild AD or 
current diagnosis of AD criteria met at Screening Visit.
b) Mini Mental State Examination (MMSE) score of 2018 to 30, inclusive, at 
Screening and no biomarker data to contradict this diagnosis.
Rationale for Change:
To improve enrollment, subjects who are diagnosed with MCI or mild at during Screening and 
enrollment age range are allowed.
The following sections also contain this change:

Section 2.0 Study Summary.

Table 6.a Overview of Treatment Cohorts.

Section 10.0 Pretreatment Events and Adverse Events.

Appendix A Schedule of Study Procedures.
Change 4: An interim analysis of the SRD and MRD cohort data has been included.
The primary change occurs in 13.2 Interim Analysis and Criteria for Early Termination:
Initial 
wording:
No formal interim analysis of safety and PK data is planned. Section 6.1.5
describes the blinded safety and available PK review that will take place after 
completion of each cohort and prior to the next dose escalation stage in the study.
Amended or 
new wording:
Section 6.1.5 describes the blinded safety and available PK review that will take 
place after completion of each cohort and prior to the next dose escalation stage in 
the study.
13.2.1 Interim Analysis of Cohorts 1 to 15 and 17 to 22 Data
Interim analysis of all data (except Cohort 16) will be completed to enable the 
planning of phase 2 studies, while Cohort 16 enrollment is ongoing. The 
interim analysis will be initiated once all SRD and MRD cohorts have 
completed the study. 
The main Takeda study team will be unblinded to the data in order to provide 
interim results to support phase 2 protocol development.


TAK-071
Study No. TAK-071-1001
Page 155 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Rationale for Change: 
To provide interim results to support phase 2 protocol development.
The following section also contain this change:
Section 8.5.2 Sponsor PD Unblinding
Change 5: To add no food effect statement for Cohort 16.
The primary change occurs in Section 7.4 Diet, Fluid, and Activity Control:
Amended or 
new wording:
16.1.1 Cohort 16
Based on the preliminary results from cohort 17, food did not appear to affect 
the systemic exposure to TAK-071. Therefore, TAK-071 and donepezil can be 
given with or without food. However on the days of blood draws for clinical 
laboratory tests, TAK-071 and placebo will be administered with 
approximately 240 mL of water after a fast of at least 8 hours. 
Rationale for Change:
To reflect change in dose administration based on preliminary PK data.
Change 6: The sponsor signatories for this protocol have been updated.
The primary change occurs in Section 1.2 Approval:
Initial 
wording:
SIGNATURES
Electronic signatures of the following responsible Takeda medical officer and other 
signatories are located on the last page of this document.
PPD


TAK-071
Study No. TAK-071-1001
Page 156 of 156
Protocol Incorporating Amendment No. 05
15 May 2017
CONFIDENTIAL
Amended or 
new wording:
SIGNATURES
Electronic signatures of the following responsible Takeda medical officer and other 
signatories are located on the last page of this document.
Rationale for Change:
To reflect personnel changes at the sponsor.
PPD




䢢
䢢
䢢
䢢
䢢
䢢
䢢
䢢
(/(&7521,&6,*1$785(6
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 



 
 



 
 



 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 





GHGDG
䣃䣯䣧䣰䣦䣯䣧䣰䣶䢢䢲䢷䢢䣶䣱䢢䣃䢢䣒䣪䣣䣵䣧䢢䢳䢢䣕䣣䣨䣧䣶䣻䢮䢢䣖䣱䣮䣧䣴䣣䣤䣫䣮䣫䣶䣻䢮䢢䣣䣰䣦䢢䣒䣪䣣䣴䣯䣣䣥䣱䣭䣫䣰䣧䣶䣫䣥䢢䣕䣶䣷䣦䣻䢢䣱䣨䢢䣇䣵䣥䣣䣮䣣䣶䣫䣰䣩䢢䣕䣫䣰䣩䣮䣧䢢䣣䣰䣦䢢䣏䣷䣮䣶䣫䣲䣮䣧
䣑䣴䣣䣮䢢䣆䣱䣵䣧䣵䢢䣱䣨䢢䣖䣃䣍䢯䢲䢹䢳䢢䣫䣰䢢䣊䣧䣣䣮䣶䣪䣻䢢䣕䣷䣤䣬䣧䣥䣶䣵䢢䣣䣰䣦䢢䣕䣷䣤䣬䣧䣥䣶䣵䢢䣙䣫䣶䣪䢢䣏䣫䣮䣦䢢䣅䣱䣩䣰䣫䣶䣫䣸䣧䢢䣋䣯䣲䣣䣫䣴䣯䣧䣰䣶䢱䣏䣫䣮䣦䢢䣃䣮䣼䣪䣧䣫䣯䣧䣴
䣆䣫䣵䣧䣣䣵䣧䢢䣣䣰䣦䢢䣔䣧䣮䣣䣶䣫䣸䣧䢢䣄䣫䣱䣣䣸䣣䣫䣮䣣䣤䣫䣮䣫䣶䣻䢢䣣䣰䣦䢢䣈䣱䣱䣦䢢䣇䣨䣨䣧䣥䣶䢢䣱䣨䢢䣖䣃䣍䢯䢲䢹䢳䢢䣫䣰䢢䣊䣧䣣䣮䣶䣪䣻䢢䣕䣷䣤䣬䣧䣥䣶䣵
%LRVWDWLVWLFV$SSURYDO
0D\87&
&OLQLFDO$SSURYDO
0D\87&
&OLQLFDO3KDUPDFRORJ\$SSURYDO
0D\87&
PPD

SAP_001.pdf: 
This may include, but is not limited to, redaction of the following: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: hase 1 Safety, Tolerability, and Pharmacokinetic Study of Escalating Single and Multiple Oral 
Doses of TAK-071 in Healthy Subjects and Subjects With Mild Cognitive Impairment/Mild 
Alzheimer Disease and Relative Bioavailability and Food Effect of TAK-071 in Healthy Subjects
NCT Number: NCT02769065
SAP Approve Date: 08 August 2017 
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content 
is masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information or company confidential information. 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
TAKEDA DEVELOPMENT CENTER
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-071-1001
A Phase 1 Safety, Tolerability, and Pharmacokinetic Study of Escalating Single and
Multiple Oral Doses of TAK-071 in Healthy Subjects and Subjects With Mild Cognitive
Impairment/Mild Alzheimer Disease and Relative Bioavailability and Food Effect of 
TAK-071 in Healthy Subjects
Phase 1 Single and Multiple Rising Dose Study of TAK-071 in Healthy Subjects and 
Subjects With Mild Cognitive Impairment/Mild Alzheimer Disease and Relative 
Bioavailability and Food Effect of TAK-071 in Healthy Subjects
Version: Final
Date: 08 August 2017
Prepared by:
Prepared by:
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.
PPD
PPD


TAK-071-1001
Page 2 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
1.1
Approval Signatures
Study Title:
A Phase 1 Safety, Tolerability, and Pharmacokinetic Study of Escalating
Single and Multiple Oral Doses of TAK-071 in Healthy Subjects and 
Subjects With Mild Cognitive Impairment/Mild Alzheimer Disease and 
Relative Bioavailability and Food Effect of TAK-071 in Healthy Subjects
Takeda Approvals:
Date
Date
Date
Date
Date
PPD
PPD
PPD
PPD
PPD


TAK-071-1001
Page 3 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................6
4.0
OBJECTIVES .................................................................................................................8
4.1
Primary Objective......................................................................................................8
4.2
Secondary Objective..................................................................................................8
4.3
Exploratory Objectives ..............................................................................................9
4.4
Study Design .............................................................................................................9
4.4.1
Overview .............................................................................................................9
4.4.2
SRD Part (Cohorts 1 to 6 and 18 to 22) ..............................................................14
4.4.3
MRD Part (Cohorts 7 to 15)...............................................................................15
4.4.4
Subjects with MCI or Mild AD (Cohort 16) .......................................................16
4.4.5
Relative BA and FE Cohort (Cohort 17).............................................................17
5.0
ANALYSIS ENDPOINTS.............................................................................................19
5.1
Primary Endpoints ...................................................................................................19
5.2
Secondary endpoints................................................................................................19
5.3
Exploratory/Additional Endpoints............................................................................20
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................22
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................23
7.1
General Principles....................................................................................................23
7.1.1
Missing Data......................................................................................................23
7.1.2
Derived Datasets and Variables..........................................................................23
7.1.3
Definition of Study Days and Baseline...............................................................24
7.2
Analysis Sets ...........................................................................................................24
7.3
Disposition of Subjects ............................................................................................24
7.4
Protocol Deviations..................................................................................................25
7.5
Demographic and Baseline Characteristics...............................................................25
7.6
Medical History and Concurrent Medical Conditions...............................................25
7.7
Medication History and Concomitant Medications...................................................26
7.8
Study Drug Exposure and Compliance.....................................................................26
7.9
Efficacy Analysis.....................................................................................................26
7.10
Pharmacokinetic Analysis........................................................................................26
7.10.1 Plasma Pharmacokinetic Concentrations ............................................................26


TAK-071-1001
Page 4 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
7.10.2 Plasma Pharmacokinetic Parameters ..................................................................29
7.10.3 Urine Pharmacokinetic Concentrations...............................................................31
7.10.4 Urine Pharmacokinetic Parameters.....................................................................32
7.10.5 CSF Pharmacokinetic Concentrations ................................................................33
7.10.6 CSF Pharmacokinetic Parameters.......................................................................33
7.10.7 Pharmacodynamic Measurements ......................................................................34
7.11
Other Outcomes.......................................................................................................34
7.12
Safety Analysis........................................................................................................34
7.12.1 Adverse Events ..................................................................................................34
7.12.2 Clinical Laboratory Evaluations .........................................................................35
7.12.3 Vital Signs .........................................................................................................37
7.12.4 12-Lead ECGs ...................................................................................................38
7.12.5 Other Observations Related to Safety.................................................................40
7.13
Interim Analysis ......................................................................................................43
7.13.1 Interim Analysis of Cohorts 1 to 15 and 17 to 22 Data .......................................43
7.13.2 Interim Analysis of PD Data ..............................................................................43
7.14
Changes in the Statistical Analysis Plan...................................................................43
8.0
REFERENCES..............................................................................................................44
LIST OF IN-TEXT TABLES
Table 4.a
Overview of Treatment Cohorts.........................................................................11
Table 4.b
Sequence Groups and Regimen Assignment for Cohort 17.................................18
LIST OF IN-TEXT FIGURES
Figure 4.a
Flow of Treatment Cohorts ................................................................................12
Figure 4.b
Schematic of Study Design for SRD Cohorts 1 to 6 and 18 to 22........................12
Figure 4.c
Schematic of Study Design for MRD Cohorts 7 and 8........................................12
Figure 4.d
Schematic of Study Design for MRD Cohorts 9 and 13 to 15.............................13
Figure 4.e
Schematic of Study Design for MRD Cohorts 10 to 12.......................................13
Figure 4.f
Schematic of Study Design for Cohort 16...........................................................13
Figure 4.g
Schematic of Study Design for Cohort 17...........................................................13


TAK-071-1001
Page 5 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
LIST OF APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values .................45
Appendix B
Criteria for Markedly Abnormal Values for Vital Signs......................................47
Appendix C
Criteria for Markedly Abnormal Values for Electrocardiograms.........................48


TAK-071-1001
Page 6 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
3.0
LIST OF ABBREVIATIONS
λz
terminal disposition rate constant
%CV
percent coefficient of variation
AD
Alzheimer disease
ADaM
Analysis Data Model
Aet
amount of drug excreted in urine from time 0 to time t
AE
adverse event
ANOVA
analysis of variance
AUC
area under the plasma concentration-time curve
AUC12
area under the concentration-time curve from time 0 to time 12 hours
AUC24
area under the concentration-time curve from time 0 to time 24 hours
AUC36
area under the concentration-time curve from time 0 to time 36 hours
AUC48
area under the concentration-time curve from time 0 to time 48 hours
AUC∞
area under the plasma 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
AUCt
area under the plasma concentration-time curve from time 0 to time t
AUCτ
area under the plasma concentration-time curve from time 0 to time tau
AUEC12
Area under the effect concentration-time curve from time 0 to 12 hours
BA
bioavailability
BMI
body mass index
BSF
Bristol Stool Form
CI
confidence interval
CLR
renal clearance
CL/F
apparent clearance after extravascular administration
CL/Fss
apparent clearance after extravascular administration at steady-state
Cmax
maximum observed concentration
CPAP
Clinical Pharmacology Analysis Plan
CSF
cerebrospinal fluid
CSR
clinic study report
DIC
drug-in-capsule
Emax
maximum observed effect 
ECG
electrocardiogram
eCRF
electronic case report form
EEG
electroencephalography
ET
early termination
FE
food effect
Fe,t
fraction of drug excreted in urine from time 0 to time t
HV
healthy volunteers
jHV
Japanese healthy volunteers
MAV
markedly abnormal value


TAK-071-1001
Page 7 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
MCI
mild cognitive impairment
MedDRA
Medical Dictionary for Regulatory Activities
MMSE
Mini-Mental State Examination
MRD
multiple-rising dose
N
number of subjects
NA
not applicable
PD
pharmacodynamic
PK
pharmacokinetic
PoM
proof-of-mechanism
PT
preferred term
QD
once daily
qEEG
quantitative electroencephalography
Rac(AUC)
accumulation ratio based on AUC24
Rac(Cmax)
accumulation ratio based on Cmax
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SI
International System of Units
SOC
system organ class
SRD
single-rising dose
t1/2z
terminal disposition half-life
TEAE
treatment-emergent adverse event
tmax
time to first occurrence of Cmax
TEmax
time from dosing to occurrence of Emax, taken directly from the change from Baseline 
data
Vz/F
volume of distribution during the terminal disposition phase after extravascular 
administration


TAK-071-1001
Page 8 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
4.0
OBJECTIVES
4.1
Primary Objective
The primary objectives of this study are as follows:

To characterize the safety, tolerability, and plasma pharmacokinetic (PK) profile of TAK-071 
when administered as single and multiple once daily (QD) oral doses at escalating dose levels 
in healthy subjects (non-Japanese).

To characterize the safety, tolerability, and plasma PK profile of TAK-071 when 
administered as single and multiple QD oral doses at escalating dose levels in healthy 
subjects (non-Japanese) in the presence of steady-state exposure of donepezil QD.

To characterize the safety, tolerability, and plasma PK profile of TAK-071 when 
administered as single and multiple QD oral doses at escalating dose levels in healthy 
Japanese subjects.

To characterize safety, tolerability, and plasma PK profile of 10 mg donepezil when 
administered as a single dose, and to compare it to combination of 10 mg 
donepezil+TAK-071.

To characterize the safety, tolerability, and plasma PK profile of TAK-071 when 
administered as multiple QD oral doses to subjects with mild cognitive impairment (MCI) or 
mild Alzheimer Disease (AD) (non-Japanese) receiving donepezil treatment for a minimum 
of 3 months.
4.2
Secondary Objective
The secondary objectives of this study are as follows:

To assess safety of 120 mg or higher single dose of TAK-071 measured by
electroencephalography (EEG).

To evaluate the urinary clearance of TAK-071 following single and multiple oral doses.

To evaluate the brain penetration of TAK-071 as measured in cerebrospinal fluid (CSF)
following single and multiple dosing.

To evaluate the dose proportionality and any time dependency in TAK-071 plasma PK.

To evaluate the effect of multiple daily doses of TAK-071 on donepezil steady-state PK.

To evaluate the relative bioavailability (BA) of TAK-071 10 mg administered as tablet
formulation compared with TAK-071 10 mg administered as drug-in-capsule (DIC)
formulation.

To evaluate potential effect of food on the TAK-071 plasma PK following a single oral dose 
of 10 mg tablet formulation.


TAK-071-1001
Page 9 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
4.3
Exploratory Objectives
The exploratory objectives of this study are as follows:
4.4
Study Design
4.4.1
Overview
This is a first-in-human, phase 1, safety, tolerability, and PK study of escalating single and
multiple oral doses of TAK-071 in healthy adult (non-Japanese and Japanese) male and female
subjects and subjects with MCI or mild AD (non-Japanese). In addition, the relative 
bioavailability of a tablet formulation (test) vs the DIC formulation as well as the effect of food 
on the PK of the tablet formulation will be assessed in healthy subjects.
The first time TAK-071 is dosed to humans will be a single oral dose administered in Cohort 1 of
the single-rising dose (SRD) part of this study. Additional cohorts (Cohorts 2 to 6, 18, and 19) 
will be used to study escalating single-dose levels.
Higher or lower dose cohort(s) may be added in the SRD part of the study to fully understand
safety and tolerability of TAK-071. The SRD part of the study will consist of a randomized,
double-blind, placebo-controlled, parallel-group ascending dose design with 8 subjects per 
cohort.
SRD cohorts (Cohorts 20 to 22) will explore the safety and tolerability of single doses of
TAK-071 (80, 60, and 40 mg, respectively; however, actual doses administered will be
determined from emerging data) when coadministered with donepezil (10 mg) in healthy
subjects. These cohorts will consist of a randomized, double-blind, placebo-controlled,
parallel-group ascending dose design with 12 subjects per cohort. These 2 cohorts will establish 
a high well-tolerated dose of TAK-071 when coadministered with donepezil for the scopolamine 
challenge proof-of-mechanism (PoM) study.
Cohorts 7 to 15 will be used in the multiple-rising dose (MRD) part of this study. The MRD will 
thus consist of a randomized, double-blind, placebo-controlled, 9-cohort, parallel-group multiple 
ascending dose design with 8 subjects in Cohorts 7 to 12 and 6 subjects in Cohorts 13 to 15.
CCI


TAK-071-1001
Page 10 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
Additional MRD cohorts (TAK-071 and/or TAK-071+donepezil) may be added to fully
understand safety and tolerability of TAK-071.
Selected MRD cohorts (Cohorts 10 to 12) will be pretreated for 3 weeks with daily oral doses of
donepezil (5 mg QD), followed by continued daily oral donepezil dosing during the TAK-071
treatment period.
Cohort 16 will include up to 8 subjects (minimum of 6) with MCI or mild AD on stable 
donepezil treatment or who consent to a donepezil run-in period of 5 mg dose for 28 days and 
titrate up to 10 mg for at least 21 days. Subjects with previous MCI/AD diagnosis who have been 
treated with 5 mg for at least 28 days prior to Screening may consent to a donepezil run-in period 
of 10 mg for at least 21 days. This cohort will be conducted as a placebo-controlled, 2-sequence, 
2-period, 2-way crossover design.
Cohort 17 will include up to 12 subjects. This cohort will be conducted in an open-label, 
3-period, 3-sequence, 3-way crossover design.
Cohorts 1 to 12, and 16 to 22 will include non-Japanese subjects. Cohorts 13 to 15 will include
Japanese subjects.
Subjects in each cohort (Cohorts 1 to 16, 18, and 19) will be randomized to receive treatment 
with TAK-071 or matching placebo using DIC in the morning following a minimum fast of 
8 hours. In Cohorts 1 to 12, 18, and 19, placebo treatments will be assigned in a 3:1 ratio (within 
each cohort of 8 subjects, 6 will receive active treatment and 2 will receive placebo).
Subjects in Cohorts 20 to 22 will be assigned in a 1:1:2 ratio to receive treatments (within each
cohort of 12 subjects, 3 will receive TAK-071 placebo+donepezil placebo, 3 subjects will 
receive TAK-071 placebo+donepezil, and 6 subjects will receive TAK-071+donepezil).
In Cohorts 13 to 15, placebo treatments will be assigned in a 5:1 ratio (within each cohort of
6 subjects, 5 will receive active treatment and 1 will receive placebo. In Cohort 16, subjects will 
be assigned to 1 of 2 possible treatment sequences (AB or BA), with Treatment A being 
TAK-071 and Treatment B being matching placebo. In Cohort 17, subjects will be assigned to 
1 of 3 possible treatments as Regimen Sequences ABC, BCA, and CAB, where, Regimen 
A=Fasted State and Capsule Formulation (10 mg DIC formulation), Regimen B=Fasted State 
and Tablet Formulation (10 mg tablet formulation), and Regimen C=Fed State and Tablet 
Formulation (10 mg tablet formulation).
The safety of TAK-071 alone or in combination with donepezil will be assessed through adverse
events (AEs), clinical laboratory results, physical examination findings, electrocardiogram 
(ECG) findings, bowel function, vital signs, and suicidal assessments. Continuous 12-lead Holter 
ECG monitoring will also be performed on selected study cohorts.
The safety and tolerability of donepezil alone will be evaluated during the donepezil dosing 
phase (before TAK-071 is given in Cohorts 10 to 12) during the 3-week pretreatment period, and 
the safety and tolerability of donepezil in combination with TAK-071 (Cohorts 20 to 22) will be
evaluated by assessing AEs, clinical laboratory results, physical examination findings, ECG
findings, bowel function, and vital signs.


TAK-071-1001
Page 11 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
In addition to safety monitoring, TAK-071 plasma and urine PK profiles will be generated and 
PK parameters derived. It is planned that CSF samples for PK analysis will be obtained in 
Cohort 3 (following a single dose) and Cohort 9 (at steady-state). Pharmacodynamic (PD)
.
Approximately 186 subjects are expected to be randomized in this study.
End of study is defined as the date of last visit of the last subject for last clinical assessment.
The treatment groups and cohorts are outlined in Table 4.a.
Table 4.a
Overview of Treatment Cohorts
jHV=Japanese healthy volunteers, FE=food effect, HV=healthy volunteers, NA=not applicable.
(a) Non-Japanese subjects.
(b) Donepezil (10 mg) will be given as a single dose as an over-encapsulated oral tablet, 24 hours post TAK-071 
dose.
(c) Donepezil (5 mg QD) will be given as an oral tablet daily for 3 weeks prior to dosing and during the TAK-071
dosing interval.
(d) Subjects with MCI or mild AD (non-Japanese) who have been stable on 10 mg donepezil treatment for at least
21 days or who consent to donepezil run-in period.
(e) Healthy subjects. Subjects will be randomized to receive TAK-071 as a DIC formulation and a tablet formulation 
under fasted condition, and as a tablet formulation under fed conditions.
CCI


TAK-071-1001
Page 12 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
The flow of planned cohorts is provided in Figure 4.a.
Figure 4.a
Flow of Treatment Cohorts
Schematic of the study design are included as Figure 4.b for Cohorts 1 to 6 and 18 to 22, 
Figure 4.c for Cohorts 7 and 8, Figure 4.d for Cohorts 9 and 13 to 15, Figure 4.e for Cohorts 10 
to 12, Figure 4.f for Cohort 16, and Figure 4.g for Cohort 17.
Figure 4.b
Schematic of Study Design for SRD Cohorts 1 to 6 and 18 to 22
(a) Subjects in Cohorts 20 to 22 will receive donepezil 10 mg or placebo as a single dose approximately 24 hours
after the TAK-071 or placebo dose.
Figure 4.c
Schematic of Study Design for MRD Cohorts 7 and 8


TAK-071-1001
Page 13 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
Figure 4.d
Schematic of Study Design for MRD Cohorts 9 and 13 to 15
Figure 4.e
Schematic of Study Design for MRD Cohorts 10 to 12
Figure 4.f
Schematic of Study Design for Cohort 16
(a) Subjects with MCI or mild AD on stable donepezil (10 mg) treatment or who consent to a donepezil run-in 
period of 5 mg dose for 28 days and titrate up to 10 mg for at least 21 days. Subjects with previous MCI/AD 
diagnosis who have been treated with 5 mg for at least 28 days prior to Screening may consent to a donepezil run-in 
period of 10 mg for at least 21 days.
Figure 4.g
Schematic of Study Design for Cohort 17
(a) Visit Day count shown as relative to Day 1 of each treatment period.
(b) The total washout period will be 21 days from the time of dosing.


TAK-071-1001
Page 14 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
For Cohorts 7 to 8 and 10 to 12, the dosing duration and for Cohorts 9 and 13 to 16, the dosing 
and/or washout duration may be adjusted if PK data from the SRD part indicate that a different 
period may be more appropriate (ie, 5 times the observed terminal disposition phase half-life 
[t1/2z]). For Cohort 17, washout period may be adjusted if PK data from previous cohorts 
warrants so.
The planned duration of dosing in all MRD cohorts will be of 21 days. If warranted based on
emerging PK data (ie, based on the observed range of t1/2z values) and assuming acceptable safety 
and tolerability in preceding cohorts, the duration of TAK-071 dosing may be reduced to at a 
minimum of 14 days or extended for up to a maximum of 28 days.
4.4.2
SRD Part (Cohorts 1 to 6 and 18 to 22)
The SRD part of the study is a randomized, double-blind, placebo-controlled, parallel-group,
ascending dose design involving single-dose escalation through 7 (or more, if needed) cohorts.
Subjects will be confined throughout the Treatment Period (from Day -1 to Day 5), with a
follow-up assessment on Day 12 (±2) days. Based on emerging preliminary PK data following
Cohort 1, an additional visit for PK collection will be done on Day 8. For Cohorts 1 to 6, 18, and
19, healthy subjects will be randomly assigned to TAK-071 or matching placebo in a 3:1 ratio.
For Cohorts 20 to 22, healthy subjects will be randomly assigned to TAK-071+donepezil,
donepezil, and placebo in a 2:1:1 ratio so that after completion of each cohort, 6 subjects had
received TAK-071+donepezil, 3 subjects had received donepezil+TAK-071 placebo, and 
3 subjects had received donepezil placebo+TAK-071 placebo.
Sentinel dosing will be used for Cohort 1 (1 subject to receive TAK-071 and 1 subject to receive
placebo) to provide safety and tolerability evaluations prior to administering TAK-071 to the
remainder of subjects within the cohort. After reviewing 24-hour postdose safety and tolerability
data from the sentinel group, the remaining 6 subjects of the cohort may be dosed provided that 
the AE profile of TAK-071 in the first 2 subjects is considered acceptable. For subsequent 
cohorts (2, 4 to 6, 18, and 19), the intent is to stagger dosing between the first 2 subjects 
(1 TAK-071 and 1 placebo) and subsequent subjects dosed, starting no earlier than the median 
time of first occurrence of maximum observed concentration (tmax) observed in earlier cohorts 
(providing that there are no issues arising in the previous cohort). Depending on the observed 
length of tmax, this could involve dosing the next day.
Sentinel dosing will be used for Cohorts 20 to 22 (1 subject to receive donepezil
placebo+TAK-071 placebo, 1 subject to receive donepezil+TAK-071 placebo, and 1 subject to
receive donepezil+TAK-071). After reviewing 24-hour postdose safety and tolerability data from
the sentinel group, the remaining 9 subjects of the cohort may be dosed provided that the AE
profile of TAK-071 in the first 3 subjects is considered acceptable.
For Cohort 3, subjects will be staggered across multiple days to facilitate CSF collection.
For Cohort 3, CSF samples will be obtained at 5 selected time points after the dose on Day 1 via 
an indwelling cannula to provide an indication of brain penetration for TAK-071 and the
concentration relative to circulating plasma concentrations. If measured CSF concentrations are


TAK-071-1001
Page 15 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
deemed to be low, ie, most time points are below the limit of quantification of the assay, 
TAK-071 CSF concentrations may also be determined in subsequent SRD cohorts until 
acceptable concentrations are attained.
 
.
4.4.3
MRD Part (Cohorts 7 to 15)
Each of the healthy subject MRD cohorts, including TAK-071 alone in non-Japanese subjects
(Cohorts 7 to 9), TAK-071 in combination with donepezil in non-Japanese subjects (Cohorts 10 
to 12), and TAK-071 alone in Japanese subjects (Cohorts 13 to 15), will be a randomized,
double-blind, placebo-controlled, 9-cohort, parallel-group, multiple ascending dose design with
8 subjects per cohort (6 active and 2 placebo) for Cohorts 7 to 12 and 6 subjects per cohort 
(5 active and 1 placebo) for Cohort 13 to 15.
Dosing will be staggered in Cohorts 7 and 8 and 10 to 11 between the first 2 subjects 
(1 TAK-071 and 1 placebo) and subsequent subjects dosed, starting no earlier than the median 
tmax. Depending on the observed length of tmax, this could involve dosing the next day. For 
Cohort 9, subjects will be staggered across multiple days to facilitate CSF collection. 
 
 Japanese 
Cohorts 13 to 15 will not require staggering since doses will be equal or lower than those in the 
corresponding non-Japanese Cohorts 7 to 9, thus effectively acting as front runner groups.
Additional MRD cohorts may be added to fully understand safety and tolerability of TAK-071.
4.4.3.1
Non-Japanese Subjects (Cohorts 7 to 9)
Dose escalation will progress through 3 cohorts. Subjects will be confined during the Treatment
Period from Day -1 to Day 22 (Cohorts 7 and 8) or Day 29 (Cohort 9).
For Cohorts 7 and 8, healthy subjects will be randomized to receive multiple doses (21 oral doses
QD) of TAK-071 or matching placebo in a 3:1 ratio.
For Cohort 9, TAK-071 or placebo will be administered as a single oral dose, followed by a 
7-day washout period and then daily dosing for 21 days or matching placebo in a 3:1 ratio. The 
7-day washout period in Cohort 9 is intended to provide sufficient time to characterize the 
TAK-071 terminal disposition phase, but it is not expected to result in complete disappearance of 
TAK-071 from plasma prior to starting repeat dosing on Day 8. Nonetheless, Day 8 trough 
concentrations are expected to be very low (ie, <5% steady state maximum observed plasma 
concentration [Cmax]).
For Cohort 9, the potential for time dependency in PK will be evaluated. CSF samples will also 
be obtained at 5 selected time points after the dose on Day 28 via an indwelling cannula to 
provide an indication of brain penetration and the concentration relative to circulating plasma 
concentrations at steady-state of TAK-071. In addition, 
 
CCI
CCI
CCI


TAK-071-1001
Page 16 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
4.4.3.2
Non-Japanese Subjects Pretreated with Donepezil (Cohorts 10 to 12)
Cohorts 10 to 12 will be conducted in a double-blind manner with respect to TAK-071 but not 
for donepezil. Therefore, healthy subjects will be randomized to receive 21 QD oral doses of 
either TAK-071 or matching placebo in a 3:1 ratio. In addition, subjects will be pretreated for 
3 weeks with daily oral doses of donepezil (5 mg), followed by continued daily oral donepezil 
QD dosing during the 21-day TAK-071 treatment period. Subjects will be confined from 
Day -22 to Day -19. Subjects will be discharged from the clinic on Day -19 and will continue 
donepezil dosing at home on Days -18 to -11. Subjects will return to clinic on Day -10 and 
remain confined until the Study Exit (Day 23) or Early Termination (ET). During outpatient 
dosing Days -18 to -11, subjects will be contacted by study site by telephone call every day to 
ensure treatment compliance.
Pupil size will be monitored as a biomarker of cholinomimetic effects at specified pre- and
postdose time points following the penultimate dose of donepezil pretreatment and the 
penultimate dose of TAK-071 plus donepezil combination treatment. 
 
Additional MRD cohorts may be added to fully understand safety and tolerability of TAK-071 in
subjects pretreated with donepezil.
4.4.3.3
Japanese Subjects (Cohorts 13 to 15)
The MRD part in Japanese subjects will involve dose escalation through 3 cohorts. Subjects will 
be confined throughout the Treatment Period from Day -1 to Day 29. Healthy Japanese subjects 
will be randomized to receive a single dose of TAK-071 or matching placebo in a 5:1 ratio, 
followed by a 7-day washout period and multiple doses (21 oral doses QD) of TAK-071 or 
placebo. The 7-day washout period in Cohorts 13 to 15 is intended to provide sufficient time to 
characterize the TAK-071 terminal disposition phase, but it is not expected to result in complete 
disappearance of TAK-071 from plasma prior to starting repeat dosing on Day 8. Nonetheless, 
Day 8 trough concentrations are expected to be very low (ie, <5% steady state Cmax).
PK parameters will include a determination of time to steady-state, potential for accumulation, 
and time dependency in PK. In addition, data will be compared with data generated in 
non-Japanese subjects to determine if there are any ethnic differences in human PK.
4.4.4
Subjects with MCI or Mild AD (Cohort 16)
Cohort 16 will have a placebo-controlled, randomized, 2-sequence, 2-period, crossover study
design to investigate the safety, tolerability, and PK in 1 of the intended target populations for
TAK-071 treatment (subjects with MCI or mild AD). Up to 8 subjects (minimum of 6) 
previously diagnosed with MCI or mild AD and receiving ongoing donepezil (10 mg) therapy or 
who consent to a donepezil run-in period of 5 mg dose for 28 days and titrate up to 10 mg for at 
least 21 days. Subjects with previous MCI/AD diagnosis who have been treated with 5 mg for at 
least 28 days prior to Screening may consent to a donepezil run-in period of 10 mg for at least 
CCI


TAK-071-1001
Page 17 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
21 days will be enrolled in Cohort 16. Subjects will continue with their donepezil therapy during 
the TAK-071 Treatment Period.
Subjects will be randomized to 1 of 2 possible treatment sequences (AB or BA) before the first
dose of study drug. In each period, subjects will receive 1 of 2 possible treatments as follows:

Treatment A: TAK-071 QD for 21 days, or

Treatment B: 21 days of matching placebo.
There will be a washout period of at least 21 days between the treatment sequences. The washout
and/or dosing duration may be adjusted with additional day(s) if PK data from the SRD/MRD 
parts indicate that a longer washout may be more appropriate (ie, 5 times the observed t1/2z).
Pupil size will be monitored as a biomarker of cholinomimetic effects.
4.4.5
Relative BA and FE Cohort (Cohort 17)
Cohort 17 will be administered in 3 single-dose regimens in a 3-way crossover design to 12 male 
and female subjects using 10 mg oral dose treatments. Subjects will receive a TAK-071 10 mg 
single oral regimen on Day 1 of each period. TAK-071 tablet or DIC will be administered with 
240 mL of water.
Regimen A – Fasted State and Capsule Formulation (10 mg in DIC formulation)
Subjects will be fasted overnight for at least 8 hours. Treatment will be administered orally with 
240 mL of water. No food should be allowed for at least 4 hours postdose. Water can be allowed 
after 2 hours postdose.
Regimen B – Fasted State and Tablet Formulation (10 mg [2× 5 mg] tablet formulation)
Subjects will be fasted overnight for at least 8 hours. Treatment will be administered orally with 
240 mL of water. No food should be allowed for at least 4 hours postdose. Water can be allowed 
as desired after 2 hours postdose.
Regimen C – Fed State and Tablet Formulation (10 mg [2× 5 mg] tablet formulation)
Subjects will be fasted overnight for at least 8 hours. After this time, subjects should start the 
standard high fat meal (~50% fats) 30 minutes prior to administration of the drug product. Study 
subjects should eat this meal in 25 minutes or less. Drug product should be dosed 30 minutes 
after the start of the meal with 240 mL of water. No food should be allowed for at least 4 hours 
postdose. Water can be allowed as desired after 2 hours postdose.
Four subjects will be randomly assigned to 1 of 3 sequence groups and receive the regimens in 
the order shown in Table 4.b.


TAK-071-1001
Page 18 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
Table 4.b
Sequence Groups and Regimen Assignment for Cohort 17
Sequence Group
Number of Subjects
Period 1 Day 1
Period 2 Day 1
Period 3 Day 1
1
4
A
B
C
2
4
B
C
A
3
4
C
A
B
Regimen A: Fasted State and Capsule Formulation (10 mg in DIC formulation).
Regimen B: Fasted State and Tablet Formulation (10 mg tablet formulation).
Regimen C: Fed State and Tablet Formulation (10 mg tablet formulation).


TAK-071-1001
Page 19 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
The following safety parameters will be analyzed as primary endpoints:

Percentage of subjects who have at least 1 treatment-emergent adverse event (TEAE).

Percentage of subjects who meet the Takeda markedly abnormal value (MAV) criteria at 
least once postdose for the following:
–
Clinical laboratory parameters.
–
Vital sign measurements.
–
ECG parameters.
PK parameters of TAK-071 in plasma following a single dose (Day 1) and at steady-state (after 
the final dose following multiple dosing) will be analyzed as primary endpoints:

tmax.

Cmax in plasma.

Area under the plasma concentration-time curve from time 0 to 24 hours (AUC24).

Area under the plasma concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration (AUC∞) (single dose only [Day 1]).
5.2
Secondary endpoints
Plasma and urine PK parameters of TAK-071 following a single dose (Day 1) and at steady-state
(after the final dose following multiple dosing), including but not limited to the following:

Area under the plasma concentration-time curve from time 0 to time t (AUCt).

t1/2z, as permitted by the data (single dose only [Day 1]).

Apparent clearance after extravascular administration (CL/F).

Apparent volume of distribution during the terminal disposition phase after extravascular 
administration (Vz/F).

Accumulation ratio based on the area under the plasma concentration-time curve (AUC) from 
time 0 to time tau (AUCτ) (Rac(AUC)).

Accumulation ratio based on plasma Cmax (Rac(Cmax)).

Amount of drug excreted in urine from time 0 to time t (Aet).

Fraction of administered dose of drug excreted in urine from time 0 to time t (fe,t).

Renal clearance (CLR).


TAK-071-1001
Page 20 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
CSF PK parameters of TAK-071 planned for the single-dose Cohort 3 and at steady-state in
Cohort 9 (after the final dose following multiple dosing), including but not limited to the
following:
!
CSF Cmax.
!
Area under the CSF concentration-time curve from time 0 to 12 hours (AUC12) (Cohort 3 
only [Day 1]).
!
Area under the CSF concentration-time curve from time 0 to 36 hours (AUC36) (Cohort 9 
only [Day 28]).
!
The ratio of CSF AUC12 to the plasma AUC12 (CSF AUC12: plasma AUC12) (Cohort 3 only 
[Day 1]).
!
The ratio of CSF AUC36 to the plasma AUC36 (CSF AUC36:plasma AUC36) (Cohort 9 only
[Day 28]).
Plasma steady-state PK parameters of donepezil (Cohorts 10 to 12) on the last donepezil
pretreatment day and after 21 daily doses of TAK-071, including but not limited to the 
following:
!
tmax.
!
Cmax.
!
AUC24.
!
Ratio of geometric mean steady-state AUC24 and Cmax for donepezil after 21 daily doses of 
TAK-071 in reference to donepezil alone and the associated 90% confidence intervals (CIs).
5.3
Exploratory/Additional Endpoints
CCI


TAK-071-1001
Page 21 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
CCI


TAK-071-1001
Page 22 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
6.0
DETERMINATION OF SAMPLE SIZE
The sample sizes chosen for the SRD and MRD parts are considered to be sufficient for 
evaluation of safety, tolerability, and PK of each cohort but are not based on statistical power 
considerations.
A sample size of 12 subjects (4 per sequence) was chosen for the 3-period, 3-sequence, crossover
design in Cohort 17. The sample size is considered sufficient to assess the bioavailability of
TAK-071 from the tablet relative to the capsule and to assess the effect of food on the
bioavailability of TAK-071 from the tablet. This sample size was not based on statistical power
considerations.
Enrolled participants who withdraw from the study for reasons other than safety may be replaced
to ensure adequate numbers of evaluable subjects. The decision to replace a withdrawn subject 
will be made at the discretion of Takeda and the investigator.
In addition, in the event of a nonsafety-related critical procedure study interpretation (ie, CSF
collection) where a subject is not withdrawn and remains in the study for the completion of all
other assessments, that subject may be replaced on a case-by-case basis to ensure evaluability of
that particular endpoint (ie, CSF, PK).


TAK-071-1001
Page 23 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles
This Statistical Analysis Plan (SAP) was developed based on International Conference on 
Harmonization E3 [1] and E9 [2] Guidelines. This SAP should be read in conjunction with the 
study protocol and electronic case report forms (eCRFs). This version of the SAP was developed 
using the information provided in Protocol TAK-071-1001 Amendment 05, dated 15 May 2017
[3].
All study-related raw data, including derived data, will be presented in data listings. Continuous 
data will be summarized using: number of subjects (N), mean, standard deviation (SD), median, 
minimum, and maximum, where appropriate. Where indicated, coefficient of variation (%CV) 
and geometric mean will also be included in the summary of continuous data. Categorical data
will be summarized using the number and percentage of subjects for each category where 
appropriate.
All statistical tests will be 2-tailed at =0.05 level for significance unless otherwise stated. The 
p-values less than or equal to (when rounded to three digits) are reported as “significant”. The 
phrase “no significant difference” indicates that all p-values for the tests are greater than . All 
computations will be performed prior to rounding.
Data collected for subjects during the study period in which they received placebo will be pooled 
together in all safety summaries for each cohort and will be analyzed as one placebo group.
7.1.1
Missing Data
There will be no imputation of incomplete or missing data. Decisions regarding inclusion or 
exclusion of data from an analysis for subjects who are noncompliant with the dose schedule, or 
who have incomplete data, will be made on a case-by-case basis, but the data will be presented in 
data listings regardless.
Plasma concentrations that are below the limit of quantification will be treated as zero in the 
summarizing of concentration values and deriving of PK parameters. 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.
7.1.2
Derived Datasets and Variables
Derived datasets will be generated according to Clinical Data Interchange Standards Consortium 
guidance documents: Analysis Data Model (ADaM) Implementation Guide, Version 1.0 (17 Dec 
2009); ADaM Data Structure for Adverse Event Analysis, Version 1.0 (10 May 2012). 
Body mass index (BMI) will be calculated as weight (kg)/(height (m))2 and will be presented to 
1 decimal place. BMI will be calculated for Screening.


TAK-071-1001
Page 24 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
7.1.3
Definition of Study Days and Baseline
For all safety endpoints, Baseline is defined as the last non-missing measurement prior to first 
dose of study drug for subjects in the SRD Cohorts (Cohorts 1 to 6 and 18 to 22), non-Japanese 
MRD cohorts (Cohorts 7 to 12) and Japanese MRD cohorts (Cohorts 13 to 15). Baseline is 
defined as the last non-missing measurement prior to first dose of study drug in the respective 
treatment period for subjects with MCI or mild AD (Cohort 16) and subjects in relative BA and 
FE Cohort (Cohort 17).
For all safety endpoints in the SRD Cohorts (Cohorts 1 to 6 and 18 to 22) and non-Japanese 
MRD cohorts (Cohorts 7 to 12) and Japanese MRD cohorts (Cohorts 13 to 15), study day will be 
calculated relative to the date of first dose. Study day prior to the first dose of treatment will be 
calculated as: date of assessment/event – date of treatment; study day on or after the date of first 
dose of treatment will be calculated as: date of assessment/event – date of treatment + 1. For
subjects with MCI or mild AD (Cohort 16) and relative BA and FE cohort (Cohort 17), study day 
will be calculated relative to the date of first TAK-071 dose in the respective treatment period.
Study day prior to the first TAK-071 dose in the respective treatment period will be calculated 
as: date of assessment/event – date of treatment; study day on or after the first TAK-071 dose in 
the respective treatment period will be calculated as: date of assessment/event – date of treatment 
+ 1.
7.2
Analysis Sets
Safety Set
The safety analysis set will consist of all subjects who are 
enrolled and received 1 dose of study drug. Subjects in this 
analysis set will be used for demographic, Baseline 
characteristics, and safety summaries.
Pharmacokinetic Set
The PK set will consist of all subjects who receive study drug and 
have at least 1 measurable plasma concentration or amount of 
drug in the urine. All subjects with valid PK parameter estimate 
will be included in the summaries and analyses for that 
parameter.
Pharmacodynamic Set
The PD set will consist of all subjects who receive study drug and 
have at least 1 postdose PD measurement.
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 PK and PD analysis but 
will be presented in the subject listings.
7.3
Disposition of Subjects
The primary reason for screen failure will be summarized.
The number and percentage of subjects who complete study drug, prematurely discontinue study 
drug and study visits will be summarized by the pooled placebo group, each TAK-071 dose 


TAK-071-1001
Page 25 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
level, TAK-071 overall, and overall total within each part (SRD cohorts, non-Japanese MRD 
cohorts, Japanese MRD cohorts, Cohort 16, and Cohort 17). In addition, the number and 
percentage of subjects will be summarized for each reason of discontinuation of study drug and 
study visits by the pooled placebo group, each TAK-071 dose level, TAK-071 overall, and 
overall total within each part (SRD cohorts, non-Japanese MRD cohorts, Japanese MRD cohorts) 
and by treatment sequence and overall total for Cohort 16 and Cohort 17. Subjects’ study 
completion data, including reasons for premature termination, will be listed for each cohort by 
study part (SRD cohorts, non-Japanese MRD cohorts, Japanese MRD cohort, Cohort 16, and 
Cohort 17) for all subjects.
The number and percentage of subjects who comprised each analysis set will be summarized by 
the pooled placebo group, each TAK-071 dose level, TAK-071 overall, and overall total for all 
subjects in each part of the study and by treatment sequence and overall total for Cohort 16 and 
Cohort 17. 
7.4
Protocol Deviations
The protocol deviations will be provided in a data listing and summarized by the pooled placebo 
group, each TAK-071 dose level, TAK-071 overall, and overall total within each part (SRD 
cohorts, non-Japanese MRD cohorts, Japanese MRD cohorts) and by treatment sequence and 
overall total for Cohort 16 and Cohort 17.
7.5
Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized by the pooled placebo group, each 
TAK-071 dose level, TAK-071 overall, and overall total within each part (SRD cohorts, non-
Japanese MRD cohorts, Japanese MRD cohorts) and by treatment sequence and overall total for 
Cohort 16 and Cohort 17. Summary statistics (N, mean, SD, median, minimum, and maximum) 
will be generated for continuous variables (eg, age, height, weight, and BMI), and the number 
and percentage of subjects within each category will be presented for categorical variables 
(eg, gender, race, ethnicity, caffeine consumption, alcohol use, reproductive status, and smoking 
status).
Demographic variables of screen failure subjects and reasons for screen failures will be 
summarized for all subjects who are screened but not enrolled in the study. Individual 
demographic characteristics, date of informed consent, any available safety data and reason for 
screen failure will also be presented in the data listing.
7.6
Medical History and Concurrent Medical Conditions
Medical history obtained includes any significant conditions or diseases that stopped at or prior 
to signing of informed consent. Concurrent medical conditions are those significant ongoing 
conditions or diseases that are present at signing of informed consent.
For subjects in Cohort 16, the following medical history will be collected: diagnosis, date of
diagnosis, Mini Mental State Examintion (MMSE) score, date of onset of donepezil treatment, 
and dose and timing of administration of donepezil (evening [bedtime] required).


TAK-071-1001
Page 26 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
Medical history and concurrent medical condition verbatim reported terms will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA), version to be delineated in the 
clinical study report (CSR). No summaries for medical history and concurrent medical 
conditions will be provided. All medical history and concurrent medical conditions will be listed.
7.7
Medication History 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.
Medication history and concomitant medications will be coded using World Health Organization 
Drug Dictionary, version to be delineated in the CSR. No summaries for medication history and 
concomitant medications will be provided. All medication history and concomitant medications 
data will be listed.
7.8
Study Drug Exposure and Compliance
The date and time of each dose for each subject will be reported in the data listing for all 
subjects. Summaries of PK and PD data will be provided by placebo (as applicable) and
TAK-071 dose level in each part of the study. No other summary statistics for the extent of 
exposure to study drug or compliance calculations will be performed for this study.
7.9
Efficacy Analysis
Not applicable.
7.10
Pharmacokinetic Analysis
7.10.1 Plasma Pharmacokinetic Concentrations
Collection of Blood Samples for Pharmacokinetic Analysis Cohorts 1 to 6, 18 and 19.
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Plasma
1
Cohorts 1 to 6: Predose (within 30 minutes before dosing) and 
0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 24, 48, 72, 96, and 
168 hours postdose
Cohorts 18 and 19: Predose (within 30 minutes before dosing) 
and 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 32, 40, 48, 56, 64, 72, 96, and 
168 hours postdose


TAK-071-1001
Page 27 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
Collection of Blood Samples for Pharmacokinetic Analysis Cohorts 7 and 8.
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Plasma
1
Predose (within 30 minutes before dosing) and 0.25, 0.5, 1, 
1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 24 hours postdose
TAK-071
Plasma
8, 14, 19, and 20
Predose (within 30 minutes before dosing)
TAK-071
Plasma
21
Predose (within 30 minutes before dosing) and 0.25, 0.5, 1, 
1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 24 hours postdose
Collection of Blood Samples for Pharmacokinetic Analysis Cohorts 9 and 13 to 15.
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Plasma
1
Predose (within 30 minutes before dosing) and 0.25, 0.5, 1, 
1.5, 2, 3, 4, 6, 8, 10, 12, 14, 24, 48, 72, and 96 hours postdose
TAK-071
Plasma
8
Predose (within 30 minutes before dosing) and 0.25, 0.5, 1, 
1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 24 hours postdose
TAK-071
Plasma
15, 20, 26, and 27
Predose (within 30 minutes before dosing of TAK-071)
TAK-071
Plasma
28
Predose (within 30 minutes before dosing) and 0.25, 0.5, 1, 
1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 24, hours postdose. For 
Cohort 9 only, an additional sample at 36 hours postdose.
Collection of Blood Samples for Pharmacokinetic Analysis Cohorts 10 to 12.
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Plasma
1
Predose (within 30 minutes before dosing) and 0.25, 0.5, 1, 
1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 24 hours postdose of 
TAK -071
TAK-071
Plasma
8, 14, 19, and 20
Predose (within 30 minutes before dosing of TAK-071)
TAK-071
Plasma
21
Predose (within 30 minutes before dosing) and 0.25, 0.5, 1, 
1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 24 hours postdose of 
TAK-071
Donepezil
Plasma
-7, -3, and -2
Predose (within 30 minutes before dosing of donepezil)
Donepezil
Plasma
-1
Predose (within 30 minutes before dosing) and 1, 2, 3, 4, 6, 8,
10, 12, 14, and 24 hours postdose of donepezil
Donepezil
Plasma
8, 14, and 20
Predose (within 30 minutes before dosing of donepezil)
Donepezil
Plasma
21
Predose (within 30 minutes before dosing) and 1, 2, 3, 4, 6, 8,
10, 12, 14, and 24 hours postdose of donepezil


TAK-071-1001
Page 28 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
Collection of Blood Samples for Pharmacokinetic Analysis Cohort 16.
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Plasma
1, 21, 42, and 62
Predose (within 30 minutes before dosing) and 0.5, 1, 2, 4, 6, 
8, 10, 12, and 24 hours postdose of TAK-071
Donepezil
Plasma
1, 21, 42, and 62
Predose (within 30 minutes before dosing of donepezil)
Collection of Blood Samples for Pharmacokinetic Analysis Cohort 17.
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Plasma
1 (each of 3 periods)
Predose (within 30 minutes before dosing) and 0.5, 1, 2, 3, 4, 
6, 8, 10, 12, 16, 24, 32, 40, 48, 72, 96 and 168 hours postdose 
of TAK-071
Collection of Blood Samples for Pharmacokinetic Analysis Cohort 20 to 22.
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Plasma
1
Predose (within 30 minutes before dosing) and 2, 4, 8, 12, 16, 
24, 25, 26, 27, 28, 30, 32, 36, 40, 48, 56, 72, 96 and 168
hours post TAK-071 dose
Donepezil
Plasma
2
Predose (within 30 minutes before dosing) and 1, 2, 3, 4, 6, 8, 
12, 16, 24, 32, 36, 40, 48, 56, 72, and 144 post donepezil dose
The concentration of TAK-071 will be summarized by TAK-071 dose level, treatment, or 
regimen, as applicable, over each scheduled sampling time using descriptive statistics (including 
N, arithmetic mean, SD, %CV, median, minimum, maximum, geometric mean and %CV of the 
geometric mean), separately for the TAK-071 SRD part (TAK-071 alone [Cohort 1 to 6, 18, and 
19]) or in presence of donepezil [Cohorts 20 to 22] for non-Japanese subjects), the MRD part 
(TAK-071 alone for non-Japanese subjects [Cohorts 7 to 9], TAK-071 alone for Japanese 
subjects [Cohorts 13 to 15], or TAK-071 in the presence of donepezil [Cohorts 10 to 12] for 
non-Japanese subjects), subjects with MCI or Mild AD (Cohort 16), and the relative BA/FE 
cohort (Cohort 17).
Similarly, the concentration of donepezil will be summarized separately for the SRD part 
([Cohorts 20 to 22] for non-Japanese subjects) and the MRD part ([Cohorts 10 to 12] for 
non-Japanese subjects). Plasma PK parameters for donepezil will also be listed and summarized 
for subjects with MCI or Mild AD (Cohort 16). 
Individual plasma concentration data versus time will be presented similarly in data listings. 
Additionally, graphical plots of individual and mean plasma concentration vs time profiles by 
treatment will be presented.


TAK-071-1001
Page 29 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
7.10.2 Plasma Pharmacokinetic Parameters
The PK parameters of plasma TAK-071 will be determined from the concentration-time profiles 
for all evaluable subjects according to standard noncompartmental analysis methods by Takeda 
or its designee. Actual sampling times, rather than scheduled sampling times, will be used in all 
computations involving sampling times. The following PK parameters will be calculated:
Symbol/Term
Definition
Plasma
AUC∞
Area under the plasma concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration using the equation: 
AUC∞=AUClast+Clast/λz
AUClast
Area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration
AUC24
Area under the concentration-time curve from time 0 to time 24 hours. AUC24 = AUCτ at 
steady-state.
AUCt
Area under the concentration-time curve from time 0 to time t
Cmax
Maximum observed concentration.
CL/F
Apparent clearance after extravascular administration, calculated as =Dose/AUC∞.
CL/Fss
Apparent clearance after extravascular administration at steady-state, calculated as 
=Dose/AUC24.
λz
Terminal disposition rate constant, calculated as the negative of the slope of the log-linear 
regression of the natural logarithm concentration-time curve during the terminal phase.
Rac(AUC)
Accumulation ratio based on AUC24, calculated as AUC24 (steady-state)/ AUC∞(Day 1)
Rac(Cmax)
Accumulation ratio based on Cmax, calculated as Cmax (steady-state)/ Cmax (Day 1)
t1/2z
Terminal disposition half-life, calculated as ln(2)/λz.
tmax
Time to first occurrence of Cmax
Vz/F
Apparent volume of distribution during the terminal disposition phase after extravascular 
administration, calculated using the observed value of the last quantifiable concentration 
using the equation: (CL/F)/λz.
For Cohort 17 the key PK parameters Cmax, tmax, and AUC∞will be determined.
In general, if AUC∞cannot be accurately estimated in a sufficient number of subjects, AUClast
will be used for statistical analysis instead. Additional plasma PK parameters may be calculated 
if necessary, in accordance with the Clinical Pharmacology Analysis Plan (CPAP). 
The plasma PK parameters of donepezil will be determined from the concentration-time profiles 
for all evaluable subjects according to standard noncompartmental analysis methods. Actual 
sampling times, rather than scheduled sampling times, will be used in all computations involving 
sampling times. The following PK parameters will be calculated: tmax, Cmax, and AUC24. 
Additional donepezil plasma PK parameters may be derived and/or reported as appropriate, in 
accordance with the CPAP.
Plasma PK parameters for TAK-071 will be listed and summarized separately for the TAK-071 
SRD part (TAK-071 alone [Cohorts 1 to 6, 18, and 19]) or in presence of donepezil [Cohorts 20 


TAK-071-1001
Page 30 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
to 22] for non-Japanese subjects), the MRD part (TAK-071 alone for non-Japanese subjects 
[Cohorts 7 to 9], TAK-071 alone for Japanese subjects [Cohorts 13 to 15], or TAK-071 in the 
presence of donepezil [Cohorts 10 to 12] for non-Japanese subjects), subjects with MCI or Mild 
AD (Cohort 16), and the relative BA/FE cohort (Cohort 17).
Plasma PK parameters for donepezil will be listed and summarized separately for the SRD part 
([Cohorts 20 to 22] for non-Japanese subjects) and the MRD part ([Cohorts 10 to 12] for 
non-Japanese subjects). Plasma PK parameters for donepezil will also be listed and summarized 
for subjects with MCI or Mild AD (Cohort 16).
Descriptive statistics (including N, arithmetic mean, SD, %CV, median, minimum, maximum) 
will be used as appropriate. Geometric mean and %CV of the geometric mean will be reported 
for AUCs and Cmax. All subjects with a valid PK parameter estimate will be included in the 
summaries and analyses for that parameter.
Dose proportionality for the SRD and MRD parts will be assessed (separately) using the 
empirical power law model [4]. This analysis will be carried out to assess the degree of dose 
proportionality based on the dose proportionality exponent (β) for the model for both Cmax and 
AUC∞on Day 1 (SRD) and for Cmax and AUC24 at steady-state (Day 21 or 28 for MRD).
Dose linearity will be examined in the event that dose proportionality cannot be established by 
using a simple linear regression on the exposure parameter.
Trough plasma concentrations measured in the MRD parts (separately for Japanese and 
non-Japanese subjects) will be summarized to assess steady-state. The time to steady-state will 
be assessed by fitting trough concentration values to a nonlinear mixed effects model in order to 
predict the average time to achieve 90% of the steady-state trough concentrations separately for 
Japanese and non-Japanese subjects. Should data be insufficient to perform the nonlinear model, 
a linear mixed model approach will be used.
Time dependency will be investigated in MRD parts (separately for Japanese [Cohorts 7 to 9] 
and non-Japanese [Cohorts 13 to 15] subjects). The time invariance of TAK-071 will be assessed 
by comparing AUC24 for the last day of dosing (Day 21 for Cohorts 7 and 8 and Day 28 for 
Cohorts 9 and 13 to 15) to the AUC∞for Day 1 using analysis of variance with a random effect 
for subject and dose level, day, and interaction of dose level by day as fixed effects. If AUC∞
cannot be robustly estimated in a sufficient number of subjects, then the AUClast will be used 
instead in statistical analyses. This analysis will also be performed similarly using TAK-071 
Cmax.
In Cohorts 10 to 12, a linear mixed effect model will be used to evaluate the effect of TAK-071 
on the steady-state PK parameters (Cmax and AUC24) of donepezil:
yijk=μ + τj + si +εij (i=1, …N; j=A, B),
where μ is a general mean of a logarithmically transformed primary variable, si is the random 
effect of subject i, τj is the fixed effect of treatment (TAK-071 plus donepezil vs donepezil 
alone) j, εij is the random error of the observation yij, and N is the number of subjects included 
in the analysis.


TAK-071-1001
Page 31 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
The model will be used to estimate 90% CIs together with their corresponding geometric mean 
ratios for the PK parameters obtained from the comparisons between the treatments. The 
comparison of interest is TAK-071 plus donepezil vs donepezil alone.
In addition, the ratio of geometric mean AUC24 and Cmax for donepezil after 21 daily doses of
TAK-071 (Day 28) in reference to donepezil after a single dose at steady-state (Day -1) and the 
associated 90% CIs will be estimated.
For the BA/FE cohort, PK parameters of TAK-071 will be summarized by regimen. A mixed 
effects analysis of variance (ANOVA) will be performed on natural logarithms of TAK-071 Cmax
and AUCs with sequence, period, and regimen as fixed effects and subject nested within 
sequence as a random effect. Within the framework of ANOVA, comparisons will be performed 
for tablet versus capsule and for fed versus fasting dosing condition to assess the relative 
bioavailability of TAK-071.
The ratios and the 90% CIs for the central values of each test regimen relative to the reference 
regimen will be provided. Wilcoxon signed-rank test will be used to compare tmax between the 
test and reference regimens.
In addition to the above, other PK analysis methodologies may be employed to further 
characterize the PK behavior of TAK-071 in healthy subjects, including conventional 
compartmental analyses and nonlinear mixed-effect modeling using TAK-071 pooled data across 
studies.
7.10.3 Urine Pharmacokinetic Concentrations
Collection of Urine Samples for Pharmacokinetic Analysis Cohorts 1 to 6, 18, and 19.
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Urine
1
Predose urine void within approximately 1 hour of dosing and 
(0 to 6), (6 to 12), (12 to 24), (24 to 48), (48 to 72), and (72 to 
96) hours postdose
Collection of Urine Samples for Pharmacokinetic Analysis Cohorts 7 and 8.
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Urine
1
Predose urine void within approximately 1 hour of dosing and 
(0 to 6), (6 to 12), and (12 to 24) hours postdose
TAK-071
Urine
21
(0 to 6), (6 to 12), and (12 to 24) hours after the last dose
Note: Subjects should void urine prior to dosing on Day 21.


TAK-071-1001
Page 32 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
Collection of Urine Samples for Pharmacokinetic Analysis Cohorts 9 and 13 to 15.
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Urine
1
Predose urine void within approximately 1 hour of dosing and 
(0 to 6), (6 to 12), (12 to 24), (24 to 48), (48 to 72), and (72 to 
96) hours postdose
TAK-071
Urine
28
(0 to 6), (6 to 12), and (12 to 24) hours postdose
Note: Subjects should void urine prior to dosing on Day 28.
Collection of Urine Samples for Pharmacokinetic Analysis Cohort 16.
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Urine
1 and 42
Predose urine void within approximately 1 hour of dosing and 
(0 to 6), (6 to 12), and (12 to 24) hours postdose
TAK-071
Urine
21 and 62
(0 to 6), (6 to 12), and (12 to 24) hours postdose
Note: Subjects should void urine prior to dosing on Day 21 and 61.
Urine samples will not be collected from Cohorts 10 to 12, 17, 20 to 22.
The timing of the urine collection intervals may be adjusted based on the preliminary emerging 
PK data collected from prior cohort(s).
The amount of TAK-071 in urine will be summarized by TAK-071 dose level over each 
scheduled collection interval using descriptive statistics (N, arithmetic mean, SD, median, 
minimum, and maximum), separately for the TAK-071 SRD part ([Cohort 1 to 6, 18, and 19]) 
for non-Japanese subjects), the MRD part (TAK-071 alone for non-Japanese subjects [Cohorts 7 
to 9] and for Japanese subjects [Cohorts 13 to 15]), and subjects with MCI or Mild AD (Cohort 
16). Individual urine concentration and amount data versus time interval along with urine volume 
will be presented in a data listing.
7.10.4 Urine Pharmacokinetic Parameters
The urine PK parameters of TAK-071 will be determined from the concentration-time profiles 
for all evaluable subjects by Takeda or its designee. Scheduled sampling times will be used in all 
computations involving urine collection times. 
The following urine PK parameters of TAK-071 will be estimated:
Symbol/Term
Definition
Aet
Amount of drug excreted in urine from time 0 to time t for each interval and cumulative
fe,t
Fraction of administered dose of drug excreted in urine from time 0 to time t for each interval and 
cumulative
CLR
Renal clearance, calculated as Aet/AUCt for Day 1and Aet/AUC24 at steady-state
Additional urine PK parameters may be derived and/or reported as appropriate, in accordance 
with the CPAP.


TAK-071-1001
Page 33 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
Descriptive statistics (including N, arithmetic mean, SD, CV%, median, minimum and 
maximum) will be used to summarize the urine PK parameters for TAK-071 by TAK-071 dose 
level, separately for the TAK-071 SRD part ([Cohort 1 to 6, 18, and 19]) for non-Japanese 
subjects), the MRD part (TAK-071 alone for non-Japanese subjects [Cohorts 7 to 9] and for 
Japanese subjects [Cohorts 13 to 15]), and subjects with MCI or Mild AD (Cohort 16).
Individual urine PK parameters will be presented in a data listing. Plots of individual and mean 
cumulative amounts excreted in urine vs time profiles will be produced.
7.10.5 CSF Pharmacokinetic Concentrations
Collection of CSF Samples for Pharmacokinetic Analysis Cohorts 3 and 9.
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
CSF
1
Cohort 3: Predose (within 30 minutes before dosing) and at 
0.5, 2, 4, 6, and 12 hours postdose
28
Cohort 9: Predose (within 30 minutes before dosing) and at 4, 
8, 12, 24 and 36 hours post last dose
If measured concentrations in Cohort 3 are excessively low, ie, most time points are below the 
limit of quantification of the assay, TAK-071 CSF concentrations may also be determined in 
subsequent SRD cohorts until a dose deemed to provide adequate brain penetration is identified
(eg, a dose that provides CSF concentrations analogous to the efficacious free [estimated] plasma 
concentrations observed in preclinical animal models). A different criterion might be applied.
CSF sampling time points may be adjusted based on the preliminary emerging PK data; the total 
number of CSF samples collected per subject will not exceed the planned number. 
The concentration of TAK-071 in CSF will be summarized by TAK-071 dose level over each 
scheduled sampling time using descriptive statistics (including N, arithmetic mean, SD, %CV, 
median, minimum, maximum, geometric mean and %CV of the geometric mean). Individual 
plasma concentration data versus time will be presented in a data listing. Additionally, graphical 
plots of individual and mean CSF concentration vs time profiles by treatment will be presented.
7.10.6 CSF Pharmacokinetic Parameters
The CSF PK parameters of TAK-071 will be determined from the CSF concentration-time 
profiles for all evaluable subjects according to standard noncompartmental analysis methods by 
Takeda or its designee. Actual sampling times, rather than scheduled sampling times, will be 
used in all computations involving sampling times. The following PK parameters will be 
calculated: CSF Cmax following a single dose (Day 1) and at steady-state (after final dose 
following multiple dosing), CSF AUC12 following a single dose (Day 1) (Cohort 3 only) and 
CSF AUC36 at steady-state (after final dose following multiple dosing) (Cohort 9 only), and the 
ratio of CSF AUC12 to the plasma AUC12 (CSF AUC12:plasma AUC12) following a single dose 
(Cohort 3) and ratio of CSF AUC36 to the plasma AUC36 (CSF AUC36:plasma AUC36) at 
steady-state (Cohort 9). In the event that CSF sampling time points are adjusted in Cohort 9 
following review of PK data from previous cohorts, ie, continuous sampling is extended to 


TAK-071-1001
Page 34 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
48 hours postdose and then the corresponding AUC for the investigated time interval (ie, AUC48) 
will be used instead of AUC36. Additional CSF PK parameters may be derived and/or reported as 
appropriate.
Additional CSF PK parameters may be derived and/or reported as appropriate, in accordance 
with the CPAP.
CSF PK parameters for TAK-071 will be listed and summarized using descriptive statistics 
(including N, arithmetic mean, SD, %CV, median, minimum, maximum, geometric mean and 
%CV of the geometric mean). Geometric mean and geometric %CV will be presented for AUC 
and Cmax only.
7.10.7 Pharmacodynamic Measurements
 
.
7.11
Other Outcomes
Not applicable.
7.12
Safety Analysis
Within each part (SRD cohorts, MRD cohorts, Cohort 16, and Cohort 17), for the non-Japanese 
and Japanese SRD and MRD cohorts separately, all safety summary tables will be presented by 
the pooled placebo group, each TAK-071 dose level, TAK-071 overall, and overall total within 
each part (SRD cohorts, non-Japanese MRD cohorts, Japanese MRD cohorts, Cohort 16, and 
Cohort 17) in the Safety Set. Safety data collected after administration of study drug under fed 
conditions will be summarized separately from data collected during administration of the same 
dose level under fasted conditions.
7.12.1 Adverse Events
A PTE will be defined as any untoward medical occurrence in a clinical investigation subject 
who has signed informed consent to participate in a study but prior to study drug (TAK-071 or 
placebo) administration or increase in dose/start of donepezil prior to TAK-071 dose. A TEAE 
will be defined as an AE or a serious AE (SAE) that occurs or gets worse after receiving the first 
dose of study drug and within 30 days (onset date – last date of dose + 1 ≤30) after the last dose 
of study drug. A TEAE may also be a pretreatment AE or a concurrent medical condition 
diagnosed prior to the date of first dose of study drug that increases in severity after the start of 
dosing. AE data with onset occurring more than 30 days after last dose of study drug (AE start 
date – last dose date >30) will be listed, but not included in the summary tables.
AE verbatim reported terms will be coded by system organ class, high-level term and preferred 
term using MedDRA, version to be delineated in the CSR.
TEAE summary tables will include numbers and percentages of subjects experiencing at least 
one AE by system organ class (SOC) and preferred term (PT) and will be tabulated for SRD 
CCI


TAK-071-1001
Page 35 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
cohorts, non-Japanese MRD cohorts, Japanese MRD cohorts, Cohort 16, and Cohort 17. TEAEs 
will be summarized according to the treatment most recently received prior to the onset of the 
event. The TEAE summaries for SRD cohorts, non-Japanese MRD cohorts, Japanese MRD 
cohorts will also include a treatment group for TAK-071 overall, including all TEAEs 
summarized for any dose level of TAK-071.
The following is a list of AE summary tables to be generated:

Overview of TEAEs.

TEAEs by SOC and PT at subject and event level.

Subject Mappings for TEAEs.

TEAEs by PT.

Most Frequent TEAEs by PT.

Most Frequent Non-Serious TEAEs by PT.

Relationship of TEAEs to Study Drug by SOC and PT.

Drug-Related TEAEs by SOC and PT.

Intensity of TEAEs by SOC and PT.

Intensity of Drug-Related TEAEs by SOC and PT.

Pretreatment Events by SOC and PT.
A subject with 2 or more different AEs within the same level of the MedDRA term and 
TAK-071 dose level and pooled placebo will be counted only once in that level using the most 
extreme incident for the intensity tables, and related events to study drug for the causality tables.
Most frequent TEAEs are defined as the AEs occurring in at least 2 subjects in any treatment 
(ie, pooled placebo or individual dose level).
Data listings will be provided for all AEs (including pretreatment events for enrolled subjects), 
AEs leading to study drug discontinuation, SAEs, and AEs resulting in death.
7.12.2 Clinical Laboratory Evaluations
For SRD Cohorts 1 to 6 and 18 to 22, blood samples for clinical laboratory tests (hematology, 
coagulation, serum chemistry, urinalysis) will be collected at Screening, at Check-in (Day -1), on 
Days 1 through 5 (Final Visit)/ ET, Day 8, and at the Follow-up Visit. On Day 1, the urine 
sample for urinalysis will be taken predose (within 2 hours prior to dosing) and the blood sample 
for these tests will be taken 1 hour postdose. On subsequent days, samples will be taken upon 
rising in the morning under fasted condition. Laboratory sample collection on Day 8 does not 
require fasting conditions.
For MRD healthy volunteer Cohorts 7 and 8, blood samples for clinical laboratory tests 
(hematology, coagulation, serum chemistry, urinalysis) will be collected at Screening, at 


TAK-071-1001
Page 36 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
Check-in (Day -1), on Days 1, 2, 5, 8, 14, 20, 21, 22, 23 (Final Visit)/ ET and at the Follow-up 
Visit. On Day 1, the urine sample for urinalysis will be taken predose (within 2 hours prior to 
dosing) and the blood sample for these tests will be taken 1 hour postdose. On subsequent days, 
samples will be taken predose upon rising in the morning under fasted condition.
For MRD healthy volunteer Cohort 9, blood samples for clinical laboratory tests (hematology, 
coagulation, serum chemistry, urinalysis) will be collected at Screening, at Check-in (Day -1), on 
Days 1, 2, 3, 8, 9 10, 15, 20, 27, 28, 29, 30 (Final Visit)/ ET and at the Follow-up Visit. On 
Day 1, the urine sample for urinalysis will be taken predose (within 2 hours prior to dosing) and 
the blood sample for these tests will be taken 1 hour postdose. On subsequent days, samples will 
be taken predose upon rising in the morning under fasted condition.
For MRD + Donepezil pretreatment healthy volunteer Cohorts 10 to 12, blood samples for 
clinical laboratory tests (hematology, coagulation, serum chemistry, urinalysis) will be collected
at Screening, at Check-in (Day -22), on Days -21, -10, -1, 1, 2, 5, 8, 11, 14, 20, 21, 23 (Final 
Visit)/ ET and at the Follow-up Visit. On Day 1, the urine sample for urinalysis will be taken 
predose (within 2 hours prior to dosing) and the blood sample for these tests will be taken 1 hour 
postdose. On subsequent days, samples will be taken predose upon rising in the morning under 
fasted condition.
For MRD Japanese healthy volunteer Cohorts 13 to 15, blood samples for clinical laboratory 
tests (hematology, coagulation, serum chemistry, urinalysis) will be collected at Screening, at 
Check-in (Day -1), on Days 1, 2, 3, 8, 9, 10, 15, 20, 27, 28, 29, 30 (Final Visit)/ ET and at the 
Follow-up Visit. On Day 1, the urine sample for urinalysis will be taken predose (within 2 hours 
prior to dosing) and the blood sample for these tests will be taken 1 hour postdose. On 
subsequent days, samples will be taken predose upon rising in the morning under fasted 
condition.
For Cohort 16 in subjects with MCI or Mild AD, blood samples for clinical laboratory tests 
(hematology, coagulation, serum chemistry, urinalysis) will be collected at Screening, at Run-in 
Period (Day -21), at Check-in (Day -1), on Days 1, 2, 11, 20, 21, 22, 41, 42, 43, 52, 61, 62, 63
(Final Visit)/ ET and at the Follow-up Visit. On Days 1 and 41, the urine sample for urinalysis 
will be taken predose (within 2 hours prior to dosing) and the blood sample for these tests will be 
taken 1 hour postdose. On all other days, samples will be taken predose upon rising in the 
morning under fasted condition.
For BA/FE Cohort 17, blood samples for clinical laboratory tests (hematology, coagulation, 
serum chemistry, urinalysis) will be collected at Screening and in each period at Check-in
(Day -1), 30 minutes postdose on Day 1, upon rising on Days 2 and 5 and, at PK visit on Day 8 
(Day 8 of Period 3 is the final visit), at ET, if occurs, and Follow-up Visit (Day 12 [±2]) of 
Period 3, as appropriate.
Descriptive statistics (N, mean, median, SD, minimum and maximum) of clinical safety 
laboratory variables will be summarized by the pooled placebo group, each TAK-071 dose level, 
TAK-071 overall, and overall total within each part (SRD cohorts, MRD cohorts, Cohort 16, and 
Cohort 17) for baseline, each postdose time point, and change from period baseline to postdose 


TAK-071-1001
Page 37 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
time points in International System of Units (SI). Only the scheduled measurements will be 
included in the summary. No statistical tests will be performed.
Individual results for hematology, chemistry, and coagulation laboratory tests will be evaluated 
against the Takeda predefined laboratory MAV criteria (Appendix A) using the result and 
criteria in SI units. All subjects with results that meet the MAV criteria will be presented in a 
data listing. The number and percentage of subjects with at least one postdose markedly 
abnormal laboratory test result will be summarized. The mapping of the subjects who meet the 
MAV criteria for postdose lab results will be listed as a table. All postdose clinical lab results, 
including scheduled and unscheduled measurements will be included in the MAV summaries.
All clinical laboratory data will be presented in both SI and conventional units in data listings.
7.12.3 Vital Signs
In subjects who are not undergoing CSF collection (Cohorts 2, 4 to 8, and 10 to 18), vital signs 
will include body temperature (oral), respiratory rate, and orthostatic blood pressure and pulse 
(bpm). For orthostatic blood pressure, a drop in systolic blood pressure of ≥20 mm Hg, or in 
diastolic blood pressure of ≥10 mm Hg, or experiencing lightheadedness or dizziness is 
considered abnormal.
In subjects who have completed enrollment for Cohort 1 at the time of the protocol amendment
03 and in subjects who are undergoing CSF collection (Cohorts 3 and 9), vital signs include body
temperature (oral), respiratory rate, supine blood pressure (resting more than 5 minutes), and 
pulse (bpm).
For SRD Cohorts 1 to 6 and 18 to 22, vital signs (oral temperature, respiration, pulse, and blood 
pressure) will be obtained at Screening, at Check-in (Day -1), on Days 1 through 5 (Final Visit)/
ET and at the Follow-up Visit. In Cohort 3, vital signs will be collected at approximately 5 hours 
postdose. In addition, orthostatic blood pressure will be measured in all cohorts except Cohort 3, 
at predose and at 2, 4, 6, 8, and 12 hours postdose in the first 24 hours after the initial dose of 
TAK-071 and then daily afterwards while subjects are confined in the phase 1 unit.
For MRD healthy volunteer Cohorts 7 and 8, vital signs (oral temperature, respiration, pulse, and 
blood pressure) will be obtained at Screening, at Check-in (Day -1), on Days 1 through 23 (Final 
Visit)/ ET and at the Follow-up Visit. In addition, orthostatic blood pressure will be measured at
predose and at 2, 4, 6, 8, and 12 hours postdose in the first 24 hours after the initial dose of 
TAK-071 and then daily afterwards while subjects are confined in the phase 1 unit.
For MRD healthy volunteer Cohort 9, vital signs (oral temperature, respiration, pulse, and blood 
pressure) will be obtained at Screening, at Check-in (Day -1), on Days 1 through 30 (Final Visit)/
ET and at the Follow-up Visit.
For MRD + Donepezil pretreatment healthy volunteer Cohorts 10 to 12, vital signs (oral 
temperature, respiration, pulse, and blood pressure) will be obtained at Screening, at Check-in 
(Day -22), on Days -21 through -19, Days -10 through -1, Days 1 through 23 (Final Visit)/ ET 
and at the Follow-up Visit. In addition, orthostatic blood pressure will be measured at predose 


TAK-071-1001
Page 38 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
and at 2, 4, 6, 8, and 12 hours postdose in the first 24 hours after the initial dose of TAK-071 and 
then daily afterwards while subjects are confined in the phase 1 unit.
For MRD Japanese healthy volunteer Cohorts 13 to 15, vital signs (oral temperature, respiration, 
pulse, and blood pressure) will be obtained at Screening, at Check-in (Day -1), on Days 1 
through 30 (Final Visit)/ ET and at the Follow-up Visit. In addition, orthostatic blood pressure 
will be measured at predose and at 2, 4, 6, 8, and 12 hours postdose in the first 24 hours after the 
initial dose of TAK-071 and then daily afterwards while subjects are confined in the phase 1 
unit.
For Cohort 16 in subjects with MCI or Mild AD, vital signs (oral temperature, respiration, pulse, 
and blood pressure) will be obtained at Screening, at Run-in Period (Day -49 and Day -21), at 
Check-in (Day -1), on Days 1, 2, 11, 20, 21, 22, 41, 42, 43, 52, 61, 62, and 63 (Final Visit)/ ET 
and at the Follow-up Visit. In addition, orthostatic blood pressure will be measured at predose 
and at 2, 4, 6, 8, and 12 hours postdose in the first 24 hours after the initial dose of TAK-071 and 
then afterwards on Days 2, 11, 20 to 22, 40 to 42, 51, and 60 to 62 (upon morning rising)/ ET.
For BA/FE Cohort 17, vital signs (oral temperature, respiration, pulse, and blood pressure) will 
be obtained at Screening and in each period at Check-in (Day -1), Day 1 (predose [within 
45 minutes prior to dosing], and at 1, 3, and 12 hours postdose), and Days 2 through 5 (upon 
rising), Day 8 PK visit, Study Exit ([Day 8 of Period 3]/ ET and Follow-up Visit (Day 12 [±2]) 
of Period 3, as appropriate.
Descriptive statistics (N, mean, median, SD, minimum and maximum) of these vital signs will be 
summarized by the pooled placebo group, each TAK-071 dose level, TAK-071 overall, and 
overall total within each part (SRD cohorts, MRD cohorts, Cohort 16, and Cohort 17) for 
baseline, each postdose time point, and change from period baseline to postdose time points. 
Only the vital signs collected at the scheduled visits or time points will be included in the 
summary. No statistical tests will be performed for the observed vital signs.
All individual vital signs that meet Takeda’s predefined criteria for markedly abnormal values
(Appendix B) will be listed. The number and percentage of subjects with at least one postdose 
markedly abnormal vital sign measurement will be summarized. The mapping of the subjects 
who meet the MAV criteria for postdose vital sign parameters will be listed as a table. All 
postdose vital signs, including both scheduled and unscheduled measurements, will be included 
in the MAV summaries.
7.12.4 12-Lead ECGs
For SRD Cohorts 1 to 6 and 18 to 22, a standard 12-lead ECG will be recorded at Screening, 
Check-in (Day -1), Day 1 (predose [within 60 minutes prior to dosing], and at 0.5, 1, 2, 4, and 
8 hours postdose), Days 2 through 5 (upon morning rising)/ ET and at the Follow-up Visit. 
Single ECGs will be taken at all visits. Continuous 12-lead Holter ECG monitoring will be 
conducted from 2 hours predose until 48 hours postdose in Cohorts 2, 4, 6, 18, and 19 only.
For MRD healthy volunteer Cohorts 7 and 8, a standard 12-lead ECG will be recorded at 
Screening, Check-in (Day -1), Day 1 (TAK-071 predose [within 60 minutes prior to dosing] and 


TAK-071-1001
Page 39 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
at 0.5, 1, 2, 4, and 8 hours postdose), Days 2 through 21 (predose), Days 22 and 23 (upon 
morning rising)/ ET and at the Follow-up Visit. Single ECGs will be taken at all visits.
Continuous 12-lead Holter ECG monitoring will be conducted from 2 hours predose until 
24 hours postdose TAK-071 on Day 1 and from 1 hour predose until 48 hours postdose 
TAK-071 on Day 21.
For MRD healthy volunteer Cohort 9, a standard 12-lead ECG will be recorded at Screening, 
Check-in (Day -1), Days 1 and 8 (TAK-071 predose [within 60 minutes prior to dosing] and at 
0.5, 1, 2, 4, and 8 hours postdose), and Days 2 to 7 and 9 to 30 upon morning rising/ ET, and at 
the Follow-up Visit. Single ECGs will be taken at all visits. Continuous 12-lead Holter ECG 
monitoring will be conducted 2 hours predose until 48 hours postdose on Day 1 and 1 hour 
predose until 48 hours postdose on Day 28.
For MRD + Donepezil pretreatment healthy volunteer Cohorts 10 to 12, a standard 12-lead ECG 
will be recorded at Screening, Check-in (Day -22) (donepezil predose [within 60 minutes prior to 
dosing]), Day -1, Day 1 (TAK-071 predose [within 60 minutes prior to dosing] and at 0.5, 1, 2, 
4, and 8 hours postdose), Days 2 to 21 (predose), and Days 22 to 23 (upon morning rising)/ ET
and at the Follow-up Visit. Single ECGs will be taken at all visits.
For MRD Japanese healthy volunteer Cohorts 13 to 15, a standard 12-lead ECG will be recorded 
at Screening, Check-in (Day -1), Days 1 and 8 (TAK-071 predose [within 60 minutes prior to 
dosing] and at 0.5, 1, 2, 4, and 8 hours postdose). On the remaining days during confinement 
12-lead ECG be recorded (upon morning rising)/ ET and at the Follow-up Visit. Single ECGs 
will be taken at all visits.
For Cohort 16 in subjects with MCI or Mild AD, a standard 12-lead ECG will be recorded at 
Screening, Check-in (Day -1), Days 1, 21, 41, and 61 (TAK-071 predose [within 60 minutes 
prior to dosing] and at 0.5, 1, 2, 4, and 8 hours postdose), Days 2, 11, 20 to 22, 40 to 42, 51, and 
60 to 62 (upon morning rising)/ ET and at the Follow-up Visit. Single ECGs will be taken at all 
visits.
For BA/FE Cohort 17, a standard 12-lead ECG will be recorded at Screening, and in each period 
at Check-in (Day -1), Day 1 (predose [within 45 minutes prior to dosing], and at 0.5, 1, 2, 4, and 
8 hours postdose), Days 2 through 5 (upon morning rising), and Day 8 of Period 1 and 2, Study 
Exit (Day 8 of Period 3)/ ET, and Follow-up Visit Day 12 (±2), as appropriate.
The investigator (or a qualified observer at the investigational site) will interpret the ECG using 
1 of the following categories: within normal limits, abnormal but NCS, or abnormal and CS. The 
following parameters will be recorded from the subject’s ECG trace: heart rate, RR interval, PR 
interval, QRS interval, and QTcF (QT interval with Fridericia correction method) and QTcB (QT 
interval with Bazett correction method) interval. 
Descriptive statistics (N, mean, SD, median, minimum, and maximum) of the quantitative ECG 
results will be presented. The changes of ECG results from baseline results will be summarized 
by the pooled placebo group, each TAK-071 dose level, TAK-071 overall, and overall total 
within each part (SRD cohorts, MRD cohorts, Cohort 16, and Cohort 17).


TAK-071-1001
Page 40 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
All individual ECGs that meet Takeda’s predefined criteria for MAV (Appendix C) will be 
listed. The number and percentage of subjects with at least one postdose markedly abnormal 
ECG measurement will be summarized. Subjects who meet the MAV criteria for postdose ECG 
will be mapped to their respective qualifying ECG result. All postdose MAV ECGs, including 
both scheduled and unscheduled measurements, will be included in the MAV summaries.
For ECG interpretation data, shift tables will be provided by visit for the number of subjects with 
each interpretation by the interpretation at baseline. 
All other ECG data will be presented in data listings. 
Dates and times for the start and stop of continuous 12-lead Holter ECG monitoring will be 
presented in a data listing. The Holter ECG recordings will be stored, and no data will be 
extracted for summary and analysis during the conduct of this study.
7.12.5 Other Observations Related to Safety
7.12.5.1 Physical Examination
For SRD Cohorts 1 to 6 and 18 to 22, physical examinations will be performed at Screening, at 
Check-in (Day -1), Day 5 (Final Visit)/ ET and at the Follow-up Visit.
For MRD healthy volunteer Cohorts 7 and 8, physical examinations will be performed at 
Screening, at Check-in (Day -1), Day 23 (Final Visit)/ ET and at the Follow-up Visit.
For MRD healthy volunteer Cohort 9, physical examinations will be performed at Screening, at 
Check-in (Day -1), Day 30 (Final Visit)/ ET and at the Follow-up Visit.
For MRD + Donepezil pretreatment healthy volunteer Cohorts 10 to 12, physical examinations 
will be performed at Screening, at Check-in (Day -22), Day 23 (Final Visit)/ ET and at the 
Follow-up Visit.
For MRD Japanese healthy volunteer Cohorts 13 to 15, physical examinations will be performed 
at Screening, at Check-in (Day -1), Day 30 (Final Visit)/ ET and at the Follow-up Visit.
For Cohort 16 in subjects with MCI or Mild AD, physical examinations will be performed at 
Screening, at Check-in (Day -1), Day 63 (Final Visit)/ ET and at the Follow-up Visit.
For BA/FE Cohort 17, physical examinations will be performed at Screening, at Check-in 
(Day -1), and at the Follow-up Visit.
A full physical examination will be conducted at Screening. All other physical examinations will 
be abbreviated/event driven. A Baseline ophthalmological assessment of the retina (fundoscopy) 
will be performed at Screening for subjects enrolled in cohorts for CSF sampling.
The physical examination findings will be presented in a data listing. No summary tables will be 
provided.
The fundoscopy examination results will be presented in a data listing. No summary tables will 
be provided.


TAK-071-1001
Page 41 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
7.12.5.2 Bowel Function
Subjects will be provided with a bowel function diary card during Screening to record their
Baseline bowel function using the BSF scale for stool consistency rating.
From Check-in through Final Visit, subjects will use the bowel function diary card to assess the
time of each bowel movement during the dosing period (and until 96 hours after the last dose),
stool consistency (pictorial BSF score), and completeness of evacuation for an exploratory
comparison of the clinical effects of TAK-071.
Stool frequency is defined as the number of episodes of defecation recorded per day in the bowel
function card; stool consistency is defined by the 7-point pictorial BSF scale, which ranges from
unformed/watery to hard pellets; and sense of complete evacuation is defined by a yes-or-no 
answer to the question “Did you feel like you completely emptied your bowels?”
For SRD Cohorts 1 to 6 and 18 to 22, at Screening, BSF scale will be obtained at Screening, at 
Check-in (Day -1), on Days 1 through 5 (Final Visit)/ ET.
For MRD healthy volunteer Cohorts 7 and 8, BSF scale will be obtained at Screening, at 
Check-in (Day -1), on Days 1 through 23 (Final Visit)/ ET.
For MRD healthy volunteer Cohort 9, BSF scale will be obtained at Screening, at Check-in 
(Day -1), on Days 1 through 30 (Final Visit)/ ET.
For MRD + Donepezil pretreatment healthy volunteer Cohorts 10 to 12, BSF scale will be 
obtained at Screening, at Check-in (Day -22), on Days -21 through -1, Days 1 through 23 (Final 
Visit)/ ET.
For MRD Japanese healthy volunteer Cohorts 13 to 15, BSF scale will be obtained at Screening, 
at Check-in (Day -1), on Days 1 through 30 (Final Visit)/ ET.
For Cohort 16 in subjects with MCI or Mild AD, BSF scale will be obtained at Screening, at 
Run-in Period (Day -49 and Day -21), at Check-in (Day -1), on Days 1 through 63 (Final Visit)/
ET.
Descriptive statistics by visit will be presented for the percentage of subjects with BSF scale 
scores ≥6 vs <6 postbaseline compared with BSF scale scores ≥6 vs <6 at Baseline and for the 
percentage of subjects with a change from Baseline in BSF scale score of ≥2. Mean change from 
Baseline in BSF score and stool frequency will also be presented. Summary statistics (N, mean, 
SD, median, minimum, and maximum) will be generated for continuous variables (eg, time to 
first stool after dosing and stool frequency), and the number and percentage of subjects within 
each category will be presented for categorical variables (eg, stool consistency).
The results will be summarized by the pooled placebo group, each TAK-071 dose level, 
TAK-071 overall, and overall total within each part (SRD cohorts, MRD cohorts, and Cohort 
16).
A plot of mean (±SD) bowel movement by study day by treatment will be presented. 
All BSF data will be presented in a data listing.


TAK-071-1001
Page 42 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
7.12.5.3 Columbia - Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is an instrument designed to systematically assess and track suicidal behavior and 
suicidal ideation throughout the trial. The C-SSRS has 4 domains, Suicidal Ideation, Ideation 
Intensity, Suicidal Behavior and Actual Suicide Attempts.
For SRD Cohorts 1 to 6 and 18 to 22, the C-SSRS will be performed at Screening, at Check-in 
(Day -1), Day 5 (Final Visit)/ ET. If clinically significant at Final Visit, C-SSRS will also be 
determined as part of the Follow-up Visit.
For MRD healthy volunteer Cohorts 7 and 8, the C-SSRS will be performed at Screening, at 
Check-in (Day -1), Day 23 (Final Visit)/ ET. If clinically significant at Final Visit, C-SSRS will 
also be determined as part of the Follow-up Visit.
For MRD healthy volunteer Cohort 9, the C-SSRS will be performed at Screening, at Check-in 
(Day -1), Day 30 (Final Visit)/ ET. If clinically significant at Final Visit, C-SSRS will also be 
determined as part of the Follow-up Visit.
For MRD + Donepezil pretreatment healthy volunteer Cohorts 10 to 12, the C-SSRS will be 
performed at Screening, at Check-in (Day -22), Day -1, Day 23 (Final Visit)/ ET. If clinically 
significant at Final Visit, C-SSRS will also be determined as part of the Follow-up Visit.
For MRD Japanese healthy volunteer Cohorts 13 to 15, the C-SSRS will be performed at 
Screening, at Check-in (Day -1), Day 30 (Final Visit)/ ET. If clinically significant at Final Visit, 
C-SSRS will also be determined as part of the Follow-up Visit.
For Cohort 16 in subjects with MCI or Mild AD, the C-SSRS will be performed at Screening, at 
Check-in (Day -1), Day 63 (Final Visit)/ ET. If clinically significant at Final Visit, C-SSRS will 
also be determined as part of the Follow-up Visit.
For BA/FE Cohort 17, the Screening/Baseline C-SSRS will be administered at Screening and the
Since Last Visit C-SSRS will be administered at Day -1 Period 1, at Study Exit (Day 8 Period 3)/ 
ET, and Follow-up Visit [Period 3 Day 12 (±2)] (as appropriate, if clinically significant at Study 
Exit).
C-SSRS data will be presented in data listings. No summary tables will be provided.
7.12.5.4 Mini Mental State Examination
The MMSE is an 11-question tool that tests 5 areas of cognitive function: orientation, 
registration, attention and calculation, recall, and language. The maximum score is 30, with 
lower scores indicating more cognitive impairment. The MMSE will be administered at 
Screening to subjects in Cohort 16 only by trained site personnel.
The MMSE results will be presented in data listings. No summary tables will be provided.
7.12.5.5 Lumbar X-Ray
Instructions for lumbar x-ray are provided in the Study Manual.
A lumbar x-ray will be performed at Screening in Cohort 3 and Cohort 9 subjects.


TAK-071-1001
Page 43 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
Lumbar x-ray data will be presented in data listings. No summary tables will be provided.
7.13
Interim Analysis
7.13.1 Interim Analysis of Cohorts 1 to 15 and 17 to 22 Data
Interim analysis of all data (except Cohort 16) will be completed to enable the planning of 
phase 2 studies, while Cohort 16 enrollment is ongoing. The interim analysis will be initiated 
once all SRD and MRD cohorts have completed the study.
The main Takeda study team will be unblinded to the data in order to provide interim results to
support phase 2 protocol development.
7.13.2 Interim Analysis of PD Data
7.14
Changes in the Statistical Analysis Plan 
Only Cohorts 1 to15 and 17 to 22 will be unblinded after the clinical database freezes. Cohort 16 
will remain blinded and be analyzed later.
CCI


TAK-071-1001
Page 44 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
8.0
REFERENCES
1. Guideline on Structure and Content of Clinical Study Reports, International Conference on 
Harmonisation, Section ICH E3, 1996.
2. Guideline on Statistical Principles for Clinical Trials, International Conference on 
Harmonisation, Section ICH E9, 1998.
3. Protocol Amendment 5: A Phase 1 Safety, Tolerability, and Pharmacokinetic Study of 
Escalating Single and Multiple Oral Doses of TAK-071 in Healthy Subjects and Subjects 
With Mild Cognitive Impairment/Mild Alzheimer Disease and Relative Bioavailability and 
Food Effect of TAK-071 in Healthy Subjects. 15 MAY 2017.
4. Gough K, Hutchison M, Keene O, Byrom B, Ellis S, Lacey L, et al. Assessment of dose
proportionality: report from the statisticians in the pharmaceutical industry/pharmacokinetics
UK joint working party. Drug Inform J 1995; 29: 1039-48.


TAK-071-1001
Page 45 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
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 × LLN
>1.5 × ULN
Platelet count
Conventional
<75 × 103/L
>600 × 103/L
SI
<75 × 109/L
>600 × 109/L
LLN=lower limit of normal, RBC=red blood cell, ULN=upper limit of normal, WBC=white blood cell. 
Coagulation—Criteria for Markedly Abnormal Values
Parameter
Unit
Low Abnormal
High Abnormal
Prothrombin 
time/international 
normalized ratio
Both
>1.5 × ULN
Activated partial 
thromboplastin time
Both
>1.5 × ULN
LLN=lower limit of normal, ULN=upper limit of normal.


TAK-071-1001
Page 46 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
Serum Chemistry—Criteria for Markedly Abnormal Values
Parameter
Unit 
Low Abnormal
High Abnormal
ALT
Both
--
>3 × ULN
AST
Both
--
>3 × ULN
GGT
Both
--
>3 × ULN
Alkaline phosphatase
Both
--
>3 × ULN
Chloride
Conventional
<75 mEq/L
>126 mEq/L
SI
<75 mmol/L
>126 mmol/L
Total bilirubin
Conventional
--
>2.0 mg/dL
SI
--
>34.2 mol/L
Direct bilirubin
Both
--
>2 ULN
Albumin
Conventional 
<2.5 g/dL
--
SI 
<25 g/L
--
Total protein
Both
<0.8 × LLN
>1.2 × ULN
Creatinine
Conventional 
--
>2.0 mg/dL
SI
--
>177 mol/L
Blood urea nitrogen
Conventional 
--
>30 mg/dL
SI
--
>10.7 mmol/L
Sodium
Conventional
<130 mEq/L
>150 mEq/L
SI
<130 mmol/L
>150 mmol/L
Potassium
Conventional
<3.0 mEq/L
>6.0 mEq/L
SI
<3.0 mmol/L
>6.0 mmol/L
Glucose
Conventional
<50 mg/dL
>350 mg/dL
SI
<2.8 mmol/L
>19.4 mmol/L
Bicarbonate
Conventional
<8.0 mEq/L
SI
<8.0 mmol/L
Creatine kinase
Conventional
--
>5 × ULN
SI
--
>5 × ULN
Calcium
Conventional
<7.0 mg/dL
>11.5 mg/dL
SI
<1.75 mmol/L
>2.88 mmol/L
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=-glutamyl transferase, LLN=lower limit of 
normal, ULN=upper limit of normal.


TAK-071-1001
Page 47 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
Appendix B
Criteria for Markedly Abnormal Values for Vital Signs
Parameter
Unit
Lower Criteria 
Upper Criteria
Pulse
bpm
<50 
>120
Systolic blood pressure
mm Hg
<85 
>180 
Diastolic blood pressure
mm Hg
<50 
>110
Body temperature
oC
<35.6
>37.7
Orthostatic systolic blood pressure
mm Hg
CHG <= -20
Orthostatic diastolic blood pressure
mm Hg
CHG <= -10
Orthostatic pulse
bpm
CHG >10


TAK-071-1001
Page 48 of 48
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
Appendix C
Criteria for Markedly Abnormal Values for Electrocardiograms
Parameter
Unit
Lower Criteria 
Upper Criteria
Heart Rate
bpm
<50
>120
QT Interval
msec
≤50
≥460
QTcB Interval
msec
≤50
≥500 
OR 
≥30 change from baseline and ≥450
QTcF Interval
msec
≤50
≥500 
OR 
≥30 change from baseline and ≥450




䢢
䢢
䢢
䢢
䢢
䢢
䢢
䢢
(/(&7521,&6,*1$785(6
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 



 
 



 
 



 
 



 
 



 
 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 




 
 
 





GG
䣖䣃䣍䢯䢲䢹䢳䢯䢳䢲䢲䢳䢢䣕䣶䣣䣶䣫䣵䣶䣫䣥䣣䣮䢢䣃䣰䣣䣮䣻䣵䣫䣵䢢䣒䣮䣣䣰䢢䢴䢲䢳䢹䢯䢲䢺䢯䢲䢹
6WDWLVWLFDO$SSURYDO
$XJ87&
&OLQLFDO93$SSURYDO
$XJ87&
%LRVWDWLVWLFV$SSURYDO
$XJ87&
6DIHW\$SSURYDO
$XJ87&
&OLQLFDO3KDUPDFRORJ\$SSURYDO
$XJ87&
PPD