Clinical trial NCT02918266
Conditions: Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2016-11-21; Completion date: 2017-08-08
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to assess the effect of a single oral dose of TAK-071 on the attenuation of cognitive deficit induced by scopolamine as measured by Groton Maze Learning Test (GMLT) (total number of errors).

Detailed description:
The drug being tested in this study is called TAK-071. This study will look at the effect of a single oral dose of TAK-071, a novel muscarinic acetylcholine receptor 1 positive allosteric modulator, on scopolamine-induced deficits in cognitive function in healthy adult male participants. The study consists of two parts: Part 1 is a substudy to explore PK profile of TAK-071 in the presence of light meal and coadministration of scopolamine to determine TAK-071 dose for the next part; Part 2 is the main the study to assess the effects of TAK-071 on scopolamine-induced cognitive impairment. The study will enroll approximately 6 participants in Part 1 and 40 participants in Part 2. Participant will be assigned to received TAK-071 along with scopolamine in Part 1 and will be randomly assigned to one of the ten treatment sequences in Part 2-which will remain undisclosed to the participants and study doctor during the study (unless there is an urgent medical need):

Part 2: Treatment Sequence ABDEC Part 2: Treatment Sequence BCEAD Part 2: Treatment Sequence CDABE Part 2: Treatment Sequence DEBCA Part 2: Treatment Sequence EACDB Part 2: Treatment Sequence ACBED Part 2: Treatment Sequence BDCAE Part 2: Treatment Sequence CEDBA Part 2: Treatment Sequence DAECB Part 2: Treatment Sequence EBADC Where A=scopolamine matching placebo SC + TAK-071 matching placebo oral (PO) + donepezil matching placebo PO; B=scopolamine 0.5 mg SC + TAK-071 matching placebo PO + donepezil matching placebo PO; C=scopolamine 0.5 mg SC + TAK-071 PO + donepezil matching placebo PO; D=scopolamine 0.5 mg SC + TAK-071 PO + donepezil 10 mg PO; and E=scopolamine 0.5 mg SC + TAK-071 matching placebo PO + donepezil 10 mg PO.

The dose of TAK-071 that was well-tolerated in the TAK-071-1001 study (NCT02769065) will be selected, based on the safety and tolerability data from the single-rising dose (SRD) study for administration in Part 1. Each participant will also receive scopolamine 0.5 mg, injection, SC, once at the time of Screening. This single center trial will be conducted in the United States. The overall time to participate in this study is approximately 5.7 weeks in Part 1 and 21 weeks in Part 2. Participants will remain confined to the clinic for 4 days during Part 1 and 3 days during the each intervention period in Part 2. Participants will be contacted by telephone on Day 12 in Part 1 and Day 9 of Period 5 in Part 2 for a follow-up assessment.

Arms: arm 1: TAK-071 80 milligram (mg), drug in capsule (DIC), orally, Day 1, followed by scopolamine 0.5 mg, injection, subcutaneously, Day 2. TAK-071 will be taken 24 hours before scopolamine injection. arm 2: TAK-071 placebo-matching DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine placebo-matching injection,SC,Day2 of Period1(A); followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period2(B);followed by TAK-071 80mg, DIC, orally,Day1, donepezil 10mg, over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period3(D);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil 10mg, over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period4(E);followed by TAK-071 80mg, DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period5(C). TAK-071 and donepezil will be taken 24 and 3 hours before scopolamine injection. A washout period of 3-weeks will be maintained between each treatment period. arm 3: TAK-071 placebo-matching DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period1(B);followed by TAK-071 80mg, DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period2(C);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil 10mg, over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period3(E);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine placebo-matching injection,SC,Day2 of Period4(A);followed by TAK-071 80mg, DIC, orally,Day1, donepezil 10mg, over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period5(D). TAK-071 and donepezil will be taken 24 and 3 hours before scopolamine injection. A washout period of 3-weeks will be maintained between each treatment period. arm 4: TAK-071 80mg, DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period1(C);followed by TAK-071 80mg, DIC, orally,Day1, donepezil 10mg, over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period2(D);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine placebo-matching injection,SC,Day2 of Period3(A);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period4(B);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil 10mg, over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period5(E). TAK-071 and donepezil will be taken 24 and 3 hours before scopolamine injection. A washout period of 3-weeks will be maintained between each treatment period. arm 5: TAK-071 80mg, DIC, orally,Day1, donepezil 10mg, over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period1(D);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil 10mg, over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period2(E);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period3(B);followed by TAK-071 80mg, DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period4(C);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine placebo-matching injection,SC,Day2 of Period5(A). TAK-071 and donepezil will be taken 24 and 3 hours before scopolamine injection. A washout period of 3-weeks will be maintained between each treatment period. arm 6: TAK-071 placebo-matching DIC, orally,Day1, donepezil 10mg, over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period1(E);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine placebo-matching injection,SC,Day2 of Period2(A);followed by TAK-071 80mg, DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period3(C);followed by TAK-071 80mg, DIC, orally,Day1, donepezil 10mg, over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period4(D);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period5(B). TAK-071 and donepezil will be taken 24 and 3 hours before scopolamine injection. A washout period of 3-weeks will be maintained between each treatment period. arm 7: TAK-071 placebo-matching DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine placebo-matching injection,SC,Day2 of Period1(A);followed by TAK-071 80mg, DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period2(C);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period3(B);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil 10mg, over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period4(E);followed by TAK-071 80mg, DIC, orally,Day1, donepezil 10mg, over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period5(D). TAK-071 and donepezil will be taken 24 and 3 hours before scopolamine injection. A washout period of 3-weeks will be maintained between each treatment period. arm 8: TAK-071 placebo-matching DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period1(B);followed by TAK-071 80mg, DIC, orally,Day1, donepezil 10mg, over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period2(D);followed by TAK-071 80mg, DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period3(C);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine placebo-matching injection,SC,Day2 of Period4(A);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil 10mg, over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period5(E). TAK-071 and donepezil will be taken 24 and 3 hours before scopolamine injection. A washout period of 3-weeks will be maintained between each treatment period. arm 9: TAK-071 80mg, DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period1(C);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil 10mg, over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period2(E);followed by TAK-071 80mg, DIC, orally,Day1, donepezil 10mg, over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period3(D);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period4(B);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine placebo-matching injection,SC,Day2 of Period5(A). TAK-071 and donepezil will be taken 24 and 3 hours before scopolamine injection. A washout period of 3-weeks will be maintained between each treatment period. arm 10: TAK-071 80mg, DIC, orally,Day1, donepezil 10mg, over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period1(D);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine placebo-matching injection,SC,Day2 of Period2(A);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil 10mg, over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period3(E);followed by TAK-071 80mg, DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period4(C); followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period5(B). TAK-071 and donepezil will be taken 24 and 3 hours before scopolamine injection. A washout period of 3-weeks will be maintained between each treatment period. arm 11: TAK-071 placebo-matching DIC, orally,Day1, donepezil 10mg, over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period1(E);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period2(B);followed by TAK-071 placebo-matching DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine placebo-matching injection,SC,Day2 of Period3(A);followed by TAK-071 80mg, DIC, orally,Day1, donepezil 10mg, over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period4(D);followed by TAK-071 80mg, DIC, orally,Day1, donepezil placebo-matching over-encapsulated tablet, orally along with scopolamine 0.5mg, injection,SC,Day2 of Period5(C). TAK-071 and donepezil will be taken 24 and 3 hours before scopolamine injection. A washout period of 3-weeks will be maintained between each treatment period.
Interventions: intervention 1: Scopolamine intervention 2: TAK-071 intervention 3: Donepezil intervention 4: Scopolamine Placebo intervention 5: TAK-071 Placebo intervention 6: Donepezil Placebo
Intervention descriptions: intervention 1: Scopolamine subcutaneous injection intervention 2: TAK-071 DIC intervention 3: Donepezil over-encapsulated tablet intervention 4: Scopolamine placebo-matching subcutaneous injection intervention 5: TAK-071 placebo-matching DIC intervention 6: 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 Randomized, Double-Blind, Sponsor Unblinded, Placebo-Controlled, 5-Period 
Crossover, Phase 1b Study To Evaluate The Effects Of Single Oral Administration of TAK-071 
On Scopolamine-Induced Cognitive Impairment In Healthy Subjects
NCT Number: NCT02918266
Protocol Approve Date: 10 March 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
TAKEDA PHARMACEUTICALS
PROTOCOL AMENDMENT
A Randomized, Double-Blind, Sponsor Unblinded, Placebo-Controlled, 5-Period Crossover, 
Phase 1b Study To Evaluate The Effects Of Single Oral Administration of TAK-071 On 
Scopolamine-Induced Cognitive Impairment In Healthy Subjects
Phase 1b TAK-071 Scopolamine-Induced Cognitive Impairment Study
Sponsor:
Takeda Development Center Americas, Inc.
One Takeda Parkway
Deerfield, IL 60015
USA
Study Number:
TAK-071-1002
IND Number:
128,849
EudraCT Number:
Not Applicable 
Compound:
TAK-071 
Date:
10 March 2017
Version/Amendment 
Number:
Amendment No. 02
Amendment History:
Date
Amendment Number
Region
05 August 2016
Initial version
Global
02 November 2016
01
Global
10 March 2017
02
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-071-1002
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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)
Fax: 
Email: 
Medical Monitor
(medical advice on protocol and compound)
, MD, PhD
 Clinical Science/CNS
TDC Americas
Responsible Medical Officer (carries overall 
responsibility for the conduct of the study)
, MD, PhD
, Clinical Science/CNS
TDC Americas
One Takeda Parkway
Deerfield, IL 60015
USA
PPD
PPD
PPD
PPD
PPD
PPD


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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 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 (or delegate) and other 
signatories are located on the last page of this document.
PPD


TAK-071
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CONFIDENTIAL
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State)
Location of Facility (Country)


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CONFIDENTIAL
1.3
Protocol Amendment No. 02 Summary of Changes
Rationale for Amendment No. 02
This document describes the changes in reference to the protocol incorporating Amendment 
No. 02.
The primary reason for this amendment is to modify the main part (Part 2) of the study design to 
include a fifth arm and change the study to a 10-sequence, 5-period crossover study. The new 
study design will provide information on the combined pharmacodynamic effect of TAK-071 and 
donepezil.
Changes in Amendment 02
1. Modify the main part (Part 2) of the study design to include a fifth arm and change the study to 
a 10-sequence, 5-period crossover study. 
2. Add an additional secondary objective and modify an exploratory/additional objective.
3. Change in inclusion criteria.
4. Update dietary and fluid consumption for Part 2.
5. Change in procedure for qEEG.
6. Change the order of pharmacodynamic (PD) assessments.
7. Change blood volume for Part 2.
8. Clarification on pretreatment event (PTE) collection period.


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment No. 02 Summary of Changes ...................................................5
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................15
3.1
Study-Related Responsibilities.................................................................................15
3.2
Principal Investigator...............................................................................................15
3.3
List of Abbreviations ...............................................................................................16
3.4
Corporate Identification...........................................................................................18
4.0
INTRODUCTION.........................................................................................................19
4.1
Background .............................................................................................................19
4.2
Rationale for the Proposed Study.............................................................................21
4.3
Benefit/Risk Profile .................................................................................................21
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................22
5.1
Objectives................................................................................................................22
5.1.1
Primary Objective .......................................................................................22
5.1.2
Secondary Objectives..................................................................................22
5.1.3
Exploratory/Additional Objectives ..............................................................22
5.2
Endpoints.................................................................................................................23
5.2.1
Primary Endpoint........................................................................................23
5.2.2
Secondary Endpoints...................................................................................23
5.2.3
Additional Endpoints ..................................................................................24
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................25
6.1
Study Design – Part 1 ..............................................................................................25
6.2
Study Design – Part 2 ..............................................................................................27
6.2.1
Pre-Enrollment Enrichment Screening – Part 2............................................27
6.2.2
Treatment Sequences – Part 2......................................................................27
6.3
Justification for Study Design, Dose, and Endpoints ................................................30
6.3.1
Justification for Design for Part 1................................................................30
6.3.2
Justification for Design for Part 2................................................................31
6.3.3
Justification for Dose ..................................................................................32
6.3.4
Justification for Endpoints...........................................................................33
6.4
Premature Termination or Suspension of Study or Study Site...................................33


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6.4.1
Criteria for Premature Termination or Suspension of the Study...................33
6.4.2
Criteria for Premature Termination or Suspension of Study Sites ................33
6.4.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s).......................................................................34
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............35
7.1
Inclusion Criteria .....................................................................................................35
7.2
Exclusion Criteria ....................................................................................................35
7.3
Additional Inclusion Criteria for Part 2 After Pre-Enrollment Enrichment 
Screening.................................................................................................................37
7.4
Excluded Medications, Supplements, Dietary Products............................................37
7.5
Diet, Fluid, and Activity Control..............................................................................38
7.5.1
Part 1 ..........................................................................................................38
7.5.2
Part 2 ..........................................................................................................38
7.6
Criteria for Discontinuation or Withdrawal of a Subject...........................................39
7.7
Procedures for Discontinuation or Withdrawal of a Subject......................................40
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................41
8.1
Study Drug ..............................................................................................................41
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling..............................41
8.1.2
Storage........................................................................................................42
8.1.3
Dose and Regimen ......................................................................................42
8.1.4
Overdose.....................................................................................................43
8.2
Study Drug Assignment and Dispensing Procedures ................................................43
8.2.1
Part 1 ..........................................................................................................43
8.2.2
Part 2 ..........................................................................................................43
8.3
Randomization Code Creation and Storage..............................................................44
8.4
Study Drug Blind Maintenance................................................................................44
8.5
Unblinding Procedure..............................................................................................44
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................44
9.0
STUDY PLAN ..............................................................................................................46
9.1
Study Procedures.....................................................................................................46
9.1.1
Informed Consent Procedure.......................................................................46
9.1.2
Demographics, Medical History, and Medication History Procedure...........46
9.1.3
Physical Examination Procedure .................................................................46
9.1.4
Weight, Height and BMI.............................................................................47
9.1.5
Vital Sign Procedure ...................................................................................47
9.1.6
Documentation of Concomitant Medications...............................................47


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9.1.7
Documentation of Concurrent Medical Conditions......................................48
9.1.8
Procedures for Clinical Laboratory Samples................................................48
9.1.9
Contraception and Pregnancy Avoidance Procedure....................................49
9.1.10
Pregnancy ...................................................................................................50
9.1.11
ECG Procedure ...........................................................................................51
9.1.12
PGx Sample Collection ...............................................................................52
9.1.13
PK Sample Collection.................................................................................53
9.1.14
PK Parameters.............................................................................................54
9.1.15
PD Assessments (Only for Part 2) ...............................................................55
9.1.16
PD Parameters (Only for Part 2)..................................................................57
9.1.17
PK/PD Assessment Order (Only for Part 2).................................................57
9.1.18
Assessment of Suicidal Ideation and Behavior ............................................58
9.1.19
Documentation of Screen Failure ................................................................58
9.1.20
Documentation of Randomization ...............................................................58
9.2
Monitoring Subject Treatment Compliance..............................................................58
9.3
Schedule of Observations and Procedures................................................................59
9.3.1
Study Exit ...................................................................................................59
9.3.2
Early Termination .......................................................................................59
9.3.3
Follow-up Visit/Telephone Call ..................................................................59
9.4
Biological Sample Retention and Destruction ..........................................................59
9.5
Blood Volume .........................................................................................................60
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................62
10.1
Definitions...............................................................................................................62
10.1.1
PTEs...........................................................................................................62
10.1.2
AEs.............................................................................................................62
10.1.3
Additional Points to Consider for PTEs and AEs.........................................62
10.1.4
SAEs...........................................................................................................64
10.1.5
Intensity of PTEs and AEs ..........................................................................65
10.1.6
Relationship of AEs to Study Drug(s) .........................................................65
10.1.7
Relationship to Study Procedures................................................................65
10.1.8
Start Date....................................................................................................66
10.1.9
Stop Date ....................................................................................................66
10.1.10
Frequency ...................................................................................................66
10.1.11
Action Concerning Study Drug ...................................................................66
10.1.12
Outcome .....................................................................................................66


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10.2
Procedures...............................................................................................................67
10.2.1
Collection and Reporting of AEs.................................................................67
10.2.2
Collection and Reporting of SAEs...............................................................68
10.2.3
Reporting of Abnormal Liver Function Tests ..............................................68
10.3
Follow-up of SAEs ..................................................................................................69
10.3.1
Safety Reporting to Investigators, IRBs, and Regulatory Authorities...........69
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................70
12.0
DATA HANDLING AND RECORDKEEPING............................................................71
12.1
eCRFs......................................................................................................................71
12.2
Record Retention .....................................................................................................71
13.0
STATISTICAL METHODS..........................................................................................73
13.1
Statistical and Analytical Plans ................................................................................73
13.1.1
Analysis Sets...............................................................................................73
13.1.2
Analysis of Demographics and Other Baseline Characteristics ....................73
13.1.3
PK Analysis ................................................................................................73
13.1.4
PD Analysis ................................................................................................74
13.1.5
Safety Analysis ...........................................................................................74
13.2
Interim Analysis and Criteria for Early Termination ................................................75
13.3
Determination of Sample Size..................................................................................75
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................76
14.1
Study-Site Monitoring Visits ...................................................................................76
14.2
Protocol Deviations..................................................................................................76
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................77
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................78
15.1
IRB..........................................................................................................................78
15.2
Subject Information, Informed Consent, and Subject Authorization .........................79
15.3
Subject Confidentiality ............................................................................................80
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................80
15.4.1
Publication and Disclosure..........................................................................80
15.4.2
Clinical Trial Registration...........................................................................81
15.4.3
Clinical Trial Results Disclosure .................................................................81
15.5
Insurance and Compensation for Injury....................................................................81
16.0
REFERENCES..............................................................................................................82


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LIST OF IN-TEXT TABLES
Table 6.a
Summary of Treatment Sequences in Study - Part 2 ...........................................28
Table 7.a
Prohibited Medications, Supplements, Dietary Products.....................................38
Table 8.a
Composition of TAK-071 for DIC and Matching Placebo ..................................41
Table 8.b
Composition of Overencapsulated Donepezil and Matching Placebo..................42
Table 9.a
Clinical Laboratory Tests...................................................................................48
Table 9.b
Collection of Blood Samples for PK Analysis – Part 1.......................................53
Table 9.c
Collection of Blood Samples for PK Analysis – Part 2.......................................54
Table 9.d
CogState Cognitive Test Battery ........................................................................55
Table 9.e
Approximate Blood Volume for Part 1...............................................................60
Table 9.f
Approximate Blood Volume for Part 2...............................................................61
Table 10.a
Takeda Medically Significant AE List................................................................65
Table 14.a
Windows for PK Blood Sample Collection ........................................................76
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design – Part 1 ...................................................................25
Figure 6.b
TAK-071 PK Assessments and Meal Timing Relative to Scopolamine 
Administration – Part 1 (Days 1 and 2) ..............................................................26
Figure 6.c
Schematic of Study Design – Part 2 ...................................................................27
Figure 6.d
PK/PD Assessments and Meal Timing Relative to Scopolamine Administration 
– Part 2 ..............................................................................................................29
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................85
Appendix B
Responsibilities of the Investigator.....................................................................90
Appendix C
Elements of the Subject Informed Consent.........................................................92
Appendix D
Investigator Consent to Use of Personal Information..........................................95
Appendix E
Collection, Storage, and Shipment of Bioanalytical Samples..............................96
Appendix F
Moderate and Strong CYP3A4, 2D6, or 2C9 Inducers/Inhibitors......................100
Appendix G
Detailed Description of Amendments to Text...................................................101


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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc.
Compound:
TAK-071
Title of Protocol: A Randomized, Double-Blind, Sponsor 
Unblinded, Placebo-Controlled, 5-Period Crossover, Phase 
1b Study To Evaluate The Effects Of Single Oral 
Administration of TAK-071 On Scopolamine-Induced 
Cognitive Impairment In Healthy Subjects
IND No.: 
128,849
EudraCT No.:
Not applicable
Study Number: TAK-071-1002
Phase: 1b
Study Design:
This study consists of 2 parts.
Part 1 is an open-label initial substudy to explore the pharmacokinetic (PK) profile of TAK-071 in the presence of a 
light meal and coadministration of scopolamine to determine TAK-071 dose for Part 2, the main study.
Part 2 is the main study to assess the effects of TAK-071 on scopolamine-induced cognitive impairment. 
Overall, a total of approximately 46 subjects (6 in Part 1 and 40 in Part 2) will be enrolled in the study.
Part 1 is a nonrandomized, open-label, 1-treatment, 1-period, 1-sequence phase 1 study to characterize the plasma PK 
of TAK-071 when administered under the same conditions as in Part 2, the main study, in conjunction with 
scopolamine, and together with a low-calorie, low-fat breakfast in healthy adult male subjects. Approximately 6 
healthy subjects will be enrolled in this substudy with a minimum of 4 completers.
Part 2 is a randomized, double-blind, sponsor unblinded, placebo-controlled, 5-treatment, 5-period, 10-sequence 
crossover phase 1b proof of mechanism study to evaluate the effects of a single oral (PO) administration of TAK-071, 
a novel muscarinic acetylcholine receptor 1 positive allosteric modulator, on scopolamine-induced deficits in 
cognitive function in healthy adult male subjects. Approximately 40 subjects are expected to be randomized in this 
part of the study, with the total of 4 subjects per sequence with a minimum of 3 completers. 
To ensure that enrolled subjects will show cognitive impairment in the presence of scopolamine but with minimal 
sedation and/or fatigue, all subjects who meet Screening inclusion/exclusion criteria will be administered a 
subcutaneous (SC) dose of scopolamine 0.5 mg.
Pre-enrollment enrichment procedures will be conducted as part of the Screening assessments between 56 and 2 days 
before Day 1, and the results will be used to accept/reject the subject for enrollment to Part 2, the main study.
Subjects will remain under observation after scopolamine administration per principal investigator’s discretion to 
ensure that scopolamine-induced effects have worn off and it is safe for the subjects to leave the study center.
Any subjects unable to perform the CogState battery after training will be excluded from entering Part 2.
In each period, subjects will check-in at the study site on Day -1 and will be confined until Day 3 (approximately 
24 hours postdose of scopolamine or matching placebo).
Blood samples for the analysis of TAK-071, scopolamine, and donepezil plasma concentrations will be obtained at 
specified time-points up to 24 hours after scopolamine dosing. 
Pharmacodynamic (PD) measures will include the completion of cognitive tests (ie, Groton Maze Learning Test 
[GMLT]) and the determination of pupil size and quantitative electroencephalography (qEEG). These tests will be 
performed at specified time-points up to 10 hours after scopolamine dosing. The level of sedation will be determined 
after the end of each set of cognitive tests using Karolinska Sleepiness Scale (KSS).
Safety and tolerability for TAK-071 in combination with scopolamine will be obtained from treatment periods in 
which active TAK-071 is administered (Treatments C and D). Safety and tolerability will be obtained during 
Treatment A for placebo, Treatment B for scopolamine alone, and during Treatment E for donepezil in combination 
with scopolamine.


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Primary Objective:

To assess the effect of a single PO dose of TAK-071 on the attenuation of cognitive deficit induced by 
scopolamine (0.5 mg SC) as measured by GMLT (total number of errors).
Secondary Objectives:

To characterize the safety and tolerability of a single PO dose of TAK-071 when coadministered with SC 
scopolamine (0.5 mg) in healthy subjects.

To characterize the single PO dose plasma PK profile of TAK-071 when coadministered both with scopolamine 
and a low-calorie, low-fat breakfast in healthy subjects.

To demonstrate assay sensitivity by using donepezil 10 mg as the positive control.

To assess the effect of a single PO dose of TAK-071 in combination with 10 mg donepezil on the attenuation of 
cognitive deficit induced by scopolamine (0.5 mg subcutaneous [SC]) as measured by Groton Maze Learning 
Test (GMLT) (total number of errors).
Subject Population: Healthy male subjects who are native English speakers.
Number of Subjects:
Part 1: 6
Part 2: Per treatment sequence: 4, total: 40
Estimated Total: 46
Number of Sites:
Estimated total: 1 site in the United States (US)
Dose Level(s):
Part 1: 
TAK-071 80 mg
Scopolamine hydrobromide 0.5 mg
Part 2: 
TAK-071 80 mg and matching placebo. This dose might be 
adjusted but will not exceed highest well tolerated dose in 
SRD cohorts or the average maximum observed plasma 
concentration (Cmax) and area under the plasma 
concentration-time curve from 0 to 24 hours (AUC24) seen 
at no-observed-adverse-effect level (NOAEL) in the 28-day 
Good Laboratory Practice (GLP) toxicology study in 
monkeys. 
Scopolamine hydrobromide 0.5 mg and matching placebo.
Donepezil hydrochloride 10 mg and matching placebo.
Route of Administration:
Part 1 : 
TAK-071, PO; Scopolamine, SC 
Part 2: 
TAK-071 and matching placebo, PO
Scopolamine and matching placebo, SC 
Donepezil and matching placebo, PO
Duration of Treatment:
Part 1: Single dose
Part 2: Single dose in each period; total number of dosing 
days: 4
Period of Evaluation:
Part 1: 40 days including Screening Period, Treatment 
Period, and Follow-up Call/Visit.
Part 2: Approximately 21 weeks including the 
Screening Period, Treatment Periods, and Follow-up 
Call/Visit. 
Main Criteria for Inclusion:

The subject is a healthy male aged 18 to 55 years, inclusive.

The subject weighs at least 50 kg and has a body mass index (BMI) from 18.0 to 30.0 kg/m2.
Additional Inclusion Criteria for Part 2 (Main Study):

Subject able to perform the CogState battery.

Change from Baseline (average) in total GMLT errors of ≤-5 at 2 hours postdose of scopolamine.

Subjects with sleepiness score <8 on the KSS at 2 hours postdose of scopolamine.

Subject passes a hearing test with at least 80% correct responses and no more than 20% false positives. This test 
can be repeated once to determine eligibility. 


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Main Criteria for Exclusion:

The subject has a known hypersensitivity to any component of the formulation of TAK-071 or placebo; or has a 
known hypersensitivity to donepezil (or to other biperidine derivatives), atropine, or scopolamine and/or to any 
component in their formulations.

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.

The subject is a shift worker (night, late or early resulting in irregular bed times) or has crossed or will cross more 
than 2 time zones within 48 hours in the period from 48 hours prior to Treatment Period 1, Day 1 until the end of 
Treatment Period 5.

The subject reports symptoms suggesting evidence of a current sleep disorder or history of sleep disorder, 
including but not limited to sleep apnea, heavy snoring, primary or chronic insomnia, narcolepsy or restless leg 
syndrome, as judged by medical history.
Main Criteria for Evaluation and Analyses:
Primary Endpoints:

Change from Baseline in GMLT, as measured by the total number of errors on the GMLT at 2 hours postdose of 
scopolamine on Day 1 by study treatment.
Secondary Endpoints:

Change from Baseline over time in total number of errors on the GMLT by study treatment and the derived PD 
parameters, as follows:
–
GMLT area under the effect curve from time 0 hours to time t (AUECt) (net area) by study treatment. 
–
GMLT maximum observed effect (Emax) by study treatment.
–
Time to reach GMLT Emax by study treatment.

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.
–
Electrocardiogram (ECG) parameters.

PK parameters of TAK-071 in plasma after a single dose on Day 1, as follows:
–
Maximum observed plasma concentration (Cmax).
–
Time of first occurrence of Cmax (tmax).
–
Area under the plasma concentration-time curve from time 0 to time t (AUCt).
–
Area under the plasma concentration-time curve from time t1 to time t2 (AUCt1-t2).
–
Area under the plasma concentration-time curve from time 0 to infinity (AUC∞), as permitted by the data.
–
Terminal disposition phase half-life (t1/2z) in plasma, as permitted by the data.
Statistical Considerations:
PK Analysis
Plasma concentrations of TAK-071, donepezil, and scopolamine will be summarized from each treatment using 
descriptive statistics.
Individual plasma concentration data versus time will be presented in a data listing.
Plasma PK parameters for TAK-071, donepezil, and scopolamine will be summarized separately.


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PD Analysis
To address the statistical hypotheses related to the time course of scopolamine effects, cognitive endpoints will be 
analyzed using a mixed analysis of variance (ANOVA) model appropriate for a 5-period crossover with fixed factors 
for period, sequence, treatment, hour, and treatment by hour. Additionally, the model will contain a random factor 
subject nested in sequence (the between-subject error) and a random residual error term (the within-subject error). A 
2-sided t test (alpha=0.05) using the within subject mean squared error from the mixed ANOVA model will be 
examined to test the primary hypothesis. Treatment differences, 2-sided 95% confidence intervals (CIs), 2-sided 
p-values, and effect sizes will be presented for all time points, with 2 hours post scopolamine being the time frame for 
the primary endpoint.
To address the statistical hypotheses related to area under the effect curve (AUEC) endpoints, cognitive endpoints will 
be analyzed using an ANOVA model appropriate for a 5-period crossover with fixed factors for treatment, period, and 
sequence. Additionally, the model will contain a random factor subject nested in sequence (the between-subject error) 
and a random residual error term (the within-subject error). A 2-sided t test (alpha=0.05) using the within subject mean 
squared error from the mixed ANOVA model will be examined to test the statistical hypothesis.
For AUEC endpoints, the natural log scale treatment differences (eg, the primary treatment comparison of 
Treatment Y −Treatment X) will be exponentiated and reported as a mean percent change along with 95% CIs for the 
true mean percent change as a summary measure. The Baseline cognitive measure will be included in the model as a 
covariate. 
Other statistical analyses will be performed as appropriate.
Safety Analysis
Adverse events (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 physical examination 
findings will be listed. Baseline, postdose and change from Baseline to postdose laboratory data, vital signs, and ECG 
parameters will be summarized as well as percentage of subjects who meets Takeda MAV criteria.
Sample Size Justification:
Part 1: A sample size of 6 with 4 completers is considered sufficient to guide dose selection in Part 2, the main study.
Part 2: A sample size of 26 subjects, approximately 3 subjects for each of the 10 sequences of the 5-period cross-over, 
will be used and is considered sufficient for evaluation of the primary cognitive endpoints for this study based on
consideration of published scopolamine model literature and expert advice. Subjects who drop-out may be considered 
for replacement on case-by-case basis. To ensure there are enough completers a total of 40 subjects will be recruited 
(4 per sequence).
Using a 2-sided alpha level of 0.05, this study has a 90% power to detect an effect size of 0.67 in the GMLT (sum of 
5 trials) total number of errors for the primary treatment comparison of TAK-071 + scopolamine vs placebo +
scopolamine, assuming a total of 26 subjects complete the study and provide primary endpoint data.
At least 26 subjects will complete the study if 40 subjects are randomized, assuming the drop-out rate does not exceed 
33%.


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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator
PPD


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3.3
List of Abbreviations
ACh
acetylcholine
AChE
acetylcholinesterase
AChEI
acetylcholinesterase inhibitor
AD
Alzheimer disease
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
APOE
apolipoprotein E
AST
aspartate aminotransferase
AUC∞
area under the plasma concentration-time curve from time 0 to infinity 
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
AUCt1-t2
area under the plasma concentration-time curve from time t1 to time t2
AUEC
area under the effect curve
AUECt
area under the effect curve from time 0 to time t
BMI
body mass index
bpm
beats per minute
CFR
Code of Federal Regulations
ChAT
choline acetyltransferase
CI
confidence interval
Cmax
maximum observed plasma concentration
CNS
central nervous system
CRO
contract research organization
CS
clinically significant
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P-450
DIC
drug-in-capsule
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form 
EEG
electroencephalograph
Emax
maximum observed effect
ERP
event-related potential
FDA
Food and Drug Administration
FIH
first-in-human
GCP
Good Clinical Practice
GLP
Good Laboratory Practice


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GGT
gamma-glutamyl transferase
GMLT
Groton Maze Learning Test
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
ICH
International Conference on Harmonisation
ID
identification
IEC
independent ethics committee
INR
international normalized ratio
IRB
Institutional Review Board
K2EDTA
potassium ethylenediamine tetraacetic acid
KSS
Karolinska Sleepiness Scale
LFT
liver function test
M1R
muscarinic acetylcholine receptor 1
MAV
markedly abnormal value
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
NCS
not clinically significant
NOAEL
no-observed-adverse-effect level
OTC
over-the-counter
PAM
positive allosteric modulator 
PD
pharmacodynamic
PGx
pharmacogenomics
PK
pharmacokinetic
PO
oral
PTE
pretreatment event
QD
once daily
qEEG
quantitative electroencephalography
RCF
relative centrifugal force
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SOP
standard operating procedure
SPL
sound pressure level
SRD
single-rising dose
SUSAR
suspected unexpected serious adverse reactions
t1/2z
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
tmax
time of first occurrence of Cmax
ULN
upper limit of normal
US 
United States


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WHODRUG
World Health Organization Drug Dictionary 
3.4
Corporate Identification 
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


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4.0
INTRODUCTION
4.1
Background
Treatment of Alzheimer disease (AD) is a significant healthcare challenge [1-4], 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 [5]. Of those patients diagnosed with AD, more than two-thirds 
will likely be categorized as having mild or moderate disease [3]. Dementia-related diseases also 
have a huge economic impact. Today, the total estimated worldwide cost of dementia is United 
States (US) $818 billion, and it will become a trillion dollar disease by 2018 [5].
Impairment of cholinergic neuronal functions leads to cognitive disturbances and memory loss, the 
hallmark symptoms of AD [6,7]. 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 [8]. 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 [9]. 
Inhibition of acetylcholinesterase (AChE), the enzyme responsible for the breakdown of ACh, is 
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 [10]. 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 [11] 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 at all subtypes of ACh muscarinic receptors (M1-M5R). At high 
concentrations, this can lead to manifestation of various mechanism-related side effects, most 
commonly vomiting, diarrhea, and muscle cramps. 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 improved efficacy and safety 
profiles.
CCI


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For full details on all the relevant nonclinical studies, please refer to the Investigator Brochure.
CCI


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4.2
Rationale for the Proposed Study
Scopolamine is a muscarinergic M1-5 receptor antagonist, and due to its anticholinergic activity, 
scopolamine produces transitory impairments of attention, memory, and executive functions. 
Cognitive impairments in AD and in some other neurodegenerative disorders are associated with 
impaired cholinergic transmission in the central nervous system (CNS): impairments in mesial 
temporal and basal forebrain cholinergic memory circuits lead to cognitive deficits, such as 
storage and retrieval of new learning, and these brain areas also have important roles in other 
aspects of cognition, such as information processing speed. AD disrupts this neurotransmission, 
and it is marked by a substantial neuron loss in the nucleus basalis of Meynert, which results in 
diminished production and availability of ACh. 
A scopolamine challenge paradigm has been used in both nonclinical models and human trials to 
confirm procognitive effects of cholinomimetic drugs (such as the cholinesterase inhibitor 
donepezil) by transiently simulating a cholinergic deficit similar to that seen in AD [12-16].
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 drugs. There may also be some 
discomfort from collection of blood samples and other study procedures.
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. The safety data from nonclinical studies with TAK-071 and clinical data from 
other cholinomimetics, such as donepezil, include side effects such as diarrhea, nausea, and 
vomiting secondary to the pharmacologic activity of the compound [17]. At the time of start of this 
study, safety, tolerability, and PK data will be available from all SRD study cohorts from the 
first-in human (FIH) study. This proof of mechanism study may therefore only start after 
completion and review of the SRD cohorts and confirmation of the acceptable single-dose safety, 
tolerability, and PK of TAK-071.
Scopolamine may cause drowsiness, dizziness or blurred vision [18]. Therefore, to minimize the 
risk to subjects (ie, due to driving or operating dangerous machinery), subjects will be kept at the 
study center for at least 8 hours and will only be allowed to leave the study center earlier than 
8 hours upon confirmation by the investigator or designee that scopolamine effects have worn off.
The most common adverse events (AEs) for donepezil are diarrhea, muscle cramps, fatigue, 
nausea, vomiting, dry mouth, and insomnia [17]. Donepezil has been previously administered to 
healthy subjects in the context of multiple phase 1 clinical trials, including bioequivalence trials 
[19,20] as well as in other scopolamine challenge studies ([21,22] and [Study ROF-ALZ_102]), 
indicating that single doses of 10 mg are safe and well tolerated in this population.
It is not expected that this study will result in any therapeutic benefit for the included study 
population. However, data generated from this study should enable the investigation of TAK-071 
in subsequent clinical efficacy studies of longer duration in the relevant subject populations 
(ie, phase 2).


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
!
To assess the effect of a single PO dose of TAK-071 on the attenuation of cognitive deficit 
induced by scopolamine (0.5 mg subcutaneous [SC]) as measured by Groton Maze Learning 
Test (GMLT) (total number of errors). 
5.1.2
Secondary Objectives
!
To characterize the safety and tolerability of a single PO dose of TAK-071 when 
co-administered with SC scopolamine (0.5 mg) in healthy subjects.
!
To characterize the single PO dose plasma PK profile of TAK-071 when co-administered both 
with scopolamine and a low-calorie, low-fat breakfast in healthy subjects.
!
To demonstrate assay sensitivity by using donepezil 10 mg as the positive control.
!
To assess the effect of a single PO dose of TAK-071 in combination with 10 mg donepezil on 
the attenuation of cognitive deficit induced by scopolamine (0.5 mg subcutaneous [SC]) as 
measured by Groton Maze Learning Test (GMLT) (total number of errors).
5.1.3
Exploratory/Additional Objectives
CCI


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5.2
Endpoints
5.2.1
Primary Endpoint
!
Change from Baseline in GMLT, as measured by the total number of errors on the GMLT at 
2 hours postdose of scopolamine on Day 1 by study treatment. 
5.2.2
Secondary Endpoints
!
Change from Baseline over time in total number of errors on the GMLT by study treatment and 
the derived pharmacodynamic (PD) parameters, as follows:
–
GMLT area under the effect curve from time 0 hours to time t (AUECt) (net area) by study 
treatment. 
–
GMLT maximum observed effect (Emax) by study treatment.
–
Time to reach GMLT Emax by study treatment.
!
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 after a single dose on Day 1, as follows:
–
Maximum observed plasma concentration (Cmax).
–
Time of first occurrence of Cmax (tmax).
–
Area under the plasma concentration-time curve from time 0 to time t (AUCt).
–
Area under the plasma concentration-time curve from time t1 to time t2 (AUCt1-t2).
–
Area under the plasma concentration-time curve from time 0 to infinity (AUC∞), as 
permitted by the data.
–
t1/2z in plasma, as permitted by the data.
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5.2.3
Additional Endpoints
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6.0
STUDY DESIGN AND DESCRIPTION
This study consists of 2 parts.
Part 1 is an open label initial substudy to explore PK profile of TAK-071 in the presence of light 
meal and coadministration of scopolamine to determine TAK-071 dose for Part 2, the main study.
Part 2 is the main the study to assess the effects of TAK-071 on scopolamine-induced cognitive 
impairment.
6.1
Study Design – Part 1
This is a nonrandomized, open-label, 1-treatment, 1-period, 1-sequence phase 1 study to 
characterize the plasma PK of TAK-071 when administered under the same conditions as in Part 2, 
the main study, this is in conjunction with scopolamine, and together with a low-calorie, low-fat 
breakfast in healthy adult male subjects. Approximately 6 healthy subjects will be enrolled in this 
substudy with a minimum of 4 completers.
A schematic of Part 1, the substudy, design is provided in Figure 6.a.
Figure 6.a
Schematic of Study Design – Part 1
Pretreatment Period
Treatment Period
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 
Subjects will check-in at the study site on Day -1 and will be confined until the completion of 
assessments on Day 4. A follow-up PK assessment will be performed on Day 8 and a final 
follow-up will occur of Day 12 (±2).
Scopolamine will be administered as a single 0.5 mg SC injection.
TAK-071 will be administered as a single PO dose (as drug-in-capsule [DIC]) 24 hours before 
scopolamine administration.
Blood samples for the analysis of TAK-071 plasma concentrations will be obtained at specified 
time-points up to 168 hours after TAK-071 dosing (144 hours after scopolamine dosing). 
Safety and tolerability of TAK-071 in combination with scopolamine will be assessed from 
physical examination, AEs, clinical laboratory tests, ECGs, etc.
The planned timing of assessments and meals relative to scopolamine dosing in Part 1 is shown in
Figure 6.b.


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Figure 6.b
TAK-071 PK Assessments and Meal Timing Relative to Scopolamine Administration – Part 1 (Days 1 and 2)
Study Drug Dosing
TAK-071
Scopolamine
TAK-071
- 24 h
- 12 h - 3 h
- 2 h
- 1 h
0 h
1 h
2 h
3 h
4 h
5 h
6 h
7 h
8 h
9 h
10 h
24 h
PK
Meals
Breakfast
Lunch
Dinner
-24.5
-20.5
-12.5
-0.5
5.5
9.5
0
0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14 
48
36
34
30
32
40
28
27
26
24
25


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6.2
Study Design – Part 2
This is a randomized, double-blind, sponsor unblinded, placebo-controlled, 5-treatment, 5-period, 
10-sequence crossover phase 1b proof of mechanism study to evaluate the effects of a single PO 
administration of TAK-071, a novel M1R PAM, on scopolamine-induced deficits in cognitive 
function in healthy adult male subjects.
Approximately 40 subjects are expected to be randomized in this study, with the total of 4 subjects 
per sequence and with a minimum of 3 completers. A schematic of the study design is provided in 
Figure 6.c.
Figure 6.c
Schematic of Study Design – Part 2
Screening Period
Treatment Periods 1 to 5
Wash-Out 
Periods 1 to 4
Follow-Up
Screening and 
Pre-Enrollment 
Enrichment
Check-in
Baseline 
PD
Single Dose 
PK/PD
PK/PD
Follow-up Telephone 
Call/Visit
Days -56 to -2
Day -1
Day 1
Day 2
Day 3
Days 4 to 20
Day 9 (±2) Period 5
Confinement 
6.2.1
Pre-Enrollment Enrichment Screening – Part 2
To ensure that enrolled subjects will show cognitive impairment in the presence of scopolamine 
but with minimal sedation and/or fatigue, all subjects who meet Screening inclusion/exclusion 
criteria will be administered an SC dose of scopolamine 0.5 mg.
Pre-enrollment enrichment procedures will be conducted as part of the Screening assessments 
between 56 and 2 days before Day 1, and the results will be used to accept/reject the subject for 
enrollment to Part 2, the main study.
Subjects will remain under observation post-scopolamine administration per principal 
investigator’s discretion to ensure that scopolamine-induced effects have worn off and it is safe for 
the subjects to leave the study center.
Any subject unable to perform the CogState battery after training will be excluded from entering
Part 2, the main study.
6.2.2
Treatment Sequences – Part 2
In each period, subjects will check-in at the study site on Day -1 and will be confined until Day 3 
(approximately 24 hours postdose of scopolamine or matching placebo). 
Subjects will be randomly assigned to 1 of 10 possible treatment sequences (described in 
Section 8.1.3) before the first dose of study drug, each consisting of 5 treatment periods 
(Table 6.a). 


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Table 6.a
Summary of Treatment Sequences in Study - Part 2
Sequence
Period 1
Period 2
Period 3
Period 4
Period 5
1
A
Minimum 
3-week 
washout
B
Minimum 
3-week 
washout
D
Minimum 
3-week 
washout
E
Minimum 
3-week 
washout
C
2
B
C
E
A
D
3
C
D
A
B
E
4
D
E
B
C
A
5
E
A
C
D
B
6
A
C
B
E
D
7
B
D
C
A
E
8
C
E
D
B
A
9
D
A
E
C
B
10
E
B
A
D
C
A=scopolamine matching placebo SC + TAK-071 matching placebo PO + donepezil matching placebo PO.
B=scopolamine 0.5 mg SC + TAK-071 matching placebo PO + donepezil matching placebo PO.
C=scopolamine 0.5 mg SC + TAK-071 PO + donepezil matching placebo PO.
D=scopolamine 0.5 mg SC + TAK-071 PO + donepezil 10 mg PO.
E=scopolamine 0.5 mg SC + TAK-071 matching placebo PO + donepezil 10 mg PO.
A 3-week (21-day) washout between treatment periods is required because of the long t1/2z of 
donepezil to minimize the potential for carryover effects.
The planned timing of assessments and meals relative to scopolamine dosing is shown in
Figure 6.d.


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Figure 6.d
PK/PD Assessments and Meal Timing Relative to Scopolamine Administration – Part 2
Study Drug Dosing
TAK-071
Donepezil
Scopolamine
TAK-071
Donepezil
Scopolamine
CogState
- 24 h
- 12 h
- 3 h
- 2 h
- 1 h
0 h
1 h
2 h
3 h
4 h
5 h
6 h
7 h
8 h
9 h
10 h
24 h
2
6
2
7
2
8
3
0
3
4
0
5
2
5
0
4
7
6
1
3
9
0
1
2
3
4
6
8
PK
PD
Meals
Breakfast
Lunch
Dinner
-25.5
-20.5
-16.0
-1.5
4.0
8.5
2
4
3
Note: Solid gray PK/PD symbols indicate predose assessments. Numbers inside symbols indicate scheduled times relative to the respective study drug dosing for 
the PK analyte. Shaded meal symbols indicate low-calorie, low-fat meals; all other meals are standard.
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Scopolamine (0.5 mg) or matching placebo will be administered as a single SC injection.
TAK-071 or matching placebo will be administered as a single PO dose (as DIC) 24 hours before 
scopolamine administration. 
The dose of TAK-071 for Part 2 will be selected depending on the results from Part 1 (initial 
substudy) and the FIH Study TAK-071-1001; however, under no circumstances will the selected 
TAK-071 dose exceed the maximum tolerated dose (MTD), or if the MTD is not attained, the 
highest dose tested in the SRD part of the FIH study. 
The precise dosing time of TAK-071 relative to scopolamine will be selected to ensure that both 
drugs reach their anticipated peak effects at approximately the same time to maximize the potential 
to observe TAK-071 procognitive effects.
Donepezil (10 mg) tablet (overencapsulated) or matching placebo will be administered as a single 
capsule PO 3 hours before injecting scopolamine to maximize the chances of observing a reversal 
of the scopolamine-induced cognitive impairment. 
Blood samples for the analysis of TAK-071, scopolamine, and donepezil plasma concentrations 
will be obtained at specified time-points up to 10 hours after scopolamine dosing. 
Information on the safety and tolerability of TAK-071 in combination with scopolamine and/or 
donepezil will be obtained from treatment periods in which active TAK-071 is administered 
(Treatments C and D). Safety and tolerability will be obtained during Treatment A for placebo, 
Treatment B for scopolamine alone, and during Treatment E for donepezil in combination with 
scopolamine.
6.3
Justification for Study Design, Dose, and Endpoints
6.3.1
Justification for Design for Part 1
An initial substudy (Part 1) has been included since to date TAK-071 has only been administered 
as a single agent under fasted conditions in Study TAK-071-1001. In the present study, TAK-071 
administration will occur 24 hours prior to scopolamine and together with a low-calorie, low-fat 
breakfast. 
Scopolamine has the potential of PK drug-drug interaction as antimuscarinics can inhibit 
gastrointestinal motility, delay gastric emptying, and prolong gastrointestinal transit time [27,28].
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6.3.2
Justification for Design for Part 2
This is a randomized, double-blind, sponsor-unblinded, placebo-controlled, 5-treatment, 5-period, 
10-sequence crossover phase 1b proof of mechanism study to evaluate the effects of single PO 
administration of TAK-071, a novel M1 PAM, on scopolamine-induced deficits in cognitive 
function in healthy adult male subjects.
The study is being conducted as double-blind and placebo-controlled to avoid subjective bias in 
the assessment of response. The crossover design was selected to reduce the sample size needed 
and to minimize intersubject variability.
Scopolamine was selected because it has long been used for the induction of deficits in 
psychomotor and cognitive function, and the impairments resemble those seen in Alzheimer 
disease. It is therefore expected that in this study, scopolamine will induce the desired cognitive 
impairment for the cognitive assessments within a short time with minimal sedation and/or fatigue. 
To ensure this, pre-enrollment enrichment Screening will be performed for all study subjects who 
meet Screening inclusion/exclusion criteria after administration of scopolamine 0.5 mg SC. Only 
subjects who display an acceptable decline in cognitive function with minimal sedation will be 
allowed to enter the main study.
Donepezil has been selected as the positive control for this study because it is the most frequently 
used medication for the symptomatic treatment of mild to moderately severe Alzheimer disease at 
the therapeutic dose of 10 mg once daily (QD). 
Combination of donepezil and TAK-071 will provide information about PD effect of an 
acetylcholinesterase inhibitor in combination with M1PAM measured by amelioration of 
scopolamine induced cognitive and EEG effects. 
The SC administration of scopolamine has a t1/2z of 3 to 4 hours and reaches Cmax within 10 to 
30 minutes. The cognitive impairment induced by SC administration of scopolamine appears to be 
maximal approximately 1 to 2 hours after administration and disappears after 6 to 8 hours 
postinjection, allowing for a minimal but sufficient period of subject supervision before subjects 
are discharged safely on Day 3. The minimum 21-day washout between the last dose in a period 
and the first dose in the subsequent period will be sufficient to ensure no drug carryover effect.
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TAK-071 and donepezil will be administered 24 and 3 hours, respectively, prior to administration 
of scopolamine so that the tmax of TAK-071 (26 hours in plasma after an 80 mg dose) and donepezil 
(approximately 3 to 4 hours in plasma) occur at approximately the same time as the maximal 
scopolamine-induced cognitive impairment effects (approximately 1 to 2 hours after SC 
administration). The time of administration of TAK-071 relative to scopolamine may be adjusted 
upon review of emerging PK data from the FIH study.
6.3.3
Justification for Dose
6.3.3.1
TAK-071
A high TAK-071 dose will be used in this study to maximize the potential for observing a 
significant reversal of scopolamine-induced cognitive impairment. The dose of TAK-071 will be 
selected depending on the results from the FIH Study TAK-071-1001; however, under no 
circumstances will the selected TAK-071 dose exceed the MTD, or if the MTD is not attained, the 
highest dose tested in the SRD part of the FIH study. At present, it is planned that the dose for the 
initial substudy (Part 1) and main study (Part 2) will be 80 mg, this the highest dose tested in an 
SRD setting to date.
If following a review of the preliminary PK results of Part 1 (initial substudy) reveals that there is 
an effect of scopolamine and/or food on the plasma exposure of TAK-071 (increase or decrease), 
the selected TAK-071 dose for Part 2 may be adjusted to ensure that exposures remain on target; 
and below the lowest no-observed-adverse-effect level (NOAEL) plasma exposure achieved in 
4-week GLP animal toxicology studies. 
The dosing time of TAK-071 relative to scopolamine will be selected to ensure that both drugs 
attain their anticipated peak effects at approximately the same time to maximize the potential to 
observe TAK-071 procognitive effects. Based on preliminary TAK-071 plasma concentration data 
following a dose of 80 mg indicating that peak concentrations occur at median time of 26 hours 
postdose, it is planned that dosing of TAK-071 should occur 24 hours prior to scopolamine 
administration. The precise timing of TAK-071 dosing may be adjusted if warranted based on 
emerging data.
6.3.3.2
Donepezil
Donepezil is the most frequently used medication for the symptomatic treatment of mild to 
moderately severe Alzheimer disease. Donepezil, administered at the therapeutic dose of 10 mg 
QD, will serve as a positive control in this study. 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 [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 the present study.


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6.3.3.3
Scopolamine
The SC dose of 0.5 mg is a safe and efficacious dose for the purpose of this study’s endpoints. This 
dose has been previously found to result in maximal cognitive impairment with minimal 
associated sedation and/or fatigue [29]. SC administration will provide the advantage of better 
reproducibility, or lower variability, in the dynamic changes in the cognitive impairment profile 
over time. This is important to ensure that most subjects will attain maximal cognitive impairment 
at approximately the same time (approximately 2 hours postdose).
6.3.4
Justification for Endpoints
The CogState GMLT will serve as the primary outcome measure in this study. From a 
psychometric perspective, the GMLT can be repeated often in an experimental setting and with 
little or no practice effect. From a construct validity aspect, the GMLT measures a variety of 
cognitive functions (immediate and short-term memory for visuospatial information), and it is 
sensitive to the detection of subclinical perseverative errors and slowed information-processing 
speed.
6.4
Premature Termination or Suspension of Study or Study Site
6.4.1
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.

Study discontinuation due to non-safety reasons such as:
–
A finding (eg, PK, PD, efficacy, biologic targets, etc) from another nonclinical or clinical 
trial using the trial treatment(s) that results in the trial being stopped for a non-safety 
related reason. 
–
Data from comparator(s), drug(s) of the same class, or methodology(ies) used in this trial 
become available and results in the trial(s) being stopped for a non-safety related reason. 
–
The study is stopped due to non-scientific and non-safety reasons, such as slow enrollment.

Study discontinuation due to safety reasons:
–
Early trial termination due to unanticipated safety concerns arising from clinical or 
nonclinical trials with the trial treatment(s), comparator(s), drug(s) of the same class or 
methodology(ies) used in this trial.
–
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.
6.4.2
Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of Good Clinical Practice (GCP), protocol, or contractual agreement, 


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is unable to ensure adequate performance of the study, or as otherwise permitted by the contractual 
agreement.
6.4.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s)
In the event that the sponsor, an institutional review board (IRB), or a regulatory authority elects to 
terminate or suspend the study or the participation of a study site, a study-specific procedure for 
early termination or suspension will be provided by the sponsor; the procedure will be followed by 
applicable study sites during the course of termination or study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to randomization. 
7.1
Inclusion Criteria
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 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 male and aged 18 to 55 years, inclusive, at the time of informed consent and first 
study drug dose.
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. A male subject who is nonsterilized* and sexually active with a female partner of childbearing 
potential* agrees to use barrier method of contraception (eg, condom with or without 
spermicide)* from signing of informed consent throughout the duration of the study and for 
70 days after the last dose of study drug. 
* Definitions and highly effective methods of contraception are defined in 
Section 9.1.9 and reporting responsibilities are defined in Section 9.1.10.
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 has received TAK-071 in a previous clinical study.
3. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in the conduct of this study 
(eg, spouse, parent, child, sibling) or may consent under duress. 
4. The subject has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, 
hepatic, renal, metabolic, gastrointestinal, or endocrine 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. The subject has a known hypersensitivity to any component of the formulation of TAK-071 or 
placebo; or has a known hypersensitivity to donepezil (or to other biperidine derivatives), 
atropine, or scopolamine and/or to any component in their formulations. 
6. The subject has a positive urine drug result for drugs of abuse (defined as any illicit drug use) at 
Screening or Check-in (Day -1) of Period 1.


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7. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse (defined as regular consumption of 4 or more units per day) within 1 year prior to the 
Screening visit or is unwilling to agree to abstain from alcohol and drugs throughout the study. 
One unit is equivalent to a half-pint of beer or 1 measure of spirits or 1 glass of wine.
8. 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 7.4.
9. Subject intends to donate sperm during the course of this study or for 70 days after the last dose 
of study drug. 
10. 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, donepezil, scopolamine, or a similar drug in the same class, or that might interfere 
with the conduct of the study. 
11. Subject has current or recent (within 6 months) gastrointestinal disease that would be expected 
to influence the absorption of drugs (ie, a history of malabsorption, esophageal reflux, peptic 
ulcer disease, erosive esophagitis, frequent [more than once per week] occurrence of 
heartburn, or any surgical intervention.
12. Subject has a history of cancer, except basal cell carcinoma which has been in remission for at 
least 5 years prior to Day 1 of Period 1. 
13. Subject has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus 
(HCV) antibody at Screening or a known history of human immunodeficiency virus infection.
14. Subject has used nicotine-containing products (including but not limited to cigarettes, pipes, 
cigars, chewing tobacco, nicotine patch or nicotine gum) within 28 days prior to Check-in 
Day -1 of Period 1. Cotinine test is positive at Screening or Check-in (Day -1) of Period 1.
15. The subject has poor peripheral venous access.
16. Subject has donated or lost 450 mL or more of his blood volume (including plasmapheresis), or 
had a transfusion of any blood product within 30 days prior to Day 1 of Period 1.
17. 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.
18. The subject is a shift worker (night, late, or early resulting in irregular bed times) or has 
crossed or will cross more than 2 time zones within 48 hours in the period from 48 hours prior 
to Treatment Period 1, Day 1 until the end of Treatment Period 5.
19. The subject reports symptoms suggesting evidence of a current sleep disorder or history of 
sleep disorder, including but not limited to sleep apnea, heavy snoring, primary or chronic 
insomnia, narcolepsy or restless leg syndrome, as judged by medical history.


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20. The subject has a Fridericia-corrected QT interval >450 ms or PR interval outside the range of 
120 to 220 ms, confirmed on repeat testing within a maximum of 30 minutes, at Screening or 
Check-in.
21. Subject has abnormal Screening or Check-in (Day -1) of Period 1 laboratory values that 
suggest a clinically significant underlying disease, confirmed upon repeat testing. 
7.3
Additional Inclusion Criteria for Part 2 After Pre-Enrollment Enrichment Screening
1. Subject able to perform the CogState battery.
2. Change from Baseline (average) in total GMLT errors of ≤-5 at 2 hours postdose of 
scopolamine.
3. Subjects with sleepiness score <8 on the KSS at 2 hours postdose of scopolamine.
4. Subject passes a hearing test with at least 80% correct responses and no more than 20% false 
positives. This test can be repeated once to determine eligibility. 
7.4
Excluded Medications, Supplements, Dietary Products
Use of the agents in Table 7.a is prohibited from the time points specified until subject completes 
PK assessment on Day 8 in Part 1, the initial substudy, or is discharged from the unit in Period 5 in 
Part 2, the main study.


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Table 7.a
Prohibited Medications, Supplements, Dietary Products 
28 Days Prior to Check-in 
(Day -1) of Period 1
7 Days Prior to Check-in 
(Day -1) of Period 1
72 Hours Prior to Check-in 
(Day -1) of Period 1
Prescription medications (other than 
donepezil, where applicable)
OTC medications (a)
Products containing caffeine
Nutraceuticals (eg, St. John’s wort, 
ginseng, kava kava, ginkgo biloba, 
Chinese herbs, and melatonin)
Vitamin supplements
poppy seeds
Intake of known OTC inhibitors/inducers 
of CYPs 3A4/5, 2C9, 2C19, 2D6, 1A2, 
2B6, 2E1, and 2A6 (b)
Intake of the following drug classes: 
anti-emetics; antidiarrhetics, 
anticholinergics, cholinergic agonists and 
laxatives
Foods or beverages containing 
grapefruit or Seville-type (sour) 
oranges and marmalade, apple, orange, 
or pineapple juices, 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
Immunization/vaccines
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) For a list of moderate/strong CYP3A4, 2D6, or 2C9 inducers/inhibitors, see Appendix F.
Subjects must be instructed not to take any medications including OTC products, without first 
consulting with the investigator.
7.5
Diet, Fluid, and Activity Control 
7.5.1
Part 1
Subjects will be confined to the clinic for the duration of the treatment period (Day -1 through 
Day 4).
During the confinement period, subjects will receive 3 meals and an evening snack. The breakfast 
on Day 1 will be a low-fat, low-calorie, defined as <300 calories and <20% fat content. The 
2 meals will have approximately 30% fat (relative to the total calories). 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. The start and end time of meals and percentage of meals consumed on Days 1 to 2 will be 
recorded in the electronic case report form (eCRF).
7.5.2
Part 2
Subjects will be confined to the clinic for the duration of each treatment period (Day -1 through 
Day 3).


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During the confinement in each treatment period, subjects will receive 3 meals and an evening 
snack. The breakfast on Day 1 of each treatment period will be a low-fat low-calorie, defined as 
<300 calories and <20% fat content. The 2 meals will have approximately 30% fat (relative to the 
total calories). The meals served on the day of dosing should be identical (same items offered) for 
each period 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. The start and end time of meals and 
percentage of meals consumed on Days 1 and 2 will be recorded in the eCRF.
TAK-071 or matching placebo will be administered with approximately 240 mL of water after a 
fast of at least 8 hours as a single PO dose (DIC) 24 hours before scopolamine dosing and 
approximately 1.5 hours following a low-calorie, low-fat breakfast. No additional food will be 
permitted for up to 4 hours after TAK-071 dosing. Donepezil will be administered with 
approximately 240 mL of water after a fast of at least 8 hours as a single PO dose 3 hours before 
scopolamine dosing. Subjects may consume water ad libitum with the exception of 1 hour before 
and 1 hour after TAK-071, donepezil, or placebo administration. Meal timings, as well as their 
caloric and fat content, may be changed in the event of adjustments to the TAK-071 administration 
time.
Subjects will remain upright (seated, standing, or ambulatory) for 1 hour 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.
7.6
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the eCRF using the following categories. For screen failure subjects, refer to 
Section 9.1.18.
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires early 
termination because continued participation imposes an unacceptable risk to the subject’s 
health or the subject is unwilling to continue because of the PTE or AE.

Liver function test (LFT) abnormalities
Study drug should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/Baseline status, see Section 9.1.8), if the following circumstances occur at any time 
during study drug treatment:
–
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8× upper limit 
of normal (ULN), or
–
ALT or AST >5× ULN and persists for more than 2 weeks, or
–
ALT or AST >3× ULN in conjunction with elevated total bilirubin >2× ULN or 
international normalized ratio (INR) >1.5, or


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–
ALT or AST >3× ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).
2. Significant protocol deviation. The discovery post-randomization that the subject failed to 
meet protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documentation.
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE should not be recorded in the “voluntary withdrawal” category).
5. Study termination. The sponsor, IRB, independent ethics committee (IEC), or regulatory 
agency terminates the study.
6. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.7
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 7.6. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
Early Termination Visit. Discontinued or withdrawn subjects will not be replaced.


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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
This section contains information regarding all medications and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of study material.
8.1
Study Drug 
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.

TAK-071 and matching placebo.

Scopolamine and matching placebo.

Donepezil and matching placebo.
8.1.1.1
Investigational Study 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 is provided in Table 8.a.
Table 8.a
Composition of TAK-071 for DIC and Matching Placebo
Components 
TAK-071 DIC
Matching Placebo
TAK-071
1-30 mg
0 mg
Hard gelatin capsule (Size: 00, Color: Swedish orange opaque)
8.1.1.2
Donepezil and Matching Placebo
Donepezil 10 mg tablet manufactured by Eisai Inc. will be overencapsulated, labeled in a blinded 
fashion with third-party dispensing, and delivered as a PO capsule. The composition of the 
overencapsulated donepezil and matching placebo is provided in Table 8.b.


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Table 8.b
Composition of Overencapsulated Donepezil and Matching Placebo
Components 
Aricept OE
Matching Placebo
Donepezil 10 mg tablet, United States Pharmacopeia
1 tablet
-
Microcrystalline cellulose, National Formulary
qs
qs
Hard gelatin capsule (Color: Swedish orange opaque)
OE=overencapsulated.
qs=quantity sufficient.
8.1.1.3
Scopolamine and Matching Placebo
Scopolamine, under generic name hyoscine hydrobromide, manufactured by Martindale 
Pharmaceuticals Ltd. will be delivered as a 0.5 mg SC injection. 
The placebo for scopolamine will be the equivalent volume of saline delivered as SC injection. 
8.1.1.4
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).
Scopolamine will be sourced from the United Kingdom as hyoscine hydrobromide 600 µg/mL 
ampoules and supplied to the clinical site by TDC Americas.
Branded Aricept (as donepezil) will be sourced locally and overencapsulated by the clinical site.
8.1.2
Storage
Based upon the recent stability study data, the recommended storage conditions for the TAK-071 
DIC are 20°C to 25°C (68°F to 77°F), with excursion permitted within 15°C to 30°C (59°F to 
86°F). Any excursions from the labeled storage conditions must be reported to Takeda 
immediately. 
Overencapsulated donepezil must be stored according to the label. 
Scopolamine must be stored according to the commercial 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 drugs 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
8.1.3.1
Part 1
TAK-071 80 mg on Day 1 (24 hours prior to scopolamine administration) administered as DIC PO
and scopolamine 0.5 mg SC on Day 2.


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8.1.3.2
Part 2
TAK-071 dose will be selected based on the SRD part of the study TAK-071-1001 and part 1 of 
this study.

Treatment A=scopolamine matching placebo SC + TAK-071 matching placebo PO + 
donepezil matching placebo PO.

Treatment B=scopolamine 0.5 mg SC + TAK-071 matching placebo PO + donepezil matching 
placebo PO.

Treatment C=scopolamine 0.5 mg SC + TAK-071 PO + donepezil matching placebo PO.

Treatment D=scopolamine 0.5 mg SC + TAK-071 PO + donepezil 10 mg PO.

Treatment E=scopolamine 0.5 mg SC + TAK-071 matching placebo PO + donepezil 10 mg 
PO.
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of study drug, to or by a 
study subject, at a dose above that which is assigned to that individual subject according to the 
study protocol.
All cases of overdose (with or without associated AEs) will be documented on an overdose page of 
the eCRF, in order to capture this important safety information consistently in the database. Cases 
of overdose without manifested signs or symptoms are not considered AEs. AEs associated with 
an overdose will be documented on AE CRF(s) according to Section 10.0.
Serious adverse events (SAEs) associated with overdose should be reported according to the 
procedure outlined in Section 10.2.2.
In the event of drug overdose, the subject should be treated symptomatically.
8.2
Study Drug Assignment and Dispensing Procedures
8.2.1
Part 1
Subjects will be assigned, in the order they are enrolled to receive treatment. Subjects will be 
assigned a 4-digit enrollment number by the clinic site personnel in sequential order beginning 
with 1001 and ending with 1006.
8.2.2
Part 2
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. 
Subjects will be assigned a 4-digit randomization number. The number will be assigned by the 
clinic site personnel in sequential order beginning with 2001 and ending with 2040. This 4-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 sample collections. This 4-digit number should only be used 


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for the purposes described in this section. It does not replace the 3-digit subject number which is 
assigned at the time the informed consent is obtained and which is used for all other procedures to 
identify the subjects throughout the study.
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. All randomization information 
will be stored in a secured area, accessible only by authorized personnel.
8.4
Study Drug Blind Maintenance 
For Part 1 (initial substudy), drug will be administered open-label.
For Part 2 (main study), 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. The study subjects, Principle Investigator, as well as all 
other clinical research site staff, will remain blinded to treatment throughout the conduct of the 
study. Sponsor staff will be unblinded, and will ensure that the blind is not accidentally broken.
8.5
Unblinding Procedure
This is applicable only to Part 2 (main study). The study drug blind shall not be broken by the 
investigator unless information concerning the study drug is necessary for the medical treatment of 
the subject. All study assessments and causality should be performed, if possible, prior to 
unblinding. In the event of a medical emergency, if possible, the medical monitor should be 
contacted before the study drug blind is broken to discuss the need for unblinding.
The sponsor must be notified as soon as possible if the study drug blind is broken. The date, time, 
and reason the blind is broken must be recorded in the source documents and the same information 
(except the time) must be recorded on the eCRF.
If any site personnel are unblinded, the site should contact the sponsor to determine if study drug 
should be stopped or if the subject should be withdrawn from the study.
No change should be made to any assessment of the subject after unblinding.
8.6
Accountability and Destruction of Sponsor-Supplied Drugs
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, donepezil, scopolamine, and matching 
placebos), 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 according to local procedures following 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 the 
medication is in good condition. If quantity and conditions are acceptable, investigator or designee 


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should acknowledge the receipt of the shipment by signing bottom half of the packing list and 
faxing per instructions provided on the form. If there are any discrepancies between the packing 
list versus the actual product received, Takeda must be contacted to resolve the issue. The packing 
list should be filed in the investigator’s essential document file.
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
(TAK-071 drug substance, DIC, donepezil, scopolamine, and matching placebos) received and 
dispensed during his or her entire participation in the study. Proper drug accountability includes, 
but is not limited to:

Continuously monitoring expiration dates if expiry date is provided to the investigator or 
designee. 

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the drug lot used to prepare each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.

A site representative or unblinded pharmacy monitor, otherwise uninvolved with study 
conduct, will review the randomization table/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, donepezil, scopolamine, and matching placebos) 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, 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.
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.


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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.
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
Pharmacogenomic 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, and smoking status of 
the subject at Screening. The following data will also be collected: years of full-time education and 
academic qualifications.
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that resolved at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.7).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 30 days prior to signing of informed consent.
9.1.3
Physical Examination Procedure
A Baseline physical examination (defined as the assessment prior to first dose of study drug) will 
consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; 
(4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; (7) extremities; 
(8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) other.
Any abnormal finding on a pretreatment physical examination assessment must be assessed as not 
clinically significant (NCS) or clinically significant (CS) by the investigator and recorded in the 


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source document and eCRF. All CS 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 9.1.7. 
On subsequent examinations, any abnormal change from the pretreatment physical examination 
assessment occurring immediately prior to the start of the study drug must be assessed as NCS or 
CS by the investigator and recorded in the source document and eCRF. Any CS change or new 
diagnosis as a result of a CS 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. 
9.1.4
Weight, Height and BMI 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. Height is recorded in centimeters without decimal places. Weight is collected in kilograms 
(kg) with 1 decimal place. BMI should be derived as:
Metric:
BMI = weight (kg)/height (m)2
Note that although height is reported in centimeters, the formula uses meters for height; meters can 
be determined from centimeters by dividing by 100. Thus, for example, if height=176 cm 
(1.76 meters) and weight=79.2 kg, then BMI=79.2/1.762=25.56818 kg/m2 
The values should be reported to 1 decimal place by rounding. Thus, in the above example BMI 
would be reported as 25.6 kg/m2. However, if the BMI is used as entry criteria, then this 
determination must be made after rounding.
9.1.5
Vital Sign Procedure
Vital signs will include body temperature (oral), respiratory rate, supine blood pressure (systolic 
and diastolic, resting more than 5 minutes), and pulse (beats per minute [bpm]).
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 or after the scheduled blood draw.
9.1.6
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 the 
sponsor. At each study visit, subjects will be asked whether they have taken any medication other 
than the study drug (used from signing of informed consent through the end of the study), and all 
medication including vitamin supplements, 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. 


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9.1.7
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 Screening examination, according the judgment of the 
investigator. The condition (ie, diagnosis) should be described.
9.1.8
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. During the 
treatment period, laboratory samples will be taken following a minimum 8 hour overnight fast on 
the days stipulated in the Schedule of Study Procedures (Appendix A).
Table 9.a lists the tests that will be obtained for each laboratory specimen.
Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Red blood cells 
White blood cells with 
differential (absolute counts)
Hemoglobin
Hematocrit
Platelets
Coagulation
PT/INR
aPTT
ALT
Albumin
Alkaline phosphatase
AST
Total bilirubin
Direct bilirubin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
GGT
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
Diagnostic Screening:
Serum
Urine
Hepatitis panel, including HBsAg and anti-HCV
Drug screen, including amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, opiates, alcohol, 
and cotinine
aPTT=activated partial thromboplastin time, GGT= gamma-glutamyl transferase, PT=prothrombin time.
The local laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible for 
reviewing and filing these results.
If subjects experience ALT or AST >3× ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed within a 


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maximum of 7 days and preferably within 48-72 hours after the abnormality is noted. (Refer to 
Section 7.6 and Section 10.2.3 for the appropriate guidance on reporting abnormal LFTs.)
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
for reporting requirements).
The investigator will maintain a copy of the laboratory accreditation and the reference ranges for 
the laboratory used.
Laboratory reports must be signed and dated by the principal investigator or sub investigator 
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 NCS before 
proceeding with enrollment/randomization.
All CS laboratory abnormalities must be recorded as a PTE/AE in the subject’s source documents 
and on the appropriate eCRF. A CS laboratory abnormality that has been verified by retesting will 
be followed until the abnormality returns to an acceptable level or a satisfactory explanation has 
been obtained.
9.1.9
Contraception and Pregnancy Avoidance Procedure
9.1.9.1
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and for 70 days after the 
last dose of study drug, nonsterilized** male subjects who are sexually active with a female 
partner of childbearing potential *must use barrier contraception (eg, condom with or without 
spermicidal cream or jelly). In addition, they must be advised not to donate sperm during this 
period. Females of childbearing potential who are partners of male subjects are also advised to use 
additional contraception as shown in the list containing highly effective/effective contraception 
below.
9.1.9.2
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A woman is considered a woman of childbearing potential, ie, fertile, following menarche and 
until becoming post-menopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, and bilateral oophorectomy. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause.
** Sterilized males should be at least 1 year post-bilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchiectomy.


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The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this study, where medications and devices containing hormones are excluded, the 
only acceptable methods of contraception are: 

Intrauterine device.

Bilateral tubal occlusion.
2. Unacceptable methods of contraception are:

Hormonal methods.

Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.

Sexual abstinence is NOT an acceptable method of contraception.
3. Subjects will be provided with information on highly effective/effective methods of 
contraception as part of the subject informed consent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy, 
donation of sperm during the course of the study.
9.1.9.3
General Guidance With Respect to the Avoidance of Pregnancy
During the course of the study all subjects will receive continued guidance with respect to the 
avoidance of pregnancy and sperm donation as part of the study procedures. Such guidance should 
include a reminder of the following:

Contraceptive requirements of the study.

Reasons for use of barrier methods (ie, condom) in males with pregnant partners.

Assessment of subject compliance through questions such as:
–
Have you used the contraception consistently and correctly since the last visit?
–
Have you forgotten to use contraception since the last visit? 
9.1.10
Pregnancy
Women of childbearing potential will not be included in this study.


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Any pregnancies in the partner of a male subject during the study or for 70 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, after Day 1 of Period 1 or 
within 70 days after the last dose of active study drug, the pregnancy should be reported 
immediately, using a pregnancy notification form, to the contact listed in Section 1.1. 
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject’s partner of their right to receive treatment information. If the subject or 
subject’s partner chooses to receive unblinded treatment information, the individual blind should 
be broken by the investigator. 
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 female partner of the subject was 
participating in a clinical study at the time she became pregnant and provide details of the study 
drug the subject received (blinded or unblinded, as applicable).
All reported pregnancies, in female partners of male subjects, 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.
9.1.11
ECG Procedure
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the study 
site) will interpret the ECG using one of the following categories: within normal limits, abnormal 
but NCS, or abnormal and CS. The following parameters will be recorded on the eCRF from the 
subject’s ECG trace: heart rate, RR interval, PR interval, QT interval, QRS interval, QT interval 
with Fridericia correction, and QT interval with Bazett correction.
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. Predose ECGs may be 
done within 1 hour prior to dosing. If an ECG coincides with a meal, the ECG will take precedence 
followed by the meal.


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9.1.12
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 of how the drug is broken down, or how the drug affects the 
body. This is called a “Pharmacogenomics research study.” Specific purposes of this study 
include:

Identifying genetic reasons why certain people respond differently to TAK-071.

Finding out more information about how TAK-071 works.

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, to increase understanding of the disease/condition 
being studied, and for improving the efficiency, design, and study methods of future research 
studies.
9.1.12.1
DNA Sample Collection
Parts 1 and 2
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.
Part 2
One 6-mL whole blood sample for DNA sample will be used to explore the relationship between
cognitive response to scopolamine and the apolipoprotein E (APOE) status of the subject. This 
sample will be collected from individuals during Screening at the pre-enrollment enrichment 
Screening Visit.
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. In addition, if the DNA sample is not collected at the 
designated time point described in the protocol, it can be collected at a later time point.
In addition, because pharmacogenomics is an evolving science, currently many genes and their 
function are not yet fully understood. Future data may suggest a role of some of these genes in drug 
response or diseases, which may lead to additional hypothesis-generating exploratory research on 
stored samples.


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9.1.12.2
RNA Sample Collection
Part 1
Two whole blood samples (2.5 mL per sample) will be collected at each time point for RNA 
analysis from each subject into a PAXgene tube.
Part 2
Two whole blood samples (2.5 mL per sample) will be collected at each time point for RNA 
analysis from each subject in each of the 5 Treatment Periods into a PAXgene tube.
Each PGx sample for a study subject should be identifiable on the requisition form with an 8-digit 
subject identification (ID), 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 storing, handling, and shipping samples are provided in the Laboratory 
Manual.
9.1.13
PK Sample Collection
9.1.13.1
Collection of Blood for PK Sampling
Instructions for sample collection, processing, and shipment are provided in Appendix E.
In Part 1, the substudy, serial blood samples for determination of TAK-071 will be collected 
according to Table 9.b.
Table 9.b
Collection of Blood Samples for PK Analysis – Part 1
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Plasma
1
Predose (within 30 minutes before TAK-071 dosing) and 0.25, 
0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 24, 25, 26, 27, 28, 30, 32, 34, 
36, 40, 48, 56, 64, 72, 96, and 168 hours post TAK-071 dose
In Part 2, the main study, serial blood samples for determination of TAK-071, scopolamine, and 
donepezil will be collected during each period according to Table 9.c.


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Table 9.c
Collection of Blood Samples for PK Analysis – Part 2
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Plasma
1
-24 hours (predose of TAK-071) and 0 (predose of scopolamine), 
1, 2, 3, 4, 6, and 10 hours postdose relative to scopolamine 
dosing.
Scopolamine
Plasma
2
Predose (predose of scopolamine) and 1, 2, 3, 4, 6, and 8 hours 
postdose relative to scopolamine dosing.
Donepezil
Plasma
2
-3 hours (predose of donepezil) and 0 (predose of scopolamine), 
1, 2, 3, 4, 6, and 10 hours postdose relative to scopolamine 
dosing.
Note: Time points relative to each study drug administration, as shown in Figure 6.d, are as follows: (a) TAK-071: 
predose (approximately 30 minutes before dosing) and 24, 25, 26, 27, 28, 30, and 34 hours postdose relative to 
TAK-071 dosing, (b) Donepezil: predose (within 30 minutes before dosing) and 3, 4, 5, 6, 7, 9, and 13 hours postdose 
relative to donepezil dosing, and c) Scopolamine: predose (predose of scopolamine) and 1, 2, 3, 4, 6, and 8 hours 
postdose relative to scopolamine dosing.
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 from the FIH 
study, but the total number of samples collected per subject should not exceed the planned number. 
Placebo samples will not be analyzed by the bioanalytical laboratory except 2 samples per subject 
receiving placebo, 1 predose and the other around the tmax to ensure from a safety perspective that 
no additional subjects could have been on active treatment. 
9.1.13.2
Bioanalytical Methods
Plasma concentrations of TAK-071, donepezil, and scopolamine will be measured by separate 
methods using high-performance liquid chromatography with tandem mass spectrometry.
9.1.14
PK Parameters 
The PK parameters of TAK-071 and its metabolites, donepezil, and scopolamine 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 for plasma concentration values of TAK-071 and its metabolites: 
Symbol/Term
Definition
Plasma
AUCt1-t2
Area under the plasma concentration-time curve from time t1 to time t2
AUCt
Area under the plasma concentration-time curve from time 0 to time t
AUC∞
Area under the plasma concentration-time curve from time 0 to infinity
Cmax
Maximum observed plasma concentration
t1/2z
Terminal disposition phase half-life
tmax
Time of first occurrence of Cmax


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In general, if AUC∞cannot be accurately estimated in a sufficient number of subjects, area under 
the concentration-time curve from time 0 to time of the last quantifiable concentration (AUClast) 
will be reported instead. Additional 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.
9.1.15
PD Assessments (Only for Part 2)
9.1.15.1
Cognitive Testing
Table 9.d
CogState Cognitive Test Battery
Task Name
Time to Complete
(mins)
Unit of Measurement
Cognitive Domain
5
Total number of errors
Executive function, problem solving, 
reasoning, episodic memory
2
Log10 milliseconds
Psychomotor function/information 
processing
3
Log10 milliseconds
Attention
6
Arcsine proportion correct Visual learning
2
Arcsine proportion correct Working memory
9.1.15.2
 
CCI
CCI
CCI
CCI


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9.1.15.3
9.1.15.4
Pupillometry
CCI
CCI
CCI
CCI


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9.1.16
PD Parameters (Only for Part 2)
The PD parameters will include the following:
Symbol/Term
Definition
AUECt
Area under the effect curve from time 0 to time t
Emax
Maximum observed effect
Time to Emax
Time from scopolamine dosing to occurrence of Emax
Additional PD parameters may be estimated and/or reported, as appropriate.
9.1.17
PK/PD Assessment Order (Only for Part 2)
For PD Baseline on Day 1 and predose to scopolamine the following order should be followed:
!
Low-calorie low-fat breakfast: Approximately 2.5 hour prior to study drug dosing.
!
qEEG and ERP: Approximately 120 minutes prior to study drug dosing.
!
Pupillometry: Approximately 100 minutes prior to study drug dosing.
!
Cognitive test: Immediately after pupillometry and approximately 90 minutes prior to study 
drug dosing.
!
Sleepiness monitoring: Immediately after cognitive testing and approximately 70 minutes 
prior to study drug dosing.
!
PK blood draw: To be taken approximately within 30 minutes of the scheduled time point.
PK/PD assessments that coincide at the same scheduled time point will be performed in the 
following order: 
!
qEEG: Approximately 40 minutes prior to scheduled time point.
!
Pupillometry: Immediately after qEEG and approximately 5 minutes prior to scheduled time 
point.
!
PK blood draw: To be taken approximately at the scheduled time.
!
Cognitive test: Immediately after PK blood draw.
CCI
CCI


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
Sleepiness monitoring: Immediately after cognitive testing.
9.1.18 Assessment of Suicidal Ideation and Behavior
The C-SSRS was developed by researchers at Columbia University as a tool to systematically 
assess suicidal ideation and behavior in subjects during participation in a clinical trial of 
centrally-acting drugs. The C-SSRS is composed of 3 questions addressing suicidal behavior and 
5 questions addressing suicidal ideation, with subquestions assessing the severity. The tool is 
administered via interview with the subject.
9.1.19
Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent. If a subject is withdrawn at 
the Screening 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.

Did not meet inclusion criteria or did meet exclusion criteria <specify reason>.

Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal (specify reason).

Study termination.

Other (specify reason).
Subject identification numbers assigned to subjects who fail Screening should not be reused. If a 
subject fails Screening, but is later successfully rescreened, the data for the subject will be entered 
as if these were two 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 the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF.
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 


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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 in Part 1, the initial substudy, and 
Part 2, the main study, are shown in Appendix A. Assessments should be completed at the 
designated visit/time points.
9.3.1
Study Exit
For Part 1, subjects will be discharged from the clinic on Day 5; for Part 2, subjects will be 
discharged from clinic on Day 3 of Period 5.
For all subjects receiving study drug, the investigator must complete the End of Study eCRF page.
9.3.2
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.
9.3.3
Follow-up Visit/Telephone Call
For Part 1, a Follow-up Visit for PK will occur on Day 8 and a final Follow-up Visit will occur on 
Day 12 (±2). 
For Part 2, the Follow-up Visit will occur on Day 9 (±2 days) of Period 5 and will be considered 
the subject’s last visit. 
If abnormal CS findings are observed at discharge, subjects must visit the clinic for re-evaluation 
per investigator’s discretion. If no abnormal CS findings are observed at study exit, follow-up will 
be conducted 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 9.1.12. 
The genetic material will be preserved and retained at 
 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 
subjects’ personal information to ensure optimal confidentiality and defined standard processes for 
sample and data collection, storage, analysis, and destruction.
PPD


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The samples will be sent to a central laboratory that processes the blood samples and serves as a 
secure storage facility. The samples will be initially stored at 
. 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.
When subjects request disposal of a stored sample during the retention period, the site will ask 
 to destroy the sample via the sponsor according to the procedure. 
 will destroy 
the sample in accordance with the procedure, and notify the site and sponsor.
The sample will be labeled with a unique sample identifier as 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 number sample identifier 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. Notify sponsor 
of consent withdrawal. 
9.5
Blood Volume
Total blood sampling volume for an individual subject for Part 1 and Part 2 are shown in Table 9.e
and Table 9.f, respectively.
Table 9.e
Approximate Blood Volume for Part 1
Sample Type
Sample 
Volume
(mL)
Number of Samples
Total 
Volume 
(mL)
Screening 
and Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 8
Clinical laboratory tests
20 mL
2 (a)
1
1
1
1
2
1
180
Serology test
8.5 mL
1
0
0
0
0
0
0
8.5
PGx DNA sample collection 
6 mL
0
1
0
0
0
0
0
6
PGx RNA sample collection 
2.5 mL
0
2
0
2
0
0
0
10
TAK-071 PK blood 
collection
3 mL
0
13
10
3
1
1
1
87
Total Approximate Blood Sampling Volume
291.5
(a) 1 each at Screening and at Check-in.
PPD
PPD
PPD


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Table 9.f
Approximate Blood Volume for Part 2
Sample Type
Sample 
Volume 
(mL)
Number of Samples
Total 
Volume 
(mL)
Screening 
Period 1
(Day -1 
to 3)
Period 2
(Day -1 
to 3)
Period 3
(Day -1 
to 3)
Period 4
(Day -1 
to 3)
Period 5
(Day -1 
to 3)
Clinical laboratory tests
20 mL
2
1
1
1
1
2
160
Serology test
8.5 mL
1
0
0
0
0
0
8.5
PGx DNA sample collection 
6 mL
1
1
0
0
0
0
12
PGx RNA sample collection 
2.5 mL
0
4
4
4
4
4
50
TAK-071 PK blood collection
3 mL
0
8
8
8
8
8
120
Scopolamine PK blood 
collection
4 mL
0
7
7
7
7
7
140
Donepezil PK blood collection
4 mL
0
8
8
8
8
8
160
Total Approximate Blood Sampling Volume
650.5
The maximum volume of blood for Part 1 at any single day is approximately 70 mL, and the 
approximate total volume of blood for the study is 291.5 mL.
The maximum volume of blood for Part 2 at any single day is approximately 120 mL, and the 
approximate total volume of blood for the study is 650.5 mL. 
Direct venipuncture is the preferred method of blood collection; however, a catheter with a single 
saline flush may be used.
A catheter with a normal saline flush may be used; however, 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). Should a catheter be used, 
the total blood volume taken during the study must not exceed 650.5 mL.


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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 administration of any study drug; it 
does not necessarily have to have a causal relationship with study participation.
10.1.2
AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory value), symptom, or disease temporally associated with the use of a drug whether or not 
it is considered related to the drug.
10.1.3
Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered PTEs or 
AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study drug or a concomitant medication.

Be considered unfavorable by the investigator for any reason. 
PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG findings are only considered to be PTEs or AEs if they 
are judged to be CS (ie, if some action or intervention is required or if the investigator judges 
the change to be beyond the range of normal physiologic fluctuation). A laboratory or ECG 
retest and/or continued monitoring of an abnormal value or findings are not considered an 


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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 etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent medical condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study drug) or an AE 
(worsening or complication occurs after start of study drug). Investigators should ensure that 
the event term recorded captures the change in the condition (eg, “worsening of…”).

If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy) any 
occurrence of an episode should only be captured as a PTE/AE if the condition becomes more 
frequent, serious, or severe in nature. Investigators should ensure that the AE term recorded 
captures the change in the condition from Baseline (eg “worsening of…”).

If a subject has a pre-existing degenerative concurrent medical condition (eg, cataracts, 
rheumatoid arthritis), worsening of the condition should only be recorded as a PTE/AE if 
occurring to a greater extent to that which would be expected. Investigators should ensure that 
the AE term recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after the start of study drug, 
the worsening or complication should be recorded as an AE. Investigators should ensure that 
the AE term recorded captures the change in the 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 intensity of AEs/Serious PTEs:

If the subject experiences changes in intensity of an AE/serious PTE, the event should be 
captured once with the maximum intensity recorded.
Preplanned 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 


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worsening of the condition should be recorded as a PTE or an AE. Complications resulting 
from any planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing 
conditions and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of 
the eCRF.
10.1.4
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. 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).


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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
Note: Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered as 
“Important Medical Events” satisfying SAE reporting requirements.
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5
Intensity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.6
Relationship of AEs to Study Drug(s)
The relationship (causality) of each AE to study drug(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant medications and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant medications, and concurrent treatments.
10.1.7
Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.


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The relationship should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as Not Related.
10.1.8
Start Date
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or investigator.
10.1.9
Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.1.10 Frequency 
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous.
10.1.11 Action Concerning Study Drug 

Drug withdrawn – a study drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not Applicable – a study drug was stopped for a reason other than the particular AE eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped before 
the onset of the AE.

Dose Interrupted – the dose was interrupted due to the particular AE.
10.1.12 Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE.

Recovering/Resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to Baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”.

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/PTE state remaining “Not 
recovered/not resolved”.


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
Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – the AEs/PTEs which are considered as the cause of death.

Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1
Collection and Reporting of AEs
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 on Day 1 for 
Part 1, or Pre-enrollment Enrichment Visit for Part 2, 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 of Period 1). Routine collection of AEs will continue until the Follow-up Visit/Call or 
Early Termination.
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. 
Non-serious 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. Intensity.


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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 must be completed, in English, and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study drug(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 


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tests as described in Section 9.1.8 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 is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. If the subject was hospitalized, copies of any 
relevant data from the hospital records (eg, ECGs, laboratory tests, discharge summary, 
postmortem results) should be sent to the addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.3.1
Safety Reporting to Investigators, IRBs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, 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 the study drug/sponsor 
supplied drug or that would be sufficient to consider changes in the study drug/sponsor supplied 
drug administration or in the overall conduct of the trial. The study site also will forward a copy of 
all expedited reports to his or her IRB in accordance with local regulations.


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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.


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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent medical conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization Drug Dictionary (WHODRUG).
12.1
eCRFs 
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply study sites with access to eCRFs. The sponsor will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor and regulatory authorities. 
eCRFs must be completed in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
The principal investigator must review the eCRFs for completeness and accuracy and must e-sign 
the appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility 
for the accuracy and authenticity of all data entered on the eCRFs.
After the lock of the study database, any change of, modification of or addition to the data on the 
eCRFs should be made by the investigator with use of change and modification records of the 
eCRFs. The principal investigator must review the data change for completeness and accuracy, 
and must sign, or sign and date.
The eCRFs will be reviewed for completeness and acceptability at the study site during periodic 
visits by the sponsor or its designee. The sponsor or its designee will be permitted to review the 
subject’s medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. The 
completed eCRFs are the sole property of the sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, 
International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 


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retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 
approval of a marketing application for a specified drug indication being investigated or, if an 
application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the study site agreement between the investigator and sponsor.
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.


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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. 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
13.1.1.1
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 demographics, Baseline characteristics, and 
safety summaries.
13.1.1.2
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.
13.1.1.3
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
Demographic and Baseline characteristics will be summarized for all randomized subjects. For 
continuous variables (eg, age, height, weight, and BMI), the summary will consist of descriptive 
statistics (number of subjects, mean, SD, minimum, median, and maximum). For categorical 
variables (eg, ethnicity and race), the summary will consist of number and percentage of subjects 
in each category.
13.1.3
PK Analysis
Plasma concentrations of TAK-071, donepezil, and scopolamine will be summarized from each 
treatment using descriptive statistics. 
Individual plasma concentration data versus time will be presented in a data listing.
Plasma PK parameters for TAK-071, donepezil, and scopolamine will be summarized separately.


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A more detailed analysis will be presented in the SAP. The relationship between PK and PD may 
be explored and detailed in a separate plan. Additional analyses may also be considered.
13.1.4
PD Analysis 
13.1.4.1
Cognitive Testing Analysis
To address the statistical hypotheses related to the time course of scopolamine effects, cognitive 
endpoints will be analyzed using a mixed analysis of variance (ANOVA) model appropriate for a 
5-period crossover with fixed factors for period, sequence, treatment, hour, and treatment by hour. 
Additionally, the model will contain a random factor subject nested in sequence (the 
between-subject error) and a random residual error term (the within-subject error). A 2-sided t-test 
(alpha=0.05) using the within subject mean squared error from the mixed ANOVA model will be 
examined to test the primary hypothesis. Treatment differences, 2-sided 95% CIs, 2-sided 
p-values, and effect sizes will be presented for all time points, with 2 hours post scopolamine being 
the time frame for the primary endpoint.
To address the statistical hypotheses related to area under the effect curve (AUEC) endpoints, 
cognitive endpoints will be analyzed using an ANOVA model appropriate for a 5-period crossover 
with fixed factors for treatment, period, and sequence. Additionally, the model will contain a 
random factor subject nested in sequence (the between-subject error) and a random residual error 
term (the within-subject error). A 2-sided t test (alpha=0.05) using the within subject mean squared 
error from the mixed ANOVA model will be examined to test the statistical hypothesis.
For AUEC endpoints, the natural log scale treatment differences (eg, the primary treatment 
comparison of Treatment Y − Treatment X) will be exponentiated and reported as a mean percent 
change along with 95% CIs for the true mean percent change as a summary measure. Other 
statistical treatments (such as multivariate analysis of covariance [ANCOVA]) will be outlined in 
the SAP. 
The Baseline cognitive measure will be included in the model as a covariate. 
Other statistical analyses will be performed as appropriate. 
13.1.4.2
13.1.5
Safety Analysis
The safety of TAK-071 in combination with scopolamine will be assessed through AEs, clinical 
laboratory results, physical examination findings, ECG findings, vital signs, and suicidal 
assessments. 
CCI
CCI


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Summary tables will include the number and percent of subjects in each treatment experiencing at 
least 1 TEAE by system organ class and preferred term. If a subject has more than 1 AE that codes 
to the same preferred term, the subject will be counted only once for that preferred term. Similarly, 
if a subject has more than 1 AE within a system organ class category, the subject will be counted 
only once for that system organ class.
TEAEs possibly or probably related to study medication will be tabulated in the same manner. 
TEAEs will also be summarized by maximum intensity. All AEs will be listed.
AEs will be summarized using the safety analysis set. All AEs will be coded using MedDRA. Data 
will be summarized using preferred term and primary system organ class.
Clinical laboratory tests (hematology, chemistry, and urinalysis), vital signs, and ECG parameters 
will be listed. The results that meet TDC markedly abnormal criteria will be flagged in the listing.
The percentage of subjects who meet TDC markedly abnormal criteria at least once postdose will 
be summarized.
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
For Part 1, a sample size of 6 enrolled and 4 completers is considered sufficient for providing 
guidance on the TAK-071 dose selection for Part 2, the main study. This is not based on any 
statistical power.
For Part 2, a sample size of 26 subjects, approximately 3 subjects for each of the 10 sequences of 
the 5-period cross-over, will be used and is considered sufficient for evaluation of the primary 
cognitive endpoints for this study based on consideration of published scopolamine model 
literature and expert advice. Subjects who drop-out will not be replaced, therefore to ensure there 
are enough completers a total of 40 subjects will be recruited (4 per sequence).
In particular, this sample-size calculation was based on a consideration of effect sizes seen in a 
similar study [21]. Using a 2-sided alpha level of 0.05, this study has a 90% power to detect an 
effect size of 0.67 in the GMLT (sum of 5 trials) total number of errors for the primary treatment 
comparison of TAK-071+scopolamine vs placebo+scopolamine, assuming a total of 26 subjects 
complete the study and provide primary endpoint data.
At least 26 subjects will complete the study if 40 subjects are randomized, assuming the drop-out 
rate does not exceed 33%.


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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the sponsor or its 
designee (contract research organization [CRO]) and by the IRB.
All aspects of the study and its documentation will be subject to review by the sponsor or the 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, study drug, subject medical records, informed consent documentation, 
documentation of subject authorization to use personal health information (if separate from the 
informed consent forms), and review of eCRFs and associated source documents. It is important 
that the investigator and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB as required). 
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment. A 
Protocol Deviation eCRF should be completed by the site and acknowledged by the sponsor or 
designee for any significant deviation from the protocol. 
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.
Table 14.a
Windows for PK Blood Sample Collection
Minutes
Nominal Sampling Time
no more than 30 minutes predose
0 hour
±5
±30 minutes 
±24 hours 
postdose to <24 hours
>24 to ≤96 hours 
>96 hours 


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14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the Food and Drug Administration [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.


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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable 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
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, informed consent form) reviewed; and state the approval date. The 
sponsor will ship drug/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 drug/notification no protocol activities, 
including Screening may occur.
Study sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent form, 
recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports, and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB, and submission of the investigator’s final status report to IRB. All IRB approvals 
and relevant documentation for these items must be provided to the sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and sponsor.


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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.


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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
Subjects who consented and provided 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. Notify sponsor 
of consent withdrawal.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical trial database or documentation via a subject identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit the monitor or the sponsor’s designee, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs to review the subject’s original medical records (source data or documents), 
including, but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and autopsy 
reports. Access to a subject’s original medical records requires the specific authorization of the 
subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the study site agreement, any public disclosure 
(including publicly accessible websites) related to the protocol or study results, other than study 
recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The 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 


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this section and the study site agreement. In the event of any discrepancy between the protocol and 
the study site agreement, the study site agreement will prevail.
15.4.2
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it sponsors anywhere in the world on www.ClinicalTrials.gov and/or 
other publicly accessible websites before start of study, as defined in Takeda Policy/Standard. 
Takeda contact information, along with investigator’s city, state, country, and recruiting status will 
be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to the sponsor providing this information to callers must provide the 
sponsor with a written notice requesting that their information not be listed on the registry site. 
15.4.3
Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on www.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 study subjects. Refer to 
the study site agreement regarding the sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the sponsor 
or sponsor’s designee.


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16.0
REFERENCES
1. Wimo A, Jonsson L, Bond J, Prince M, Winblad B. The worldwide economic impact of 
dementia 2010. Alzheimers Dement 2013;9(1):1-11 e3.
2. Wimo A. Clinical and economic outcomes--friend or foe? Int Psychogeriatr 
2007;19(3):497-507.
3. 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.
4. Alzheimer's Disease International. Policy Brief for Heads of Government: The Global Impact 
of Dementia 2013-2050. Published December 2013.
5. 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.
6. Davies P, Maloney AJ. Selective loss of central cholinergic neurons in Alzheimer's disease. 
Lancet 1976;2(8000):1403.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. van der Staay FJ, Bouger PC. Effects of the cholinesterase inhibitors donepezil and metrifonate 
on scopolamine-induced impairments in the spatial cone field orientation task in rats. Behav 
Brain Res 2005;156(1):1-10.
13. Bartus RT. Evidence for a direct cholinergic involvement in the scopolamine-induced amnesia 
in monkeys: effects of concurrent administration of physostigmine and methylphenidate with 
scopolamine. Pharmacol Biochem Behav 1978;9(6):833-6.
14. Taffe MA, Weed MR, Gold LH. Scopolamine alters rhesus monkey performance on a novel 
neuropsychological test battery. Brain Res Cogn Brain Res 1999;8(3):203-12.
15. Wesnes KA, Simpson PM, White L, Pinker S, Jertz G, Murphy M, et al. Cholinesterase 
inhibition in the scopolamine model of dementia. Ann N Y Acad Sci 1991;640:268-71.


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CONFIDENTIAL
16. Lenz RA, Baker JD, Locke C, Rueter LE, Mohler EG, Wesnes K, et al. The scopolamine 
model as a pharmacodynamic marker in early drug development. Psychopharmacology (Berl) 
2012;220(1):97-107.
17. Aricept (donepezil hydrochloride) 5 mg and 10 mg film-coated tablets. Summary of Product 
Characteristics. Hatfield, United Kingdom: Eisai Ltd., Revised 18 February 2013.
18. Clader JW, Wang Y. Muscarinic receptor agonists and antagonists in the treatment of 
Alzheimer's disease. Curr Pharm Des 2005;11(26):3353-61.
19. Farlow M, Veloso F, Moline M, Yardley J, Brand-Schieber E, Bibbiani F, et al. Safety and 
tolerability of donepezil 23 mg in moderate to severe Alzheimer's disease. BMC Neurol 
2011;11:57.
20. Kim KA, Lim JL, Kim C, Park JY. Pharmacokinetic comparison of orally disintegrating and 
conventional donepezil formulations in healthy Korean male subjects: a single-dose, 
randomized, open-label, 2-sequence, 2-period crossover study. Clin Ther 2011;33(7):965-72.
21. Cho W, Maruff P, Connell J, Gargano C, Calder N, Doran S, et al. Additive effects of a 
cholinesterase inhibitor and a histamine inverse agonist on scopolamine deficits in humans. 
Psychopharmacology (Berl) 2011;218(3):513-24.
22. Zangara A, Edgar C, Wesnes K, Scalfaro P, Porchet HC. The effectiveness of ZT-1 and 
donepezil in reversing scopolamine-induced cognitive impairment in elderly volunteers. Int J 
Neuropsychopharmacol 2004;7:S377.
23. Blatter K, Cajochen C. Circadian rhythms in cognitive performance: methodological 
constraints, protocols, theoretical underpinnings. Physiol Behav 2007;90(2-3):196-208.
24. Gundel A, Witthoft H. Circadian rhythm in the EEG of man. Int J Neurosci 
1983;19(1-4):287-92.
25. Aeschbach D, Matthews JR, Postolache TT, Jackson MA, Giesen HA, Wehr TA. Two 
circadian rhythms in the human electroencephalogram during wakefulness. Am J Physiol 
1999;277(6 Pt 2):R1771-9.
26. Loving RT, Kripke DF, Glazner LK. Circadian rhythms in the human pupil and eyelid. Am J 
Physiol 1996;271(2 Pt 2):R320-4.
27. Greiff JM, Rowbotham D. Pharmacokinetic drug interactions with gastrointestinal motility 
modifying agents. Clin Pharmacokinet 1994;27(6):447-61.
28. American Society of Health-System Pharmacists Inc. Digoxin. American Society of 
Health-System Pharmacists Inc; Published 01 May 2004. Updated 08 February 2016. 
Accessed 25 October 2016. Available at: https://www.drugs.com/monograph/digoxin.html.
29. Ebert U, Siepmann M, Oertel R, Wesnes KA, Kirch W. Pharmacokinetics and 
pharmacodynamics of scopolamine after subcutaneous administration. J Clin Pharmacol 
1998;38(8):720-6.


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30. 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.


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Appendix A
Schedule of Study Procedures
Part 1
Day
Screening
Check-in
Treatment
Final Visit
PK Follow-Up Follow-Up (a)
-28 to -2
Day -1
Day 1
Day 2
Day 3
Day 4
(Day 5)/ ET
Day 8
Day 12 (±2)
Informed consent 
X
Demographics and medical 
history
X
Medication history
X
HBsAg and anti-HCV
X
Inclusion/exclusion criteria
X
X
Height, weight and BMI (b)
X
X
Pregnancy avoidance 
counseling
X
X
X
X
Physical exam 
X
X
X
(X)
Urine drug and urine 
alcohol screen
X
X
Clinical laboratory 
evaluations (c)
X
X
X
X
X
X
X
X
(X)
Vital signs (d)
X
X
X
X
X
X
X
X
(X)
Concomitant medications 
(e)
X
X
X
X
X
X
X
X
X
12-lead ECG (f)
X
X
X
X
X
X
X
X
(X)
Confinement
X
X
X
X
X
TAK-071 dosing (g)
X
Scopolamine dosing (h)
X
PGx DNA collection (i)
X
PGx RNA collection (i)
X
X
TAK-071 PK (j)
X
X
X
X
X (k)
X
Food intake (l)
X
X
CSSRS (m)
X
X
X
(X)
AE assessment (n)
X
X
X
X
X
X
X
X
X
Footnotes are on last table page.


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Appendix A
Schedule of Study Procedures (continued)
ET=Early Termination Visit, h=hours.
(a) 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. Assessments indicated in parentheses (X) are only to be performed in case of attendance to study site.
(b) Height and BMI will be collected at Screening only.
(c) Blood samples for clinical laboratory tests (hematology, coagulation, serum chemistry, urinalysis) will be collected upon rising after a minimum 8-hour overnight fast. 
(d) Vital signs (oral temperature, respiration, pulse, and blood pressure) will be obtained as indicated.
(e) All ongoing medications will be recorded from Screening and throughout the study.
(f) A standard 12-lead ECG will be recorded at Screening and at Check-in (Day -1), Day 1 (predose [within 60 minutes prior to dosing]), and upon rising on Days 2, 3, 4 and 5, final 
visit and follow-up visit (Day 8).
(g) TAK-071 DIC will be administered on Day 1 (-24.0 hours relative to scopolamine dose).
(h) Scopolamine will be administered on Day 2.
(i) Blood samples for PGx analysis will be collected as follows: 6 mL for DNA on Day 1; 2×2.5 mL for RNA predose on Day 1, and 24 hours pos t scopolamine dose.
(j) 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) for plasma 
measurement of TAK-071 predose (within 30 minutes prior to dosing) and the specified time points (see Table 9.b).
(k) A PK blood sample should be collected at the ET Visit if possible.
(l) Food intake will be recorded on Days 1 and 2. On Day 1, breakfast will be served at 30 minutes prior to TAK-071 dose, lunch will be at served at approximately 3.5 hours post 
TAK-071 dose, and dinner will be served at 11.5 hours post TAK-071 dose. On Day 2, breakfast will be served at 30 minutes prior to scopolamine dose, lunch will be at served at 
approximately 5.5 hours post scopolamine dose, and dinner will be served at 9.5 hours post scopolamine dose.
(m) 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.
(n) PTEs will be collected from signing of informed consent to predose of study drug on Day 1. Any events that occur after dosing with study drug on Day 1 will be captured as an AE.


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Appendix A
Schedule of Study Procedures (continued)
Part 2
Screening
Periods 1, 2, 3, 4 and 5
Study Exit (a)
Follow-
up (b)
Day
Days
-56 to -2
Check-in 
Day -1
Day 1
Day 2
Day 3 
(Periods 1 
to 4)
(Day 3 of 
Period 5)/ ET
Day 9 (±2)
of Period 5
Scheduled Time Relative 
to Scopolamine Dosing (c)
-26 h
-25 h
-24 h
-3 h
0 h
1, 2, and 
3 h
4 h
6 h
8 h
10 h
24 h 
Informed consent 
X
Demographics and medical 
history
X
Medication history
X
HBsAg and anti-HCV
X
Inclusion/exclusion criteria
X
X (d)
Vital signs (e)
X
X
X
X
X
(X)
Height, weight and BMI (f)
X
X (d)
Concomitant medications 
(g)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy avoidance 
counseling
X
X
X
X
Physical exam 
X
X
X
X
(X)
Urine drug and urine alcohol 
screen
X
X
Randomization
X (d)
Clinical laboratory 
evaluations (h)
X
X
X
(X)
Footnotes are on last table page.


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Appendix A
Schedule of Study Procedures (continued)
Screening
Periods 1, 2, 3, 4 and 5
Study Exit (a)
Follow-
up (b)
Day
Days
-56 to -2
Check-in 
Day -1
Day 1
Day 2
Day 3 
(Periods 1 
to 4)
(Day 3 of 
Period 5)/ ET
Day 9
(±2) of 
Period 5
Scheduled Time Relative 
to Scopolamine Dosing (c)
-26 h
-25 h
-24 h
-3 h
0 h
1, 2, and 
3 h
4 h
6 h
8 h
10 h
24 h 
12-lead ECG (i)
X
X
X
X
X
(X)
Confinement
X
X
X
X
X
X
X
X
X
X
X
X
X
TAK-071 dosing (c) (j)
X
Donepezil dosing
X
Scopolamine dosing
X (k)
X
PGx DNA collection (l)
X
X (d)
PGx RNA collection (l)
X
X
X
TAK-071 PK (c) (m)
X#
X
X
X
X
X
X (a)
Donepezil PK (n)
X^
X
X
X
X
X
X (a)
Scopolamine PK (o)
X*
X
X
X
X
X (a)
CogState battery tests 
X (k) (p)
X (q)
X (r)
X
X
X
X
X
Sedation assessment (s)
X (k)
X
X
X
X
X
X
P300 ERP (t)
X
X
X
X
C-SSRS (v)
X
X
X
X
(X)
AE assessment (w)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Footnotes are on last table page.
CCI
CCI


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Appendix A
Schedule of Study Procedures (continued)
ET=Early Termination Visit, h=hours.
* Predose of scopolamine; # Predose of TAK-071; ^Predose of donepezil.
(a) A PK blood sample should be collected at the ET Visit if possible.
(b) Follow-up will occur by telephone on Day 9 (±2) of Period 5 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. Assessments indicated in parentheses (X) are only to be performed in case of attendance to study site.
(c) TAK-071 dosing time relative to scopolamine dosing and nominal times for scheduled assessments in Days 1 to 3 of each treatment period will be confirmed once actual TAK-071 
clinical PK data becomes available. The times at which the assessments occur relative to scopolamine dosing may be changed and assessment time points might be removed, but the 
number of assessments will not be increased over the planned total number.
(d) Period 1 only.
(e) Vital signs (oral temperature, respiration, pulse, and blood pressure) will be obtained as indicated.
(f) Height and BMI will be collected at Screening only.
(g) All ongoing medications will be recorded from Screening and throughout the study.
(h) Blood samples for clinical laboratory tests (hematology, coagulation, serum chemistry, urinalysis) will be collected upon rising after a minimum 8-hour overnight fast. 
(i) A standard 12-lead ECG will be recorded at Screening and at Check-in (Day -1), Day 1 (predose [within 60 minutes prior to dosing]), and Day 3 of each treatment period.
(j) DIC will be dispensed for treatment.
(k) Pre-enrollment enrichment procedures are to be performed after all other Screening assessments have been performed and deemed to be in compliance with study requirements. 
The GMLT will be performed at Baseline (after sufficient practice) and 1, 2, and 3 hours postdose. Baseline assessment will be done on 2 occasions (separated by 30 minutes) prior 
to administration of scopolamine, and the average will be derived.
(l) Blood samples for PGx analysis will be collected as follows: 6 mL for APOE at pre-enrollment enrichment Screening Visit, 6 mL for DNA on Day 1 of Period 1 only; 2×2.5 mL 
for RNA predose on Day 1, and 24 hours post scopolamine dose of each period.
(m) 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) for 
plasma measurement of TAK-071 predose (within 30 minutes prior to dosing) and the specified time points (See Table 9.c).
(n) Blood samples (one 4-mL sample per scheduled time) for PK analysis of plasma donepezil will be collected into chilled Vacutainers containing anticoagulant sodium heparin (See 
Table 9.c).
(o) Blood samples (one 4-mL sample per scheduled time) for PK analysis of plasma scopolamine will be collected into chilled Vacutainers containing anticoagulant K2EDTA (See 
Table 9.c).
(p) GMLT (only) will be undertaken at Baseline and at 1, 2 and 3 hours postdose of scopolamine (other CogState Battery tests will not be performed at this visit). Baseline assessment 
will be done on 2 occasions, separated by 30 minutes, prior to administration of scopolamine.
(q) Subjects will be required to practice the cognitive test battery on up to 3 occasions, at investigator discretion.
(r) Baseline assessment will be done on 2 occasions, separated by 30 minutes.
(s) Level of sedation will be assessed after each cognitive test.
(t) qEEG and P300 ERP will be measured at the time points outlined.
(u)
.
(v) 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.
(w) PTEs will be collected from signing of informed consent to pre-dosing of study drug on Day 1. Any events that occur after dosing with study drug on Day 1 will be captured as an 
AE.
CCI


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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures; including study specific (nonroutine/nonstandard panel) 
Screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.


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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. 
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.


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Appendix C
Elements of the Subject Informed Consent 
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 


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legally acceptable representative may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of 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/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study drug(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.


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25. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study and for 70 days after 
the last dose of study drug after last dose. If the partner or wife of the subject is found to be 
pregnant during the study, the investigator will offer the subject the choice to receive 
unblinded treatment information. 
26. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as www.ClinicalTrials.gov. 


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Appendix D
Investigator Consent to Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study drug.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.


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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 using 1.5 to 3.5 mL polypropylene cryotubes. A 
minimum of approximately 0.5 mL needs to be obtained for each sample. Labeling may 
include protocol number (TAK-071-1002), analyte (TAK-071), sample matrix (ie, plasma) 
randomization 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 
. 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 using 1.5 to 3.5 mL polypropylene cryotubes. A 
minimum of approximately 0.8 mL needs to be obtained for each sample. Labeling may 
include protocol number (TAK-071-1002), analyte (donepezil), sample matrix (ie, plasma) 
randomization 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 
. No more than 
45-60 minutes will elapse between blood collection and freezing the plasma sample.
PPD
PPD


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Instructions for Processing of Plasma Samples for PK Analysis of Scopolamine
1. Collect 4 mL of venous blood into a chilled Becton-Dickinson Vacutainer. All scopolamine 
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 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 using 1.5 to 3.5 mL polypropylene cryotubes. A 
minimum of approximately 0.8 mL needs to be obtained for each sample. Labeling may 
include protocol number (TAK-071-1002), analyte (scopolamine), sample matrix (ie, plasma) 
randomization 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 
. No more than 
45-60 minutes will elapse between blood collection and freezing the plasma sample.
Shipping of Plasma 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) 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. 
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 4-digit randomization sequence number, sample matrix 
(plasma) 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.”
PPD


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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-071-1002), 
investigator’s name, sample type (plasma), subject randomization 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 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 Samples for TAK-071 and Donepezil
 
Phone: 
Fax: 
email: 
Plasma Samples for Scopolamine
Attn: 
2701 Kent Ave.
West Lafayette, IN 47906
Phone: 
email: 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PP
D
PPD


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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 and donepezil samples, please email 
 at 
to notify him of next day delivery. After shipping of the 
scopolamine samples, please email 
 at 
 to notify him of 
next day delivery. When calling, provide the following information:
Name of courier or transport company
Time and date the shipment left the clinical site
Airway bill number
PPD
PPD
PPD
PPD


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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.
CYP Isoform
Strong Inhibitors
Moderate Inhibitors
CYP3A4
indinavir
nelfinavir
lopinavir /ritonavir
ritonavir
clarithromycin
erythromycin
itraconazole
ketoconazole
nefazodone
saquinavir
saquinavir/ritonavir
telithromycin
boceprevir
conivaptan
grapefruit /grapefruit juice
mibefradil
posaconazole
telaprevir
voriconazole
aprepitant
atazanavir
atazanavir/ritonavir
fluconazole
verapamil
diltiazem 
amprenavir 
atazanavir
ciprofloxacin 
darunavir/ritonavir
fosamprenavir
grapefruit/grapefruit juice
imatinib
cimetidine
cyclosporin
fluvoxamine
posaconazole
CYP2C9
NA
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
NA
CYP2D6
dexamethasone, rifampin
NA
Other food products to be avoided
Star fruit/star fruit juice, pomegranates/pomegranate juice, papaya/papaya juice, Séville oranges/Séville orange juice 
Sources: Polasek et al. [30], http://medicine.iupui.edu/clinpharm/ddis/main-table/, 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm
NA=not applicable.


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Appendix G
Detailed Description of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment No. 02 are indicated. 
The corresponding text has been revised throughout the protocol.
Change 1: Modify the main part (Part 2) of the study design to include a fifth arm and change the 
study to a 10-sequence, 5-period crossover study.
The primary change is described in Sections 6.2 Study Design – Part 2.
Initial 
wording:
This is a randomized, double-blind, sponsor unblinded, placebo-controlled, 
4-treatment, 4-period, 4-sequence crossover phase 1b proof of mechanism study to 
evaluate the effects of a single PO administration of TAK-071, a novel M1R PAM, on 
scopolamine-induced deficits in cognitive function in healthy adult male subjects.
Approximately 32 subjects are expected to be randomized in this study, with the total 
of 8 subjects per sequence, with a minimum of 6 completers. A schematic of the study 
design is provided in Figure 6.c. 
[Original Figure 6.c Schematic of Study Design – Part 2]
6.2.1 Pre-Enrollment Enrichment Screening – Part 2
…
Subjects will remain under observation for a minimum of 8 hours post-scopolamine 
administration to ensure that scopolamine-induced effects have worn off and it is safe 
for the subjects to leave the study center.
Any subjects unable to perform the CogState battery after training will be excluded 
from entering Part 2, the main study.
6.2.2 Treatment Sequences – Part 2
In each period, subjects will check-in at the study site on Day -1 and will be confined 
until Day 3 (approximately 24 hours postdose of scopolamine). 
Subjects will be randomly assigned to 1 of 4 possible treatment sequences (described 
in Section 8.1.3) before the first dose of study drug, each consisting of 4 treatment 
periods (Table 6.a). 
[Original Table 6.a Summary of Treatment Sequences in Study - Part 2]
…
Scopolamine will be administered as a single 0.5 mg SC injection.
…
Donepezil will be administered as a single 10 mg capsule PO 3 hours before injecting 
scopolamine to maximize the chances of observing a reversal of the 


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scopolamine-induced cognitive impairment. 
…
Information on the safety and tolerability of TAK-071 in combination with 
scopolamine will be obtained from treatment periods in which active TAK-071 is 
administered (Treatment B). Safety and tolerability will be obtained during Treatment 
A for scopolamine alone and during Treatment C for donepezil in combination with 
scopolamine.
Amended 
or new 
wording
This is a randomized, double-blind, sponsor unblinded, placebo-controlled, 
4 5-treatment, 4 5-period, 4 10-sequence crossover phase 1b proof of mechanism 
study to evaluate the effects of a single PO administration of TAK-071, a novel M1R 
PAM, on scopolamine-induced deficits in cognitive function in healthy adult male 
subjects.
Approximately 32 40 subjects are expected to be randomized in this study, with the 
total of 8 4 subjects per sequence, with a minimum of 6 3 completers. A schematic of 
the study design is provided in Figure 6.c.
[Revised Figure 6.c Schematic of Study Design – Part 2]
[Figure 6.c revisions:

“Treatment Periods 1-4” column revised to “Treatment Periods 1 to 5”. 

Column added for “Wash out Periods 1 to 4” with “Days 4 to 20”.

“Follow-Up” column; days revised from “Day 72 (±2)” to “Day 9 (±2) 
Period 5”.]
6.2.1 Pre-Enrollment Enrichment Screening – Part 2
…
Subjects will remain under observation for a minimum of 8 hours post-scopolamine
post-scopolamine administration per principal investigator’s discretion to ensure 
that scopolamine-induced effects have worn off and it is safe for the subjects to leave 
the study center.
Any subjects subject unable to perform the CogState battery after training will be 
excluded from entering Part 2, the main study.
6.2.2 Treatment Sequences – Part 2
In each period, subjects will check-in at the study site on Day -1 and will be confined 
until Day 3 (approximately 24 hours postdose of scopolamine or matching placebo). 
Subjects will be randomly assigned to 1 of 4 10 possible treatment sequences 
(described in Section 8.1.3) before the first dose of study drug, each consisting of 
4 5 treatment periods (Table 6.a).


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Table 6.a
Summary of Treatment Sequences in Study - Part 2
Sequence
Period 1
Period 2
Period 3
Period 4
Period 5
1
A
Minimum 
3-week 
washout
B
Minimum 
3-week 
washout
D
Minimum 
3-week 
washout
C E
Minimum 
3-week 
washout
C
2
B
C
A E
D A
D
3
C
D
B A
A B
E
4
D
A E
C B
B C
A
5
E
A
C
D
B
6
A
C
B
E
D
7
B
D
C
A
E
8
C
E
D
B
A
9
D
A
E
C
B
10
E
B
A
D
C
A=scopolamine + matching placebos for placebo SC + TAK-071 and matching placebo PO + donepezil; matching 
placebo PO.
B=TAK-071, scopolamine, and 0.5 mg SC + TAK-071 matching placebo for PO + donepezil; matching placebo 
PO.
C=donepezil, scopolamine, and 0.5 mg SC + TAK-071 PO + donepezil matching placebo for TAK-071; PO.
D=all placebo scopolamine 0.5 mg SC + TAK-071 PO + donepezil 10 mg PO.
E=scopolamine 0.5 mg SC + TAK-071 matching placebo PO + donepezil 10 mg PO.
Scopolamine (0.5 mg) or matching placebo will be administered as a single 0.5 mg
SC injection.
TAK-071 or matching placebo will be administered as a single PO dose (as DIC) 24
hours before scopolamine administration. 
…
Donepezil (10 mg) tablet (overencapsulated) or matching placebo will be 
administered as a single 10 mg capsule PO 3 hours before injecting scopolamine to 
maximize the chances of observing a reversal of the scopolamine-induced cognitive 
impairment. 
…
Information on the safety and tolerability of TAK-071 in combination with 
scopolamine and/or donepezil will be obtained from treatment periods in which 
active TAK-071 is administered (Treatment B Treatments C and D). Safety and 
tolerability will be obtained during Treatment A for placebo, Treatment B for
scopolamine alone, and during Treatment C E for donepezil in combination with 
scopolamine.
Rationale for Change:
The new study design will provide information on the combined pharmacodynamic effect of 
TAK-071 and donepezil.


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The following sections also contain this change:
!
Title Page.
!
Section 2.0 STUDY SUMMARY.
!
Section 6.3.2 Justification for Design for Part 2.
!
Section 7.5.2 Part 2.
!
Section 8.1.3.2 Part 2. 
!
Section 8.2.2 Part 2.
!
Section 8.6 Accountability and Destruction of Sponsor-Supplied Drugs.
!
Section 9.1.12.2 RNA Sample Collection Part 2.
!
Section 9.3.1 Study Exit.
!
Section 9.3.3 Follow-up Visit/Telephone Call.
!
Section 13.1.4.1 Cognitive Testing Analysis.
!
Section 13.3 Determination of Sample Size.
!
Appendix A Schedule of Study Procedures Part 2.
Change 2: Add an additional secondary objective and modify an exploratory/additional objective.
The primary change is described in Sections 5.1.2 and 5.1.3:
Initial 
wording
5.1.2 Secondary Objectives
!
To characterize the safety and tolerability of a single PO dose of TAK-071 when 
co-administered with SC scopolamine (0.5 mg) in healthy subjects.
!
To characterize the single PO dose plasma PK profile of TAK-071 when 
co-administered both with scopolamine and a low-calorie, low-fat breakfast in 
healthy subjects.
!
To demonstrate assay sensitivity by using donepezil 10 mg as the positive control.
5.1.3 Exploratory/Additional Objectives
CCI


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Amended 
or new text
5.1.2 Secondary Objectives
!
To characterize the safety and tolerability of a single PO dose of TAK-071 when 
co-administered with SC scopolamine (0.5 mg) in healthy subjects.
!
To characterize the single PO dose plasma PK profile of TAK-071 when 
co-administered both with scopolamine and a low-calorie, low-fat breakfast in 
healthy subjects.
!
To demonstrate assay sensitivity by using donepezil 10 mg as the positive control.
!
To assess the effect of a single PO dose of TAK-071 in combination with 
10 mg donepezil on the attenuation of cognitive deficit induced by 
scopolamine (0.5 mg subcutaneous [SC]) as measured by Groton Maze 
Learning Test (GMLT) (total number of errors).
5.1.3 Exploratory/Additional Objectives
CCI
CCI


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Rationale for Change:
To include additional objective(s) for the updated study design.
The following sections also contain this change:
!
Section 2.0 STUDY SUMMARY.
!
Appendix A Schedule of Study Procedures Part 2.
Change 3: Change in inclusion criteria.
The primary change is described in Section 7.3:
Initial 
wording
7.3 Additional Inclusion Criteria for Part 2 After Pre-Enrollment Enrichment 
Screening
1. Subject able to perform the CogState battery.
2. Change from Baseline (average) in total GMLT errors of ≤-5 at 2 hours postdose 
of scopolamine.
3. Subjects with sleepiness score <8 on the KSS at 2 hours postdose of 
scopolamine.
4. Subject passes a hearing test with at least 90% correct responses and no more 
than 10% false positives. This test can be repeated once to determine eligibility.
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Amended or 
new text
7.3 Additional Inclusion Criteria for Part 2 After Pre-Enrollment Enrichment 
Screening
1. Subject able to perform the CogState battery.
2. Change from Baseline (average) in total GMLT errors of ≤-5 at 2 hours 
postdose of scopolamine.
3. Subjects with sleepiness score <8 on the KSS at 2 hours postdose of 
scopolamine.
4. Subject passes a hearing test with at least 9080% correct responses and no 
more than 1020% false positives. This test can be repeated once to determine 
eligibility.
Rationale for Change:
Revision in the criteria.
The following section also contain this change:

Section 2.0 STUDY SUMMARY.
Change 4: Update dietary and fluid consumption for Part 2.
The primary change is described in Section 7.5.2 Part 2:
Initial 
wording
TAK-071 will be administered as a single PO dose (DIC) 24 hours before scopolamine 
dosing approximately 1.5 hours following a low-calorie, low-fat breakfast. No 
additional food will be permitted for up to 4 hours after TAK-071 dosing. Subjects 
may consume water ad libitum with the exception of 1 hour before and 1 hour after 
TAK-071 drug administration. Meal timings, as well as their caloric and fat content, 
may be changed in the event of adjustments to the TAK-071 administration time.
Amended 
or new text
TAK-071 or matching placebo will be administered with approximately 240 mL of 
water after a fast of at least 8 hours as a single PO dose (DIC) 24 hours before 
scopolamine dosing and approximately 1.5 hours following a low-calorie, low-fat 
breakfast. No additional food will be permitted for up to 4 hours after TAK-071 
dosing. Donepezil will be administered with approximately 240 mL of water after 
a fast of at least 8 hours as a single PO dose 3 hours before scopolamine dosing.
Subjects may consume water ad libitum with the exception of 1 hour before and 1 hour 
after TAK-071 drug, donepezil, or placebo administration. Meal timings, as well as 
their caloric and fat content, may be changed in the event of adjustments to the 
TAK-071 administration time.
Rationale for Change:
To include additional treatments and provide further clarifications.


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Change 5: Change in procedure for qEEG.
The primary change is described in Section 9.1.15.3 qEEG:
Initial 
wording
The electroencephalographs (EEGs) will be acquired using the Brain Atlas Bio-logic 
system; and signal will be recorded from 20 electrodes attached to the scalp according 
to the international 10-20 system. A 10-minute EEG recording will be made for each 
subject while they rest with their eyes closed; minimum of 60 seconds artifact-free 
epochs are going to be subsequently selected for processing. Frequency domains will 
be obtained from the corresponding frequency bands by using the Fourier transform 
and the following: δ (1-3.5 Hz), θ (4-7.5 Hz), αl (8-9.5 Hz), α2 (10-11.5 Hz), ßl
(12-20.5 Hz), ß2 (21-30.5 Hz) and γ (30-50 Hz) frequency bands.
Baseline assessment for qEEG will be done on 2 occasions approximately 24 hours 
apart. The average of the 2 Baseline assessments will be used for any calculations 
involving Baseline (ie, estimation of change from Baseline). 
An additional assessment may be made at another suitable time point if it is judged 
that this will add additional learning/information given the observations at the earlier 
time points. 
A brief hearing test will be performed for the purpose of documenting that subjects 
have adequate hearing to participate in the auditory ERP procedure. A series of 60 
tones between 1 and 3 seconds apart are presented at 70 dB SPL. If the subject presses 
a key within 500 ms after the presentation of the tone, a CORRECT response is 
recorded. If the subject presses a key more than 1000 ms after the presentation of the 
tone (but before the next tone), a FALSE_POSITIVE is recorded. Subjects who pass 
with at least 90% correct responses and no more than 10% false positives will be 
eligible to participate in the auditory ERP procedure. 
A score sheet that includes subject ID, date, percent correct, and percent of false 
positives will be created for each subject. A Pass/Fail determination will be provided 
as well. If the 90 percent/10 percent criteria is not met, the procedure can be repeated 
once. No additional data will be transferred to sponsor.
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Amended 
or new text
A brief hearing test will be performed for the purpose of documenting that subjects 
have adequate hearing to participate in the auditory ERP procedure. A series of 60 
tones between 1 and 3 seconds apart are presented at 70 dB SPL. If the subject presses 
a key within 500 ms after the presentation of the tone, a CORRECT response is 
recorded. If the subject presses a key more than 1000 ms after the presentation of the 
tone (but before the next tone), a FALSE_POSITIVE is recorded. Subjects who pass 
with at least 90% correct responses and no more than 10% false positives will be 
eligible to participate in the auditory ERP procedure. (Three-Stimulus Auditory 
Oddball Task). The test will present three types of stimulus tones for a total of 
100 stimuli: Standard Tones (70%), Target Tones (15%), and Distractor Tones 
(15%).
All three tones are brief 75ms binaural sound stimuli, which differ in pitch but 
no in loudness (70dB sound pressure level [SPL]). Subjects attend to the tones 
which occur every 1.2 seconds and respond when a tone is heard. Subjects who 
pass with at least 80% correct responses (hits) and no more than 20% incorrect 
responses (false alarms) will be eligible to participate in the auditory ERP 
procedure.
A paper score sheet that includes subject ID, date, percent correct, and percent of false 
positivesalarms will be created for each subject. Aand a Pass/Fail determination will 
be provided as well. If the 9080 percent/1020 percent criteria is not met, the procedure 
can be repeated once. No additional data will be transferred to sponsor.
CCI


TAK-071
Study No. TAK-071-1002
Page 110 of 113
Protocol Incorporating Amendment No. 02 
10 March 2017
CONFIDENTIAL
Rationale for Change:
Amended to capture recent procedural change.
Change 6: Change the order of pharmacodynamic (PD) assessments.
The primary change is described in Section 9.1.17 PK/PD Assessment Order (Only for Part 2):
Initial 
wording
For PD Baseline on Day 1 and predose to Scopolamine the following order should be 
followed:

Low-calorie low-fat breakfast: Approximately 2 hour prior to study drug dosing.

Pupillometry: Approximately 90 minutes prior to study drug dosing.

qEEG and ERP: Immediately after pupillometry and approximately 85 minutes 
prior to study drug dosing.

Cognitive test: Immediately after qEEG and approximately 60 minutes prior to 
study drug dosing.

Sleepiness monitoring: Immediately after cognitive testing and approximately 45 
minutes prior to study drug dosing.

PK blood draw: To be taken approximately within 30 minutes of the scheduled 
time point.
PK/PD assessments that coincide at the same scheduled time point will be performed 
in the following order: 

Pupillometry: Approximately 20 minutes prior to scheduled time point.

qEEG: Immediately after pupillometry and approximately 15 minutes prior to 
scheduled time point.

PK blood draw: To be taken approximately at the scheduled time.

Cognitive test: Immediately after PK blood draw.

Sleepiness monitoring: Immediately after cognitive testing.


TAK-071
Study No. TAK-071-1002
Page 111 of 113
Protocol Incorporating Amendment No. 02 
10 March 2017
CONFIDENTIAL
Amended 
or new text
For PD Baseline on Day 1 and predose to scopolamine the following order should be 
followed:

Low-calorie low-fat breakfast: Approximately 2.5 hours prior to study drug 
dosing.

qEEG and ERP: Approximately 120 minutes prior to study drug dosing.

Pupillometry: Approximately 90 minutes prior to study drug dosing.

qEEG and ERP: Immediately after pupillometry and approximately 85100 
minutes prior to study drug dosing.

Cognitive test: Immediately after qEEGpupillometry and approximately 6090
minutes prior to study drug dosing.

Sleepiness monitoring: Immediately after cognitive testing and approximately 
4570 minutes prior to study drug dosing.

PK blood draw: To be taken approximately within 30 minutes of the scheduled 
time point.
PK/PD assessments that coincide at the same scheduled time point will be performed 
in the following order: 

PupillometryqEEG: Approximately 2040 minutes prior to scheduled time point.

qEEGPupillometry: Immediately after pupillometryqEEG and approximately 
155 minutes prior to scheduled time point.

PK blood draw: To be taken approximately at the scheduled time.

Cognitive test: Immediately after PK blood draw.

Sleepiness monitoring: Immediately after cognitive testing.
The following sections also contain one or more of these changes:

Section 9.1.15.4
Rationale for Change:
To obtain accurate PD assessments.


TAK-071
Study No. TAK-071-1002
Page 112 of 113
Protocol Incorporating Amendment No. 02 
10 March 2017
CONFIDENTIAL
Change 7: Change blood volume for Part 2.
The primary change is described in Section 9.5 Blood Volume.
Initial 
wording:
[Original Table 9.f Approximate Blood Volume for Par 2]
…
The maximum volume of blood for Part 2 at any single day is approximately 120 mL, 
and the approximate total volume of blood for the study is 536.5 mL. 
…
A catheter with a normal saline flush may be used; however, 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). Should a catheter be used, the total blood volume taken during the study 
must not exceed 550 mL.
Amended or new wording:
Table 9.f
Approximate Blood Volume for Part 2
Sample Type
Sample 
Volume 
(mL)
Number of Samples
Total 
Volume 
(mL)
Screening 
Period 1
(Day -1 
to 3)
Period 2
(Day -1 
to 3)
Period 3
(Day -1 
to 3)
Period 4
(Day -1 
to 3)
Period 5
(Day -1 
to 3)
Clinical laboratory tests
20 mL
2
1
1
1
1
2
140160
Serology test
8.5 mL
1
0
0
0
0
0
8.5
PGx DNA sample 
collection 
6 mL
1
1
0
0
0
0
12
PGx RNA sample collection 2.5 mL
0
4
4
4
4
4
4050
TAK-071 PK blood 
collection
3 mL
0
8
8
8
8
8
96120
Scopolamine PK blood 
collection
4 mL
0
7
7
7
7
7
112140
Donepezil PK blood 
collection
4 mL
0
8
8
8
8
8
128160
Total Approximate Blood Sampling Volume 536.5650.5


TAK-071
Study No. TAK-071-1002
Page 113 of 113
Protocol Incorporating Amendment No. 02 
10 March 2017
CONFIDENTIAL
...
The maximum volume of blood for Part 2 at any single day is approximately 120 mL, 
and the approximate total volume of blood for the study is 536650.5 mL.
….
A catheter with a normal saline flush may be used; however, 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). Should a catheter be used, the total blood volume taken during the study 
must not exceed 550650.5 mL.
Rationale for Change:
To account for samples in the additional period.
Change 8: Clarification on pretreatment event (PTE) collection period.
The primary change is described in Section 10.2.1.1 PTE and AE Collection Period:
Initial 
wording
Collection of PTEs will commence from the time the subject signs the informed 
consent to participate in the study and continue until the subject is first administered 
study drug (Day 1 of Period 1) or until screen failure. For subjects who discontinue 
prior to study drug administration, PTEs are collected until the subject discontinues 
study participation.
Amended 
or new text
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 (on Day 1 for of PeriodPart 1), or Pre-enrollment Enrichment Visit for 
Part 2, or until screen failure. For subjects who discontinue prior to study drug 
administration, PTEs are collected until the subject discontinues study participation.
Rationale for Change:
To make correction.


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PPD
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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:  A Randomized, Double-Blind, Sponsor Unblinded, Placebo-Controlled, 5-Period 
Crossover, Phase 1b Study To Evaluate The Effects Of Single Oral Administration of TAK-071 On 
Scopolamine-Induced Cognitive Impairment In Healthy Subjects
NCT Number: NCT02918266
SAP Approve Date: 22 March 2018 
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.


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CONFIDENTIAL INFORMATION
Do not distribute outside of Takeda without a confidentiality agreement.
TAKEDA DEVELOPMENT CENTER
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-071-1002
A Randomized, Double-Blind, Sponsor Unblinded, Placebo-Controlled, 5-Period 
Crossover, Phase 1b Study To Evaluate The Effects Of Single Oral Administration of 
TAK-071 On Scopolamine-Induced Cognitive Impairment In Healthy Subjects
Phase 1b TAK-071 Scopolamine-Induced Cognitive Impairment Study
Version: Final
Date: 22 March 2018
Prepared by:
, PhD
 Pharmaceutical Product Development
Prepared by:
, BA
, Pharmaceutical Product Development
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
PPD
PPD


PPD


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1.0
TABLE OF CONTENTS
1.0
TITLE PAGE
1
1.1.
APPROVAL SIGNATURES ......................................................................................2
1.0
TABLE OF CONTENTS..............................................................................................................3
2.0
LIST OF ABBREVIATIONS........................................................................................................5
3.0
OBJECTIVES.............................................................................................................................6
1.2.
PRIMARY OBJECTIVE ..................................................................................................6
1.3.
SECONDARY OBJECTIVES............................................................................................6
1.4.
EXPLORATORY/ADDITIONAL OBJECTIVES ......................................................................6
1.5.
STUDY DESIGN ..........................................................................................................7
4.4.1.
OVERVIEW.................................................................................................................7
4.4.2.
STUDY DESIGN – PART 1 ............................................................................................7
4.4.3.
STUDY DESIGN – PART 2 ............................................................................................8
4.4.3.1.
PRE-ENROLLMENT ENRICHMENT SCREENING – PART 2 .....................................................8
4.4.3.2.
TREATMENT SEQUENCES – PART 2.................................................................................9
4.0
ANALYSIS ENDPOINTS ..........................................................................................................12
5.1
PRIMARY ENDPOINT .................................................................................................. 12
5.2
SECONDARY ENDPOINTS ...........................................................................................12
5.3
EXPLORATORY/ADDITIONAL ENDPOINTS ..................................................................... 12
5.0
DETERMINATION OF SAMPLE SIZE ......................................................................................13
6.0
METHODS OF ANALYSIS AND PRESENTATION................................................................... 14
7.1
GENERAL PRINCIPLES...............................................................................................14
7.1.1.
MISSING DATA .........................................................................................................14
7.1.2.
DERIVED DATASETS AND VARIABLES ..........................................................................14
7.1.3.
DEFINITION OF STUDY DAYS AND BASELINE ................................................................14
7.2
ANALYSIS SETS........................................................................................................ 15
7.3
DISPOSITION OF SUBJECTS........................................................................................15
7.4
PROTOCOL DEVIATIONS ............................................................................................15
7.5
DEMOGRAPHIC AND BASELINE CHARACTERISTICS........................................................15
7.6
MEDICAL HISTORY AND CONCURRENT MEDICAL CONDITIONS........................................16
7.7
MEDICATION HISTORY AND CONCOMITANT MEDICATIONS .............................................16
7.8
STUDY DRUG EXPOSURE AND COMPLIANCE ................................................................16
7.9
EFFICACY ANALYSIS ................................................................................................. 16
7.10
PHARMACOKINETIC ANALYSIS ....................................................................................16
7.10.1
PLASMA PHARMACOKINETIC CONCENTRATIONS...........................................................16
7.10.2
PLASMA PHARMACOKINETIC PARAMETERS.................................................................. 17
7.10.3
PHARMACODYNAMIC PARAMETERS.............................................................................18


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7.11
SAFETY ANALYSIS .................................................................................................... 18
7.11.1
ADVERSE EVENTS .................................................................................................... 18
7.11.2
CLINICAL LABORATORY EVALUATIONS ........................................................................19
7.11.3
VITAL SIGNS ............................................................................................................20
7.11.4
12-LEAD ECGS .......................................................................................................20
7.11.5
OTHER OBSERVATIONS RELATED TO SAFETY..............................................................21
7.11.5.1
PHYSICAL EXAMINATION............................................................................................21
7.11.5.2
COLUMBIA - SUICIDE SEVERITY RATING SCALE (C-SSRS)............................................21
7.12
INTERIM ANALYSIS.................................................................................................... 22
7.13
CHANGES IN THE STATISTICAL ANALYSIS PLAN ............................................................22
7.0
REFERENCES .........................................................................................................................23
LIST OF APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values .................24
Appendix B
Criteria for Markedly Abnormal Values for Vital Signs......................................26
Appendix C
Criteria for Markedly Abnormal Values for Electrocardiograms.........................27


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2.0
LIST OF ABBREVIATIONS
ADaM
Analysis Data Model
bpm
beats per minute
CV%
percent coefficient of variation
AE
adverse event
AUC∞
area under the plasma concentration-time curve from time 0 to infinity
AUClast
area under the plasma concentration-time curve from time 0 to time of the last 
quantifiable concentration
BMI
body mass index
Cmax
maximum observed plasma concentration
CS
clinically significant
C-SSRS
Columbia - Suicide Severity Rating Scale
DIC
drug-in-capsule
ECG
Electrocardiogram
eCRF
electronic case report form
ET
early termination
GMLT
Groton Maze Learning Test
KSS
Karolinska Sleepiness Scale
MedDRA
Medical Dictionary for Regulatory Activities
N
number of subjects
NCS
not clinically significant
PD
pharmacodynamic
PK
Pharmacokinetic
PO
single oral
PT
preferred term
qEEG
quantitative electroencephalography
SAE
serious adverse event
SC
Subcutaneous
SD
standard deviation
SOC
system organ class
t1/2z
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
tmax
time to first occurrence of Cmax


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3.0
OBJECTIVES
Note: Enrollment was paused in July 2017 
. At that time, 
Part 1 was complete and 12 subjects had enrolled in Part 2. The Part 2 subjects were 
discontinued at that time. Subsequently, in January 2018, the global product team decided not to 
resume enrollment in the study. Therefore, only certain safety and pharmacokinetic (PK)-related 
endpoints will be analyzed. The original study objectives are given below.
1.2.
PRIMARY OBJECTIVE
The primary objective of this study is as follows:
!
To assess the effect of a single oral (PO) dose of TAK-071 on the attenuation of cognitive 
deficit induced by scopolamine (0.5 mg subcutaneous [SC]) as measured by Groton Maze 
Learning Test (GMLT) (total number of errors).
1.3.
SECONDARY OBJECTIVES
The secondary objectives of this study are as follows:
!
To characterize the safety and tolerability of a single PO dose of TAK-071 when co-
administered with SC scopolamine (0.5 mg) in healthy subjects.
!
To characterize the single PO dose plasma PK profile of TAK-071 when co-administered 
both with scopolamine and a low-calorie, low-fat breakfast in healthy subjects.
!
To demonstrate assay sensitivity by using donepezil 10 mg as the positive control.
!
To assess the effect of a single PO dose of TAK-071 in combination with 10 mg donepezil 
on the attenuation of cognitive deficit induced by scopolamine (0.5 mg [SC]) as measured by 
GMLT (total number of errors).
1.4.
EXPLORATORY/ADDITIONAL OBJECTIVES
The exploratory objectives of this study are as follows:
CCI
CCI


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1.5.
STUDY DESIGN
4.4.1.OVERVIEW
This study consists of 2 parts.
Part 1 is an open-label initial substudy to explore the PK profile of TAK-071 in the presence of a 
light meal and co-administration of scopolamine to determine TAK-071 dose for Part 2, the main 
study.
Part 2 is the main study to assess the effects of TAK-071 on scopolamine-induced cognitive 
impairment.
4.4.2.STUDY DESIGN – PART 1
This is a nonrandomized, open-label, 1-treatment, 1-period, 1-sequence phase 1 study to 
characterize the plasma PK of TAK-071 when administered under the same conditions as in 
Part 2, the main study. This is in conjunction with scopolamine, and together with a low-calorie, 
low-fat breakfast in healthy adult male subjects. Approximately 6 healthy subjects are enrolled in 
this substudy with a minimum of 4 completers.
A schematic of Part 1, the substudy, design is provided in Figure 4.a.
Figure 4.a Schematic of Study Design – Part 1
Subjects check-in at the study site on Day -1 and are confined until the completion of
assessments on Day 4. A follow-up PK assessment is performed on Day 8 and a final follow-up 
occurs of Day 12 (±2).
Scopolamine is administered as a single 0.5 mg SC injection.
TAK-071 is administered as a single PO dose (as drug-in-capsule [DIC]) 24 hours before
scopolamine administration.
Blood samples for the analysis of TAK-071 plasma concentrations are obtained at specified
time-points up to 168 hours after TAK-071 dosing (144 hours after scopolamine dosing).
Safety and tolerability of TAK-071 in combination with scopolamine are assessed from physical 
examination, adverse events (AEs), clinical laboratory tests, electrocardiograms (ECGs), etc.
The planned timing of assessments and meals relative to scopolamine dosing in Part 1 is shown 
in Figure 4.b.
CCI


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Figure 4.b TAK-071 PK Assessments and Meal Timing Relative to Scopolamine 
Administration – Part 1 (Days 1 and 2)
4.4.3. STUDY DESIGN – PART 2
This is a randomized, double-blind, sponsor unblinded, placebo-controlled, 5-treatment, 5-period, 
10-sequence crossover phase 1b proof of mechanism study to evaluate the effects of a single PO 
administration of TAK-071, a novel M1R PAM, on scopolamine-induced deficits in cognitive 
function in healthy adult male subjects.
Approximately 40 subjects are expected to be randomized in this study, with the total of 4
subjects per sequence, with a minimum of 3 completers. A schematic of the study design is 
provided in Figure 4.c.
Figure 4.c Schematic of Study Design – Part 2
4.4.3.1.
PRE-ENROLLMENT ENRICHMENT SCREENING – PART 2
To ensure that enrolled subjects show cognitive impairment in the presence of scopolamine but 
with minimal sedation and/or fatigue, all subjects who meet Screening inclusion/exclusion 
criteria are administered an SC dose of scopolamine 0.5 mg.


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Pre-enrollment enrichment procedures are conducted as part of the Screening assessments
between 56 and 2 days before Day 1, and the results are used to accept/reject the subject for
enrollment to Part 2, the main study.
Subjects remain under observation post-scopolamine administration per principal investigator’s 
discretion to ensure that scopolamine-induced effects have worn off and it is safe for the subjects 
to leave the study center.
Any subjects unable to perform the CogState battery after training are excluded from entering
Part 2, the main study.
4.4.3.2.
TREATMENT SEQUENCES – PART 2
In each period, subjects check-in at the study site on Day -1 and are confined until Day 3 
(approximately 24 hours postdose of scopolamine or matching placebo).
Subjects are randomly assigned to 1 of 10 possible treatment sequences before the first dose of 
study drug, each consisting of 5 treatment periods (Table 4.a).
Table 4.a Summary of Treatment Sequences in Study - Part 2
A 3-week (21-day) washout between treatment periods is required because of the long t1/2z of 
donepezil to minimize the potential for carryover effects.
The planned timing of assessments and meals relative to scopolamine dosing is shown in Figure 
4.d.
Scopolamine is administered as a single 0.5 mg SC injection.
TAK-071 or matching placebo is administered as a single PO dose (as DIC) 24 hours before 
scopolamine administration.
The dose of TAK-071 for Part 2 is selected depending on the results from Part 1 (initial substudy) 
and the FIH Study TAK-071-1001; however, under no circumstances does the selected TAK-071 


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dose exceed the maximum tolerated dose (MTD), or if the MTD is not attained, the highest dose 
tested in the SRD part of the FIH study.
Figure 4.d PK/Pharmacodynamic (PD) Assessments and Meal Timing Relative to 
Scopolamine Administration – Part 2
The precise dosing time of TAK-071 relative to scopolamine is selected to ensure that both drugs 
reach their anticipated peak effects at approximately the same time to maximize the potential to 
observe TAK-071 procognitive effects.
The precise dosing time of TAK-071 relative to scopolamine is selected to ensure that both drugs 
reach their anticipated peak effects at approximately the same time to maximize the potential to 
observe TAK-071 procognitive effects.
Donepezil (10 mg) tablet (overencapsulated) or matching placebo is administered as a single 
capsule PO 3 hours before injecting scopolamine to maximize the chances of observing a 
reversal of the scopolamine-induced cognitive impairment.
Blood samples for the analysis of TAK-071, scopolamine, and donepezil plasma concentrations 
are obtained at specified time-points up to 10 hours after scopolamine dosing.
CCI
CCI


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Information on the safety and tolerability of TAK-071 in combination with scopolamine and/or 
donepezil is obtained from treatment periods in which active TAK-071 is administered 
(Treatments C and D). Safety and tolerability are obtained during Treatment A for placebo, 
Treatment B for scopolamine alone, and during Treatment E for donepezil in combination with 
scopolamine.


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4.0
ANALYSIS ENDPOINTS
Note: Some of the planned endpoints have been removed or modified due to the early study 
termination. See Section 7.10.17.13 for details.
5.1
PRIMARY ENDPOINT
No longer applicable. 
5.2
SECONDARY 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 after a single dose on Day 1, for Part 1 only, as 
follows:
–
Maximum observed plasma concentration (Cmax).
–
Time of first occurrence of Cmax (tmax).
–
Area under the plasma concentration-time curve from time 0 to time of last 
quantifiable concentration (AUClast).
–
Area under the plasma concentration-time curve from time 0 to time t (AUCt).
–
Area under the plasma concentration-time curve from time 0 to infinity (AUC∞), as 
permitted by the data.
–
t1/2z in plasma, as permitted by the data.
5.3
EXPLORATORY/ADDITIONAL ENDPOINTS
No longer applicable


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5.0
DETERMINATION OF SAMPLE SIZE
For Part 1, a sample size of 6 enrolled and 4 completers is considered sufficient for providing 
guidance on the TAK-071 dose selection for Part 2, the main study. This is not based on any 
statistical power.
For Part 2, a sample size of 26 subjects, approximately 3 subjects for each of the 10 sequences of 
the 5-period cross-over, is used and is considered sufficient for evaluation of the primary 
cognitive endpoints for this study based on consideration of published scopolamine model 
literature and expert advice. Subjects who drop-out are not replaced, therefore to ensure there are
enough completers a total of 40 subjects are recruited (4 per sequence).
In particular, this sample-size calculation was based on a consideration of effect sizes seen in a 
similar study [5]. Using a 2-sided alpha level of 0.05, this study has a 90% power to detect an 
effect size of 0.67 in the GMLT (sum of 5 trials) total number of errors for the primary treatment 
comparison of TAK-071 + scopolamine vs placebo + scopolamine, assuming a total of 26
subjects complete the study and provide primary endpoint data.
At least 26 subjects will complete the study if 40 subjects are randomized, assuming the drop-out 
rate does not exceed 33%.


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6.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
GENERAL PRINCIPLES
This Statistical Analysis Plan (SAP) was developed based on International Conference on 
Harmonization E3 [6] and E9 [7] 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-071-1002 Amendment 02, dated 10 March
2017 [8].
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.
Due to the timing of the early study termination, no subjects began Period 2 and only 12 subjects 
were enrolled in Part 2. Therefore all data for Part 2 will be summarized by treatment, but not by 
sequence.
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 CDISC 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.
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 Part 1. Baseline is defined as the last non-missing 


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measurement prior to first dose of study drug in the respective treatment period for subjects in 
Part 2, unless otherwise specified.
For all safety endpoints in Part 2, study day will be calculated relative to the date of first dose in 
the respective treatment period. Study day prior to the first dose of treatment in the respective 
treatment period will be calculated as: date of assessment/event – date of treatment; study day on 
or after the first dose of treatment 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 consists of all subjects who are enrolled 
and received 1 dose of study drug. Subjects in this analysis set 
are used for demographic, baseline characteristics, and safety 
summaries.
Pharmacokinetic Set
The PK set consists of all subjects who receive study drug and 
have at least 1 measurable plasma concentration. All subjects 
with valid PK parameter estimate will be included in the 
summaries and analyses for that parameter.
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 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 do not complete all study visits will be summarized overall for Part 1, and by 
treatment and overall for Part 2. In addition, the number and percentage of subjects will be 
summarized for each reason of discontinuation of study drug and study visits. Subjects’ study 
completion data, including reasons for premature termination, will be listed by study part for all 
subjects.
The number and percentage of subjects who comprised each analysis set will be summarized for 
Part 1 by overall and for Part 2 by treatment and overall total for all subjects. 
7.4
PROTOCOL DEVIATIONS
The significant protocol deviations will be provided in a data listing and summarized by 
treatment (Part 2 only) and overall total. 
7.5
DEMOGRAPHIC AND BASELINE CHARACTERISTICS
Demographic and baseline characteristics will be summarized for all randomized subjects by 
treatment sequence (Part 2 only) and overall total. Summary statistics (N, mean, SD, median, 
minimum, and maximum) will be generated for continuous variables (i.e., age, height, weight,
and BMI, and years of full-time education), and the number and percentage of subjects within 


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each category will be presented for categorical variables (i.e. gender, race, ethnicity, caffeine 
consumption, alcohol use, academic qualifications, 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 determining whether the subjects has any significant 
conditions or diseases relevant to the disease under study that resolved at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions.
Medical history and concurrent medical condition verbatim reported terms will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). 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 relevant to eligibility criteria 
stopped at or within 30 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. 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 data will be provided by treatment. 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 – Part 1
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Plasma
1
Predose (within 30 minutes before TAK-071 dosing) and 
0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 24, 25, 26, 27, 28, 
30, 32, 34, 36, 40, 48, 56, 64, 72, 96, and 168 hours post 
TAK-071 dose


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Collection of Blood Samples for Pharmacokinetic Analysis – Part 2
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
TAK-071
Plasma
1
-24 hours (predose of TAK-071) and 0 (predose of 
scopolamine), 1, 2, 3, 4, 6, and 10 hours postdose relative to 
scopolamine dosing.
Scopolamine
Plasma
1
Predose (predose of scopolamine) and 1, 2, 3, 4, 6, and 8 
hours postdose relative to scopolamine dosing.
Donepezil
Plasma
1
-3 hours (predose of donepezil) and 0 (predose of 
scopolamine), 1, 2, 3, 4, 6, and 10 hours postdose relative to 
scopolamine dosing.
Note: For Part 2 time points relative to each study drug administration are as follows: 
TAK-071: predose (approximately 30 minutes before dosing) and 24, 25, 26, 27, 28, 30, and 34 hours postdose 
relative to TAK-071 dosing;
Donepezil: predose (within 30 minutes before dosing) and 3, 4, 5, 6, 7, 9, and 13 hours postdose relative to 
donepezil dosing;
Scopolamine: predose (predose of scopolamine) and 1, 2, 3, 4, 6, and 8 hours postdose relative to scopolamine 
dosing.
The concentration of TAK-071 and donepezil will be summarized separately by treatment, 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).
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 will 
be presented for Part 1 (TAK-071) only.
No listings or summaries from the scopolamine concentration data will be presented.
7.10.2
PLASMA PHARMACOKINETIC PARAMETERS
Since Part 2 of the study was terminated early, the following parameters will only be computed 
for Part 1. 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. Actual sampling times, rather than scheduled sampling times, will be used in all 
computations involving sampling times. 


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The following PK parameters will be calculated for plasma concentration values of TAK-071:
Symbol/Term
Definition
Plasma
AUClast
Area under the plasma concentration-time curve from time 0 to time of last quantifiable 
concentration.
AUC∞
Area under the plasma concentration-time curve from time 0 to infinity, as permitted by the 
data.
Cmax
Maximum observed plasma concentration.
t1/2z
Terminal disposition phase half-life.
tmax
Time to first occurrence of Cmax, as permitted by the data.
Additional plasma PK parameters may be calculated if necessary, in accordance with the Clinical 
Pharmacology Analysis Plan.
Plasma PK parameters for TAK-071 will be listed and summarized separately by treatment. 
Descriptive statistics (including N, arithmetic mean, SD, CV%, median, minimum, maximum, 
geometric mean, and CV% of the geometric mean) will be used as appropriate. Geometric mean 
and CV% of the geometric mean will be reported for AUCs and Cmax only. All subjects with a 
valid PK parameter estimate will be included in the summaries and analyses for that parameter.
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
PHARMACODYNAMIC PARAMETERS
Since Part 2 was terminated early, these endpoints will not be listed or summarized.
7.11 SAFETY ANALYSIS
The safety of TAK-071 in combination with scopolamine will be assessed through AEs, clinical
laboratory results, physical examination findings, ECG findings, vital signs, and suicidal 
assessments. All safety summary tables are presented by treatment group within Part 1 and 
Part 2.
7.11.1
ADVERSE EVENTS
A TEAE is defined as an adverse event or a serious adverse event (SAE) that occurs or gets 
worse after receiving the first dose of study drug (the dose administered on Day 1 for Part 1 and 
on Day 1 of Period 1 for Part 2; run-in scopolamine is considered study drug) until the Follow-up 
Visit/Call or Early Termination. A TEAE may also be a pretreatment adverse event 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. 
Adverse event verbatim reported terms will be coded by system organ class, high-level term and 
preferred term using MedDRA.


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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 by treatment 
group within Part 1 and Part 2. TEAEs will be summarized according to the treatment most 
recently received prior to the onset of the event. 
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.
If a subject has more than one AE that codes to the same PT, the subject will be counted only 
once for that PT. If a subject has more than one AE within an SOC category, the subject will be 
counted only once for that SOC. TEAEs possibly or probably related to study medication will be 
tabulated in the same manner. TEAEs will also be summarized by maximum intensity.
Most frequent TEAEs are defined as the AEs occurring in at least 2 subjects in any treatment (ie, 
Treatment A).
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.
7.11.2
CLINICAL LABORATORY EVALUATIONS
All samples are collected in accordance with acceptable laboratory procedures. During the 
treatment period, laboratory samples are taken following a minimum 8 hour overnight fast on the 
days stipulated in the Schedule of Study Procedures (refer to Appendix A in protocol). 
For Part 1, blood samples for clinical laboratory tests (hematology, coagulation, serum chemistry, 
urinalysis) are collected at Screening, at Check-in (Day -1), on Days 1 through 5 (Final Visit)/
Early Termination (ET), Day 8, and at the Follow-up Visit. 
For Part 2, blood samples for clinical laboratory tests (hematology, coagulation, serum chemistry, 
urinalysis) are collected at Screening and in each period at Check-in (Day -1), at Study Exit (on 
Day 3 of Period 5/ET), and Follow-up (on Day 9 [±2] of Period 5), as appropriate.
Individual results for hematology, chemistry, and coagulation laboratory tests are evaluated 
against the Takeda predefined laboratory markedly abnormal value (MAV) criteria (Appendix 
A) using the result and criteria in SI units.


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Clinical laboratory tests (hematology, chemistry, and urinalysis) will be listed. The results that 
meet MAV criteria will be flagged in the listing. For Part 1 only, baseline, postdose and change 
from Baseline to postdose laboratory data will be summarized. Baseline is defined as the last 
non-missing measurement prior to first dose of study drug.
The percentage of subjects who meet MAV criteria at least once postdose will be summarized by 
overall total for Part 1 and by treatment and overall total for Part 2..
7.11.3
VITAL SIGNS
Vital signs include body temperature (oral), respiratory rate, supine blood pressure (systolic and 
diastolic, resting more than 5 minutes), and pulse (beats per minute [bpm]).
All measurements are recorded on the source documents and in the eCRF.
When vital signs are scheduled at the same time as blood draws, the blood draw takes priority 
and vital signs are obtained within 0.5 hour before or after the scheduled blood draw.
For Part 1, vital signs (oral temperature, respiration, pulse, and blood pressure) are obtained 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 12). 
For Part 2, vital signs (oral temperature, respiration, pulse, and blood pressure) are obtained at 
Screening and in each period at Check-in (Day -1), Day 1 (-26 hours predose), and Day 3 (period 
1 to 4), Study Exit ([Day 3 of Period 5]/ ET), and Follow-up (Day 9 [±2]) of Period 5, as
appropriate.
Individual vital signs are evaluated against Takeda’s predefined criteria for MAV (Appendix B). 
All vital signs will be listed. The results that meet MAV criteria will be flagged in the listing.
Baseline, postdose and change from Baseline to postdose vital signs parameters will be 
summarized. Baseline is defined as the last non-missing measurement prior to first dose of study 
drug for subjects in Part 1. Baseline is defined as the last non-missing measurement prior to first 
dose of study drug in the respective treatment period for subjects in Part 2
The percentage of subjects who meet MAV criteria of vital signs at least once postdose will be 
summarized by overall total for Part 1 and by treatment and overall total for Part 2.
7.11.4
12-LEAD ECGS
A standard 12-lead ECG is recorded. 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 (NCS), or abnormal and clinically significant (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. 
If an ECG is scheduled at the same time as blood draws or vital signs, the ECG is obtained 
within 0.5 hours before the scheduled blood draw/vital sign assessment. Predose ECGs may be 
done within 1 hour prior to dosing. If an ECG coincides with a meal, the ECG takes precedence 
followed by the meal.


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For Part 1, a standard 12-lead ECG is recorded at Screening, Check-in (Day -1), Day 1 (predose 
[within 60 minutes prior to dosing]), on Days 2 through 5 (upon morning rising)/ ET, Day 8, and 
at the Follow-up (on Day 12[±2]).
For Part 2, a standard 12-lead ECG is recorded at Screening, and in each period at Check-in 
(Day -1), Day 1 (predose [within 60 minutes prior to dosing], Day 3 (Period 1 to 4), Study Exit 
(Day 8 of Period 5)/ ET, and Follow-up (Day 9 [±2] of Period 5), as appropriate.
Individual ECGs are evaluated against Takeda’s predefined criteria for MAV (Appendix C). All 
ECGs will be listed. The results that meet MAV criteria will be flagged in the listing. Baseline, 
postdose and change from Baseline to postdose ECG parameters will be summarized. Baseline is 
defined as the last non-missing measurement prior to first dose of study drug for subjects in 
Part 1. Baseline is defined as the last non-missing measurement prior to first dose of study drug 
in the respective treatment period for subjects in Part 2
The percentage of subjects who meet MAV criteria of ECGs at least once postdose will be 
summarized by overall total.
7.11.5
OTHER OBSERVATIONS RELATED TO SAFETY
7.11.5.1
PHYSICAL EXAMINATION
A Baseline physical examination (defined as the assessment prior to first dose of study drug) will 
consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; 
(4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; (7) extremities; (8) 
musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) other.
Any abnormal finding on a pretreatment physical examination assessment must be assessed as 
NCS or CS by the investigator and recorded in the source document and eCRF. All CS 
findings/changes will be recorded as a PTE or concurrent medical condition in the source 
document and on the appropriate eCRF. 
On subsequent examinations, any abnormal change from the pretreatment physical examination 
assessment occurring immediately prior to the start of the study drug must be assessed as NCS or 
CS by the investigator and recorded in the source document and eCRF. Any CS change or new
diagnosis as a result of a CS change, as determined by the investigator, will be recorded as an AE 
in source documentation and on the PTE/AE eCRF.
For Part 1, physical examinations are performed at Screening, at Check-in (Day -1), Final Visit 
(Day 5/ET), and at the Follow-up (on Day 12[±2]).
For Part 2, physical examinations are performed at Screening, in each period at Check-in 
(Day -1), Day 3 (Period 1 to 4), Study Exit (Day 3 of Period 5/ET), and at the Follow-up (on Day 
9[±2] of Period 5).
The physical examination findings will be presented in a data listing. No summary tables will be 
provided.
7.11.5.2
COLUMBIA - SUICIDE SEVERITY RATING SCALE (C-SSRS)
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 


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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.
For Part 1, the C-SSRS is performed at Screening, at Check-in (Day -1), and Final Visit (Day 5 / 
ET). If clinically significant at Final Visit, C-SSRS will also be determined as part of the Follow-
up (on Day 12[±2]).
For Part 2, the C-SSRS is performed at Screening, in each period at Check-in (Day -1), Day 3 
(Period 1 to 4), and Study Exit (Day 5 of Period 5/ ET). If clinically significant at Final Visit, C-
SSRS will also be determined as part of the Follow-up (on Day 9[±2] of Period 5).
C-SSRS data will be presented in data listings. No summary tables will be provided.
7.12 INTERIM ANALYSIS
Not applicable.
7.13 CHANGES IN THE STATISTICAL ANALYSIS PLAN 
One derived PK endpoint, area under the plasma concentration-time curve from time t1 to 
time t2, has been removed from Part 1.
CCI


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7.0
REFERENCES
1. Blatter K, Cajochen C. Circadian rhythms in cognitive performance: methodological 
constraints, protocols, theoretical underpinnings. Physiol Behav 2007;90(2-3):196-208.
2. Gundel A, Witthoft H. Circadian rhythm in the EEG of man. Int J Neurosci 1983;19(1-
4):287-92.
3. Aeschbach D, Matthews JR, Postolache TT, Jackson MA, Giesen HA, Wehr TA. Two
circadian rhythms in the human electroencephalogram during wakefulness. Am J Physiol 
1999;277(6 Pt 2):R1771-9.
4. Loving RT, Kripke DF, Glazner LK. Circadian rhythms in the human pupil and eyelid. 
Am J Physiol 1996;271(2 Pt 2):R320-4.
5. Cho W, Maruff P, Connell J, Gargano C, Calder N, Doran S, et al. Additive effects of a 
cholinesterase inhibitor and a histamine inverse agonist on scopolamine deficits in 
humans. Psychopharmacology (Berl) 2011;218(3):513-24.
6. Guideline on Structure and Content of Clinical Study Reports, International Conference 
on Harmonisation, Section ICH E3, 1996.
7. Guideline on Statistical Principles for Clinical Trials, International Conference on 
Harmonisation, Section ICH E9, 1998.
8. Protocol: A Randomized, Double-Blind, Sponsor Unblinded, Placebo-Controlled, 4-
Period Crossover, Phase 1b Study To Evaluate The Effects Of Single Oral 
Administration of TAK-071 On Scopolamine-Induced Cognitive Impairment In Healthy 
Subjects. 10MAR2017.


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Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values
Hematology—Criteria for Markedly Abnormal Values
Parameter
Unit
Low Abnormal
High Abnormal
Hemoglobin
Both 
< 0.8 × LLN
> 1.2 × ULN
Hematocrit
Both
< 0.8 × LLN
> 1.2 × ULN
RBC count 
Both
< 0.8 × LLN 
> 1.2 × ULN
WBC count 
Both 
<0.5 × 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.
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


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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.


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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


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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