Conditions: Healthy Volunteers
Keywords: Drug therapy
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 12
Healthy volunteers: yes

Brief summary:
The purpose of this study is to determine brain penetration of single oral doses of TAK-041 and its effects on amphetamine-induced dopamine release in the Central Nervous System (CNS).

Detailed description:
The drug being tested in this study is called TAK-041. This study will look at brain penetration of single oral doses of TAK-041 and its effects on amphetamine-induced dopamine release in the CNS.

The study will enroll participants until 12 evaluable participants complete all study procedures. The first 4 participants enrolled in this study will receive a dose of 20 mg TAK-041 and 0.50 milligram per kilogram (mg/kg) dose of amphetamine. The dose for subsequent participants will be determined based on the results of amphetamine-induced dopamine release in the first 4 participants (5 to 40 for TAK-041 and 0.25 or 0.50 mg/kg for the amphetamine).

This single-center trial will be conducted in the United Kingdom. The overall time to participate in this study is approximately 92 days. Participants will remain confined to the clinic for 3 to 4 days during 2 confinement periods. Participants will make monthly visits during Days 8-64 and a final visit 30 days later.

Arms:
arm 1: \[11C\] PHNO 180 megabecquerel (MBq), injection, intravenously, prior to positron emission tomography (PET) scan on Day 1, followed by amphetamine (AMPH) 0.5 milligram per kilogram (mg/kg), tablet, orally, once and \[11C\] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 2 of Confinement Period 1, followed by a 5 to 45 days of interval period, further followed by TAK-041 20 mg, suspension, orally, once, followed by AMPH 0.5 mg, tablet, orally, once and \[11C\] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 1 of Confinement Period 2. arm 2: \[11C\] PHNO 180 MBq, injection, intravenously, prior to PET scan on Day 1, followed by AMPH 0.5 mg/kg, tablet, orally, once and \[11C\] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 2 of Confinement Period 1, followed by a 5 to 45 days of interval period, further followed by TAK-041 40 mg, suspension, orally, once, followed by AMPH 0.5 mg, tablet, orally, once and \[11C\] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 1 of Confinement Period 2.

Interventions: intervention 1: Amphetamine intervention 2: TAK -041 intervention 3: [11C] (+)-4-propyl-(+)-4-propyl-9-hydroxynaphthoxazine (PHNO)
Intervention descriptions: intervention 1: Amphetamine tablets. intervention 2: TAK-041 oral suspension. intervention 3: \[11C\]PHNO injection.

Protocol document:
Prot_001.pdf: 


•
Title: A Phase 1, Open-Label Positron Emission Tomography Study in Healthy Subjects to 
Determine the Effect of TAK-041 on Amphetamine-Induced Dopamine Release in the CNS After 
Single-Dose Oral Administration
NCT Number: NCT02959892
Protocol Approve Date: 21 February 2017
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


PROTOCOL AMENDMENT
A Phase 1, Open-Label Positron Emission Tomography Study in Healthy Subjects to 
Determine the Effect of TAK-041 on Amphetamine-Induced Dopamine Release in the CNS 
After Single-Dose Oral Administration
Phase 1 TAK-041 Single-Dose PET Study 
Sponsor:
Takeda Development Centre Europe Ltd.
61 Aldwych 
London, WC2B 4AE
United Kingdom
Study Number:
TAK-041-1002
IND Number:
Not Applicable
EudraCT Number:
2016-002346-23
Compound:
TAK-041 
Date:
21 February 2017
Amendment History:
Date
Amendment Number
Amendment Type
Region
19 July 2016
Initial version
Not applicable
London, UK
07 October 2016
01
Substantial
London, UK
21 February 2017
02
Substantial
London, UK
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1.0
ADMINISTRATIVE INFORMATION 
1.1
Contacts 
A separate contact information list will be provided to each site.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines should 
be provided to the site.
Contact Type / Role
Contact
Serious adverse event and pregnancy reporting
Medical Monitor (medical advice on protocol and 
compound)
Responsible Medical Officer (carries overall 
responsibility for the conduct of the study)
PPD
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1.2
Approval
REPRESENTATIVES OF TAKEDA
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation E6 Good Clinical Practice Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page. Electronic Signatures may be found on the last page of this 
document.
PPD
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and any 
other product information provided by the sponsor. I agree to conduct this study in accordance 
with the requirements of this protocol and also to protect the rights, safety, privacy, and well-being 
of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B – Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Date
Date
PPD
PPD
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1.3
Protocol Amendment 02 Summary of Changes 
Rationale for Amendment 02
This document describes the changes in reference to the protocol incorporating amendment 
No. 02.
The primary reasons for this amendment are to change TAK-041 doses and procedures. Minor 
grammatical, editorial, and formatting changes are included for clarification purposes only. 
For specific descriptions of text changes and where the changes are located, see Appendix F. 
Changes in Amendment 02
1. Preliminary results from first-in-human (FIH) study TAK-041-1001 were updated.
2. Single doses of TAK-041 ranging from 5 to 40 mg may be evaluated in this study.
3. Possible dose combinations of TAK-041 and amphetamine (AMPH) have changed.
4. Primary and secondary endpoints were revised.
5. An additional PET analysis was added and revisions were made to an existing analysis.
6. PET procedures were modified.
7. Following discharge from Confinement Period 2, subjects will return to the site for 
pharmacokinetic (PK) and safety assessments after 7 ±2 days, and then return for 
approximately 3 Follow-up safety and PK assessment Visits (once every 4 weeks) or until the 
concentration of TAK-041 in plasma is <5% of the subject’s maximum observed plasma 
concentration (Cmax).
8. At the end of each Follow-up Visit, the next visit will be scheduled ~4 weeks later. If, when the 
PK results are available, the subject’s PK was <5% of their Cmax value, the site and subject will 
be informed that their next scheduled visit will be considered their Study Exit/Final Visit.
9. Discrepancies between clinical laboratory tests listed in Table 9.b and Appendix A were 
resolved:
a) Leukocytes were removed from urinary analysis.
b) Diagnostic Screening tests were clarified and inconsistencies corrected.
10. The duration for collection of treatment-emergent adverse events (TEAEs) was changed.
11. Names and credentials of the signatory clinical pharmacologist and statistician for this study 
were updated.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 02 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................16
3.1
Study-Related Responsibilities.................................................................................16
3.2
Investigators ............................................................................................................16
3.3
List of Abbreviations ...............................................................................................17
3.4
Corporate Identification...........................................................................................18
4.0
INTRODUCTION.........................................................................................................19
4.1
Background .............................................................................................................19
4.1.1
TAK-041 ...........................................................................................................19
4.1.2
PHNO and [11C]PHNO Background...................................................................20
4.1.2.1 PHNO and [11C]PHNO Clinical Experience .................................................20
4.1.2.2 Nonclinical Pharmacology and Toxicology ..................................................21
4.1.2.3 Dosimetry ....................................................................................................21
4.2
Rationale for the Proposed Study.............................................................................21
4.3
Benefit/Risk Profile .................................................................................................22
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................23
5.1
Objectives................................................................................................................23
5.1.1
Primary Objective ..............................................................................................23
5.1.2
Secondary Objective ..........................................................................................23
5.1.3
Exploratory/Additional Objectives .....................................................................23
5.2
Endpoints.................................................................................................................23
5.2.1
Primary Endpoint...............................................................................................23
5.2.2
Secondary Endpoint ...........................................................................................23
5.2.3
Exploratory/Additional Endpoints......................................................................23
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................25
6.1
Study Design ...........................................................................................................25
6.1.1
Dose Decisions ..................................................................................................27
6.2
Justification for Study Design, Dose, and Endpoints ................................................28
6.2.1
Study Design......................................................................................................28
6.2.2
Doses.................................................................................................................29
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6.2.3
Endpoints...........................................................................................................29
6.3
Premature Termination or Suspension of Study or Investigational Site.....................30
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................30
6.3.2
Criteria for Premature Termination or Suspension of Study Sites .......................31
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site..................................................................................31
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............32
7.1
Inclusion Criteria .....................................................................................................32
7.2
Exclusion Criteria ....................................................................................................32
7.3
Excluded Medications, Dietary Products..................................................................34
7.4
Diet, Fluid, and Activity Control..............................................................................35
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................36
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................37
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................38
8.1
Study Medication and Materials...............................................................................38
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................38
8.1.1.1 TAK-041......................................................................................................38
8.1.1.2 Amphetamine...............................................................................................38
8.1.1.3 [11C]PHNO ..................................................................................................38
8.1.1.4 Sponsor-Supplied Drug ................................................................................39
8.1.2
Storage...............................................................................................................39
8.1.3
Dose and Regimen .............................................................................................39
8.1.4
Overdose............................................................................................................39
8.2
Investigational Drug Assignment and Dispensing Procedures ..................................40
8.3
Accountability and Destruction of Sponsor-Supplied Drugs.....................................40
9.0
STUDY PLAN ..............................................................................................................42
9.1
Study Procedures.....................................................................................................42
9.1.1
Informed Consent Procedure..............................................................................42
9.1.2
Demographics, Medical History, and Medication History Procedure..................42
9.1.3
Physical Examination Procedure ........................................................................42
9.1.4
Weight, Height, and BMI...................................................................................43
9.1.5
Vital Sign Procedure..........................................................................................43
9.1.6
Documentation of Concomitant Medications......................................................44
9.1.7
Documentation of Concurrent Medical Conditions.............................................44
9.1.8
Wearable Devices Procedures ............................................................................44
9.1.9
Procedures for Clinical Laboratory Samples.......................................................45
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9.1.10 Contraception and Pregnancy Avoidance Procedure...........................................46
9.1.11 Pregnancy ..........................................................................................................47
9.1.12 ECG Procedure..................................................................................................48
9.1.13 Screening MRI of Brain .....................................................................................49
9.1.14 Assessment of Suicidal Ideation and Behavior ...................................................49
9.1.15 Pharmacogenomic Sample Collection ................................................................49
9.1.16 Pharmacokinetic Sample Collection...................................................................50
9.1.16.1
Collection of Plasma for Pharmacokinetic Sampling...............................50
9.1.16.2
Bioanalytical Methods............................................................................50
9.1.17 Pharmacokinetic Analyses .................................................................................50
9.1.18 [11C]PHNO PET Imaging Procedure, Image Processing and Analysis................51
9.1.18.1
PET Imaging Procedures ........................................................................51
9.1.18.2
Image Processing and Analysis...............................................................51
9.1.18.3
PET Data Analysis .................................................................................52
9.1.19 Biometric Monitoring Using the Wearable Devices............................................52
9.1.20 Documentation of Screen Failure .......................................................................53
9.1.21 Documentation of Study Enrollment ..................................................................53
9.2
Monitoring Subject Treatment Compliance..............................................................53
9.3
Schedule of Observations and Procedures................................................................54
9.3.1
Screening...........................................................................................................54
9.3.2
Follow-up Visits ................................................................................................54
9.3.3
Study Exit/Final Visit or Early Termination (ET)...............................................55
9.4
Blood Volume .........................................................................................................55
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................57
10.1
Definitions...............................................................................................................57
10.1.1 PTEs..................................................................................................................57
10.1.2 AEs....................................................................................................................57
10.1.3 Additional Points to Consider for PTEs and AEs................................................57
10.1.4 SAEs..................................................................................................................59
10.1.5 Severity of PTEs and AEs..................................................................................60
10.1.6 Causality of AEs ................................................................................................60
10.1.7 Relationship to Study Procedures.......................................................................60
10.1.8 Start Date...........................................................................................................61
10.1.9 Stop Date...........................................................................................................61
10.1.10
Frequency ....................................................................................................61
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10.1.11
Action Concerning Study Drug ....................................................................61
10.1.12
Outcome.......................................................................................................61
10.2
Procedures...............................................................................................................62
10.2.1 Collection and Reporting of AEs........................................................................62
10.2.1.1
PTE and AE Collection Period ...............................................................62
10.2.1.2
PTE and AE Reporting ...........................................................................62
10.2.2 Collection and Reporting of SAEs......................................................................63
10.2.3 Reporting of Abnormal Liver Function Tests .....................................................63
10.3
Follow-up of SAEs ..................................................................................................64
10.3.1 Safety Reporting to Investigators, IRB or IEC, and Regulatory Authorities........64
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................65
12.0
DATA HANDLING AND RECORDKEEPING............................................................66
12.1
CRFs (Electronic)....................................................................................................66
12.2
Record Retention .....................................................................................................66
13.0
STATISTICAL METHODS..........................................................................................68
13.1
Statistical and Analytical Plans ................................................................................68
13.1.1 Analysis Sets......................................................................................................68
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................68
13.1.3 Pharmacokinetic Analysis ..................................................................................68
13.1.4 Safety Analysis ..................................................................................................69
13.2
Determination of Sample Size..................................................................................69
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................70
14.1
Study-Site Monitoring Visits ...................................................................................70
14.2
Protocol Deviations..................................................................................................70
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................70
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................72
15.1
IRB or IEC Approval...............................................................................................72
15.2
Subject Information, Informed Consent, and Subject Authorization .........................73
15.3
Subject Confidentiality ............................................................................................74
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................74
15.4.1 Publication and Disclosure.................................................................................74
15.4.2 Clinical Trial Registration..................................................................................75
15.4.3 Clinical Trial Results Disclosure ........................................................................75
15.5
Insurance and Compensation for Injury....................................................................75
16.0
REFERENCES..............................................................................................................76
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LIST OF IN-TEXT TABLES
Table 4.a
Maximal Exposure Estimation for Study Subjects..............................................21
Table 7.a
Prohibited Medications, Supplements, Dietary Products.....................................35
Table 8.a
Composition of 0.5% Tween 80 in 0.5% (w/v) Methylcellulose Vehicle ............38
Table 8.b
Composition of TAK-041 Oral Suspension ........................................................38
Table 9.a
Schedule for Recording Vital Signs....................................................................43
Table 9.b
Clinical Laboratory Tests...................................................................................45
Table 9.c
Schedule of ECG Recordings.............................................................................48
Table 9.d
C-SSRS Schedule of Assessments......................................................................49
Table 9.e
Collection of Blood Samples for Pharmacokinetic Analysis ...............................50
Table 9.f
Approximate Blood Volume ..............................................................................56
Table 10.a
Takeda Medically Significant AE List................................................................60
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................27
LIST OF APPENDICES
Appendix A 
Schedule of Study Procedures............................................................................78
Appendix B
Responsibilities of the Investigator.....................................................................82
Appendix C
Elements of the Subject Informed Consent.........................................................84
Appendix D
Investigator Consent to Use of Personal Information..........................................87
Appendix E
Collection, Storage, and Shipment of Bioanalytical Samples..............................88
Appendix F
Detailed Description of Amendments to Text.....................................................92
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Centre Europe Ltd.
Compound:
TAK-041
Title of Protocol: A Phase 1, Open-Label, Positron 
Emission Tomography Study in Healthy Subjects to 
Determine the Effect of TAK-041 on 
Amphetamine-Induced Dopamine Release in the CNS After 
Single-Dose Oral Administration 
IND: Not Applicable
EudraCT:
2016-002346-23 
Study Number: TAK-041-1002
Phase: 1
Study Design:
This is a phase 1, open-label clinical study utilizing positron emission tomography (PET) and the radiolabeled 
dopamine-2 and -3 (D2/D3) receptor agonist PET ligand [11C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho 
[1,2-b][1,4]oxazin-9-ol ([11C]PHNO) to evaluate the effects of single oral doses of TAK-041 on amphetamine 
(AMPH)-induced dopamine release in the brain in 12 healthy male subjects. 
Subjects will continue to be enrolled until 12 evaluable subjects complete all procedures. Each subject will have 1 
magnetic resonance imaging (MRI) brain scan and 3 [11C]PHNO PET scans. The MRI brain scan will be performed 
without gadolinium contrast for all subjects and will be interpreted at the 
 during the 
Screening Period to determine eligibility. The results of this MRI brain scan will also be used during the study to 
delineate the anatomical regions of interest for individual PET images.
The study consists of 2 Confinement Periods for each subject during which the PET scans will occur at the
 
. Confinement Periods 1 and 2 will be separated by an interval of 5 to 45 days. 
Confinement Period 1:

The first [11C]PHNO PET scan occurs on Day 1 to serve as the Baseline scan to determine the nondisplaceable 
binding potential (BPND) in striatum under untreated conditions for each subject.

On Day 2, the subject will receive a single oral 0.5 mg/kg dose of AMPH, followed by a [11C]PHNO PET scan at 
approximately 3 hours post-AMPH dose in order to establish BPND in striatum after AMPH-induced dopamine 
release as compared to Baseline.
Confinement Period 2:

On Day 1, the subject will receive a single oral dose of TAK-041 up to 40 mg, followed by a single oral 0.5 mg/kg 
dose of AMPH approximately 2 hours after the dose of TAK-041, followed by a [11C]PHNO PET scan at 
approximately 3 hours post-AMPH administration.
Blood samples for pharmacokinetic (PK) analysis of AMPH will be collected prior to AMPH administration, 1 and 
2 hours post-AMPH administration, and immediately prior to and after the [11C]PHNO PET scan to measure plasma 
levels of AMPH. PK blood samples for TAK-041 will also be collected 1, 2, 12, and 24 hours after TAK-041 
administration, immediately prior to and after the [11C]PHNO PET scan, and during each Follow-up Visit. Following 
discharge from Confinement Period 2, subjects will return to the site for PK and safety assessments after 7 ±2 days, 
and then return for approximately 3 Follow-up Visits (once every 4 weeks) or until the concentration of TAK-041 in 
plasma is <5% of the subject’s Cmax.
Using data from the TAK-041-1001 study, AMPH will be administered at the approximate time to reach Cmax (tmax) 
(plasma) of TAK-041. The [11C]PHNO PET scan will start at the approximate tmax (plasma) of AMPH (estimated to be 
3 hours post-AMPH dose). The starting dose of TAK-041 in this study will be 20 mg, a dose that has been 
demonstrated to be well-tolerated in the TAK-041-1001 study and has achieved exposures indicative of the predicted 
pharmacologically active exposures of TAK-041. A single dose of 40 mg TAK-041 has also been shown to be 
well-tolerated in the TAK-041-1001 study and may be evaluated in this study to explore the exposure-response 
relationship of TAK-041. The highest dose of AMPH that will be administered will be an oral dose of 0.5 mg/kg. This 
dose has been demonstrated to be safe and well-tolerated in healthy subjects and is a dose which has been shown to 
CCI
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induce dopamine release in AMPH-challenge studies.
Safety and tolerability will be assessed through all study visits, including collecting blood and urine samples for 
laboratory tests. Subjects will complete scheduled study assessments according to the Schedule of Study Procedures.
Each subject will report to 
 ~8 occasions:
1.
Screening Visit to determine eligibility (-28 to -2 days prior to Confinement Period 1/Day 1): The screening brain 
MRI may be performed on a separate day from the other screening procedures, and will be performed and 
interpreted at the 
 after the other screening activities have been performed and results 
assessed. MRI should be performed early enough so that MRI scan results are available prior to Baseline Imaging 
admission for Confinement Period 1. 
2.
Confinement Period 1: admission to 
 (Day -1), 1 day prior to Baseline [11C]PHNO PET imaging on Day 1; 
AMPH administration and postdose [ C]PHNO PET imaging on Day 2; discharge on Day 3, the day following 
the postdose [11C]PHNO PET imaging. All subjects will undergo 1 predose [11C]PHNO PET scan on Day 1 and 1 
postdose [11C]PHNO PET scan on Day 2.
3.
Confinement Period 2 (5 to 45 days after discharge from Confinement Period 1): admission to 
 (Day -1) 
1 day prior to TAK-041 and AMPH administrations and postdose [11C]PHNO PET imaging on Day 1; discharge 
on Day 2, the day following the postdose [11C]PHNO PET imaging. All subjects will undergo a single postdose 
[11C]PHNO PET scan on Day 1.
4.
Follow-up Safety and PK Assessment Visits: Following discharge from Confinement Period 2, subjects will 
return to the site for PK and safety assessments after 7 ±2 days, and then return for approximately 3 Follow-up 
safety and PK assessment Visits (once every 4 weeks) or until the concentration of TAK-041 in plasma is <5% of 
the subject’s Cmax.
5.
Study Exit/Final Visit Day: At the end of each Follow-up Visit, the next visit will be scheduled approximately 
4 weeks later. If, when the PK results are available, the subject’s PK was <5% of their Cmax value, the site and 
subject will be informed that their next scheduled visit will be considered their Study Exit/Final Visit. Subjects 
who prematurely discontinue the study will have the assessments for Study Exit/Final Visit performed if possible 
on their last day in the study.
If logistical limitations (such as tracer synthesis failure) prevent the Baseline PET scan from being performed at the 
scheduled time point, the Confinement Period may be extended or cut short and rescheduled. If a postdose PET scan is 
delayed, it may be necessary to end the Confinement Period early and reschedule. 
This study will utilize an adaptive design to determine the doses of AMPH and TAK-041 to be administered:

The first 4 subjects in this study will receive a 20 mg dose of TAK-041 and a 0.5 mg/kg dose of AMPH. 

If the results from these subjects do not show at least 10% blunting (lower bound of the one-sided 95% confidence 
interval [CI] ≤10%) in the AMPH-induced dopamine release in the striatum (as measured by changes in BPND), 
the next 4 subjects will receive a 40 mg dose of TAK-041 and a 0.5 mg/kg dose of AMPH.

If the results from the first 4 subjects show 10% or more blunting (lower bound of the one-sided 95% CI >10%) in 
the AMPH-induced dopamine release in the striatum (as measured by changes in BPND), the next 4 subjects will 
receive a 5 mg dose of TAK-041 (based on observed exposures in the TAK-041-1001 study) and a 0.5 mg/kg 
dose of AMPH.

Depending on the results from the first 8 subjects, the last 4 subjects may receive either: 
–
A dose of TAK-041 between 5 and 40 mg (based on exposures evaluated in the TAK-041-1001 study) and a 
0.5 mg/kg dose of AMPH (if both previously tested TAK-041 dose levels showed a blunting of 
AMPH-induced dopamine release); or
–
A 40 mg dose of TAK-041 and a 0.25 mg/kg dose of AMPH.
The decision regarding the doses of TAK-041 and AMPH for Subjects 5 to 12 will be based on discussions between 
Takeda and the
. The dose range for TAK-041 is limited by exposures observed in the 
TAK-041-1001 study. Previous studies with AMPH used doses ranging from 0.3 to 0.5 mg/kg. Testing with the lower 
AMPH dose is driven by considerations to avoid overstimulation of the dopamine system.
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Primary Objective:
To determine brain penetration of single oral doses of TAK-041 and its effects on AMPH-induced dopamine release in 
the central nervous system (CNS).

Hypothesis: at 1 or more dose levels, TAK-041 will produce 10% or more blunting in the AMPH-induced 
dopamine release in the striatum.
Secondary Objective: 
To determine a dose/exposure response relationship of TAK-041 on AMPH-induced dopamine release in the CNS.
Exploratory/Additional Objective: 
Subject Population: Healthy male subjects, aged 20 to 55 years, inclusive. 
Number of Subjects:
Subjects will continue to be enrolled until 12 evaluable 
subjects complete all procedures.
Number of Sites:
2 centers in the United Kingdom (
 clinical 
research unit and
)
Study Drugs and Dose Levels:
Three of the following TAK-041/AMPH (dexamfetamine 
sulphate) dose combinations will be evaluated (each in a 
group of 4 subjects):

20 mg TAK-041 and 0.5 mg/kg AMPH.

40 mg TAK-041 and 0.25 mg/kg AMPH.

5 to 40 mg TAK-041 and 0.5 mg/kg AMPH.

5 mg TAK-041 and 0.5 mg/kg AMPH.
Route of Administration:
Oral dose of TAK-041 suspension.
Oral dose of dexamfetamine sulphate tablet. 
Intravenous (IV) injection of [11C]PHNO.
Duration of Treatment:
A single oral dose of TAK-041.
Two single oral doses of AMPH (dexamfetamine sulphate).
Three IV injections of [11C]PHNO.
Period of Evaluation:
Approximately 103 to 173 days from Screening to 
Study Exit/Final Visit.
Main Criteria for Inclusion:

The subject understands, signs and dates a written, informed consent form and any required privacy authorization 
prior to the initiation of any study procedures and is willing to comply with the study protocol requirements.

The subject is a healthy male aged between 20 and 55 years, inclusive.

The subject weighs at least 45 kg and has a body mass index between 18.0 and 30.0 kg/m2. 
Main Criteria for Exclusion:

Subject has evidence of current cardiovascular, central nervous system, hepatobiliary disease including history of 
biliary tree disorders and/or cholecystectomy, hematopoietic disease, renal dysfunction, metabolic or endocrine 
dysfunction, serious allergy, asthma, hypoxemia, hypertension, seizures, or allergic skin rash. There is any 
finding in the subject’s medical history, physical examination, or safety laboratory test results (including elevated 
alkaline phosphatase [ALP], total bilirubin [TBILI], γ-glutamyl transferase [GGT], or 5’-nucleotidase) that 
represent a reasonable suspicion of a disease that would contraindicate taking TAK-041, or that might interfere 
with the conduct of the study. This includes, but is not limited to, peptic ulcer disease, seizure disorders, and 
cardiac arrhythmias.
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
The subject has abnormal Screening laboratory values that suggest a clinically significant underlying disease or 
subject has the following lab abnormalities: alanine aminotransferase (ALT) and/or aspartate aminotransferase 
(AST) >1.5 × the upper limits of normal (ULN); ALP >1.5 × ULN in conjunction with elevated TBILI, GGT, 
5’-nucleotidase, or AST/ALT; ALP >2 × ULN persisting longer than 3 days; or ALP >3 × ULN. 

Subject has a sustained resting heart rate outside the range 50 to 100 beats per minute (bpm), confirmed on repeat 
testing within a maximum of 30 minutes at Screening or Check-in.

Contraindication to MRI based on the standard MRI screening questionnaire. Contraindications include 
ferromagnetic foreign bodies (eg, shrapnel, ferromagnetic fragments in the orbital area), certain implanted 
medical devices (eg, aneurysm clips, cardiac pacemakers), or claustrophobia. 

Subjects who have had previous research-related exposure to ionizing radiation, such that, in combination with 
the exposure from this study, their exposure will be >10 mSv/for the previous year.

Subjects who have a known hypersensitivity to any component of the formulation of TAK-041 or related 
compounds, AMPH, or related compounds, or to [11C]PHNO or to any of its components.

Findings on screening brain MRI scan that will potentially compromise subject safety or the scientific integrity of 
the study data, if the subject were to participate in this study. 
Main Criteria for Evaluation and Analyses
Primary Endpoint: The change in BPND in the AMPH+TAK-041 condition compared to AMPH alone.
Secondary Endpoint: The change in BPND in the AMPH+TAK-041 condition compared to AMPH alone as a 
function of the dose of TAK-041 administered.
Exploratory/Additional Endpoints: 
Statistical Considerations:
Safety: 
Descriptive statistics will be provided for safety, demographics, and subject disposition data. Descriptive statistics for 
continuous data will include means, medians, SDs, and ranges, while categorical data may be summarized using 
frequency counts and percentages. 
Imaging Data: 
1.
Individual BPND values and descriptive statistics for high uptake regions of interest for all PET scans. Descriptive 
statistics for BPND values will include means, medians, SDs, ranges, and 95% CI.
2.
The change in BPND for the AMPH+TAK-041 condition compared to the BPND for the AMPH alone condition 
(100*[BPND AMPH+TAK-041- BPND AMPH]/ BPND AMPH).
3.
The relative change in BPND for the AMPH alone condition (100*[Baseline – Post-AMPH]/Baseline) and the 
relative change in BPND for the AMPH+TAK-041 condition (100*[Baseline – Post-AMPH+TAK-041]/Baseline).
4.
In order to establish a potential dose-dependent effect, we will explore via plots the magnitude of the relative 
change in BPND in the AMPH+TAK-041 condition as a function of the dose of TAK-041 administered.
5.
Additional analyses may be performed for exploratory purposes.
Pharmacokinetics: 
and PK parameters will be summarized by dose and treatment using 
descriptive statistics.
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Sample Size Justification: Using previously reported data, assuming a 16% standard deviation for the relative change 
in BPND for high uptake regions of interest, 12 subjects will provide approximately 80% power to detect a 20% relative 
change in BPND when values from the TAK-041 + AMPH condition are compared to AMPH alone condition using a 
2-sample 2-sided t-test with 0.05 significance level. The power for the other regions of interest will be more than 80%.
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study Related Responsibilities template. The vendors identified in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor. 
3.2
Investigators
Coordinating Investigator 
Imaging Center Investigator 
PPD
PPD
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3.3
List of Abbreviations
%CV
percent coefficient of variation
[11C]PHNO
radiolabeled dopamine D2 ligand 
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AMPH
amphetamine
AST
aspartate aminotransferase
AUC24
area under the plasma concentration-time curve from time 0 to 24 hours
BMI
body mass index
bpm
beats per minute
BPND
nondisplaceable binding potential
CI
confidence interval
Cmax
maximum observed plasma concentration
CNS
central nervous system
CS
clinically significant
C-SSRS
Columbia-Suicide Severity Rating Scale
CT
computed tomography
CV
cardiovascular
D2/D3
dopamine-2 and -3
ECG
electrocardiogram
eCRF
electronic case report form
EMA
European Medicines Agency
ET
early termination
FDA
Food and Drug Administration
FIH
first-in-human
GCP
Good Clinical Practice
GGT
-glutamyl transferase
GPR139
G-protein-coupled receptor 139
HBsAg
hepatitis B virus surface antigen
HCV
hepatitis C virus
hERG
human ether-à-go-go–related gene
HIV
human immunodeficiency virus
ICH
International Conference on Harmonisation
ICRP
International Commission on Radiological Protection 
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
IV
intravenous
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K2EDTA
potassium ethylenediamine tetraacetic acid
LFT
liver function test
MC
methylcellulose
MedDRA
Medical Dictionary for Regulatory Activities
MRD
multiple-rising dose
MRI
magnetic resonance imaging
NCS
not clinically significant
NOAEL
no-observed-adverse-effect level
OTC
over-the-counter
PET
positron emission tomography
PHNO
(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol
PI
principal investigator
PK
pharmacokinetic(s)
PO
oral
PTE
pretreatment event
QTcB
QT interval with Bazett correction method
QTcF
QT interval with Fridericia correction method
RCF
relative centrifugal force
SAE
serious adverse event
SAP
statistical analysis plan
SERT
serotonin transporter
SRD
single-rising dose
SUSAR
suspected unexpected serious adverse reaction
t1/2z
terminal elimination half-life
TBILI
total bilirubin
TEAE
treatment-emergent adverse event
tmax
time to reach Cmax
ULN
upper limit of normal
WHODRUG
World Health Organization Drug Dictionary
3.4
Corporate Identification 
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
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4.0
INTRODUCTION
4.1
Background
4.1.1
TAK-041
TAK-041 is an orally available, small molecule G-protein-coupled receptor 139 (GPR139) agonist 
that dose-dependently improves social interaction in animal models of social deficit and has the 
potential for the treatment of schizophrenia, particularly negative symptoms, and disorders 
associated with social and cognitive dysfunction.
GPR139 is a novel class A orphan receptor that is expressed in the medial habenula, the septum, 
hypothalamus, basal ganglia, and thalamus [1,2]. The CNS localization of this receptor suggests its 
potential contribution to movement and metabolism with a special focus on attention, learning and 
cognition, motivation and reward, as well as response to stress and social interaction [1,3]. 
Because patients with schizophrenia are afflicted with behavioral and cognitive deficits in these 
domains, TAK-041 may provide therapeutic benefit by ameliorating the symptoms linked to this 
disorder.
In vitro studies support the specificity and the selectivity of TAK-041 for binding to and activating 
GPR139, as evidenced by increased cellular signaling events downstream of receptor activation. 
Specifically, with the exception of serotonin transporter (SERT) inhibition at approximately 2 µM, 
TAK-041 was a potent and selective agonist for GPR139. In vivo studies demonstrated both a 
cognitive benefit and an enhancement of social interaction in animal models exhibiting cognitive 
and social interaction deficits that were either pharmacologically induced or naturally occurring. 
In the safety pharmacology assessment, TAK-041 had no effect on the CNS or respiratory 
parameters in rats at single oral (PO) doses up to 200 mg/kg/day, which was the 
no-observed-adverse-effect level (NOAEL) in the rat repeat-dose toxicity study. At high 
concentrations (at ≥1 µM or 392 ng/mL free drug), an effect was observed on the human 
ether-à-go-go–related gene (hERG) potassium currents. The hERG alteration did not translate into 
an electrocardiogram (ECG) effect at doses up to 125 mg/kg/day, which is associated with a Cmax
of 10,700 ng/mL. The cause for the increase in systolic blood pressure (approximately 15 mmHg 
or 10%) noted acutely at 125 mg/kg in the dog cardiovascular study 0.5 to 6 hours postdose is 
unclear; however, neither heart rate nor diastolic blood pressure were elevated. No changes in 
blood pressure or ECG parameters were noted at 125 mg/kg/day in the 4-week repeat-dose toxicity 
study in dogs after the 26th or 27th dose, respectively. A diminished trend for systolic blood 
pressure that occurred at 15 mg/kg was not considered biologically relevant; no effect on systolic 
blood pressure occurred at 5 mg/kg.
Schizophrenia involves diminished or altered motivation, deficits in social behavior, and 
difficulties with complex cognitive tasks. To date, there are no effective therapies for the negative 
and cognitive symptoms, which remain a significant unmet medical need.
Experimental evidence supports the use of TAK-041, a GPR139 agonist, as a potential therapeutic 
for the negative symptoms and cognitive impairment associated with schizophrenia. Toxicological 
studies of TAK-041 in rats and dogs with up to 4 weeks of exposure support proceeding with a 
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study in humans. TAK-041 has been studied in vitro and in vivo to demonstrate its potency and 
selectivity for binding to and activating GPR139 as well as its efficacy in animal models exhibiting 
cognitive and social interaction deficits.
Further information from the nonclinical studies, summarized above, can be found in the current 
Investigator’s Brochure. 
To date, the FIH study TAK-041-1001 has enrolled and dosed a total of 16 subjects (12 active and 
4 placebo) in an alternating panel design (2 cohorts) at 5, 10, 20, and 40 mg. Cohort 1 received 
5 and 20 mg single doses and Cohort 2 received 10 and 40 mg single doses. Preliminary PK data 
from 12 healthy subjects who received single oral administrations of TAK-041 doses of 5, 10, 20, 
and 40 mg indicate that TAK-041 has a mean terminal elimination half-life (t1/2z) of approximately 
11 days. Following single oral dose administrations of TAK-041 (5, 10, 20, and 40 mg) under 
fasted conditions, TAK-041 was rapidly absorbed (median time to reach Cmax [tmax] of 1 to 2 hours) 
with well-characterized plasma concentration-time profiles up to the last sampled time point. 
Inter-subject variability across the 5 to 40 mg dose range was low-to-moderate with percent 
coefficient of variation (%CV) values of approximately 11% to 20% and 9% to 28% for Cmax and 
area under the plasma concentration-time curve from time 0 to 24 hours (AUC24), respectively. 
Following an 8-fold increase in dose from 5 to 40 mg, mean Cmax and AUC24 for TAK-041 
increased by approximately 5.3- and 7.2-fold, respectively.
4.1.2
PHNO and [11C]PHNO Background
4.1.2.1
PHNO and [11C]PHNO Clinical Experience
As of 10 June 2016, both 
(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol [PHNO] and 
radiolabeled [11C]PHNO have been extensively validated in clinical studies. (+)-PHNO is a potent 
dopamine D2 receptor agonist that was tested in several phase 2 clinical studies for treatment of 
Parkinson disease [4-7]. Up to 60 mg/day PHNO was safely administered in a 12-week, 
placebo-controlled, double-blind study in patients with Parkinson disease [4]. These doses are 
significantly higher than the single dose of 0.5 µg [11C]PHNO to be used per positron emission 
tomography (PET) scan in this study. Wilson, et al. [8] demonstrated PHNO as a suitable 
candidate radiotracer for in vivo measurement of D2 receptors using PET. Subsequently 
[11C]PHNO has been used extensively as a dopamine-2 and -3 (D2/3) agonist PET ligand at 
, as well as other PET centers world-wide 
 
). To date 
>250 PET examinations have been conducted at 
 using [ C]PHNO, and >400 world-wide 
(for examples, see Boileau, et al. 2009, Boileau et al. 2014, Searle et al. 2013, and Shotbolt et al. 
2012 [9-12]. [11C]PHNO has been evaluated in healthy volunteers as well as patients with 
Parkinson disease, pathological gambling, alcohol abuse, cocaine abuse, and schizophrenia, with 
individual subjects receiving up to 3 administrations each. 
Initial human studies with [11C]PHNO revealed that some subjects experienced transient nausea 
following administration. Subsequent investigation revealed that limiting the injected dose to 
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≤30 ng/kg eliminated these adverse events [13]. All studies at 
 maintain this limit and 
their experience is consistent with other centers as reported by Mizrahi and colleagues.
4.1.2.2
Nonclinical Pharmacology and Toxicology 
Wilson, et al. [8] reported the radio synthesis and evaluation of the potent D2 agonist,
(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol. Labeled with 
carbon-11, [11C]PHNO readily crossed the blood/brain barrier in ex vivo biodistribution studies in 
rat brain, with saturable binding to dopamine D2 receptors and an excellent signal-to-noise ratio. 
Binding was highly stereospecific and blocking and displacement studies were consistent with 
selective and specific binding to the dopamine D2 receptors. Furthermore, [11C]PHNO showed 
marked and appropriate sensitivity to both increases and decreases in the levels of endogenous 
dopamine and full D2 agonistic properties [8], making it an excellent radiotracer to evaluate the 
dopamine D2/D3 receptor system in humans with PET.
4.1.2.3
Dosimetry 
The whole body distribution and dosimetry of [11C]PHNO has been measured in 6 healthy 
volunteers [14]. The mean effective dose was estimated to be 4.5 ± 0.3 µSv/MBq when all subjects 
were included and the male model was applied for the dosimetry calculation. The organ receiving 
the highest dose was the liver (17.9 ± 3.9 µSv/MBq), followed by the kidneys (14.3 ± 
3.6 µSv/MBq) and the urinary bladder wall (13.5 ± 3.7 µSv/MBq). The maximum radiation 
exposure for each subject in the study is presented in Table 4.a.
Table 4.a
Maximal Exposure Estimation for Study Subjects
Assessments 
Maximum Number 
of PET Scans
Radiation Activity
[11C]PHNO Injected 
Activity Estimated 
for Each PET Scan
Maximal Allowed 
Exposure for an 
Individual
PET emission scan 
3
4.5 µSv/MBq
180 MBq
2.43 mSv
Low-dose CT scan (for 
attenuation correction)
3
0.36 mSv
NA
1.08 mSv
Total
3.51 mSv
CT=computed tomography, NA=not applicable.
A maximal study exposure of 3.51 mSv per subject places this study in Category IIb (<10 mSv) of 
the guidance published by the International Commission for Radiation Protection (ICRP). There is 
no dose limit for research purposes in the United Kingdom but, like many European Union 
member states, the United Kingdom follows the ICRP 62 guidance that provides a guideline of 
≤10 mSv per study where research subjects are not expected to benefit personally [15].
4.2
Rationale for the Proposed Study
Microdialysis studies in rats showed that pretreatment with TAK-041 caused a significant 
attenuation of amphetamine-induced synaptic dopamine release in the nucleus accumbens, a brain 
region critical for cognitive processing of aversion, motivation, pleasure, reward, and 
reinforcement learning. The amphetamine pharmacology model has been used in early clinical 
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development for centrally acting compounds and has been shown to induce dopamine release in 
amphetamine challenge studies [16]. PET and [11C]PHNO have been validated as clinical tools to 
assess amphetamine-induced dopamine release in humans. Therefore, this translational biomarker 
approach will be utilized to determine whether TAK-041 is brain-penetrant in healthy human 
volunteers and demonstrates central pathway modulation by blunting amphetamine-induced 
dopamine release. The assessment of brain penetration of TAK-041 and its effects on 
amphetamine (AMPH)-induced dopamine release will inform dose selection for subsequent 
clinical studies. 
4.3
Benefit/Risk Profile
As this is a healthy volunteer study, there is no expected clinical benefit to the study participants. 
TAK-041 has the potential to be a first-in-class drug; therefore, there are no known class effects. 
Potential risks are based on clinical findings, the mechanism of action, nonclinical findings, and 
the known risks of other GPR139 receptor agonists. Preliminary results from the FIH study 
TAK-041-1001 indicate that single doses of TAK-041 at 5, 10, 20, and 40 mg are well tolerated. 
To fully assess the safety and PK profile of TAK-041 in subjects receiving 20 and 40 mg TAK-041 
doses, follow-up PK blood draws were performed until TAK-041 plasma concentrations were 
below the lower level of quantitation of the assay. Six AEs were observed that were mild, deemed 
not related to study drug, and resolved without treatment. No serious AEs and no clinically 
meaningful safety laboratory results (including 5’-nucleotidase, sorbitol dehydrogenase, and urine 
osmolality), and no clinically significant physical examination, vital signs, or ECG results were
reported for the 16 subjects who received 5 to 40 mg doses of TAK-041 crystalline suspension or 
matching placebo in TAK-041-1001 Cohorts 1 and 2. The potential risks can be monitored 
clinically and/or with laboratory tests and are considered in setting up the stopping rules for this 
clinical study. Appropriate exclusion criteria that exclude individuals with past history or 
concurrent conditions that increase the risk will be applied. 
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
To determine brain penetration of single oral doses of TAK-041 and its effects on AMPH-induced 
dopamine release in the CNS. 

Hypothesis: at 1 or more dose levels, TAK-041 will produce 10% or more blunting in the 
AMPH-induced dopamine release in the striatum.
5.1.2
Secondary Objective 
To determine a dose/exposure response relationship of TAK-041 on AMPH-induced dopamine 
release in the CNS.
5.1.3
Exploratory/Additional Objectives
5.2
Endpoints
5.2.1
Primary Endpoint
The change in nondisplaceable binding potential (BPND) in the AMPH+TAK-041 condition 
compared to AMPH alone.
5.2.2
Secondary Endpoint
The change in BPND in the AMPH+TAK-041 condition compared to AMPH alone as a function of 
the dose of TAK-041 administered.
5.2.3
Exploratory/Additional Endpoints
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 1, open-label clinical study utilizing PET and the D2/D3 receptor agonist and 
radiolabeled ligand [11C]PHNO to evaluate the effects of single oral doses of TAK-041 on 
AMPH-induced dopamine release in the brain. 
Subjects will continue to be enrolled until 12 evaluable subjects complete all procedures. Each 
subject will have 1 magnetic resonance imaging (MRI) brain scan and 3 [11C]PHNO PET scans. 
The MRI brain scan will be performed for all subjects without gadolinium contrast and will be 
interpreted at the 
 during the Screening Period to determine eligibility. 
The results of this MRI brain scan will also be used during the study to delineate the anatomical 
regions of interest for individual PET images.
The study consists of 2 Confinement Periods for each subject during which the PET scans occur at 
the 
. Confinement Periods 1 and 2 will be separated by a 5 to 45 day 
interval. 

Confinement Period 1:
–
The first [11C]PHNO PET scan occurs on Day 1 to serve as the Baseline scan to determine 
the BPND in striatum under untreated conditions for each subject.
–
On Day 2, the subject will receive a single oral 0.5 mg/kg dose of AMPH, followed by a 
[11C]PHNO PET scan at approximately 3 hours post-AMPH dose in order to establish 
BPND in striatum after AMPH-induced dopamine release as compared to Baseline.

Confinement Period 2:
–
On Day 1, the subject will receive a single oral dose of TAK-041 up to 40 mg, followed by 
a single oral 0.5 mg dose of AMPH approximately 2 hours after the dose of TAK-041, 
followed by a [11C]PHNO PET scan at approximately 3 hours post-AMPH administration.
Blood samples for PK analysis of AMPH will be collected prior to AMPH administration, 1 and 
2 hours post-AMPH administration, and immediately prior to and after the [11C]PHNO PET scan 
to measure plasma levels of AMPH. PK blood samples will be collected 1, 2, 12, and 24 hours after 
TAK-041 administration, and immediately prior to and after the [11C]PHNO PET scan to measure 
plasma levels of TAK-041.
Only TAK-041 dose levels that were well-tolerated in the TAK-041-1001 study and had achieved 
exposures indicative of the predicted pharmacologically active exposures of TAK-041 will be 
administered in this study. 
Amphetamine tablets will be provided as the commercial product dexamfetamine sulphate
[17] with the manufacturer’s original label, and will be sourced locally by the study site. 
Amphetamine will be administered at the time that approximately coincides with the tmax of 
TAK-041 to allow an informative evaluation of TAK-041 coadministered with amphetamine. The 
highest dose of AMPH that will be administered will be an oral dose of 0.5 mg/kg. This dose has 
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been demonstrated to be safe and tolerated in healthy subjects and is a dose which has been shown 
to induce dopamine release in AMPH-challenge studies [16,18].
Safety and tolerability will be assessed through all study visits, including collecting blood and 
urine samples for laboratory tests. Subjects will complete scheduled study assessments according 
to the Schedule of Study Procedures (Appendix A).
Each subject will report to 
 on approximately
8 occasions:
1. Screening to determine eligibility (-28 to -2 days prior to Confinement Period 1/Day -1): The 
Screening brain MRI may be performed on a day separate from the other screening procedures, 
and will be performed and interpreted at the 
 after the other screening 
activities have been performed and results assessed. MRI should be performed early enough so 
that MRI scan results are available prior to Baseline Imaging for Confinement Period 1. 
2. Confinement Period 1 (Day -1 to Day 3): admission to 
 (Day -1), 1 day prior to Baseline 
[11C]PHNO PET imaging on Day 1; AMPH administration and postdose [11C]PHNO PET 
imaging (Day 2); discharge on the day following the postdose [11C]PHNO PET imaging (Day 
3). All subjects will undergo a single Baseline [11C]PHNO PET scan on Day 1 and a single 
postdose [11C]PHNO PET scan on Day 2.
3. Confinement Period 2 (5 to 45 days after discharge from Confinement Period 1): admission to 
 (Day -1) 1 day prior to TAK-041 and AMPH administration and postdose [11C]PHNO 
PET imaging (Day 1), discharge on the day following the postdose [11C]PHNO PET imaging 
(Day 2). All subjects will undergo a single [11C]PHNO PET scan on Day 1 of Confinement 
Period 2.
4. Follow-up Safety and PK Assessment Visits (Days 8-92): Following discharge from 
Confinement Period 2, subjects will return to the site for PK and safety assessments after 
7±2 days, and then return for approximately 3 Follow-up PK and safety assessment Visits 
(once every 4 weeks) or until the concentration of TAK-041 in plasma is <5% of the subject’s 
Cmax (see Section 9.3.2 and Appendix A).
5. Study Exit/Final Visit: At the end of each Follow-up Visit, the next visit will be scheduled 
approximately 4 weeks later. If, when the PK results are available, the subject’s PK was <5% 
of their Cmax value, the site and subject will be informed that their next scheduled visit will be 
considered their Study Exit/Final V
3.3 and Appendix A). Subjects who 
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prematurely discontinue the study will have the same assessments on their last day in the study, 
if possible.
A schematic of the study design is shown in Figure 6.a. The Schedule of Study Procedures is in 
Appendix A. 
Figure 6.a
Schematic of Study Design
Screening
Confinement Period 1
Interval 
(a)
Confinement Period 2
Follow-up 
Visits (b)
Study 
Exit/Final 
Visit 
ET (c)
Days 
-28 to -2 
Day -1
Day 1
Day 2
Day 3
5-45 days
Day -1
Day 1
Day 2
Days 8-92
(±2)
Check-in
PET 
Imaging
Baseline
Discharge
 
Check-in
 
Discharge
Return to 
 for 
safety and 
PK 
assessments
Return to 
 for 
safety 
assessments
AMPH 
TAK-041 + 
AMPH 
PET 
Imaging
postdose
PET 
Imaging
postdose
ET=early termination
Note: Subjects who drop out prior to completion of all PET scans will have assessments done as described in Section 9.3.3 and 
Appendix A for ET and a follow-up telephone call approximately 2 days after the ET Visit. 
(a) There will be a 5 to 45 day interval between confinement periods beginning after discharge from Confinement Period 1.
(b) Following discharge from Confinement Period 2, subjects will return to the site for PK and safety assessments after 7 ±2 days, 
and then return for approximately 3 Follow-up PK and safety assessment Visits (once every 4 weeks) or until the concentration of 
TAK-041 in plasma is <5% of the subject’s Cmax.
(c) At the end of each Follow-up Visit, the next visit will be scheduled approximately 4 weeks later. If, when the PK results are 
available, the subject’s PK was <5% of their Cmax value, the site and subject will be informed that their next scheduled visit will be 
considered their Study Exit/Final Visit.
If logistical limitations (such as tracer synthesis failure) prevent a Baseline PET scan from being 
performed at the scheduled time point, the Confinement Period may be extended or cut short and 
rescheduled. If a postdose PET scan is delayed, it may be necessary to end the Confinement Period 
early and reschedule after a sufficient interval.
The date the final subject completes the Follow-up Call/Visit will be considered the end of study 
date for transparency reporting. 
6.1.1
Dose Decisions
All decisions concerning dose levels will be made by the sponsor and the 
 
.
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This study will utilize an adaptive design to determine the dose(s) of AMPH and TAK-041 to be 
administered:

The first 4 subjects in this study will receive a 20 mg dose of TAK-041 and a 0.5 mg/kg dose of 
AMPH. 

If the results from these subjects do not show at least 10% blunting (lower bound of the 
one-sided 95% CI ≤10%) in the AMPH-induced dopamine release in the striatum (as measured 
by changes in BPND), the next 4 subjects will receive a 40 mg dose of TAK-041 and a 
0.5 mg/kg dose of AMPH.

If the results from the first 4 subjects show 10% or more blunting (lower bound of the 
one-sided 95% CI >10%) in the AMPH-induced dopamine release in the striatum (as measured 
by changes in BPND), the next 4 subjects will receive a 5 mg dose of TAK-041 (based on 
observed exposures in the TAK-041-1001 study) and a 0.5 mg/kg dose of AMPH.

Depending on the results from the first 8 subjects, the last 4 subjects may receive either: 
–
A dose between 5 and 40 mg of TAK-041 (based on exposures evaluated in the 
TAK-041-1001 study) and a 0.5 mg/kg dose of AMPH (if both previously tested TAK-041 
dose levels showed a blunting in AMPH-induced dopamine release); or
–
A 40 mg dose of TAK-041 and a 0.25 mg/kg dose of AMPH.
Decisions regarding the doses of TAK-041 and AMPH that Subjects 5 to 12 will receive will be 
based on discussions between Takeda and the 
 Investigator. The dose 
range for TAK-041 is limited by exposures observed in the TAK-041-1001 study. Previous studies 
with AMPH used doses ranging from 0.3 to 0.5 mg/kg. Testing with the lower AMPH dose is 
driven by considerations to avoid overstimulation of the dopamine system.
6.2
Justification for Study Design, Dose, and Endpoints
6.2.1
Study Design
The primary objective of this study is to determine brain penetration of single oral doses of 
TAK-041 and its effects on AMPH-induced dopamine release in the brain in healthy subjects. The 
study will therefore be conducted in healthy subjects to ensure that the evaluation of pathway 
modulation of TAK-041 is not confounded by disease or concomitant medications that are 
frequently taken in the target population (patients with schizophrenia). As reproductive toxicity 
studies have not been completed, only male subjects will be eligible for enrollment and male 
subjects who are sexually active with a female partner of childbearing potential will be required to 
use an acceptable form of contraception (see Section 9.1.10).
Some studies have found that AMPH-induced receptor internalization affects the time course of 
subsequent ligand binding [12]. An interval of 5 to 45 days between the 2 Confinement Periods is 
therefore included to control for potential effects of sensitization.
The preliminary PK data from Study TAK-041-1001 indicate that TAK-041 has a mean terminal 
elimination half-life of approximately 11 days. Therefore, a fixed-order study design wherein 
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TAK-041 is administered in Confinement Period 2 only is appropriate (see Figure 6.a, Study 
Schematic). Subjects in the TAK-041-1001 study who received single doses of 20 and 40 mg 
TAK-041 were followed approximately weekly until the plasma concentrations of TAK-041 were 
<1 ng/mL (up to 146 days) and there were no clinically significant safety issues. Subjects in this 
study who receive TAK-041 will be monitored monthly until the concentration of TAK-041 in 
plasma is <5% of the subject’s Cmax. Following discharge from Confinement Period 2, subjects 
will return to the site for PK and safety assessments after 7 ±2 days, and then return for 
approximately 3 Follow-up Visits (once every 4 weeks) or until the concentration of TAK-041 in 
plasma is <5% of the subject’s Cmax.
6.2.2
Doses
Overall there is an expectation of sufficient systemic exposure to TAK-041 and duration of action 
in humans. Taking account of the exposure required for efficacy in animal models and current 
available evidence of the modeling of the human PK, it is expected that the dose ranges of 
TAK-041 that will be evaluated will achieve a sufficient range of plasma exposures with a margin 
above and beyond the predicted pharmacologically active exposures (4 to 60 ng/mL).
The starting dose of TAK-041 that will be evaluated in this study is 20 mg, a dose that has been 
demonstrated to be well-tolerated in the TAK-041-1001 study and has achieved exposures 
indicative of the predicted pharmacologically active exposures of TAK-041. A single dose of 
40 mg TAK-041 has also been shown to be well-tolerated in the TAK-041-1001 study and may be 
evaluated to explore the exposure-response relationship of TAK-041.
The highest dose of AMPH (dexamfetamine sulphate) to be administered is 0.5 mg/kg. The 
0.5 mg/kg dose regimen has been demonstrated to be safe and tolerated in healthy subjects and has 
been shown to induce dopamine release in amphetamine challenge studies [16,18]. Previous 
studies with AMPH used doses ranging from 0.3 to 0.5 mg/kg [12,19]. Evaluating with a lower 
AMPH dose of 0.25 mg/kg will be driven by considerations to avoid overstimulation of the 
dopamine system.
The intravenous (IV) dose of the ligand [11C]PHNO of approximately 180 MBq is based on the 
experiences of 
 and other sites using this radiotracer in clinical studies [12].
6.2.3
Endpoints
Preclinical data have shown that TAK-041 blunted AMPH-induced, striatal dopamine release in 
rodents (see the current Investigator’s Brochure). PET and [11C]PHNO have been validated as 
clinical tools to assess AMPH-induced dopamine release in humans [12]. We are therefore 
proposing to utilize this translational biomarker approach to establish whether single oral doses of 
TAK-041 is brain-penetrant in human volunteers, and whether it demonstrates central pathway 
modulation by blunting AMPH-induced dopamine release.
Within subject test-retest variability of [11C]PHNO, BPND has been demonstrated to be less than 
10% for high uptake regions in the basal ganglia (eg, caudate, putamen, ventral striatum, and 
globus pallidus) [20]. The purpose of the first dose-level group of 4 subjects is to demonstrate 
whether TAK-041 has any appreciable blunting effect on AMPH-induced dopamine release as 
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measured with [11C]PHNO BPND change from Baseline. Given that due to the above mentioned 
existing human test-retest variability, it is estimated that one can be reasonably confident to detect 
an at least 10% change from baseline, this was defined as the “minimum effect level.” In line with 
that expectation, any change less than 10% will be regarded as “no effect,” and, consequently, 
different dose levels of AMPH and/or TAK-041 may be tested.
6.3
Premature Termination or Suspension of Study or Investigational Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied that 
require temporary suspension or early termination of the study.
1. New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the TAK-041 such that the risk is 
no longer acceptable for subjects participating in the study.
2. Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
3. Two or more subjects experience any of the Takeda Medically Significant List events (as 
outlined in Table 10.a).
4. Two or more subjects experience alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) elevations >5 × upper limit of normal (ULN) in the absence of a 
concomitant bilirubin increase [see #6 below].
5. One or more subjects experience ALT and/or AST elevations >3 × ULN in the presence of a 
total bilirubin (TBILI) increase >2 × ULN or an international normalized ratio (INR) 
>1.5 without findings of cholestasis or alternative etiology to explain the elevations (ie, “Hy’s 
Law cases”).
6. Two or more subjects experience ALT and/or AST elevations >3 × ULN with the appearance 
of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%).
7. One or more subjects experience alkaline phosphatase (ALP) elevations >1.5 × ULN in 
conjunction with elevated TBILI, -glutamyl transferase (GGT), ALT, or AST.
8. One or more subjects experience ALP elevations >2 × ULN that persist for longer than 3 days.
9. One or more subjects experience ALP elevations >3 × ULN.
Please note that the study may be terminated prior to full attainment of these criteria (eg, if just 
1 subject experiences 1 of these events) if warranted by safety data from the other subjects dosed in 
the study to that date.
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6.3.2
Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC) or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by the investigational site 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 enrollment on Day 1 of 
Confinement Period 1. 
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject signs and dates a written, informed consent form and any required privacy 
authorization prior to the initiation of any study procedures. 
3. The subject is in good health as determined by physical examination, ECG, and laboratory 
evaluations.
4. The subject is a healthy male aged 20 to 55 years, inclusive, at the time of informed consent.
5. The subject weighs at least 45 kg and has a body mass index (BMI) from 18.0 to 30.0 kg/m2, 
inclusive, at Screening.
6. A male subject who is nonsterilized* and sexually active with a female partner of childbearing 
potential* agrees to use adequate contraception* from signing of informed consent throughout 
the duration of the study and for a period of 167 days (ie, 90 days after 7 half-lives, estimated 
using an average half-life value) following TAK-041 administration. The female partner of a 
male subject should also be advised to use a highly effective method of contraception.
*Definitions and acceptable methods of contraception are listed in Section 9.1.10;
reporting responsibilities are defined in Section 9.1.11.
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 or device within 3 months prior to the 
first Screening Visit.
2. 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.
3. 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. It is the responsibility of the investigator to assess the 
clinical significance; however, consultation with the Takeda Medical Monitor may be 
warranted.
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4. The subject has a known hypersensitivity to any component of the formulation of TAK-041 or 
related compounds, AMPH (dexamfetamine sulphate) or related compounds, or [11C]PHNO or 
any of its components. 
5. The subject has a positive urine/blood drug result for drugs of abuse (defined as any illicit drug 
use) at Screening or Check-in (Day -1).
6. 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 more than 21 units per week) 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 8 grams of pure alcohol, which is equivalent to 10 mL of pure 
ethanol (alcohol) or approximately a half-pint of beer, 1 measure of spirits, or 1 glass of wine. 
7. The subject has taken any medication, supplements, or food products during the time periods 
listed in the Prohibited Medications, Supplements, Dietary Products Table 7.a.
8. Subject has evidence of current cardiovascular, central nervous system, hepatobiliary disease 
including history of biliary tree disorders and/or cholecystectomy, hematopoietic disease, renal 
dysfunction, metabolic or endocrine dysfunction, serious allergy, asthma, hypoxemia, 
hypertension, or seizures. There is any finding in the subject’s medical history, physical 
examination, or safety laboratory test results (including elevated ALP, TBILI, GGT, or 
5’-nucleotidase) giving reasonable suspicion of a disease that would contraindicate taking 
TAK-041 or amphetamine or a similar drug in the same class, or that might interfere with the 
conduct of the study. This includes, but is not limited to, peptic ulcer disease, seizure disorders, 
and cardiac arrhythmias.
9. The 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 know to impact absorption (eg, bariatric 
surgery or bowel resection).
10. The subject has a history of cancer, except basal cell carcinoma that has been in remission for 
at least 5 years prior to Day 1 of Confinement Period 1.
11. The subject has a positive test result for hepatitis B virus surface antigen (HBsAg), hepatitis C 
virus (HCV) antibody, or human immunodeficiency virus (HIV) infection at Screening.
12. 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 on 
Day -1. Cotinine test is positive at Screening or Check-in (Day -1). 
13. The subject has poor peripheral venous access.
14. The subject has donated or lost 450 mL or more of his blood volume (including 
plasmapheresis), or had a transfusion of any blood product within 90 days prior to 
Confinement Period 1.
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15. Subject has a Screening or Check-in (Day -1) abnormal (CS) ECG. Entry of any subject with 
an abnormal (not clinically significant [NCS]) ECG must be approved, and documented by 
signature by both the principal investigator and the Takeda Medical Monitor.
16. Subject has abnormal Screening laboratory values that suggest a clinically significant 
underlying disease or subject has the following lab abnormalities: ALT and/or AST >1.5 × 
ULN; ALP >1.5 × ULN in conjunction with elevated TBILI, GGT, 5’-nucleotidase, AST, or 
ALT; ALP >2 × ULN persisting longer than 3 days; or ALP >3 × ULN.
17. The subject has a sustained resting heart rate outside the range 50 to 100 beats per minute 
(bpm), confirmed on repeat testing within a maximum of 30 minutes, at Screening or Check-in.
18. The subject has a QT interval with Fridericia correction method (QTcF) >450 ms or PR outside 
the range 120 to 220 ms, confirmed on repeat testing within a maximum of 30 minutes, at the 
Screening Visit or Check-in (Day -1).
19. The subject has a risk of suicide according to the investigator’s clinical judgment (eg, per 
C-SSRS) or has made an attempt in the previous 6 months from Screening.
20. The subject has had previous research-related exposure to ionizing radiation such that, in 
combination with the exposure from this study, their exposure will be >10 mSv for the 
previous year. 
21. The subject has a contraindication to MRI based on the standard MRI screening questionnaire. 
Contraindications include ferromagnetic foreign bodies (eg, shrapnel, ferromagnetic 
fragments in the orbital area), certain implanted medical devices (eg, aneurysm clips, cardiac 
pacemakers), or claustrophobia. 
22. The subject has findings on the screening brain MRI scan that will potentially compromise 
subject safety or the scientific integrity of the study data if the subject were to participate in this 
study. 
23. Subject has a history of significant allergic skin reactions (hypersensitivity) to adhesives, 
metals, or plastic.
 
.
7.3
Excluded Medications, Dietary Products 
Use of the agents in Table 7.a (prescription or nonprescription) is prohibited from the time points 
specified until study completion for each subject.
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Table 7.a
Prohibited Medications, Supplements, Dietary Products
21 Days Prior to Check-in for 
Confinement Period 1 
7 Days Prior to Check-in (Day-1)
72 Hours Prior to Check-in 
(Day -1)
Prescription medications
OTC medications (a)
Products containing caffeine or 
xanthine
Nutraceuticals (eg, St. John’s wort, 
ginseng, kava kava, ginkgo biloba, 
Chinese herbs, and melatonin)
Vitamin supplements
Immunization/vaccines (b)
Foods or beverages containing 
grapefruit or Seville-type (sour) 
oranges and marmalade, star fruit,
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
Intake of known OTC inhibitors/inducers 
of CYPs 3A4/5, 2C9, 2C19, 2D6, 1A2, 
2B6, 2E1, and 2A6 (c)
CYP=cytochrome P-450, OTC=over-the-counter. 
(a) Occasional use of acetaminophen/paracetamol (1 g/day) or other medication is allowed as approved by Takeda on 
a case-by-case basis. 
(b) Inclusive of, but not limited to, H1N1 and flu vaccinations.
(c) Omeprazole, lansoprazole, cimetidine, ranitidine, and chlorpheniramine.
Subjects must be instructed not to take any medications, including OTC products, without first 
consulting with the investigator, until their participation in the study is completed.
7.4
Diet, Fluid, and Activity Control 
PET scans and imaging-related procedures will take place in the 
. 
Subjects will be confined overnight at
until discharge on Day 3 of Confinement Period 1 and 
Day 2 of Confinement Period 2 (see Appendix A). 
During confinement, subjects will be given a standard menu that includes 3 meals and an evening 
snack, each containing approximately 30% fat (relative to the total calories). The meals served on 
the day of TAK-041 dosing should be similar in nutritional content for each subject in the study. 
The meal start and stop time, meal contents, and percentage of the meal will be recorded in the 
source for all meals served on Confinement Days for all subjects. 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. 
If a blood draw or any study procedure coincides with a meal, the blood draw will take precedence 
followed by the study procedure and then the meal. 
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TAK-041 (oral suspension) will be administered following a fast of at least 8 hours. Subjects will 
fast for an additional 2 hours after dosing with AMPH. Two hours after the AMPH dose, they can 
be offered a snack. During confinement on nondosing days, subjects will be given 3 meals and an 
evening snack, each containing approximately 30% fat (relative to the total calories). Some meals 
may not be served on dosing days. Water can be consumed ad libitum, except for 1 hour before and 
after dosing.
Subjects will remain upright (seated, standing, or ambulatory) for 4 hours following the dose 
administration, except as necessitated by the occurrence of an AE/or study procedures 
(eg, obtaining 12-lead ECG, lying on the PET scanner table for start of first postdose PET scan). 
Subjects will refrain from strenuous exercise from 72 hours before Check-in Day-1 in 
Confinement Period 1 through the Study Exit/Final Visit or ET.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the source and electronic case report form (eCRF) using the 
following categories. For screen failure subjects, refer to Section 9.1.19.
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires early 
termination because continued participation imposes an unacceptable risk to the subject’s 
health or the subject is unwilling to continue because of the PTE or AE.

Liver Function Test (LFT) Abnormalities
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.9), if any of the following circumstances occur at 
any time during study medication treatment:
–
ALT or AST >8 ×ULN.
–
ALT or AST >5 ×ULN and persists for more than 2 weeks.
–
ALT or AST >3 ×ULN in conjunction with elevated total bilirubin >2 ×ULN or INR 
>1.5.
–
ALT or AST >3 ×ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).
–
ALP > 1.5 × ULN in conjunction with elevated total bilirubin or elevated GGT or 
elevated AST/ALT.
–
ALP > 2 × ULN, persisting for longer than 3 days.
–
ALP > 3 × ULN.
2. Significant protocol deviation. The discovery 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.
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3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented.
4. Voluntary withdrawal. The subject wishes to withdraw from the study.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded. Withdrawal due to an AE 
should not be recorded in the voluntary withdrawal category.
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
6. Other. The specific reason should be recorded in the “specify” field of the eCRF.
–
Skin reactions (cutaneous hypersensitivity) to one of the wearable digital devices will lead 
to removal of that device for the remainder of the study and, dependent on the principal 
investigator’s (PI) assessment, the subject would not be required to discontinue the study.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The coordinating investigator or the 
 investigator may discontinue a 
subject’s study participation at any time during the study when the subject meets the study 
termination criteria described in Section 7.5. In addition, a subject may discontinue his 
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 coordinating 
investigator. In addition, efforts should be made to perform all procedures scheduled for the ET
Visit. Discontinued or withdrawn subjects may be replaced at the discretion of the sponsor in 
consultation with the investigators until up to 12 evaluable subjects have completed the study.
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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material.
8.1
Study Medication and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
The TAK-041 oral suspension will be used in this study. The TAK-041 crystalline drug substance 
(milled) will be labeled in an open-label fashion and compounded into oral suspensions that will be 
labeled for third party dispensing. A pharmacy staff member will manage and prepare doses as 
needed throughout the study. The oral suspensions will contain 5 to 40 mg of TAK-041 per dose. 
Compounding instructions will be provided to the clinical site. 
8.1.1.1
TAK-041
The oral suspension will be prepared at the site by weighing an appropriate amount of crystalline 
TAK-041 (milled) into a dosing bottle and mixing with 70 mL of 0.5% Tween 80 in 0.5% 
methylcellulose (MC) vehicle (Tween/MC vehicle). The composition of the Tween/MC vehicle is 
in Table 8.a. The composition of crystalline TAK-041 oral suspension is listed in Table 8.b.
Table 8.a
Composition of 0.5% Tween 80 in 0.5% (w/v) Methylcellulose Vehicle
Component
Composition per 100 mL of Water
Methylcellulose, Ph Eur or USP
500 mg
Tween 80, Ph Eur or NF
500 mg
Sterile water for irrigation, Ph Eur
100 mL 
NF=National Formulary, Ph Eur=European Pharmacopeia, USP=United States Pharmacopeia. 
Table 8.b
Composition of TAK-041 Oral Suspension 
Component
Quantity per Dose 
Crystalline TAK-041 (milled)
(a) mg
Tween/MC vehicle
70 mL 
(a) Amount shall be in the range of 5 to 40 mg TAK-041, and a concentration range of 0.07 to 0.57 mg/mL TAK-041.
8.1.1.2
Amphetamine
Amphetamine tablets will be sourced locally by 
 as the commercial product dexamfetamine 
sulphate [17] with the manufacturer’s original label, and will be sourced locally by 
8.1.1.3
[11C]PHNO 
The PET ligand drug substance, [11C]PHNO, is formulated in sterile, non-pyrogenic solution.
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8.1.1.4
Sponsor-Supplied Drug
TAK-041 drug substance (milled) will be supplied in powder form, in appropriate packaging, and 
each container will bear a single panel label that includes all pertinent study information.
8.1.2
Storage
TAK-041 must be kept in an appropriate, limited-access, secure place until it is used or returned to 
the sponsor or designee for destruction. TAK-041 drug substance (milled) is stored at controlled 
room temperature (20°C to 25°C with excursions allowed from 15°C to 30°C).
Dexamfetamine sulphate must be stored under the conditions specified on the label, and remain in 
the original container until dispensed.
[11C]PHNO for injection will be prepared prior to use on site.
8.1.3
Dose and Regimen
The investigator or investigator’s designee will instruct the subject on dosing procedures. All 
dosing will be administered to the subjects by the investigator or investigator’s designee. The exact 
time of dose will be recorded in the source documents and on the appropriate eCRF.
Subjects will receive the TAK-041 doses by drinking the entire suspension from the dosing bottle. 
The dosing bottle will then be rinsed with 35 mL of water and the rinse will be administered in the 
same manner as the suspension. The rinse and administration will be repeated one more time. 
From the commercially available dexamfetamine sulphate tablet strengths (eg, 5 mg), the study 
site will calculate the amphetamine oral dose of 0.5 mg/kg for each subject based on the subject’s 
body weight. For example, for a 70 kg subject, the dose of dexamfetamine sulphate to be 
administered will be 35 mg. If the calculation results in a fraction of a mg, the dose should be 
rounded down to nearest 5 mg. Dexamfetamine sulphate tablets will be administered with 240 mL 
of still water. The dose administered should be as close as possible to the required dose based on 
the tablet strengths available. Dosing instructions for TAK-041 and dexamfetamine sulphate will 
be provided in the Pharmacy Manual.
Intravenous [11C]PHNO injection will be administered as a slow bolus of a 20-mL volume over 
20 seconds. The maximum administered mass of PHNO will not exceed 30 ng/kg for each PET 
scan. The maximum administered dose of [11C]PHNO will not exceed 180 MBq for each PET 
scan.
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study subject, at a dose above that which is assigned to that individual subject according 
to the study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
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with an overdose will be documented on AE eCRF(s) according to Section 10.0, Pretreatment 
Events and Adverse Events.
Serious adverse events (SAEs) associated with overdose should be reported according to the 
procedure outlined in Section 10.2.2, Collection and Reporting of SAEs.
In the event of drug overdose, the subject should be treated symptomatically.
8.2
Investigational Drug Assignment and Dispensing Procedures
Subjects will also be assigned a 4-digit enrollment number. For each dose level X, the number will 
be assigned by the clinical research unit personnel in sequential order beginning with X001. For 
example, the enrollment numbers will be 1001 to 1006 if there are 6 subjects for dose level 1, and 
2001 to 2006 if there are 6 subjects for dose level 2, etc.
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. It should also be contained on 
the PK transport vials shipped to the bioanalytical laboratory, and will be used by the laboratory to 
report the subject data results. This 4-digit number should only be used for the purposes described 
in this section. It does not replace the 3-digit subject number that is assigned at the time the 
informed consent is obtained and that is used for all other procedures to identify the subjects 
throughout the study.
8.3
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at 
before being returned to the sponsor or 
designee or destroyed at 
The coordinating 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, the investigator or designee must maintain records of all 
sponsor-supplied drug delivery to 
or the 
, site inventory, 
dispensation and use by each subject, and return to the sponsor or designee.
Upon receipt of sponsor-supplied drug, the coordinating investigator or designee must verify the 
contents of the shipments against the packing list. The verifier should ensure that the quantity is 
correct, and the medication is in good condition. If quantity and conditions are acceptable, 
investigator or designee should acknowledge the receipt of the shipment. 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 coordinating investigator or designee must maintain 100% accountability for all 
sponsor-supplied drugs received and dispensed during his or her entire participation in the study. 
Proper drug accountability includes, but is not limited to:

Continuously monitoring expiration dates if expiry or retest date is provided to the investigator 
or designee. 
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
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.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The coordinating investigator or designee must record the current inventory of all 
sponsor-supplied drugs on a sponsor-approved drug accountability log. The following information 
can be included but is not limited to: protocol number and title, name of investigator, 
 unit 
identifier and number, description of sponsor-supplied drugs, date and amount dispensed, 
including initials or signature of the person dispensing the drug, including the initials or signature 
of the person receiving the sponsor-supplied drug. The log should include all required information 
as a separate entry for each subject to whom sponsor-supplied drug is dispensed.
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 coordinating investigator or 
designee cannot destroy study drug without the sponsor’s approval. The coordinating 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 coordinating 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.
A unique subject identification number (site 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.
Participation in the wearable device study component is optional for the study subjects.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth or age, sex, race as described by 
the subject, caffeine consumption, ethanol (alcohol) use, and tobacco use of the subject at 
Screening. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that stopped at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions and recorded 
as medical history.
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 physical examination 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.
The physical examination will be performed at Screening, Check-in (Day -1) in both Periods and 
Study Exit/Final Visit or ET.
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 described in Section 10.0.
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On subsequent examinations, any abnormal change from the pretreatment physical examination 
assessment occurring immediately prior to the start of the first administration of PET tracer 
[11C]PHNO 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. 
A directed physical examination will be performed before discharge from Confinement Periods 1 
and 2 and at each Follow-up Visit. A directed physical examination includes an examination of the 
affected body system(s).
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 measured at Screening only. BMI is calculated at Screening only using metric units 
with the formula provided below. 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 based on a value 
between 18 and 30 mg/m2 cut-off point, then this determination must be made after rounding.
Weight (only) will also be collected at Check-in (Day -1) in Confinement Periods 1 and 2, each 
Follow-up Visit, and at the Study Exit/Final Visit or ET (see Appendix A).
9.1.5
Vital Sign Procedure
Vital signs will include measurement of oral body temperature, blood pressure, respiratory rate, 
and pulse (bpm). Pulse and blood pressure will be measured after 5 minutes supine. Orthostatic 
pulse and blood pressure will be measured after standing for 2 minutes.
Vital signs will be recorded according to the schedule in Table 9.a.
Table 9.a
Schedule for Recording Vital Signs
Dosing
Time Points 
Overview
Screening (Days -28 to -2), Check-in (Day -1 both confinement periods), Follow-up Visits 
(Days 8-92), and Study Exit/Final Visit or ET.
AMPH only
Within 60 minutes prior to AMPH dosing; at 1, 2, 4, 8, and 12 hours post-AMPH dose; and 
prior to Confinement Period 1 discharge.
TAK-041 + AMPH
Within 60 minutes prior to TAK-041 dosing; at 3, 4, 6, 10, and 14 hours post-TAK-041 dose; 
and prior to Confinement Period 2 discharge.
See Appendix A for the schedules of vital sign assessments.
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Orthostatic pulse and blood pressure will be measured after standing for 2 minutes at Screening,
Check-in (Day -1), prior to discharge in both Confinement Periods, during Follow-up Visits, and 
at Study Exit/Final Visit or ET.
If a vital signs assessment is scheduled to occur while the subject is in the PET scanner, the 
assessment should be deferred until the PET scan is completed.
Vital signs may be repeated. All measurements will be recorded on the source documents and in 
the eCRF. See Appendix A for schedules of vital sign assessments.
If a vital sign is found to be abnormal postdose, it will be collected every 30 minutes until it returns 
to Baseline or within normal range.
When postdose 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 over the counter. Concomitant medication is not provided 
by the sponsor. At each study visit, subjects will be asked whether they have taken any medication 
other than the study drug (used from signing of informed consent through the end of the study), 
and all medication including vitamin supplements, OTC medications, and oral herbal preparations, 
must be recorded in the eCRF. Documentation will include generic medication name, dose, unit, 
frequency, route of administration, start and end dates, and reason for use.
9.1.7
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 examinations, according the judgment of the 
investigator. The condition (ie, diagnosis) should be described.
9.1.8
Wearable Devices Procedures
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9.1.9
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. Laboratory 
samples will be taken according to the Schedule of Study Procedures (Appendix A).
Table 9.b lists the tests that will be obtained for each laboratory specimen.
Table 9.b
Clinical Laboratory Tests
Hematology
Chemistry
Urinalysis
Erythrocytes/RBC
Leukocytes/WBC with 
differential [define 
components as absolute 
values]
Hemoglobin
Hematocrit
Platelets 
ALT
Albumin
Alkaline phosphatase
AST
TBILI
Direct bilirubin
Protein (total protein)
Creatinine
Urea
Creatine kinase
GGT
Potassium
Sodium
Glucose
Chloride
Bicarbonate
Calcium 
Total serum cholesterol
Triglycerides
pH
Specific gravity
Protein
Glucose
Blood 
Nitrite
Ketones
Bilirubin
Urobilinogen
Microscopic Analysis^ :
Erythrocytes/RBC/high 
power field
Epithelial cells, casts, etc./ 
low power field
^To be performed if 
abnormal for blood, 
protein or nitrite
Diagnostic Screening:
Serum
Urine Drug Screen and Ethanol Breath Test
Hepatitis panel (including HBsAg and anti-HCV), 
HIV, TSH, and 5’-nucleotidase
Drug screen includes amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, opiates, and 
cotinine. Breath test for ethanol (alcohol).
RBC=red blood cells, WBC=white blood cells, TSH=thyrotropin.
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. All laboratory safety data will be transferred electronically to 
Takeda or designee in the format requested by Takeda. The investigator will maintain a copy of 
laboratory accreditation and the reference ranges for the laboratory used. 
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If subjects experience ALT or AST >3 ×ULN, ALP > 1.5 × ULN in conjunction with elevated 
TBILI, GGT, AST or ALT; ALP > 2 × ULN persisting for longer than 3 days, or ALP > 3 × ULN, 
follow-up laboratory tests (at a minimum, serum ALP, ALT, AST, total bilirubin, GGT, 
5’-nucleotidase, and INR) should be performed within a maximum of 7 days and preferably within 
48-72 hours after the abnormality was noted.
Please refer to Section 7.5 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests in relation to the elevated liver enzyme 
values listed above. Initiate close observation for subjects enrolled with Baseline elevations in 
liver enzymes that are not >3 × ULN, yet worsen by 2-fold increases above Baseline values after 
study drug exposure.
If the ALT, AST, or ALP 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 medication, discussion of the relevant subject details 
and possible alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 10.2.3 Reporting of Abnormal Liver Function Tests for reporting requirements).
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 coordinating investigator or subinvestigator 
indicating that the report has been reviewed and any abnormalities have been assessed for clinical 
significance. Any abnormalities identified prior to first dose will require clear and complete 
documentation in the source documents as to the investigator’s assessment of NCS before 
proceeding with enrollment.
All CS laboratory abnormalities must be recorded as an 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.
9.1.10 Contraception and Pregnancy Avoidance Procedure
Only male subjects may participate in this study. 
From signing of informed consent, throughout the duration of the study, and for a period of 
167 days (ie, 90 days after 7 half-lives, estimated using an average half-life value) following 
TAK-041 administration, nonsterilized** male subjects who are sexually active with a female 
partner of childbearing potential* must use barrier contraception (eg, condom with spermicidal 
cream or jelly), or sexual abstinence, if it is the preferred and usual lifestyle of the subject. Subjects 
practicing abstinence as a method of contraception must refrain from heterosexual intercourse 
throughout the duration of the study and for a period of 167 days (ie, 90 days after 7 half-lives, 
estimated using an average half-life value) following TAK-041 administration. In addition, they 
must be advised not to donate sperm during this period.
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*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (eg, defined 
as at least 1 year since last regular menses with a follicle stimulating hormone >40 IU/L or at least 
5 years since last regular menses).
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate.
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for sperm donation.
During the course of the study, subjects will receive continued guidance with respect to 
contraception and sperm donation as part of the study procedures (Appendix A).
9.1.11 Pregnancy
Women are not included in this study.
There are no nonclinical teratogenicity/fetotoxicity data on TAK-041 as no embryo-fetal 
development toxicity studies have been conducted with the compound. Based on the results of 
nonclinical toxicity studies, TAK-041 was not mutagenic or clastogenic. 
As such, the effect of TAK-041 on fetal development is unknown at this time. TAK-041 has not 
been administered to women who are pregnant or lactating. No nonclinical reproductive and 
developmental toxicity studies have been conducted. TAK-041 should not be administered to 
pregnant or lactating women at this stage in development. Based on this, it is recommended that 
women of childbearing potential be excluded from this study. Male subjects who are sexually 
active with a woman of childbearing potential should use a highly effective method of 
contraception (<1% failure rate/year), which has low user dependency while participating in this 
study (see Section 9.1.10).
If any female partner of a male subject is found to be pregnant during the treatment period of the 
study or within 167 days (ie, 90 days after 7 half-lives, estimated using an average half-life value) 
following TAK-041 administration, and if she 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 
treatment the subject received (blinded or unblinded, as applicable).
If the pregnancy occurs during administration of active study medication, eg, after Day 1 or within 
167 days (ie, 90 days after 7 half-lives, estimated using an average half-life value) following 
TAK-041 administration, the pregnancy should be reported immediately, using a pregnancy 
notification form, to the contact listed in Section 1.0.
All reported pregnancies will be followed up to final outcome, using the pregnancy form. The 
outcome, including any premature terminations, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted.
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9.1.12 ECG Procedure 
Standard 12-lead ECGs will be recorded at Screening, at multiple time points throughout the study 
(see Appendix A) and at the final safety evaluation at Study Exit or Early Termination. Additional 
unscheduled ECGs may be recorded where clinically necessary for subject safety. ECGs will be 
administered according to the schedules shown in Table 9.c. Single ECGs will be taken at all time 
points. If an assessment is scheduled to occur while the subject is in the PET scanner, the 
assessment should be deferred until the PET scan is completed.
Table 9.c
Schedule of ECG Recordings
Dosing
Time Points 
Overview
Screening (Days -28 to -2), Check-in (Day -1 both confinement periods), Follow-Up Visits 
(Days 8-92), and Study Exit/Final Visit.
AMPH only
Within 60 minutes prior to AMPH dosing; at 1, 2, 4, 8, and 12 hours post-AMPH dose; and 
prior to Confinement Period 1 discharge.
TAK-041 + AMPH
Within 60 minutes prior to TAK-041 dosing; at 3, 4, 6, 10, and 14 hours post-TAK-041 dose;
and prior to Confinement Period 2 discharge. 
When an ECG is scheduled at the same time as the blood draws or vital signs, then the blood draws 
and vital signs will take priority and the ECG will be obtained within 30 minutes before or after the 
scheduled blood draw/vital sign assignment. If an ECG coincides with a meal, the ECG will take 
precedence followed by the meal.
All 12-lead ECG machines will be supplied by 
 Subjects should be in a supine position 
following an approximate 5 minute rest period for ECG recordings. Should technical difficulties 
occur during recording of the ECG, a reasonable attempt should be made to repeat the ECG shortly 
after the failed attempt.
ECGs will be read automatically and the investigator (or a cardiologist at the investigational site) 
will interpret the ECG using 1 of the following categories: within normal limits, abnormal but 
NCS, or abnormal and CS. The following parameters will be recorded on the eCRF from the 
subject’s ECG trace: heart rate, RR interval, PR interval, QT interval, QRS interval, and QT 
interval with the Bazett correction method (QTcB). QTcB will be calculated automatically by the 
ECG machine. However, the QT interval with the Fridericia correction method (QTcF) and the RR 
interval may be calculated manually by the site or automatically by the ECG machine. The QTcF 
interval is calculated as shown below:
ECG assessment and parameters will be captured in Takeda eCRF. 
 unit uses a fully 
validated ECG system. The coordinating investigator assessment is recorded electronically within 
this system.
All ECGs will be recorded at the time points detailed in the Schedule of Study Procedures 
(Appendix A). 
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9.1.13 Screening MRI of Brain
As part of Screening, eligible subjects will undergo an MRI scan without gadolinium contrast at 
the 
 to ensure that there are no brain findings that might potentially 
compromise subject safety or scientific integrity of the study data. The screening MRI may be 
performed on a separate day from the other screening procedures. Additionally, the images will be 
used to identify and delineate the anatomical regions of interest for individual PET images and to 
aid in image analysis. 3D-T1-weighted images will be acquired on a Siemens 3T scanner. Further 
details of the complete scanning procedure will be provided by the
 in the 
MRI Scanning Manual for this study. The screening brain MRI will be performed and interpreted 
at the 
 after the other screening activities have been performed and results 
assessed. MRI should be performed early enough so that MRI scan results are available prior to 
Check-in. 
In case of a subject being re-screened, an MRI (without any abnormality) obtained at the 
 
r made within 90 days prior to Baseline Imaging Check-in is acceptable for 
eligibility.
9.1.14 Assessment of Suicidal Ideation and Behavior
Suicidality will be assessed by the use of the C-SSRS. The C-SSRS is a 3-part scale that measures 
suicidal ideation (eg, subject endorses thoughts about a wish to be dead or has other thoughts of 
suicide), intensity of ideation (frequency, duration, controllability, deterrents, and reasons for 
ideation), and suicidal behavior (actually, interrupted, and aborted attempts at suicide) [21].
Two versions of the C-SSRS will be used in this study: the Screening/Baseline C-SSRS Lifetime 
Version 14Jan2009 and the Since-Last-Visit C-SSRS Version 14Jan2009. These will be 
administered according to the schedules shown in Appendix A and Table 9.d. 
Table 9.d
C-SSRS Schedule of Assessments
Study Part
Version
Time Points 
Screening/Baseline
Screening (Days -28 to -2)
Confinement Part 1
Since-Last-Visit
Day 3 (discharge)
Confinement Part 2
Since-Last-Visit
Day 2 (discharge)
Since-Last-Visit
Study Exit/Final Visit or ET
9.1.15 Pharmacogenomic Sample Collection
Pharmacogenomic samples are not being collected in this study.
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9.1.16 Pharmacokinetic Sample Collection
9.1.16.1 Collection of Plasma for Pharmacokinetic Sampling
Blood samples (one 6-mL sample per scheduled time) for PK analysis of AMPH will be collected 
into chilled blood collection tubes (Vacutainer) containing anticoagulant ethylenediamine 
tetraacetic acid (K2EDTA) according to the schedules in Appendix A.
Blood samples (one 4-mL sample per scheduled time) for PK analysis of TAK-041 and its
metabolites (if possible) will be collected into chilled blood collection tubes (Vacutainer) 
containing anticoagulant K2EDTA according to the schedules in Appendix A.
Serial blood samples for determination of AMPH and TAK-041 will be collected according to 
Table 9.e.
Table 9.e
Collection of Blood Samples for Pharmacokinetic Analysis
Analyte
Matrix
Period
Scheduled Time (hours)
AMPH
Plasma
1 and 2
Predose (within 60 minutes prior to dosing), 1 and 2 hours post-AMPH 
administration, and immediately prior to and after [11C]PHNO PET scan.
TAK-041
Plasma
1 or 2
1, 2, 12, and 24 hours post-TAK-041 administration, immediately prior to and 
after the [11C]PHNO PET scan, and during each Follow-up Visit.
Blood samples for TAK-041 PK will also be collected at ET if TAK-041 was administered. All 
efforts will be made to obtain the PK samples at the exact nominal time relative to dosing. When 
the timing of safety measurements coincides with a PK blood collection, the order should be safety 
assessments followed by PK blood sample collection at the nominal time. 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 concentration data 
collected from prior subjects, but the total number of samples collected per subject should not 
exceed the planned number.
When ET is within 1 hour of a scheduled PK sample collection time point and study drug has been 
administered, the PK sample should be collected.
Instructions for sample processing and shipment are provided in Appendix E.
9.1.16.2 Bioanalytical Methods
 
9.1.17 Pharmacokinetic Analyses
Plasma concentrations of AMPH and TAK-041 will be listed and only descriptive summaries by 
dose and (nominal) time points including, arithmetic mean, standard deviation, median, lower and 
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upper quartiles, and minimum and maximum values will be calculated. Further details of statistical 
methods will be outlined in the statistical analysis plan (SAP).
9.1.18 [11C]PHNO PET Imaging Procedure, Image Processing and Analysis
PET scans will be acquired on a Siemens Biograph PET/CT scanner at the 
 
. The procedure is briefly summarized here. The details of the PET imaging procedure, 
image processing and analysis will be provided by the
 in a 
TAK-041-1002 PET Imaging Manual. 
9.1.18.1 PET Imaging Procedures
Subjects will undergo a total of 3 PET scans with [11C]PHNO during 2 confinement periods in this 
study. PET scans will be scheduled such that the post-AMPH scans are performed at the 
approximately the same time of day for a given subject.
Environmental conditions should be controlled for approximately 6 hours prior to [11C]PHNO 
administration (covering the total time for TAK-041 and AMPH uptake) to minimize dopamine 
release due to environmental stimuli, including video game playing on cell phones. 
On PET scan days, the subject will undergo preinjection assessments including vital signs (blood 
pressure, pulse, respiratory rate, and temperature) (see Appendix A). A venous catheter will be 
placed in the forearm or antecubital vein for pre-PET scan PK sample collection and [11C]PHNO 
administration. Additional PK samples will be collected through direct venipuncture or a second 
catheter will be placed in the opposite forearm or antecubital vein. 
The subject will be positioned in the scanner and sufficient padding will be used to minimize head 
movements during imaging acquisition. The subject will be monitored continuously by a qualified 
PET technologist. A low dose CT scan will be performed before each injection of [11C] PHNO for 
subsequent attenuation and scatter correction of the PET data. After the transmission CT scan, the 
subject will receive a bolus injection of up to 180 mBq of [11C]PHNO administered as a slow bolus 
over 20 seconds. Dynamic PET imaging will commence at the onset of the tracer injection and 
continue for approximately 90 minutes. The total time may be shortened based on ongoing 
analysis of brain tracer dynamics. The technical details of the PET acquisition are contained in the 
PET Imaging Manual.
9.1.18.2 Image Processing and Analysis
The person performing the PET data analysis will be informed of which is the baseline condition 
for each subject; however, they will be blinded as to whether the remaining scans they are 
evaluating for that subject are the TAK-041 + AMPH or the AMPH only scans.
Following reconstruction, scatter correction and attenuation correction, the PET data will be 
corrected for motion (if required) and coregistered to each subject’s structural MRI image. 
Anatomic regions of interest will be defined using each subject’s MRI. Those regions will include,
but not be limited to, the caudate, cerebellum, putamen, substantia nigra, and ventral striatum. The 
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regions of interest will then be applied to the PET emission data to derive regional time-activity 
curves. 
Decay-corrected time-activity curves will be analyzed using a simplified reference tissue model
[22,23], with the cerebellum as the reference region to derive regional estimates of BPND. BPND is 
proportional to the available concentration of receptor sites [24]. 
9.1.18.3 PET Data Analysis
A separate imaging report prepared by the 
 will describe the following: 
1. Individual BPND values and descriptive statistics for high uptake regions of interest for all PET 
scans. Descriptive statistics for BPND values will include means, medians, SDs, ranges, and 
95% CI.
2. The change in BPND for the AMPH+TAK-041 condition compared to the BPND for the AMPH 
alone condition (100*[BPND AMPH+TAK-041- BPND AMPH]/ BPND AMPH).
3. The relative change in BPND for the AMPH alone condition (100*[Baseline –
Post-AMPH]/Baseline) and the relative change in BPND for the AMPH+TAK-041 condition 
(100*[Baseline – Post-AMPH+TAK-041]/Baseline).
4. In order to establish a potential dose-dependent effect, we will explore via plots the magnitude 
of the relative change in BPND in the AMPH+TAK-041 condition as a function of the dose of 
TAK-041 administered.
5. Additional analyses may be performed for exploratory purposes.
9.1.19 Biometric Monitoring Using the Wearable Devices
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9.1.20 Documentation of Screen Failure
Investigator must account for all subjects who sign informed consent. If the subject is found to be 
not eligible at this visit, the investigator should complete the eCRF screen failure form.
The primary reason for screen failure is recorded in the eCRF using the following categories:

PTE/AE.

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 numbers assigned to subjects who fail screening should not be reused. If a subject fails 
screening, but is later successfully rescreened, the data for the subject will be entered as if these 
were 2 separate subjects. Therefore the data should be entered as follows:
1. The screen failure data should be entered as a screen failure subject.
2. Rescreened subjects should be assigned a new subject number and treated as a stand-alone 
subject.
9.1.21 Documentation of Study Enrollment
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for entrance into the treatment phase.
If the subject is found to be not eligible for entrance, 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 
or the 
. Following administration of the study medication, appropriate mouth 
checks will be performed to ensure that the dose is swallowed and then 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 medication supplies dispensed will be performed by 
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.
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9.3
Schedule of Observations and Procedures
Schedules for all study-related procedures are shown in Appendix A. Assessments should be 
completed at the designated visit/time point(s) detailed in Appendix A footnotes.
9.3.1
Screening

Informed consent.

Brain MRI.

Inclusion/exclusion criteria.

Demographics and medical history.

Medication history.

Physical examination.

Vital signs.

Height, weight, and BMI.

Concurrent medical conditions.

Concomitant medications.

12-lead ECG.

Safety laboratory evaluations.

Urine drug screen and ethanol breath test.

Hepatitis panel (including HBsAg and anti-HCV), HIV, TSH, and 5’-nucleotidase.

PTE assessment.

C-SSRS.
9.3.2
Follow-up Visits

Directed physical examination.

Vital signs.

Weight.

Concomitant medications.

12-lead ECG.

Safety laboratory evaluations.
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
PK blood collection for TAK-041.

AE assessments.

Return of Actiwatch at first Follow-up Visit. (Skin Patch device is removed 2 days after 
discharge [CP1 and CP2].)
9.3.3
Study Exit/Final Visit or Early Termination (ET)

Physical examination.

Vital signs.

Concomitant medications.

12-lead ECG.

Safety laboratory evaluations.

AE assessments.

C-SSRS.

Only at ET: 
–
PK blood collection for TAK-041, if possible.
9.4
Blood Volume
Total blood sampling volume for an individual subject is shown in Table 9.f. Every effort has been 
made to minimize the blood volumes for the blood tests in this study.
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Table 9.f
Approximate Blood Volume
Sample Type
Sample 
Volume
(mL)
Number of Samples
Total 
Volume 
(mL)
Screening 
Confinement
Follow-Up
Visits (a)
Study 
Exit/ Final 
Visit
ET (b)
CP1
CP2
Safety laboratory tests 
9.5
1
0
0
0
0
9.5
Safety laboratory tests
4.5
2
2
4
1
40.5
PGx sample collection 
NA
NA
PK blood collection (TAK-041)
4.0
0
0
6 
4
1 (c)
44.0
PK blood collection (AMPH) 
6.0
0
5
5
0
0
60.0
Total Approximate Blood Sampling Volume
154.00
NA=not applicable, PGx=pharmacogenomics.
Note: Volumes do not include unscheduled/repeat or additional blood samples.
(a) Four Follow-up Visits are scheduled: one 7 ±2 days after TAK-041 administration in Confinement Period 2 and 3 
Follow-up Visits approximately 4 weeks apart or until TAK-041 concentration in plasma is <5% of the subject’s Cmax.
(b) The Study Exit/Final Visit may occur instead of the last scheduled Follow-up Visit. 
(c) Blood samples for TAK-041 PK will be collected at ET if TAK-041 was administered.
The maximum volume of blood in any single day is approximately 50.0 mL. The total volume of 
blood for each subject is approximately 154.0 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 first administration of PET tracer 
[11C]PHNO; 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 CS abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a drug whether or not it is 
considered related to the drug.
10.1.3 Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions underlying disease should not be considered PTEs or AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason. 

PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if they 
are judged to be 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 re-test 
and/or continued monitoring of an abnormal value are not considered an intervention. In 
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addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE(worsening or complication occurs before start of study medication) or 
an AE (worsening or complication occurs after start of study medication). Investigators should 
ensure that the event term recorded captures the change in the condition (eg, “worsening 
of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after starting administration of 
the study medication, the worsening or complication should be recorded appropriately as an 
AE. Investigators should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”).
Changes in severity of AEs /Serious PTEs:

If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded.
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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 
worsening of the condition should be captured appropriately as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of 
the eCRF.
10.1.4 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
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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
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5 Severity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.6 Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments.
10.1.7 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.
The relationship should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as Not Related.
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10.1.8 Start Date
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or physician.
10.1.9 Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.1.10
Frequency 
Once: a onetime occurrence; episodic AEs (eg, vomiting) or those which occur repeatedly over a 
period of consecutive days are intermittent. All other events are continuous.
10.1.11
Action Concerning Study Drug

Drug withdrawn – a study drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study drug was stopped for a reason other than the particular AE (eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped before 
the onset of the AE).

Dose reduced – the dose was reduced due to the particular AE.

Dose increased – the dose was increased due to the particular AE.

Dose interrupted – the dose was interrupted due to the particular AE.
10.1.12
Outcome

Recovered/resolved – subject returned to first assessment status with respect to the AE/PTE.

Recovering/resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to Baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”.

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/PTE state remaining “Not 
recovered/not resolved”.

Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).
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
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 first injection of the ligand [11C]PHNO for the 
Baseline PET scan in Confinement Period 1 or until screen failure. For subjects who discontinue 
prior to study medication administration, PTEs are collected until the subject discontinues study 
participation.
Collection of AEs will commence from the time that the subject is first administered [11C]PHNO. 
Routine collection of AEs will continue through the Study Exit/Final Visit.
10.2.1.2 PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or there is a satisfactory explanation for the change. 
Nonserious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
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. Pattern of AE (Frequency).
4. Severity/Intensity.
5. Investigator’s opinion of the causal relationship between the event and administration of study 
medication(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.
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7. Action concerning study medication (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 medication(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, or ALP >3 ×ULN and TBILI >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 9.1.9 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Takeda SAE form (as per Section 10.2.2).
10.3
Follow-up of SAEs
If information 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. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.3.1 Safety Reporting to Investigators, IRB or IEC, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency (EMA), investigators and IRBs or IECs, in accordance with national 
regulations in the countries where the study is conducted. Relative to the first awareness of the 
event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to 
the regulatory authorities as expedited report within 7 days for fatal and life-threatening events and 
15 days for other serious events, unless otherwise required by national regulations. The sponsor 
will also prepare an expedited report for other safety issues where these might materially alter the 
current benefit-risk assessment of an investigational medicinal product or that would be sufficient 
to consider changes in the investigational medicinal products administration or in the overall 
conduct of the trial. The investigational site also will forward a copy of all expedited reports to his 
or her IRB or IEC in accordance with national regulations.
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11.0
STUDY-SPECIFIC COMMITTEES
No study-specific committees are 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 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
CRFs (Electronic)
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with eCRFs. The sponsor will make 
arrangements to train appropriate site staff in the use of the eCRF. Data are captured in 
database or on paper (C-SSRS for example) and then transcribed into the eCRFs. These eCRF 
forms are used to transmit the information collected in the performance of this study to the sponsor 
and regulatory authorities. eCRFs must be completed in English. 
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included.
The coordinating investigator must review the eCRFs for completeness and accuracy and must 
sign and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
After the lock of the clinical study database, any change of, modification of or addition to the data 
on the provided by the sponsor should be made by the investigator with use of change and 
modification records of the eCRFs. The coordinating investigator must review the data change for 
completeness and accuracy, and must sign, and date.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigators 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), 
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electronic copy of eCRFs, including the audit trail, as well as the MRI scans and PET scans 
(attenuation-corrected, nonattenuation corrected, and attenuation correction scans), 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 retain essential documents specified in ICH E6 (Section 8) until at least 
2 years after the last approval of a marketing application for a specified drug indication being 
investigated or, if an application is not approved, until at least 2 years after the investigation is 
discontinued and regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that 
the study records should be retained until an amount of time specified by applicable regulatory 
requirements or for a time specified in the Clinical Study Site Agreements between the 
investigator(s) and sponsor.
Refer to the Phase 1 Site Specifications document for the sponsor’s requirements on record 
retention. The investigator should contact and receive written approval from the sponsor before 
disposing of any such documents.
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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A 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.
A targeted data review will be conducted prior to database lock. This review will assess the 
accuracy and completeness of the study database, subject evaluability, and appropriateness of the 
planned statistical methods.
13.1.1 Analysis Sets
Safety Set
The safety set will consist of all subjects who are enrolled and receive an investigational drug 
([11C]PHNO, AMPH alone, or TAK-041 and AMPH) as part of this study. Subjects in this analysis 
set will be used for demographic, baseline characteristics, and safety summaries.
Pharmacokinetic Set
The PK set will consist of all subjects who receive study drug (TAK-041 and AMPH, or AMPH 
alone) and have at least one measurable plasma concentration for TAK-041 or AMPH.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic data will be summarized by TAK-041 dose level and overall. Descriptive statistics 
(N, mean, SD, median, minimum, and maximum) will be generated for continuous demographic 
variables and baseline characteristics variables (eg, age, height, weight, and BMI). The number 
and percentage of subjects in each class of the categorical demographic variables and baseline 
characteristics variables (eg, sex, race, tobacco use) will also be tabulated. Individual subject 
demographic and baseline characteristics data will be listed.
Demographic variables of screen failure subjects and reasons for screen failures will be 
summarized overall for subjects who are screened, but not enrolled in the study. Individual 
demographic characteristics, date of informed consent, and reason for screen failure will be listed.
13.1.3 Pharmacokinetic Analysis
All measured concentrations will be listed and descriptive summaries by treatment arm and (nominal) 
time points including n, arithmetic mean, SD, median, lower and upper quartiles and minimum and 
maximum values will be made. In addition, geometric mean, standard deviation (SD) of log 
transformed values and %CV will also be presented. 
A more detailed analysis will be presented in the SAP.
The data points will be used for population PK meta-analysis, which will be described in an analysis 
plan and reported separately.
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13.1.4 Safety Analysis
All AEs will be coded by system organ class and preferred term using MedDRA. TEAEs with 
onset occurring up until Study Exit/Final Visit will be listed and included in the summary tables. 
TEAEs will be summarized overall, by relationship to study drug, and by severity for each 
treatment and overall. Similar summary tables will be generated for TEAEs assessed by the 
investigator as related to study drug.
Individual results for clinical laboratory tests, vital sign, and ECG parameters that meet TDC’s 
markedly abnormal criteria to be defined in the SAP will be listed and summarized. Baseline, 
postdose, and change from Baseline to postdose clinical laboratory tests, vital signs, and ECG 
parameters will be summarized for each regimen.
Shift tables will be generated for the investigator’s ECG interpretations for each regimen. All ECG 
data will be provided in the data listings. Physical examination data and suicidal assessments will 
be presented in data listings. 
13.2
Determination of Sample Size
Using previously reported data [12], and assuming a 16% standard deviation for the relative
change in BPND for high uptake regions of interest, 12 subjects will provide approximately 80% 
power to detect a 20% relative change in BPND when values from the AMPH + TAK-041 condition 
are compared to AMPH alone condition using a 2-sample 2-sided t-test with 0.05 significance 
level. The power for the other regions of interest will be more than 80%. 
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site(s) will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee, 
including but not limited to the Investigator’s Binder, study medication, 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 or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol. 
The timing of the scheduled assessments may be adjusted as necessary to avoid interfering with the 
PET and fMRI scans and transfer between 
 unit and the 
.
The investigator should document all protocol deviations.
Every attempt will be made to collect each PK blood sample at the designated time points, and the 
actual time of each blood sample will be recorded on the source document and eCRF. 
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the Food and Drug Administration [FDA], the United Kingdom 
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Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices 
Agency of Japan). If the study sites are 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 or IEC Approval
IRBs or IECs 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 or IEC. If any member of the IRB or IEC 
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 IRB or IEC 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 or IEC for approval. The IRB’s or IEC’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 or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will notify site once the sponsor has confirmed 
the adequacy of site regulatory documentation and, when applicable, the sponsor has received 
permission from competent authority to begin the study. Until the site receives notification, no 
protocol activities, including screening may occur.
The site must adhere to all requirements stipulated by the IRB or IEC. This may include 
notification to the IRB or IEC 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 IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB or IEC 
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 or IEC 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 are 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.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the IRB 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).
Subjects who decline to participate in the wearable device optional component, or who consent 
and later withdraw from this part of the study, may continue to participate in the remainder of the 
study.
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
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this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
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.
15.4.2 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations, and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for US investigators), country, and 
recruiting status will be registered and available for public viewing. For some registries, Takeda 
will assist callers in locating trial sites closest to their homes by providing the investigator name, 
address, and phone number to the callers requesting trial information. Once subjects receive 
investigator contact information, they may call the site requesting enrollment into the trial. The 
investigative sites are encouraged to handle the trial inquiries according to their established subject 
screening process. If the caller asks additional questions beyond the topic of trial enrollment, they 
should be referred to the sponsor. Any investigator who objects to Takeda providing this 
information to callers must provide Takeda with a written notice requesting that their information 
not be listed on the registry site.
15.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.
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16.0
REFERENCES
1. Liu C, Bonaventure P, Lee G, Nepomuceno D, Kuei C, Wu J, et al. GPR139, an Orphan 
Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino 
Acids L-Tryptophan and L-Phenylalanine. Mol Pharmacol 2015;88(5):911-25.
2. Isberg V, Andersen KB, Bisig C, Dietz GP, Brauner-Osborne H, Gloriam DE. Computer-aided 
discovery of aromatic l-alpha-amino acids as agonists of the orphan G protein-coupled 
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3. van Os J, Kapur S. Schizophrenia. Lancet 2009;374(9690):635-45.
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7. Weiner WJ, Factor SA, Sanchez-Ramos JR. The efficacy of 
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8. Wilson AA, McCormick P, Kapur S, Willeit M, Garcia A, Hussey D, et al. Radiosynthesis and 
evaluation of 
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potential radiotracer for in vivo imaging of the dopamine D2 high-affinity state with positron 
emission tomography. J Med Chem 2005;48(12):4153-60.
9. Searle GE, Beaver JD, Tziortzi A, Comley RA, Bani M, Ghibellini G, et al. Mathematical 
modelling of [11C]-(+)-PHNO human competition studies. Neuroimage 2013;68:119-32.
10. Boileau I, Payer D, Chugani B, Lobo DS, Houle S, Wilson AA, et al. In vivo evidence for 
greater amphetamine-induced dopamine release in pathological gambling: a positron emission 
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11. Boileau I, Guttman M, Rusjan P, Adams JR, Houle S, Tong J, et al. Decreased binding of the 
D3 dopamine receptor-preferring ligand [11C]-(+)-PHNO in drug-naive Parkinson's disease. 
Brain 2009;132(Pt 5):1366-75.
12. Shotbolt P, Tziortzi AC, Searle GE, Colasanti A, van der Aart J, Abanades S, et al. 
Within-subject comparison of [11C]-(+)-PHNO and [11C]raclopride sensitivity to acute 
amphetamine challenge in healthy humans. J Cereb Blood Flow Metab 2012;32(1):127-36.
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13. Mizrahi R, Houle S, Vitcu I, Ng A, Wilson AA. Side effects profile in humans of 
11C-(+)-PHNO, a dopamine D(2/3) agonist ligand for PET. J Nucl Med 2010;51(3):496-7.
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radiation dosimetry of [11C]-(+)-PHNO, a D2/3 agonist ligand. J Nucl Med 
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16. Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M, et al. Increased striatal 
dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 
1998;155(6):761-7.
17. Dexamfetamine sulphate 5 mg tablets. Summary of Product Characteristics. Middlesex, UK: 
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18. Weidner LD, Paris A, Frankle WG, Narendran R. Safety of oral amphetamine administered 
during positron emission tomography scans in medically screened humans. PLoS One 
2015;10(12):e0140647.
19. Narendran R, Frankle WG, Mason NS, Rabiner EA, Gunn RN, Searle GE, et al. Positron 
emission tomography imaging of amphetamine-induced dopamine release in the human 
cortex: a comparative evaluation of the high affinity dopamine D2/3 radiotracers [11C]FLB 
457 and [11C]fallypride. Synapse 2009;63(6):447-61.
20. Willeit M, Ginovart N, Graff A, Rusjan P, Vitcu I, Houle S, et al. First human evidence of 
d-amphetamine induced displacement of a D2/3 agonist radioligand: A [11C]-(+)-PHNO 
positron emission tomography study. Neuropsychopharmacology 2008;33(2):279-89.
21. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from 
three multisite studies with adolescents and adults. Am J Psychiatry 2011;168(12):1266-77.
22. Gunn RN, Lammertsma AA, Hume SP, Cunningham VJ. Parametric imaging of 
ligand-receptor binding in PET using a simplified reference region model. Neuroimage 
1997;6(4):279-87.
23. Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. 
Neuroimage 1996;4(3 Pt 1):153-8.
24. Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, et al. Consensus 
nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow 
Metab 2007;27(9):1533-9.
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Appendix A
Schedule of Study Procedures
Periods
Days
-28 to -2
Confinement Period 1
I
Confinement Period 2
Follow-up 
Period
Study 
Exit/ 
Final 
Visit
(f)
ET
Study Day
Day -1
Day 1
Day 2
Day 3
Day -1
Day 1
Day 2
Procedures
Screening 
(a)
Check-
in (b)
PET 
Scan
Baseline
PET 
Scan
Postdose
Discharge 
(c)
(d)
Check-in
(b)
PET Scan 
Postdose
Discharge 
(c)
Days 8-92
(±2) (e)
(g)
Informed consent
X
Brain MRI
X
Check into 
X
X
Confinement (h)
X
X
X
X
X
X
X
Release from 
X
X
Inclusion/exclusion criteria
X
X
X
Demographics and medical 
history
X
Medication history
X
Physical examination (i)
X
X
X
X
X
Directed physical 
examination (j)
X
X
X
Vital signs (k)
X
X
X
X
X
X
X
X
X
X
Height, weight, and BMI (l)
X
X
X
X
X
X
Concomitant medications 
X
X
X
X
X
X
X
X
X
Concurrent medical 
conditions
X
X
12-lead ECG (m)
X
X
X
X
X
X
X
X
X
X
Footnotes on last table page.
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Appendix A
Schedule of Study Procedures (continued)
Study Day
Days
-28 to -2
Confinement Period 1
I
Confinement Period 2
Follow-up 
Period
Study 
Exit/ 
Final 
Visit
(f)
ET
Day -1
Day 1
Day 2
Day 3
Day -1
Day 1
Day 2
Procedures
Screening 
(a)
Check-
in (b)
PET 
Scan
Baseline
PET 
Scan
Postdose
Discharge 
(c)
(d)
Check-in
(b)
PET Scan 
Postdose
Discharge 
(c)
Days 8-92
(±2) (e)
(g)
Safety laboratory 
evaluations (n)
X
X
X
X
X
X
X
X
Urine drug screen and 
ethanol breath test
X
X
X
Hepatitis panel (including 
HBsAg and anti-HCV), 
HIV, TSH, 5’nucleotidase
X
AMPH dosing (o) 
X
X
TAK-041 dosing (p)
X
Insertion of venous catheter
X
X
[11C]PHNO PET tracer 
injection
X
X
X
PET scan
X
X
X
PK blood collection AMPH 
(q)
X
X
PK blood collection 
TAK-041 (r)
X
X
X
X
PTE assessment
X
X
AE assessment (s)
X
X
X
X
X
X
X
X
X
X
Footnotes on last table page.
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Appendix A
Schedule of Study Procedures (continued)
Study Day
Days
-28 to -2
Confinement Period 1
I
Confinement Period 2
Follow-
up 
Period
Study 
Exit/ 
Final 
Visit
(f)
ET
Day -1
Day 1
Day 2
Day 3
Day -1
Day 1
Day 2
Procedures
Screening 
(a)
Check-
in (b)
PET 
Scan
Baseline
PET Scan
Postdose
Discharge 
(c)
(d)
Check-
in
(b)
PET Scan 
Postdose
Discharge 
(c)
Days 
8-92 (±2)
(e)
(g)
C-SSRS (t)
X
X
X
X
X
(a) The MRI may be scheduled on a second Screening visit.
(b) Admission to 
(c) Discharge from 
(d) There will be a 5 to 45 day interval (I) between Confinement Periods.
(e) Following discharge from Confinement Period 2, subjects will return to the site for PK and safety assessments after 7 ±2 days, and then return for approximately 
3 Follow-up safety and PK assessment Visits (once every 4 weeks) or until the concentration of TAK-041 in plasma is <5% of the subject’s Cmax.
(f) At the end of each Follow-up Visit, the next visit will be scheduled ~4 weeks later. If, when the PK results are available, the subject’s PK was <5% of their Cmax
value, the site and subject will be informed that their next scheduled visit will be considered their Study Exit/Final Visit.
(g) Subjects who drop out prior to completion of all PET scans will have assessments done as described for ET and a follow-up telephone call approximately 2 days 
after the ET Visit.
(h) Subjects will be remain at 
 from Check-in through discharge on Day 3 in Period 1 or Day 2 in Period 2 except when the imaging scans are performed at the 
.
(i) Physical examinations will take place at Screening, Check-in (Day -1) in both Periods, and at Study Exit/Final Visit or ET.
(j) A directed physical examination will be performed as necessary at discharge in Confinement Periods 1 and 2, and at each Follow-up Visit.
(k) Vital signs will be recorded at Screening (Days -28 to -2) and at Check-in (Day -1) in both Confinement Periods. When both TAK-041 and AMPH are 
administered, vital signs will be recorded relative to the TAK-041 dose: within 60 minutes prior to TAK-041 dosing; at 3, 4, 6, 10, and 14 hours post-TAK-041 dose, 
and prior to Confinement Period 2 discharge or ET. When only AMPH is dosed, vital signs will be recorded relative to the AMPH dose: within 60 minutes prior to 
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AMPH dosing; at 1, 2, 4, 8, and 12 hours post-AMPH dose and prior to Confinement Period 1 discharge. Vital signs will also be recorded during each Follow-up 
Visit and at the Study Exit/Final Visit or ET. Orthostatic pulse and blood pressure will be measured after standing for 2 minutes at Screening, Check-in (Day -1) and 
prior to discharge in both Confinement Periods, during each Follow-up Visit, and at Study Exit/Final Visit or ET. 
(l) Weight only will be recorded at Check-in for Confinement Periods 1 and 2, at each Follow-up Visit, and at the Study Exit/Final Visit or ET. Height is collected
only at Screening; BMI is calculated only at Screening.
(m) ECGs will be recorded at Screening (Days -28 to -2) and at Check-in (Day -1) in both Confinement Periods. When only AMPH is dosed, ECGs will be recorded 
relative to the AMPH dose: within 60 minutes prior to AMPH dosing; at 1, 2, 4, 8, and 12 hours post-AMPH dose; and prior to Confinement Period 1 discharge.
When both TAK-041 and AMPH are administered, ECGs will be recorded relative to the TAK-041 dose: within 60 minutes prior to TAK-041 dosing and at 3, 4, 6, 
10, and 14 hours post-TAK-041 dose, and prior to Confinement Period 2 discharge. ECGs will also be recorded during each Follow-up Visit and at the Study 
Exit/Final Visit or ET. 
(n) Clinical safety laboratory tests (hematology, chemistry, and urinalysis) will be collected at Screening, upon Check-in and prior to Discharge in both confinement 
periods, during each Follow-Up Visit, and at the Study Exit/Final Visit or ET. 
(o) AMPH dosing: On Day 2 of Confinement Period 1, subjects will receive a single dose of AMPH alone. On Day 1 of Confinement Period 2, subjects will receive 
a single dose of TAK-041 followed by a single dose of AMPH at the approximate tmax of TAK-041.
(p) TAK-041 dosing: on Day 1 of Confinement Period 2, subjects will receive a single dose of TAK-041 followed by a single dose of AMPH at the approximate tmax
of TAK-041.
(q) PK AMPH: Confinement Periods 1 & 2, predose (within 60 minutes prior to dosing), 1 and 2 hours after AMPH administration, and immediately prior to and 
after the [11C]PHNO PET scan.
(r) PK TAK-041: During Confinement Period 2 at 1, 2, 12, and 24 hours after TAK-041 administration, immediately prior to and after the [11C]PHNO PET scan and 
during each Follow-Up Visit.
(s) Adverse events: Collection of AEs will commence from the time that the subject is first administered [11C]PHNO. Routine collection of AEs will continue 
through the Study Exit/Final Visit.
(t) C-SSRS: The Baseline C-SSRS will be administered at Screening. The Since Last Visit C-SSRS will be administered on Day 3 (Confinement Period 1), Day 2 
(Confinement Period 2), and Study Exit/Final Visit or ET).
(u) 
 
(v)
 
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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 investigator agrees to assume the following responsibilities:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that 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 
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 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.
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. 
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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 may discontinue 
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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. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
23. 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 medication(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.
e) that the subject’s identity will remain confidential in the event that study results are 
published.
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24. Male subjects must use adequate contraception (as defined in the informed consent) from 
Screening and throughout the duration of the study and for 90 days after last dose of study 
medication. 
25. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov. 
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Appendix 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 medication.

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-041 and 
Amphetamine
1. Collect 4 mL (TAK-041) or 6 mL (AMPH) of venous blood for plasma into a chilled 
Becton-Dickinson Vacutainer. All TAK-041 and AMPH 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 1500 (relative centrifugal force 
[RCF]) at 4°C. Note: if using a collection device other than Becton-Dickinson, refer to 
manufacturer’s instruction for proper centrifugation force and time.
4. Immediately following centrifugation, gently remove plasma from the packed cells. To ensure 
a more homogeneous sample, all plasma should first be transferred into 1 aliquot. From there, 
split the plasma evenly between the 2 aliquots. A minimum of 0.8 mL final plasma volume 
after centrifugation needs to be obtained for each sample. Labeling may include protocol 
number (TAK-041-1002), sample matrix (ie, TAK-041 or AMPH) enrollment number, period, 
profile day and time, and either “SET 1” (for original sample) or “SET 2” (for duplicate 
sample).
5. Cap the labeled storage tubes and freeze the plasma samples immediately in either -20°C 
or -70°C freezer (stability established at both temperatures) until shipment to PPD, Middleton, 
WI, USA. No more than 45 minutes should elapse between blood collection and freezing the 
plasma sample.
Shipping of TAK-041 Plasma Samples 
The following instructions are recommended unless they differ from the site’s standard operating 
procedures for labeling, packaging, or shipping of plasma 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:
a) Separate the duplicate SET 2 samples from the SET 1 samples.
b) Place SET 1 samples for each subject into self-sealing bag (eg, Ziploc) containing 
additional absorbent material.
c) Using a permanent marker, write the 4-digit enrollment sequence number, sample matrix 
(ie, plasma or urine), number of samples, and “SET 1” on each self-sealing bag.
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d) 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 2a through 2c above when preparing duplicate samples for shipment, except 
self-sealing bags should be marked “SET 2.”
3. An inventory of individual samples should accompany each shipment and should include the 
sponsor’s name (Takeda), study medication (TAK-041), protocol number (TAK-041-1002), 
investigator’s name, sample type (ie, plasma), enrollment number, period, nominal collection 
day and time, and intended sample storage conditions. When duplicate SET 2 samples are 
being shipped, make a copy of the original SET 1 sample inventory and mark as “SET 2.” 
Place the inventory paperwork into a large self-sealing bag. SET 1 samples will be shipped 
first on dry ice, followed by shipment of duplicate SET 2 samples after SET 1 samples have 
been received by the analytical laboratory.
4. 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.
5. 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.
6. Mark the outside of shipping carton(s) with a tally number (eg, 1 of 5, 2 of 5).
7. Affix an address label to each shipping carton. Complete the address label with the following 
information:
Plasma Samples for TAK-041
Jay Schaefgen
PPD - Middleton
3230 Deming Way
Middleton, WI 53562
Phone: 608-662-7706
Fax: 608-662-9025
8. 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)
9. 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.
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10. Obtain the airway bill number and a receipt of shipment from the carrier.
After shipping of the TAK-041 samples, e-mail Jay Schaefgen at jay.schaefgen@ppdi.com and 
Betty Katz at betty.katz@takeda.com or call Betty at 224-554-2160 to notify them 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
Shipping of Amphetamine Plasma Samples
The following instructions are recommended unless they differ from the site’s standard operating 
procedures for labeling, packaging, or shipping of plasma 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:
a) Separate the duplicate SET 2 samples from the SET 1 samples.
b) Place SET 1 samples for each subject into self-sealing bag (eg, Ziploc) containing 
additional absorbent material.
c) Using a permanent marker, write the 4-digit randomization sequence number, sample 
matrix (ie, plasma or urine), number of samples, and “SET 1” on each self-sealing bag.
d) 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 2a through 2c above when preparing duplicate samples for shipment, except 
self-sealing bags should be marked “SET 2.”
3. An inventory of individual samples should accompany each shipment and should include the 
sponsor’s name (Takeda), study medication (amphetamine), protocol number 
(TAK-041-1002), investigator’s name, sample type (ie, plasma), 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.
4. 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 
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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.
5. 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.
6. Mark the outside of shipping carton(s) with a tally number (eg, 1 of 5, 2 of 5).
7. Affix an address label to each shipping carton. Complete the address label with the following 
information:
Plasma Samples for Amphetamine
QPS, LLC
Delaware Technology Park
3 Innovation Way, Suite 240
Attn: Sample team 
Newark, DE 19711
Phone: 302-369-5601
8. 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)
9. 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.
10. Obtain the airway bill number and a receipt of shipment from the carrier.
11. After shipping of the Amphetamine samples, e-mail Yongdong.Zhu@qps.com and Betty Katz
at betty.katz@takeda.com or 224-554-2160 to notify them 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
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Appendix F
Detailed Description of Amendments to Text
This document describes changes in reference to Protocol TAK-041-1002 Incorporating 
Amendment No. 02.
Change 1: Preliminary results from first-in-human (FIH) study TAK-041-1001 were updated.
The primary change occurs in Section 4.3 Benefit/Risk Profile:
Initial 
wording:
As this is a healthy volunteer study, there is no expected clinical benefit to the study 
participants. TAK-041 has the potential to be a first-in-class drug; therefore, there are 
no known class effects. Potential risks are based on clinical findings, the mechanism 
of action, nonclinical findings, and the known risks of other GPR139 receptor 
agonists. Preliminary results from the FIH study TAK-041-1001 indicate that single 
doses of TAK-041 at 5, 10, 20, and 40 mg are well tolerated. To date, no adverse 
events and no clinically meaningful safety laboratory, physical examination, vital 
signs, or ECG results have been reported for the 16 subjects who received TAK-041 or 
placebo. The potential risks can be monitored clinically and/or with laboratory tests 
and are considered in setting up the stopping rules for this clinical study. Appropriate 
exclusion criteria that exclude individuals with past history or concurrent conditions 
that increase the risk will be applied.
Amended 
or new 
wording:
As this is a healthy volunteer study, there is no expected clinical benefit to the study 
participants. TAK-041 has the potential to be a first-in-class drug; therefore, there are 
no known class effects. Potential risks are based on clinical findings, the mechanism 
of action, nonclinical findings, and the known risks of other GPR139 receptor 
agonists. Preliminary results from the FIH study TAK-041-1001 indicate that single 
doses of TAK-041 at 5, 10, 20, and 40 mg are well tolerated. To date, no adverse 
events and no clinically meaningful safety laboratory, physical examination, vital 
signs, or ECG results have been reported for the 16 subjects who received TAK-041 or 
placebo. To fully assess the safety and PK profile of TAK-041 in subjects 
receiving 20 and 40 mg TAK-041 doses, follow-up PK blood draws were 
performed until TAK-041 plasma concentrations were below the lower level of 
quantitation of the assay. Six AEs were observed that were mild, deemed not 
related to study drug, and resolved without treatment. No serious AEs and no 
clinically meaningful safety laboratory results (including 5’-nucleotidase, 
sorbitol dehydrogenase, and urine osmolality), and no clinically significant 
physical examination, vital signs, or ECG results were reported for the 16 
subjects who received 5 to 40 mg doses of TAK-041 crystalline suspension or 
matching placebo in TAK-041-1001 Cohorts 1 and 2. The potential risks can be 
monitored clinically and/or with laboratory tests and are considered in setting up the 
stopping rules for this clinical study. Appropriate exclusion criteria that exclude 
individuals with past history or concurrent conditions that increase the risk will be 
applied.
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TAK-041
Study No. TAK-041-1002
Page 93 of 102
Protocol Incorporating Amendment No. 02
21 February 2017
Rationale for Change:
Safety results were updated because all follow-up PK and safety assessments from all subjects in 
the FIH study who had received 20 or 40 mg doses of TAK-041 were complete. 
The following sections also contain this change:
Section 6.1.1 Dose Decisions.
Section 6.2.1 Study Design
Section 6.2.2 Doses
Change 2: Single doses of TAK-041 ranging from 5 to 40 mg may be evaluated in this study.
The primary change occurs in Section 6.2.2 Doses:
Initial 
wording:
The starting dose of TAK-041 that will be evaluated in this study will be 20 mg, a dose 
that does not exceed the highest dose evaluated in the TAK-041-1001 study that has 
been demonstrated to be well-tolerated, and has achieved exposures indicative of the 
predicted pharmacologically active exposures of TAK-041. Further dose levels may 
be evaluated to explore the exposure-response relationship of TAK-041.
Amended 
or new 
wording:
The starting dose of TAK-041 that will be evaluated in this study will be is 20 mg, a 
dose that does not exceed the highest dose evaluated in the TAK-041-1001 study that 
has been demonstrated to be well-tolerated, and has achieved exposures indicative of 
the predicted pharmacologically active exposures of TAK-041. A single dose of 
40 mg TAK-041 has also been shown to be well-tolerated in the TAK-041-1001 
study and Further dose levels may be evaluated to explore the exposure-response 
relationship of TAK-041.
Rationale for Change:
Results from the TAK-041-1001 study have confirmed that a single 40 mg dose of TAK-041 was 
well-tolerated and presented no safety issues.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY. 

Section 6.2.1 Study Design.

Section 8.1.1.1 TAK-041, Table 8.b, footnote (a).
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TAK-041
Study No. TAK-041-1002
Page 94 of 102
Protocol Incorporating Amendment No. 02
21 February 2017
Change 3: Possible dose combinations of TAK-041 and amphetamine (AMPH) have changed.
The primary change occurs in Section 6.1.1 Dose Decisions:
Initial 
wording:

The first 4 subjects in this study will receive a 20 mg dose of TAK-041 and a 
0.50 mg/kg dose of AMPH. 

If the results from these subjects show less than 10% blunting (lower bound of 
95% confidence interval [CI]) in the AMPH-induced dopamine release in the 
striatum (as measured by changes in BPND), the next 4 subjects will receive the 
same 20 mg dose of TAK-041, and a 0.25 mg/kg dose of AMPH.

If the results from the first 4 subjects show 10% or more (lower bound of 95% CI) 
blunting in the AMPH-induced dopamine release in the striatum (as measured by 
changes in BPND), the next 4 subjects will receive a 5 mg dose of TAK-041 (based 
on observed exposures in the TAK-041-1001 study), and a 0.50 mg/kg dose of 
AMPH.

Depending on the results from the first 8 subjects, the last 4 subjects may receive 
either: 
–
A dose between 5 and 20 mg of TAK-041 (based on exposures evaluated in the 
TAK-041-1001 study) and a 0.50 mg/kg dose of AMPH (if both previously 
tested TAK-041 dose levels showed a blunting in AMPH-induced dopamine 
release); or
–
A 5 mg dose of TAK-041 and a 0.25 mg/kg dose of AMPH (if previously a 
blunting of AMPH-induced dopamine release was only observed with the high 
dose of TAK-041 and the low AMPH dose).
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TAK-041
Study No. TAK-041-1002
Page 95 of 102
Protocol Incorporating Amendment No. 02
21 February 2017
Amended 
or new 
wording:
This study will utilize an adaptive design to determine the dose(s) of AMPH and 
TAK-041 to be administered:

The first 4 subjects in this study will receive a 20 mg dose of TAK-041 and a 0.50
0.5 mg/kg dose of AMPH. 

If the results from these subjects do not show less than at least 10% blunting 
(lower bound of the one-sided 95% CI ≤10%) in the AMPH-induced dopamine 
release in the striatum (as measured by changes in BPND), the next 4 subjects will 
receive the same 20 a 40 mg dose of TAK-041 and a 0.25 0.5 mg/kg dose of 
AMPH.

If the results from the first 4 subjects show 10% or more (lower bound of the 
one-sided 95% CI >10%) blunting in the AMPH-induced dopamine release in the 
striatum (as measured by changes in BPND), the next 4 subjects will receive a 5 mg 
dose of TAK-041 (based on observed exposures in the TAK-041-1001 study) and 
a 0.50 0.5 mg/kg dose of AMPH.

Depending on the results from the first 8 subjects, the last 4 subjects may receive 
either: 
–
A dose between 5 and 20 40 mg of TAK-041 (based on exposures evaluated in 
the TAK-041-1001 study) and a 0.50 0.5 mg/kg dose of AMPH (if both 
previously tested TAK-041 dose levels showed a blunting in AMPH-induced 
dopamine release); or
–
A 5 40 mg dose of TAK-041 and a 0.25 mg/kg dose of AMPH (if previously a 
blunting of AMPH-induced dopamine release was only observed with the high 
dose of TAK-041 and the low AMPH dose).
Rationale for Change: The addition of a 40 mg dose allows greater flexibility in the TAK-041 
and AMPH dose combinations to better analyze blunting of AMPH-induced dopamine release.
The following section also contains this change:

Section 2.0 STUDY SUMMARY
Initial 
wording:
Study Drugs and Dose Levels:
Three of the following TAK-041/AMPH (dexamfetamine sulphate) dose combinations will be 
evaluated (each in a group of 4 subjects):

20 mg TAK-041 and 0.50 mg/kg AMPH.

20 mg TAK-041 and 0.25 mg/kg AMPH.

5 to 20 mg TAK-041 and 0.50 mg/kg AMPH.

5 mg TAK-041 and 0.50 mg/kg AMPH.

5 mg TAK-041 and 0.25 mg/kg AMPH.
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TAK-041
Study No. TAK-041-1002
Page 96 of 102
Protocol Incorporating Amendment No. 02
21 February 2017
Amended 
or new 
wording:
Study Drugs and Dose Levels:
Three of the following TAK-041/AMPH (dexamfetamine sulphate) dose combinations will be 
evaluated (each in a group of 4 subjects):

20 mg TAK-041 and 0.50 0.5 mg/kg AMPH.

20 40 mg TAK-041 and 0.25 mg/kg AMPH.

5 to 20 40 mg TAK-041 and 0.50 0.5 mg/kg AMPH.

5 mg TAK-041 and 0.50 0.5 mg/kg AMPH.

5 mg TAK-041 and 0.25 mg/kg AMPH.
Change 4: Primary and secondary endpoints were revised.
The primary change occurs in Section 5.2 Endpoints:
Initial 
wording:
Section 5.2.1 Primary Endpoint
The relative change in nondisplaceable binding potential (BPND) in the 
AMPH+TAK-041 condition compared to AMPH alone.
Section 5.2.2 Secondary Endpoint
The relative change in BPND in the AMPH+TAK-041 condition compared to AMPH 
alone as a function of the dose of TAK-041 administered.
Amended 
or new 
wording:
Section 5.2.1 Primary Endpoint
The relative change in nondisplaceable binding potential (BPND) in the 
AMPH+TAK-041 condition compared to AMPH alone.
Section 5.2.2 Secondary Endpoint
The relative change in BPND in the AMPH+TAK-041 condition compared to AMPH 
alone as a function of the dose of TAK-041 administered.
Rationale for Change: To clarify the endpoints.
The following section also contains this change:

Section 2.0 STUDY SUMMARY
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TAK-041
Study No. TAK-041-1002
Page 97 of 102
Protocol Incorporating Amendment No. 02
21 February 2017
Change 5: An additional PET analysis was added and revisions were made to an existing analysis.
The primary change occurs in Section 9.1.18.3 PET Data Analysis:
Initial 
wording:
A separate imaging report prepared by the
 will describe the 
following: 
1. Individual BPND values and descriptive statistics for high uptake regions of 
interest for all PET scans. Descriptive statistics for BPND values will include 
means, medians, SDs, ranges, and 95% CIs.
2. The relative change in BPND for the AMPH alone condition (Baseline –
Post-AMPH/Baseline) and the relative change in BPND for the AMPH+TAK-041 
condition (Baseline – Post-AMPH+TAK-041/Baseline.
3. In order to establish a potential dose-dependent effect, we will explore the 
magnitude of the relative change in BPND in the AMPH+TAK-041 condition as a 
function of the dose of TAK-041 administered via plots.
4. Additional analyses may be performed for exploratory purposes.
Amended 
or new 
wording:
A separate imaging report prepared by the 
 will describe the 
following: 
1. Individual BPND values and descriptive statistics for high uptake regions of 
interest for all PET scans. Descriptive statistics for BPND values will include 
means, medians, SDs, ranges, and 95% CI.
2. The change in BPND for the AMPH+TAK-041 condition compared to the 
BPND for the AMPH alone condition (100*[BPND AMPH+TAK-041- BPND
AMPH]/ BPND AMPH).
3. The relative change in BPND for the AMPH alone condition (100*[Baseline –
Post-AMPH]/Baseline) and the relative change in BPND for the AMPH+TAK-041 
condition (100*[Baseline – Post-AMPH+TAK-041]/Baseline).
4. In order to establish a potential dose-dependent effect, we will explore via plots 
the magnitude of the relative change in BPND in the AMPH+TAK-041 condition as 
a function of the dose of TAK-041 administered.
5. Additional analyses may be performed for exploratory purposes.
Rationale for Change:
The PET analysis methods were revised to provide more robust analyses of results.
Section 2.0 STUDY SUMMARY also contains this change.
CCI
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TAK-041
Study No. TAK-041-1002
Page 98 of 102
Protocol Incorporating Amendment No. 02
21 February 2017
Change 6: PET procedures were modified.
The primary change occurs in Section 9.1.18.1 PET Imaging Procedures:
Initial 
wording:
On PET scan days, the subject will undergo preinjection assessments including vital 
signs (blood pressure, pulse, respiratory rate, and temperature) (see Appendix A). A 
venous catheter will be placed in the forearm or antecubital vein for [11C]PHNO 
administration. A second catheter will be placed in the opposite forearm or antecubital 
vein for blood PK collections.
Amended 
or new 
wording:
On PET scan days, the subject will undergo preinjection assessments including vital 
signs (blood pressure, pulse, respiratory rate, and temperature) (see Appendix A). A 
venous catheter will be placed in the forearm or antecubital vein for pre-PET scan 
PK sample collection and [11C]PHNO administration. Additional PK samples will 
be collected through direct venipuncture or a second catheter will be placed in the 
opposite forearm or antecubital vein for blood PK collections.
Rationale for Change: The PET procedure was clarified.
Change 7: Following discharge from Confinement Period 2, subjects will return to the site for 
pharmacokinetic (PK) and safety assessments after 7 ±2 days, and then return for approximately 3 
Follow-up safety and PK assessment Visits (once every 4 weeks) or until the concentration of 
TAK-041 in plasma is <5% of the subject’s maximum observed plasma concentration (Cmax).
The primary change occurs in Section 6.2.1 Study Design:
Initial 
wording:
The preliminary PK data from Study TAK-041-1001 indicate that TAK-041 has a 
mean terminal elimination half-life of approximately 11 days. Therefore, a fixed-order 
study design wherein TAK-041 is administered in Confinement Period 2 only is 
appropriate (see Figure 6.a, Study Schematic). For the same reason, after discharge 
from Confinement Period 2, subjects will return to the study site for weekly Follow-up 
Visits to assess safety and PK until TAK-041 plasma concentrations are below LLOQ.
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TAK-041
Study No. TAK-041-1002
Page 99 of 102
Protocol Incorporating Amendment No. 02
21 February 2017
Amended 
or new 
wording:
The preliminary PK data from Study TAK-041-1001 indicate that TAK-041 has a 
mean terminal elimination half-life of approximately 11 days. Therefore, a fixed-order 
study design wherein TAK-041 is administered in Confinement Period 2 only is 
appropriate (see Figure 6.a, Study Schematic). For the same reason, after discharge 
from Confinement Period 2, subjects will return to the study site for weekly Follow-up 
Visits to assess safety and PK until TAK-041 plasma concentrations are below LLOQ.
Subjects in the TAK-041-1001 study who received single doses of 20 and 40 mg 
TAK-041 were followed approximately weekly until the plasma concentrations 
of TAK-041 were <1 ng/mL (up to 146 days) and there were no clinically 
significant safety issues. Subjects in this study who receive TAK-041 will be 
monitored monthly until the concentration of TAK-041 in plasma is <5% of the 
subject’s Cmax. Following discharge from Confinement Period 2, subjects will 
return to the site for PK and safety assessments after 7 ±2 days, and then return 
for approximately 3 Follow-up Visits (once every 4 weeks) or until the 
concentration of TAK-041 in plasma is <5% of the subject’s Cmax.
Rationale for Change: Results from the FIH study TAK-041-1001 with both 20 and 40 mg single 
doses indicated that the 11-day half-life of TAK-041 did not present safety concerns. Therefore, it 
is possible to maintain safety while reducing the number of follow-up visits and the duration of 
follow-up. 
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 6.1 Study Design

Section 6.1.1 Dose Decisions, Figure 6.a Schematic of Study Design, footnote (b).

Section 9.4 Blood Volume, Table 9.f Approximate Blood Volume, footnote (a).

Appendix A Schedule of Study Procedures, footnote (e).
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TAK-041
Study No. TAK-041-1002
Page 100 of 102
Protocol Incorporating Amendment No. 02
21 February 2017
Change 8: At the end of each Follow-up Visit, the next visit will be scheduled ~4 weeks later. If, 
when the PK results are available, the subject’s PK was <5% of their Cmax value, the site and 
subject will be informed that their next scheduled visit will be considered their Study Exit/Final 
Visit.
The primary change occurs in Section 6.1 Study Design:
Initial 
wording:
Study Exit/Final Visit Day 62 (±4 days): Subjects will return to 
 12 to 16 days 
after the last weekly safety and PK Follow-up Visit for final safety assessments (see 
Section 9.3.3 and Appendix A). Subjects who prematurely discontinue the study will 
have the same assessments on their last day in the study, if possible.
Amended 
or new 
wording:
Study Exit/Final Visit Day 62 (±4 days): Subjects will return to 
 12 to 16 days 
after the last weekly safety and PK Follow-up Visit for final safety assessments At the 
end of each Follow-up Visit, the next visit will be scheduled approximately 4 
weeks later. If, when the PK results are available, the subject’s PK was <5% of 
their Cmax value, the site and subject will be informed that their next scheduled 
visit will be considered their Study Exit/Final Visit (see Section 9.3.3 and 
Appendix A). Subjects who prematurely discontinue the study will have the same 
assessments on their last day in the study, if possible.
Rationale for Change: Rather than scheduling an additional visit for the Final Visit, the time 
between follow-up visits is sufficient to have received the PK results so that subjects and sites can 
be informed in advance to change the next scheduled follow-up visit to a Final Visit.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY. 

Section 6.1.1 Dose Decisions, Figure 6.a Schematic of Study Design, footnote (c).

Section 6.2.1 Study Design.

Section 9.4 Blood Volume, Table 9.f Approximate Blood Volume, footnote (b).

Appendix A Schedule of Study Procedures, footnote (e).
CCI
CCI
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TAK-041
Study No. TAK-041-1002
Page 101 of 102
Protocol Incorporating Amendment No. 02
21 February 2017
Change 9: Discrepancies between clinical laboratory tests listed in Table 9.b and Appendix A 
were resolved:
a) Leukocytes were removed from urinary analysis.
b) Diagnostic Screening tests were clarified and inconsistencies corrected.
The primary changes occur in Section 9.1.9 Procedures for Clinical Laboratory Samples, Table 9.b
Clinical Laboratory Tests:
a) Initial 
wording:
Under Urinalysis column/ Microscopic Analysis^ : Leukocytes/WBC/high power 
field
^To be performed if abnormal for blood, protein, nitrite or leukocyte esterase
Amended 
or new 
wording:
Under Urinalysis column/ Microscopic Analysis^ : Leukocytes/WBC/high power 
field
^To be performed if abnormal for blood, protein, or nitrite or leukocyte esterase
b) Initial 
wording:
Diagnostic Screening:
Serum
Hepatitis panel, including HBsAg, anti-HIV, and anti-HCV 
TSH
5’-nucleotidase
Amended or 
new 
wording:
Diagnostic Screening:
Serum
Hepatitis panel (including HBsAg, anti-HIV, and anti-HCV), HIV, TSH, and 5’-nucleotidase
Rationale for Change: Corrected mistakes in the table and Appendix A.
The following sections also contain this change:

Section 9.3.1 Screening.

Appendix A Schedule of Study Procedures
Change 10: The duration for collection of treatment-emergent adverse events (TEAEs) was 
changed.
The primary change occurs in Section 10.2.1.1 PTE and AE Collection Period:
Initial 
wording:
Collection of AEs will commence from the time that the subject is first administered 
[11C]PHNO. Routine collection of AEs will continue through the Follow-up Visit.
Amended 
or new 
wording:
Collection of AEs will commence from the time that the subject is first administered 
[11C]PHNO. Routine collection of AEs will continue through the Follow-up Visit
Study Exit/Final Visit.
Rationale for Change: To correct the protocol text.
Section 13.1.4 Safety Analysis also contains this change.
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TAK-041
Study No. TAK-041-1002
Page 102 of 102
Protocol Incorporating Amendment No. 02
21 February 2017
Change 11: Names and credentials of the signatory clinical pharmacologist and statistician for this 
study were updated.
The change occurs in Section 1.2 Approval:
Initial 
wording:
Amended 
or new 
wording:
PPD
PPD
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ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d68056a548
A Phase 1, Open-Label, Positron Emission Tomography Study in Healthy Subjects to Determine the Effect of
TAK-041 on Amphetamine-Induced Dopamine Release in the CNS After Single-Dose Oral Administration
Clinical VP Approval
22-Feb-2017 14:52 UTC
Clinical Pharmacology Approval
22-Feb-2017 18:05 UTC
Clinical Approval
23-Feb-2017 03:45 UTC
Biostatistics Approval
23-Feb-2017 13:00 UTC
PPD
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

SAP_000.pdf: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1, Open-Label Positron Emission Tomography Study in Healthy Subjects to Determine 
the Effect of TAK-041 on Amphetamine-Induced Dopamine Release in the CNS After Single-Dose 
Oral Administration
NCT Number: NCT02959892
SAP Approve Date: 19 May 2017
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information or 
company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-041-1002
A Phase 1, Open-Label Positron Emission Tomography Study in Healthy 
Subjects to Determine the Effect of TAK-041 on Amphetamine-Induced 
Dopamine Release in the CNS After Single-Dose Oral Administration
Phase 1 TAK-041 Single-Dose PET Study
PHASE 1
Version: Final
Date: 19 May 2017
Prepared by:
Based on:
Protocol Version: Amendment 02
Protocol Date: 21 February 2017
PPD
Property of Takeda: For 
Proto
Prot
commercial use only and subject to the applicable Terms of Use
phy Stu
phy St
Amphe
Amph
ose Or
se O
Dose PE
ose PE
SE 1
SE 1
Versi
Version
o
Date
Date:
P
r non-co


TAK-041-1002
Page 2 of 27
Statistical Analysis Plan
19 May 2017
1.1
Approval Signatures
Study Title:
A Phase 1, Open-Label Positron Emission Tomography Study in Healthy 
Subjects to Determine the Effect of TAK-041 on Amphetamine-Induced 
Dopamine Release in the CNS After Single-Dose Oral Administration
Approvals:
PPD
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
thy
thy
duced 
uced 
rati
ation
on
eda: For non-commercial use only and subject to the app


TAK-041-1002
Page 3 of 27
Statistical Analysis Plan
19 May 2017
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objective......................................................................................................7
4.2
Secondary Objective..................................................................................................7
4.3
Additional Objectives ................................................................................................7
4.4
Study Design .............................................................................................................7
4.4.1
Dose Decisions ..................................................................................................10
5.0
ANALYSIS ENDPOINTS.............................................................................................12
5.1
Primary Endpoint.....................................................................................................12
5.2
Secondary Endpoint.................................................................................................12
5.3
Exploratory/Additional Endpoints............................................................................12
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................13
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................14
7.1
General Principles....................................................................................................14
7.1.1
Conventions for Missing Data............................................................................14
7.1.2
Definition of Study Days and Baseline...............................................................14
7.1.3
Derived Datasets and Variables..........................................................................15
7.2
Analysis Sets ...........................................................................................................15
7.3
Disposition of Subjects ............................................................................................15
7.4
Demographic and Other Baseline Characteristics.....................................................16
7.5
Medical History and Concurrent Medical Conditions...............................................16
7.6
Medication History and Concomitant Medications...................................................16
7.7
Study Drug Exposure and Compliance.....................................................................17
7.8
Efficacy Analysis.....................................................................................................17
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................17
7.9.1
Pharmacokinetic Analysis ..................................................................................17
7.9.2
Pharmacodynamic Analysis ...............................................................................18
7.10
Other Outcomes.......................................................................................................18
7.11
Safety Analysis........................................................................................................18
7.11.1 Adverse Events ..................................................................................................18
7.11.2 Clinical Laboratory Evaluations .........................................................................19
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...2
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...
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...
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RESENT
ESEN
.........
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Days 
y
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and 
.........
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7.9
7.9


TAK-041-1002
Page 4 of 27
Statistical Analysis Plan
19 May 2017
7.11.3 Vital Signs .........................................................................................................20
7.11.4 12-Lead ECGs ...................................................................................................21
7.11.5 Other Observations Related to Safety.................................................................22
7.12
Interim Analysis ......................................................................................................22
7.13
Changes in the Statistical Analysis Plan...................................................................22
8.0
REFERENCES..............................................................................................................23
LIST OF IN-TEXT FIGURES
Figure 4.a
Schematic of Study Design ................................................................................10
Figure 7.a
Collection of Blood Samples for Pharmacokinetic Analysis ...............................17
LIST OF APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values .................24
Appendix B
Criteria for Abnormal Changes from Baseline of Vital Signs..............................25
Appendix C
Criteria for Identification of Markedly Abnormal Orthostatic Changes...............26
Appendix D
Criteria for Markedly Abnormal Values for the 12-Lead ECG Parameters..........27
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22
22
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22
.........
......
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TAK-041-1002
Page 5 of 27
Statistical Analysis Plan
19 May 2017
3.0
LIST OF ABBREVIATIONS
%CV
percent coefficient of variation
[11C]PHNO
radiolabeled dopamine D2 ligand
ADaM
Analysis Data Model
AE
adverse event
ALT
alanine aminotransferase
AMPH
amphetamine
aPTT
activated prothrombin time
AST
aspartate aminotransferase
BMI
body mass index
bpm
beats per minute
BPND
nondisplaceable binding potential
CDISC
Clinical Data Interchange Standards Consortium
CI
confidence interval
Cmax
maximum observed plasma concentration
CNS
central nervous system
CPK
creatine phosphokinase
CS
clinically significant
C-SSRS
Columbia-Suicide Severity Rating Scale
CV
conventional units
D2/D3
dopamine-2 and -3
ECG
electrocardiogram
eCRF
electronic case report form
ET
early termination
GGT
!-glutamyl transferase
ICH
International Conference on Harmonization
INR
international normalized ratio
LLN
lower limit of normal
LLOQ
lower limit of quantitation
NCS
not clinically significant
MAV
markedly abnormal value
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
PET
positron emission tomography
PHNO
(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol
PK
pharmacokinetics
PT
preferred term
PT
prothrombin
PTE
pretreatment event
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TAK-041-1002
Page 6 of 27
Statistical Analysis Plan
19 May 2017
QTcB
QT interval corrected with the Bazett correction method
QTcF
QT interval corrected with the Fridericia correction method
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SI
international system of units
SOC
system organ class
TEAE
treatment-emergent adverse event
tmax
time to reach maximum observed plasma concentration 
ULN
upper limit of normal
WBC
white blood cell
WHODrug
World Health Organization Drug Dictionary


TAK-041-1002
Page 7 of 27
Statistical Analysis Plan
19 May 2017
4.0
OBJECTIVES
4.1
Primary Objective
To determine brain penetration of single oral doses of TAK-041 and its effects on amphetamine 
(AMPH)-induced dopamine release in the central nervous system (CNS).
∀
Hypothesis: at 1 or more dose levels, TAK-041 will produce 10% or more blunting in the 
AMPH-induced dopamine release in the striatum.
4.2
Secondary Objective
To determine a dose/exposure response relationship of TAK-041 on AMPH-induced dopamine 
release in the CNS.
4.3
Additional Objectives
4.4
Study Design
This is a phase 1, open-label clinical study utilizing positron emission tomography (PET) and the 
radiolabeled dopamine-2 and -3 (D2/D3) receptor agonist PET ligand [11C]-(+)-4-propyl-
3,4,4a,5,6,10b-hexahydro-2H-naphtho [1,2-b][1,4]oxazin-9-ol ([11C]PHNO) to evaluate the 
effects of single oral doses of TAK-041 on AMPH-induced dopamine release in the brain in 12 
healthy male subjects. 
Subjects will continue to be enrolled until 12 evaluable subjects complete all procedures. Each 
subject will have 1 magnetic resonance imaging (MRI) brain scan and 3 [11C]PHNO PET scans. 
The MRI brain scan will be performed for all subjects without gadolinium contrast and will be 
interpreted at the 
 during the Screening Period to determine eligibility. 
The results of this MRI brain scan will also be used during the study to delineate the anatomical 
regions of interest for individual PET images.
The study consists of 2 Confinement Periods for each subject during which the PET scans will 
occur at the 
. Confinement Periods 1 and 2 will be separated by an 
interval of 5 to 45 days.
∀
Confinement Period 1:
–
The first [11C]PHNO PET scan occurs on Day 1 to serve as the Baseline scan to 
determine the nondisplaceable binding potential (BPND) in striatum under untreated 
conditions for each subject.
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TAK-041-1002
Page 8 of 27
Statistical Analysis Plan
19 May 2017
–
On Day 2, the subject will receive a single oral 0.5 mg/kg dose of AMPH, followed by a 
[11C]PHNO PET scan at approximately 3 hours post-AMPH dose in order to establish 
BPND in striatum after AMPH-induced dopamine release as compared to Baseline.
∀
Confinement Period 2:
–
On Day 1, the subject will receive a single oral dose of TAK-041 up to 40 mg, followed 
by a single oral 0.5 mg/kg dose of AMPH approximately 2 hours after the dose of TAK-
041, followed by a [11C]PHNO PET scan at approximately 3 hours post-AMPH 
administration.
Blood samples for pharmacokinetic (PK) analysis of AMPH will be collected prior to AMPH 
administration, 1 and 2 hours post-AMPH administration, and immediately prior to and after the 
[11C]PHNO PET scan to measure plasma levels of AMPH. PK blood samples will be collected 1, 
2, 12, and 24 hours after TAK-041 administration, immediately prior to and after the [11C]PHNO 
PET scan, and during each Follow-up Visit. Following discharge from Confinement Period 2, 
subjects will return to the site for PK and safety assessments after 7 ±2 days, and then return for 
approximately 3 Follow-up Visits (once every 4 weeks) or until the concentration of TAK-041 in 
plasma is <5% of the subject’s maximum observed plasma concentration (Cmax).
Amphetamine tablets will be provided as the commercial product dexamfetamine sulphate [1] 
with the manufacturer’s original label, and will be sourced locally by the study site. Using data 
from the TAK-041-1001 study, AMPH will be administered at the approximate time to reach 
Cmax (tmax) (plasma) of TAK-041 to allow an informative evaluation of TAK-041 coadministered 
with amphetamine. The [11C]PHNO PET scan will start at the approximate tmax (plasma) of 
AMPH (estimated to be 3 hours post-AMPH dose). The starting dose of TAK-041 in this study 
will be 20 mg, a dose that has been demonstrated to be well-tolerated in the TAK-041-1001 
study and has achieved exposures indicative of the predicted pharmacologically active exposures 
of TAK-041. A single dose level of 40 mg TAK-041 has also been shown to be well-tolerated in 
the TAK-041-1001 study and may be evaluated in this study to explore the exposure-response 
relationship of TAK-041. The highest dose of AMPH that will be administered will be an oral 
dose of 0.5 mg/kg. This dose has been demonstrated to be safe and well-tolerated in healthy 
subjects and is a dose which has been shown to induce dopamine release in AMPH-challenge 
studies [2, 3].
Safety and tolerability will be assessed through all study visits, including collecting blood and 
urine samples for laboratory tests. Subjects will complete scheduled study assessments according 
to the Schedule of Study Procedures in the protocol [4].
CCI
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TAK-041-1002
Page 9 of 27
Statistical Analysis Plan
19 May 2017
Each subject will report to 
 on approximately 8 
occasions:
1. Screening Visit to determine eligibility (-28 to -2 days prior to Confinement Period 1/Day -
1): The Screening brain MRI may be performed on a day separate from the other screening 
procedures, and will be performed and interpreted at the 
 after the 
other screening activities have been performed and results assessed. MRI should be 
performed early enough so that MRI scan results are available prior to Baseline Imaging for 
Confinement Period 1.
2. Confinement Period 1 (Day -1 to Day 3): admission to 
 (Day -1), 1 day prior to 
Baseline [11C]PHNO PET imaging on Day 1; AMPH administration and postdose 
[11C]PHNO PET imaging on Day 2; discharge on Day 3, the day following the postdose 
[11C]PHNO PET imaging. All subjects will undergo a single predose [11C]PHNO PET scan 
on Day 1 and a single postdose [11C]PHNO PET scan on Day 2.
3. Confinement Period 2 (5 to 45 days after discharge from Confinement Period 1): admission 
to 
 (Day -1) 1 day prior to TAK-041 and AMPH administration and postdose 
[11C]PHNO PET imaging (Day 1), discharge on Day 2, the day following the postdose 
[11C]PHNO PET imaging. All subjects will undergo a single postdose [11C]PHNO PET scan 
on Day 1 of Confinement Period 2.
4. Follow-up Safety and PK Assessment Visits (Days 8-92): Following discharge from 
Confinement Period 2, subjects will return to the site for PK and safety assessments after 
7±2 days, and then return for approximately 3 Follow-up safety and PK assessment Visits 
(once every 4 weeks) or until the concentration of TAK-041 in plasma is <5% of the 
subject’s Cmax (see Section 9.3.2 in the protocol [4]). 
5. Study Exit/Final Visit: At the end of each Follow-up Visit, the next visit will be scheduled 
approximately 4 weeks later. If, when the PK results are available, the subject’s plasma PK 
concentration value was <5% of their Cmax value, the site and subject will be informed that 
their next scheduled visit will be considered their Study Exit/Final Visit (see Section 9.3.3 in 
the protocol [4]). Subjects who prematurely discontinue the study will have the same 
assessments for Study Exit/Final Visit performed on their last day in the study, if possible.
A schematic of the study design is shown in Figure 4.a. 
If logistical limitations (such as tracer synthesis failure) prevent a Baseline PET scan from being 
performed at the scheduled time point, the Confinement Period may be extended or cut short and 
rescheduled. If a postdose PET scan is delayed, it may be necessary to end the Confinement 
Period early and reschedule after a sufficient interval.
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TAK-041-1002
Page 10 of 27
Statistical Analysis Plan
19 May 2017
The date the final subject completes the Follow-up Call/Visit will be considered the end of study 
date for transparency reporting.
Figure 4.a
Schematic of Study Design
Screening
Confinement Period 1
Interval 
(a)
Confinement Period 2
Follow-up 
Visits (b)
Study 
Exit/Final 
Visit
ET(c)
Days
-28 to -2
Day -1
Day 1
Day 2
Day 3
5-45 days
Day -1
Day 1
Day 2
Days 8-92 
(±2)
 
Check-in
PET 
Imaging 
Baseline
 
Discharge
 
Check-in
 
Discharge
Return to 
 for 
safety and 
PK 
assessments
Return to 
 for 
safety 
assessments
AMPH
TAK-041+ 
AMPH
PET 
Imaging 
postdose
PET 
Imaging 
postdose
ET=early termination
Note: Subjects who drop out prior to completion of all PET scans will have assessments done as described in Section 9.3.3 of the 
protocol [4] for ET and a follow-up telephone call approximately 2 days after the ET Visit. 
(a) There will be a 5 to 45 day interval between confinement periods beginning after discharge from Confinement Period 1.
(b) Following discharge from Confinement Period 2, subjects will return to the site for PK and safety assessments after 7 ±2 
days, and then return for approximately 3 Follow-up PK and safety assessment Visits (once every 4 weeks) or until the 
concentration of TAK-041 in plasma is <5% of the subject’s Cmax.
(c) At the end of each Follow-up Visit, the next visit will be scheduled approximately 4 weeks later. If, when the PK results are 
available, the subject’s PK was <5% of their Cmax value, the site and subject will be informed that their next scheduled visit will 
be considered their Study Exit/Final Visit.
4.4.1
Dose Decisions
All decisions concerning dose levels will be made by the sponsor and the 
 
.
This study will utilize an adaptive design to determine the dose(s) of AMPH and TAK-041 to be 
administered:
∀
The first 4 subjects in this study will receive a 20 mg dose of TAK-041 and a 0.5 mg/kg dose 
of AMPH.
∀
If the results from these subjects do not show at least 10% blunting (lower bound of the one-
sided 95% confidence interval [CI] ≤10%) in the AMPH-induced dopamine release in the 
striatum (as measured by changes in BPND), the next 4 subjects will receive a 40 mg dose of 
TAK-041, and a 0.5 mg/kg dose of AMPH.
CCI
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TAK-041-1002
Page 11 of 27
Statistical Analysis Plan
19 May 2017
∀
If the results from the first 4 subjects show 10% or more blunting (lower bound of the one-
sided 95% CI >10%) in the AMPH-induced dopamine release in the striatum (as measured 
by changes in BPND), the next 4 subjects will receive a 5 mg dose of TAK-041 (based on 
observed exposures in the TAK-041-1001 study) and a 0.5 mg/kg dose of AMPH.
∀
Depending on the results from the first 8 subjects, the last 4 subjects may receive either:
–
A dose of TAK-041 between 5 and 40 mg (based on exposures evaluated in the TAK-
041-1001 study) and a 0.5 mg/kg dose of AMPH (if both previously tested TAK-041 
dose levels showed a blunting of AMPH-induced dopamine release); or
–
A 40 mg dose of TAK-041 and a 0.25 mg/kg dose of AMPH.
Decisions regarding the doses of TAK-041 and AMPH that Subjects 5 to 12 will receive will be 
based on discussions between Takeda and the 
. The dose range for 
TAK-041 is limited by exposures observed in the TAK-041-1001 study. Previous studies with 
AMPH used doses ranging from 0.3 to 0.5 mg/kg. Testing with the lower AMPH dose is driven 
by considerations to avoid overstimulation of the dopamine system.
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TAK-041-1002
Page 12 of 27
Statistical Analysis Plan
19 May 2017
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
∀
The change in BPND in the TAK-041+AMPH condition compared to AMPH alone.
The primary endpoint will be collected, analyzed, and processed by an outside vendor. No 
analyses are planned on these measures as part of this statistical analysis plan (SAP).
5.2
Secondary Endpoint
∀
The change in BPND in the TAK-041+AMPH condition compared to AMPH alone as a 
function of the dose of TAK-041 administered.
The secondary endpoint will be collected, analyzed, and processed by an outside vendor. No 
analyses are planned on these measures as part of this SAP.
5.3
Exploratory/Additional Endpoints
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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-041-1002
Page 13 of 27
Statistical Analysis Plan
19 May 2017
6.0
DETERMINATION OF SAMPLE SIZE
Using previously reported data [5], and assuming a 16% standard deviation for the relative 
change in BPND for high uptake regions of interest, 12 subjects will provide approximately 80% 
power to detect a 20% relative change in BPND when values from the TAK-041+AMPH 
condition are compared to AMPH alone condition using a 2-sample 2-sided t-test with 0.05 
significance level. The power for the other regions of interest will be more than 80%.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
%
05 5


TAK-041-1002
Page 14 of 27
Statistical Analysis Plan
19 May 2017
7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
This SAP was developed based on International Conference on Harmonization (ICH) E3 and E9 
Guidelines. This SAP should be read in conjunction with the study protocol and electronic case 
report forms (eCRF). This version of the SAP was developed using the information provided in 
Protocol TAK-041-1002, amendment 02, dated 21 February 2017 [4].
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. Categorical data will be summarized using the 
number and percentage of subjects for each category where appropriate. 
Arithmetic means, geometric means, and medians will be presented to 1 more decimal place than 
the recorded data. SDs will be presented to 2 more decimal places than the recorded data.
PET, MRI, and wearable device data collected on the eCRF will be included in listings. PET, 
MRI, and wearable device data collected by outside vendors will not be listed. All other study 
related raw and derived data for enrolled subjects will be presented in listings.
All data analyses will be generated using SAS System® Version 9.2 or higher.
7.1.1
Conventions for 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 lower limit of quantitation (LLOQ) 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
Definition of Study Days and Baseline
Study Day 1 is defined as the date of the first dose of [11C]PHNO PET tracer. Study days prior to 
the first dose of [11C]PHNO will be calculated as: {date of assessment/event - date of first dose 
of [11C]PHNO}. Study days on or after the first dose of [11C]PHNO will be calculated as: {date 
of assessment/event - date of first dose of [11C]PHNO + 1}.
Day within a period is relative to the date of first dose of study drug ([11C]PHNO, AMPH, or 
TAK-041) in each confinement period. 
Study baseline is defined as the last observed value prior to the first administration of study drug 
([11C]PHNO, AMPH, or TAK-041).
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-041-1002
Page 15 of 27
Statistical Analysis Plan
19 May 2017
7.1.3
Derived Datasets and Variables
Derived datasets will be generated according to Clinical Data Interchange Standards Consortium
(CDISC) guidance documents: Analysis Data Model (ADaM) Implementation Guide, Version 
1.0 or higher. 
7.2
Analysis Sets
The following analysis sets will be used for analysis and presentation of the study data:
Safety Set
The safety set will consist of all subjects who are enrolled and receive a dose of study drug 
([11C]PHNO, AMPH, or TAK-041) as part of this study. Subjects in this analysis set will be used 
for demographic, baseline characteristics, and safety summaries.
Pharmacokinetic Set
The PK set will consist of all subjects who receive either AMPH or TAK-041 and have at least 
1 measurable plasma concentration for AMPH or TAK-041.
7.3
Disposition of Subjects
Disposition of all screened subjects will be tabulated (count and percent); there will be no 
inferential analysis of subject disposition data. 
Disposition of screen failure subjects including the primary reasons for failure (i.e., pretreatment 
event (PTE)/AE, significant protocol deviation, lost to follow-up, voluntary withdrawal, study 
termination, did not meet entrance criteria, or other) will be presented in a data listing. 
Disposition of all enrolled subjects will be tabulated by TAK-041+AMPH dose combination and 
overall. Categories will include:
∀
All subjects dosed (denominator).
∀
Subjects who were enrolled but not dosed, if applicable.
∀
Subjects who completed all study drugs.
∀
Subjects who prematurely discontinued study drugs.
∀
Subjects who completed all study visits.
∀
Subjects who prematurely discontinued study visits.
Primary reasons for discontinuation of study drugs and/or study visits, as entered on the eCRF, 
will be tabulated. Reasons for discontinuation include PTE/AE, significant protocol deviation, 
lost to follow-up, voluntary withdrawal, study termination, and other.
Disposition information for enrolled subjects, including study drug dose level, date of first dose
of study drug, date and study day of last dose of study drug, date and study day of last visit, and 
reason for premature discontinuation of study drugs/study visits (if applicable), will be listed. A 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
data:
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TAK-041-1002
Page 16 of 27
Statistical Analysis Plan
19 May 2017
listing of inclusion/exclusion criteria not met will be provided for enrolled subjects who did not 
meet at least one entrance criterion.
Significant protocol deviations captured on the eCRF will be listed.
7.4
Demographic and Other Baseline Characteristics
Demographic data will be summarized by assigned TAK-041+AMPH dose combination and 
overall. Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be generated 
for continuous demographic variables and baseline characteristics variables (e.g., age at informed 
consent, height (cm) at screening, weight (kg) at baseline, and body mass index (BMI, kg/m2) at 
screening). The number and percentage of subjects in each class of the categorical demographic 
variables and baseline characteristics variables (e.g., gender, race, smoking history, alcohol 
history, and caffeine consumption) will also be tabulated. Individual subject demographic and 
baseline characteristics data will be listed by site and subject number.
Individual demographic characteristics, date of informed consent, and reason for screen failure 
will be listed for subjects who are screened but not enrolled in the study.
Race will be recorded on the eCRF as American Indian or Alaska Native, Asian, Black or 
African American, Native Hawaiian or Other Pacific Islander, and White. Subjects who identify 
themselves as belonging to more than 1 race on the eCRF will be classified as multiracial for 
summaries and each race selected will be listed.
There will be no inferential analysis of demographic and baseline characteristics.
7.5
Medical History and Concurrent Medical Conditions
Medical history is defined as significant conditions or diseases relevant to the disease under 
study that stopped at or prior to signing of informed consent. Concurrent medical conditions are
defined as significant conditions or diseases ongoing or present at signing of informed consent.
Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Drug Regulatory Activities (MedDRA, version 19 or higher) coding system. 
All medical history and concurrent medical condition data will be listed by site and subject 
number. The listing will contain subject identifier, study drug dose level, system organ class 
(SOC), preferred term (PT), and a detail of the medical history or concurrent condition. 
There will be no inferential analysis of medical history and concurrent medical conditions.
7.6
Medication History and Concomitant Medications
Medication history information includes any medication relevant to eligibility criteria stopped at 
or within 30 days prior to signing of informed consent. Concomitant medications include any 
medications, other than study drug, taken at any time between informed consent and the end of 
the study. 
Medication history and concomitant medications will be coded using the World Health 
Organization Drug Dictionary (WHOD
h 2016 Enhanced or higher.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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listing
preferred
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will 
7.6
7.6
Me
M


TAK-041-1002
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Statistical Analysis Plan
19 May 2017
All medication history and concomitant medications will be listed by site and subject number. 
The listings will contain subject identifier, study drug dose level, WHODrug preferred 
medication name, dose, unit, frequency, route, start date, stop date, whether the medication was 
ongoing, and reason for use. 
There will be no inferential analysis of medication history and concomitant medications.
7.7
Study Drug Exposure and Compliance
The date and time of each study drug ([11C]PHNO, AMPH, or TAK-041) for each subject will be 
reported in the data listing. Listings and descriptive statistics of PK plasma concentrations for
AMPH and TAK-041will be provided for all subjects. No other summary statistics for the extent 
of exposure to study drug or compliance calculations will be performed for this study.
7.8
Efficacy Analysis
Not applicable.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
Serial blood samples for determination of AMPH and TAK-041 will be collected according to 
Figure 7.a.
Figure 7.a
Collection of Blood Samples for Pharmacokinetic Analysis
Analyte
Matrix
Period
Scheduled Time (hours)
AMPH
Plasma
1 and 2
Predose (within 60 minutes prior to dosing), 1 and 2 hours post-AMPH 
administration, and immediately prior to and after [11C]PHNO PET scan.
TAK-041
Plasma
2 
1, 2, 12, and 24 hours post-TAK-041 administration, immediately prior to 
and after the [11C]PHNO PET scan, and during each Follow-up Visit.
Blood samples for TAK-041 PK will also be collected at ET if TAK-041 has been administered. 
All PK summaries and analyses will be based on the PK set.
Concentrations of AMPH and TAK-041 in plasma will be summarized by dose level over each 
scheduled sampling time point using descriptive statistics (n, arithmetic mean, SD, %CV, 
median, minimum, and maximum). Individual plasma concentration data versus time will be 
presented in a data listing.
Plasma concentrations that are below the LLOQ will be treated as zero in the summarization of 
concentration values. 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.
The need of using the plasma concentrations collected from this study in a PK analysis will be 
evaluated. If deemed appropriate, a PK analysis plan will be prepared and address the planned 
analysis.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-041-1002
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Statistical Analysis Plan
19 May 2017
7.9.2
Pharmacodynamic Analysis
Not applicable. 
7.10
Other Outcomes
PET, MRI, and wearable device data collected on the eCRF will be included in listings.
The imaging analysis (PET and MRI) will be conducted by an outside vendor and are not 
included in this SAP. 
7.11
Safety Analysis
The safety endpoints including AEs, clinical laboratory parameters, vital sign parameters, 12-
lead ECG parameters will be summarized and described in data listings. The Safety Set will be 
used for all summaries of safety parameters. Physical examination and C-SSRS will be described 
in data listings.
7.11.1 Adverse Events
A treatment-emergent adverse event (TEAE) is defined as an AE or a serious AE that occurs or 
gets worse after receiving the first study drug ([11C]PHNO, AMPH, or TAK-041) and until Study 
Exit/Final Visit. A PTE is defined as any untoward medical occurrence occurs prior to first study 
drug ([11C]PHNO, AMPH, or TAK-041).
PTE and TEAE verbatim reported terms will be coded by SOC and PT using MedDRA (version 
19 or higher) coding system.
TEAEs will be listed and included in the summary tables. TEAEs will be summarized by 
assigned TAK-041+AMPH dose combination and overall. For each TAK-041+AMPH dose 
combination, TEAE will be summarized by [11C]PHNO Alone (Period 1 Day 1 after the dosing 
of [11C]PHNO tracer and before the dosing of AMPH on Day 2 of Period 1), AMPH Alone 
(Period 1 Day 2 after the dosing of AMPH and before the dosing of the tracer), 
AMPH+[11C]PHNO (after the tracer administration on Day 2 of Period 1 and before the TAK-
041 administration on Day 1 of Period 2), TAK-041 Alone (Period 2 Day 1 after the TAK-041 
dosing and before the dosing of AMPH), TAK-041+AMPH (Period 2 Day 1 after the dosing of 
AMPH and before the dosing of tracer), and TAK-041+AMPH+[11C]PHNO (Period 2 Day 1 
after the tracer administration to Study Exit/Final Visit) according to time of onset, and the 
Entire Study (after the first dose of study drug and until Study Exit/Final Visit).
In general, TEAEs will be tabulated at the following levels: overall summary (subjects with at 
least 1 AE), by the MedDRA SOC and the MedDRA PT. The tables will include the number and 
percentage (N [%]) of subjects. The following summary tables will be generated: 
∀
Overview of Treatment-Emergent Adverse Events.
∀
Treatment-Emergent Adverse Eve
Class and Preferred Term.
CCI
ers, vi
s, vita
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TAK-041-1002
Page 19 of 27
Statistical Analysis Plan
19 May 2017
∀
Treatment-Emergent Adverse Events by Preferred Term, sorted by the frequency of the 
overall summary from the most to the least.
∀
Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term.
∀
Relationship of Treatment-Emergent Adverse Events to Study Drug by System Organ Class 
and Preferred Term.
∀
Drug-Related Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term.
∀
Intensity of Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term.
∀
Intensity of Drug-Related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term.
In addition, subject mappings for the TEAEs by SOC and PT will be generated.
When calculating the frequency and percentage of subjects who reported TEAEs, a subject will 
be counted only once for each SOC or PT when multiple TEAEs are coded to the same SOC or 
PT. For the intensity or relatedness summaries, if a subject reports multiple TEAEs coded to the 
same SOC or PT, the TEAE with maximum intensity or strongest relationship will be included in 
the summary.
For TEAE summaries by treatment interval ([11C]PHNO Alone, AMPH Alone, 
AMPH+[11C]PHNO, TAK-041 Alone, TAK-041+AMPH, and TAK-
041+AMPH+[11C]PHNO), subjects reporting more than one occurrence within a treatment 
interval for the term (level) being summarized will be counted only once for that interval using 
the most extreme incident (most severe for the severity tables and related for the relationship to 
study drug tables). For summaries by Entire Study, subjects reporting more than one occurrence 
during the Entire Study for the term (level) being summarized will be counted only once using 
the most extreme incident (most severe for the severity tables and related for the relationship to 
study drug tables). 
AEs with missing intensity will be listed as such in the AE listings, however, will be summarized 
as severe in summary tables. If the relationship of an event is missing, the relationship for the 
event will be considered to have been related.
Data listings will be provided for TEAEs and PTEs.
7.11.2 Clinical Laboratory Evaluations
Clinical safety laboratory tests include hematology, chemistry, urinalysis, and diagnostic 
screening. Please refer to Table 9.b in the protocol [4] for a list of all clinical laboratory tests.
All laboratory test parameters will be displayed in individual subject data listings in both 
International System of Units (SI) and conventional units (CV). For test results not in SI units, 
the conversion to SI units will be done in derived analysis data sets using the known conversion 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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7.11.2
7.11.2
Cli


TAK-041-1002
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Statistical Analysis Plan
19 May 2017
factors. All summaries and analyses will be based on the values using SI units unless otherwise 
stated. 
Descriptive statistics (N, mean, SD, median, minimum, and maximum) of clinical laboratory 
tests for baseline, post-baseline, and change from baseline to each post-baseline visit will be 
presented by assigned TAK-041+AMPH dose combination and overall for Confinement Period 1 
and Confinement Period 2 through Study Exit. Baseline is defined as the last observed value 
prior to the first administration of study drug ([11C]PHNO, AMPH, or TAK-041). Unscheduled 
laboratory assessments will be excluded from the summary statistics unless it is for the baseline 
derivation. Note that urinalysis tests with character results, such as protein and nitrite, will only 
be listed. No inferential statistics will be presented.
Individual results for hematology and chemistry laboratory tests that meet the Takeda predefined 
laboratory markedly abnormal value (MAV) criteria in Appendix A will be indicated in the data 
listing. If a subject has a MAV for a particular laboratory test, all visits for that subject for that 
parameter will be listed. The number and percentage of subjects with at least 1 post-baseline 
markedly abnormal laboratory test result will be summarized by TAK-041+AMPH dose 
combination and overall. The mapping of the subjects who meet the MAV criteria will be listed 
as a table by TAK-041+AMPH dose combination and overall. All observations, including ones 
at unscheduled visits, will be included in the MAV mapping and summaries.
All clinical laboratory data will be listed. The listing will include site number, subject identifier, 
age (at informed consent), gender, study drug dose level, study visit, and sample collection date. 
Laboratory data outside of the normal reference range will be indicated in the data listing. In 
addition, MAVs will be flagged.
7.11.3 Vital Signs
Vital sign parameters include oral body temperature, blood pressure, respiratory rate, pulse, and 
weight. Pulse and blood pressure will be measured after 5 minutes supine. Orthostatic pulse and 
blood pressure will be measured after standing for 2 minutes. Please refer to Table 9.a in the 
protocol [4] for schedules of vital sign assessments.
Descriptive statistics (N, mean, SD, median, minimum, and maximum) of vital sign parameters 
for baseline, post-baseline, and change from baseline to each post-baseline visit will be 
summarized by TAK-041+AMPH dose combination and overall by scheduled time point. 
Baseline is defined as the last observed value prior to the first administration of study drug 
([11C]PHNO, AMPH, or TAK-041). Unscheduled vital sign assessments will be excluded from 
the summary statistics unless it is for the baseline derivation. No inferential statistics will be 
presented.
Individual results for vital sign measurements that meet the Takeda predefined vital signs MAV 
criteria in Appendix B will be indicated in the data listing. If a subject has a MAV for a 
particular vital sign parameter, all visits for that subject for that parameter will be listed. The 
number and percentage of subjects with at least 1 post-baseline markedly abnormal vital sign 
measurement will be summarized by TAK-041+AMPH dose combination and overall. The 
mapping of the subjects who meet the 
listed as a table by TAK-
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-041-1002
Page 21 of 27
Statistical Analysis Plan
19 May 2017
041+AMPH dose combination and overall. All observations, including ones at unscheduled 
visits, will be included in the MAV mapping and summaries.
Orthostatic hypotension, identified by the criteria defined in Appendix C, will be calculated at 
every time point where standing and supine measurements are available using the formula: 
standing vital measurement - supine vital measurement. The mapping of the subjects who meet 
the criteria for orthostatic hypotension will be listed as a table by TAK-041+AMPH dose 
combination and overall. All orthostatic hypotension observations, including ones at unscheduled 
visits, will be included in the subject mapping.
All vital sign data will be presented in the data listing. The listing will include site number, 
subject identifier, age (at informed consent), gender, study drug dose level, study visit, and 
sample collection date. Vital sign MAVs will be flagged.
7.11.4 12-Lead ECGs
ECG parameters include heart rate, PR interval, RR interval, QRS interval, QT interval, QT 
interval corrected with the Bazett correction method (QTcB), and QT interval corrected with the 
Fridericia correction method (QTcF). Please refer to Table 9.c in the protocol [4] for schedules 
of ECG assessments.
Descriptive statistics (N, mean, SD, median, minimum, and maximum) of ECG parameters for 
baseline, post-baseline, and change from each baseline to each post-baseline visit will be 
summarized by TAK-041+AMPH dose combination and overall by scheduled time point. 
Baseline is defined as the last observed value prior to the first administration of study drug 
([11C]PHNO, AMPH, or TAK-041). Only the scheduled measurements will be included in the 
summary unless it is for the baseline derivation. No inferential statistics will be presented.
Individual results for 12-lead ECG measurements that meet the Takeda predefined 12-lead ECG 
MAV criteria in Appendix D will be indicated in the data listing. If a subject has a MAV for a 
particular ECG parameter, all visits for that subject for that parameter will be listed. The number 
and percentage of subjects with at least 1 post-baseline markedly abnormal 12-lead ECG 
measurement will be summarized by TAK-041+AMPH dose combination and overall. The 
mapping of the subjects who meet the MAV criteria will be listed as a table by TAK-
041+AMPH dose combination and overall. All observations, including ones at unscheduled 
visits, will be included in the MAV mapping and summaries.
Overall ECG interpretation category (within normal limits, abnormal not clinically significant 
[NCS], abnormal clinically significant [CS]) is collected in the eCRF at each scheduled visit. 
Shifts in ECG interpretation will be presented as cross-tabulations (baseline versus each post-
baseline visit) of numbers of subjects with normal, abnormal NCS, and abnormal CS 
interpretations with missing, if applicable, and total categories by TAK-041+AMPH dose 
combination and overall by scheduled time point. Baseline is defined as the last observed value 
prior to the first administration of study drug ([11C]PHNO, AMPH, or TAK-041). Unscheduled 
ECG assessments will be excluded unless it is for the baseline derivation.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-041-1002
Page 22 of 27
Statistical Analysis Plan
19 May 2017
All ECG data will be presented in the data listing. The listing will include site number, subject 
identifier, age (at informed consent), gender, study drug dose level, study visit, and sample 
collection date. ECG MAVs will be flagged.
7.11.5 Other Observations Related to Safety
Physical examination findings and C-SSRS will be presented in data listings. No summary tables 
will be provided.
7.12
Interim Analysis
No formal interim analysis is planned. 
7.13
Changes in the Statistical Analysis Plan 
Analyses described in the statistical analysis plan do not differ from those specified in the 
protocol.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
mary
mary tab
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TAK-041-1002
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Statistical Analysis Plan
19 May 2017
8.0
REFERENCES
1. Dexamfetamine sulphate 5 mg tablets. Summary of Product Characteristics. Middlesex, UK: 
Auden Mckenzie (Pharma Division) Ltd, Revised 16 November 2015.
2. Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M, et al. Increased striatal 
dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 
1998;155(6):761-7.
3. Weidner LD, Paris A, Frankle WG, Narendran R. Safety of oral amphetamine administered 
during positron emission tomography scans in medically screened humans. PLoS One 
2015;10(12):e0140647.
4. A Phase 1, Open-Label Positron Emission Tomography Study in Healthy Subjects to 
Determine the Effect of TAK-041 on Amphetamine-Induced Dopamine Release in the CNS 
After Single-Dose Oral Administration. Takeda Development Center Europe, Ltd., Protocol 
No. TAK-041-1002, Amendment 02, dated 21 February, 2017.
5. Shotbolt P, Tziortzi AC, Searle GE, Colasanti A, van der Aart J, Abanades S, et al.Within-
subject comparison of [11C]-(+)-PHNO and [11C]raclopride sensitivity to acute amphetamine 
challenge in healthy humans. J Cereb Blood Flow Metab 2012;32(1):127-36.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
stri
striatal
ata
ychiatry
ychiatry
ne admin
e admi
s. PLoS 
PLoS
ealalthy S
thy 
l
opamine
pam
nt Center
Cente
2017.
017.
der Aart
er Aar
aclopride
oprid
w Metab
w Meta


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Statistical Analysis Plan
19 May 2017
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values
Hematology—Criteria for Markedly Abnormal Values
Parameter
Unit
Low Abnormal
High Abnormal
Hemoglobin
Both 
<0.8 × LLN
>1.2 × ULN
Hematocrit
Both
<0.8 × LLN
>1.2 × ULN
RBC count 
Both
<0.8 × LLN 
>1.2 × ULN
WBC count 
Both 
<0.5 x LLN
>1.5 x ULN
Platelet count
Conventional
<75 x 103/#L
>600 x 103/#L
SI
<75 x 109/L
>600 x 109/L
PT/INR
Both
--
>1.5 × ULN
aPTT
Both
--
>1.5 × ULN
aPTT= activated prothrombin time, INR=international normalized ratio, LLN=lower limit of normal, RBC=red 
blood cell, ULN=upper limit of normal, WBC=white blood cell, PT=prothrombin. 
Serum Chemistry—Criteria for Markedly Abnormal Values
Parameter
Unit 
Low Abnormal
High Abnormal
ALT
Both
--
>3x ULN
AST
Both
--
>3x ULN
GGT
Both
--
>3x ULN
Alkaline phosphatase
Both
--
>3x ULN
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
<0.8x LLN
>1.2x ULN
Creatinine
Conventional 
--
>2.0 mg/dL
SI
--
>177 #mol/L
Blood urea nitrogen
Conventional 
--
>30 mg/dL
SI
--
>10.7 mmol/L
Sodium
Conventional
<130 mEq/L
>150 mEq/L
SI
<130 mmol/L
>150 mmol/L
Potassium
Conventional
<3.0 mEq/L
>6.0 mEq/L
SI
<3.0 mmol/L
>6.0 mmol/L
CPK
Both
--
>5x ULN
Glucose
Conventional
< 50 mg/dL
>350 mg/dL
SI
< 2.8 mmol/L
>19.4 mmol/L
Creatine kinase
Conventional
--
>5 × ULN
SI
--
>5 × ULN
Bicarbonate
Conventional
<8.0 mEq/L
--
SI
<8.0 mmol/L
--
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, CPK=creatine phosphokinase, GGT=!-glutamyl 
transferase, LLN=lower limit of normal, ULN
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
Ter
T
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TAK-041-1002
Page 25 of 27
Statistical Analysis Plan
19 May 2017
Appendix B
Criteria for Abnormal Changes from Baseline of 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
°C
<35.6
>37.7
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
ms
er
T
ble
ca
pl


TAK-041-1002
Page 26 of 27
Statistical Analysis Plan
19 May 2017
Appendix C
Criteria for Identification of Markedly Abnormal Orthostatic Changes
Parameter
Criteria
Orthostatic Hypotension
(Orthostatic Systolic Blood Pressure <-20 mm Hg OR
Orthostatic Diastolic Blood Pressure <-10 mm Hg) AND
Heart Rate Increase >20 beats/min
Note: Orthostatic measurement = standing vital measurement - supine vital measurement.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
m
R
e T
Hg) AND
) AND
p


TAK-041-1002
Page 27 of 27
Statistical Analysis Plan
19 May 2017
Appendix D
Criteria for Markedly Abnormal Values for the 12-Lead ECG Parameters
Parameter
Lower Criteria
Upper Criteria
Heart rate
<50 beats per minute
>120 beats per minute
PR
≤80 milliseconds
≥200 milliseconds
QT Interval
≤300 milliseconds
≥460 milliseconds
QTcB Interval
≤300 milliseconds
≥500 milliseconds OR 
≥30 milliseconds change from baseline and 
≥450 milliseconds
QTcF Interval
≤300 milliseconds
≥500 milliseconds OR 
≥30 milliseconds change from baseline and
≥450 milliseconds
QRS
≤80 milliseconds
≥180 milliseconds
Property of Takeda: For non-commercial use only and subject to the a
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