A Randomized, Double-Blind, Placebo Controlled, Two-Period Cross-Over, Proof of Activity Study to Evaluate the Effects of TAK-041 on Motivational Anhedonia as Add-On to Antipsychotics in Subjects With Stable Schizophrenia
Phase: PHASE2
Conditions: Stable Schizophrenia
Sponsor: Neurocrine Biosciences




Title: A Randomized, Double-Blind, Placebo Controlled, Two-Period Cross-Over, Proof of Activity 
Study to Evaluate the Effects of TAK-041 on Motivational Anhedonia as Add-On to Antipsychotics in 
Subjects With Stable Schizophrenia
NCT Number: NCT03319953
Protocol Approve Date: 10 August 2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company confidential 
information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.

TAKEDA PHARMACEUTICALS
PROTOCOL
A Randomized, Double-Blind, Placebo Controlled, Two-Period Cross-Over, Proof of 
Activity Study to Evaluate the Effects of TAK-041 on Motivational Anhedonia as 
Add-On to Antipsychotics in Subjects With Stable Schizophrenia
Sponsor:
Takeda Development Centre Europe Ltd.
61 Aldwych 
London, WC2B 4AE
United Kingdom
Study Number:
TAK-041-2001
Compound:
TAK-041
Date:
10 August 2018
Version/Amendment 
Number:
04
Amendment History:
Date
Amendment Number
Amendment Type (for regional 
European purposes only)
Region
25 April 2017
Initial version
Not applicable
Global
24 July 2017
01
Non-Substantial
Global
07 September 2017
02
Substantial
Global
02 April 2018
03
Substantial
Global
10 August 2018
04
Substantial
Global
Property o
on-commercial use only and subject to the applicable Terms of Use

TAK-041
Study No. TAK-041-2001
Page 2 of 101
Protocol Incorporating Amendment No. 04
10 August 2018
TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................7
1.1
Protocol Amendment 04 ..........................................................................................13
2.0
STUDY SCHEMATIC..................................................................................................14
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................15
4.0
INTRODUCTION.........................................................................................................24
4.1
Background .............................................................................................................24
4.2
Rationale for the Proposed Study.............................................................................24
4.3
Benefit/Risk Profile .................................................................................................25
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................26
5.1
Objectives................................................................................................................26
5.1.1
Primary Objective ..............................................................................................26
5.1.2
Secondary Objectives.........................................................................................26
5.1.3
.......................................................................................26
5.2
Endpoints.................................................................................................................26
5.2.1
Primary Endpoints .............................................................................................26
5.2.2
Secondary Endpoints..........................................................................................27
5.3
.............................................................................................27
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................29
6.1
Study Design ...........................................................................................................29
6.2
Rationale for Study Design, Dose, and Endpoints ....................................................31
6.2.1
Rationale of Study Design and Regimen ............................................................31
6.2.2
Rationale for Dose .............................................................................................31
6.2.3
Rationale for Endpoints......................................................................................32
6.2.4
Critical Procedures Based on Study Objectives: Timing of Procedures...............35
6.3
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................36
6.4
Study Beginning and End/Completion .....................................................................37
6.4.1
Definition of Beginning of the Study..................................................................37
6.4.2
Definition of End of the Study ...........................................................................37
6.4.3
Definition of Study Completion .........................................................................37
6.4.4
Definition of Study Discontinuation...................................................................37
6.4.5
Criteria for Premature Termination or Suspension of the Study..........................37
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............39
7.1
Inclusion Criteria .....................................................................................................39
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7.2
Exclusion Criteria ....................................................................................................39
7.3
Excluded Medications, Supplements, and Dietary Products .....................................41
7.4
Diet, Fluid, Activity.................................................................................................44
7.4.1
Diet and Fluid ....................................................................................................44
7.4.2
Activity..............................................................................................................44
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................44
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................46
7.7
Subject Replacement................................................................................................46
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................47
8.1
Clinical Study Drug .................................................................................................47
8.1.1
Investigational Drug...........................................................................................47
8.1.2
Storage...............................................................................................................47
8.1.3
Dose and Regimen .............................................................................................48
8.1.4
Overdose............................................................................................................48
8.1.5
Clinical Study Drug Labeling.............................................................................48
8.1.6
Clinical Study Drug Inventory ...........................................................................48
8.1.7
Clinical Study Drug Blinding.............................................................................48
8.1.8
Randomization Code Creation and Storage ........................................................48
8.1.9
Clinical Study Blind Maintenance/Unblinding Procedure...................................49
8.1.10 Accountability and Destruction of Sponsor-Supplied Drugs...............................49
9.0
STUDY PROCEDURES...............................................................................................50
9.1
Administrative Procedures.......................................................................................50
9.1.1
Informed Consent Procedure..............................................................................50
9.1.2
Inclusion and Exclusion Criteria.........................................................................50
9.1.3
Medical History/Demographics..........................................................................51
9.1.4
Prior and Concomitant Medication Review ........................................................51
9.2
Clinical Procedures and Assessments.......................................................................51
9.2.1
Full Physical Exam ............................................................................................51
9.2.2
Height and Weight .............................................................................................51
9.2.3
Body Mass Index ...............................................................................................51
9.2.4
Vitals (Body Temperature, Heart Rate, Blood Pressure).....................................51
9.2.5
12-Lead ECG.....................................................................................................51
9.2.6
Study Drug Administration ................................................................................52
9.2.7
Cognitive Assessments.......................................................................................52
9.2.8
AE Monitoring...................................................................................................53
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9.2.9
.......................................................................................53
9.2.10 Laboratory Procedures and Assessments ............................................................53
9.2.11 C-SSRS..............................................................................................................55
9.3
Biomarker, PK, PD, and 
.....................................................................55
9.3.1
PK Measurements..............................................................................................55
9.3.2
Biomarker Measurements...................................................................................56
9.3.3
............................................................................................56
9.3.4
Confinement ......................................................................................................57
10.0
ADVERSE EVENTS ....................................................................................................58
10.1
Definitions and Elements of AEs .............................................................................58
10.1.1 SAEs..................................................................................................................60
10.2
AE Procedures.........................................................................................................61
10.2.1 Assigning Severity/Intensity of AEs...................................................................61
10.2.2 Assigning Causality of AEs................................................................................61
10.2.3 Start Date...........................................................................................................61
10.2.4 Stop Date...........................................................................................................61
10.2.5 Frequency ..........................................................................................................61
10.2.6 Action Concerning Study Drug ..........................................................................61
10.2.7 Outcome ............................................................................................................62
10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs ..................................................................................................................62
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....64
11.0
STATISTICAL METHODS..........................................................................................65
11.1
Statistical and Analytical Plans ................................................................................65
11.1.1 Analysis Sets......................................................................................................65
11.1.2 Analysis of Demographics and Other Baseline Characteristics...........................65
11.1.3 PK Analysis .......................................................................................................65
11.1.4 PD Analysis .......................................................................................................66
11.1.5 Safety Analysis ..................................................................................................66
11.2
Interim Analysis and Criteria for Early Termination ................................................67
11.3
Determination of Sample Size..................................................................................67
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................68
12.1
Study-Site Monitoring Visits ...................................................................................68
12.2
Protocol Deviations..................................................................................................68
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................68
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................69
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13.1
IRB and/or IEC Approval ........................................................................................69
13.2
Subject Information, Informed Consent, and Subject Authorization .........................70
13.3
Subject Confidentiality ............................................................................................71
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................71
13.4.1 Publication and Disclosure.................................................................................71
13.4.2 Clinical Trial Registration..................................................................................72
13.4.3 Clinical Trial Results Disclosure ........................................................................72
13.5
Insurance and Compensation for Injury....................................................................72
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................73
14.1
Administrative Information......................................................................................73
14.1.1 Study Contact Information .................................................................................73
14.1.2 Investigator Agreement......................................................................................74
14.1.3 Study-Related Responsibilities...........................................................................75
14.1.4 List of Abbreviations .........................................................................................76
15.0
DATA HANDLING AND RECORDKEEPING............................................................78
15.1
CRFs (Electronic and Paper)....................................................................................78
15.2
Record Retention .....................................................................................................78
16.0
REFERENCES..............................................................................................................80
17.0
APPENDICES...............................................................................................................82
LIST OF IN-TEXT TABLES
Table 3.a 
Schedule of Study Procedures............................................................................15
Table 6.a
Sequence Groups ...............................................................................................30
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................41
Table 8.a
...................................................................47
Table 8.b
......................................47
Table 9.a
Primary Specimen Collections ...........................................................................55
Table 10.a
Takeda Medically Significant AE List................................................................60
LIST OF IN-TEXT FIGURES
Figure 2.a
TAK-041-2001 Study Schematic........................................................................14
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LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................82
Appendix B
Elements of the Subject Informed Consent.........................................................84
Appendix C
Investigator Consent to Use of Personal Information..........................................87
Appendix D
Pregnancy and Contraception.............................................................................88
Appendix E
Detailed Description of Amendments to Text.....................................................90
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

TAK-041
Study No. TAK-041-2001
Page 7 of 101
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1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Centre Europe Ltd.
61 Aldwych
London, WC2B 4AE
United Kingdom
Compound:
TAK-041
Study Number:
TAK-041-2001
Phase:1
Protocol Title: A Randomized, Double-Blind, Placebo Controlled, Two-Period Cross-Over, Proof of Activity Study 
to Evaluate the Effects of TAK-041 on Motivational Anhedonia as Add-On to Antipsychotics in Subjects With Stable 
Schizophrenia
Study Design:
This study is a randomized, double-blind, placebo-controlled, 2-period, crossover phase 2 study to evaluate the 
pharmacodynamic (PD) effects, safety, tolerability, and pharmacokinetics (PK) of single doses of oral TAK-041 in 
adult subjects with schizophrenia, particularly negative symptoms characterized by reduced motivation. The study is 
designed to evaluate the effect of TAK-041, a G protein-coupled receptor 139 orphan receptor agonist, as an add-on to 
antipsychotics in attenuating the impairment in motivational anhedonia as well as cognitive function using 
motivation/reward battery tests as well as brain imaging 
 
 in subjects with stable 
schizophrenia. Subjects should be stable on their existing medicine (ie, second generation antipsychotics) for at least 2 
months prior to screening. A planned unblinded interim analysis (IA) for efficacy may be conducted when 
approximately12 subjects have completed the Day 14 procedures in both periods at sponsors discretion. The IA 
objective is to determine whether to continue the TAK-041 dose after the IA, or revise to a different dose, based on the 
results of the IA. Any dose change to explore dose/exposure relationships on the PD endpoints at other dose levels will 
be supported by emerging safety, tolerability and PK data.
The study will consist of 2 treatment periods, with a single dose of study drug administered in each period. There will 
be a 35-day (+7 days) washout interval between the 2 doses to reduce the potential for residual TAK-041 to impact the 
PD endpoints. Treatment Period 2 begins at the end of the Treatment Period 1 washout. Because subjects are not 
confined in this study, they will come to the clinic for the following visits:
!
Screening Visit (between Days -35 to -2) covering full medical and psychiatric examinations.
!
Baseline Assessments Visit (Day -1 in each Treatment Period), covering motivation/reward and cognitive testing 
baseline, except fMRI.
!
Dosing and First Testing Visit (Day 1 in each Treatment Period).
!
Second Testing Visit (Day 14 in each Treatment Period).
!
Follow-up Visit (Day 49 [ ±4 days] for Treatment Period 2 only).
!
End of Period 1 Visit (Day 35 [+7 days] postdose in Period 1). This visit will serve to conduct end of Period 1 
procedures and the Day -1 Baseline assessments for Period 2.
!
Study Exit occurs at the Final Visit (77 ±7 days postdose in Period 2).
The trial population will include subjects with stable schizophrenia aged 18 to 60 years, inclusive, considered eligible 
on the basis of the trial inclusion and exclusion criteria. The trial will enroll up to 32 subjects dosed to ensure 
24 subjects complete. 
On Day 1 of Period 1, eligible subjects will be randomized in a ratio of 1:1 to 1 of the 2 treatment sequences (shown 
below) and will receive each trial treatment according to the randomized sequence group. The initial dose of TAK-041 
will be 40 mg. Higher doses will be considered depending on emerging safety, tolerability and PK data. After the IA, 
the dose level may also be changed based on the IA results. The decision criteria will be predefined in the SAP before 
unblinding.
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Study No. TAK-041-2001
Page 8 of 101
Protocol Incorporating Amendment No. 04
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Sequence
Period 1
Period 2
1
TAK-041 + antipsychotic
Placebo + antipsychotic
2
Placebo + antipsychotic
TAK-041 + antipsychotic
During the Screening Visit (Days -35 to -2), subjects meeting Diagnostic and Statistical Manual of Mental Disorders 
fifth edition (DSM-5) criteria for schizophrenia and on stable antipsychotic therapy for at least 2 months will complete 
medical and psychiatric examinations, electrocardiogram (ECG), and laboratory safety tests. At the Baseline 
Assessments Visit (Day -1), subjects will complete practice sessions of the motivation/reward and cognitive battery in 
order to minimize potential practice effects at subsequent treatment visits, will be familiarized with the magnetic 
resonance imaging (MRI) environment, and further will be tested for baseline assessments (except fMRI). Practice 
sessions will be conducted in Period 1 only. Subjects meeting all inclusion criteria and no exclusion criteria will be 
administered study medication or placebo in the clinic based on the randomization schedule on Day 1 of Treatment 
Periods 1 and 2.
On Day 1 of each Treatment Period, following study drug administration, subjects will take PD tests for a total of 
approximately 4 hours and blood samples will be collected at various times after dosing to assess the PK of TAK-041. 
After the last PK collection at 6 hours postdose, subjects will leave the clinic. On Day 14 of each Treatment Period, 
subjects will take the second set of PD tests along with a single time point PK collection. Samples for PK will also be 
collected on Day 49 and Final Visit of the second Treatment Period. There will be a washout period of 35 days (+ 7 
days) between doses in each Treatment Period to reduce the potential for residual TAK-041 to impact the PD 
endpoints.
PD testing will be performed in 3 blocks, separated by two breaks. The first block will comprise the Grip Effort Task, 
the Progressive Ratio Test, and the Brief Assessment of Cognition in Schizophrenia (BACS). 
 
 
 
 
 
 
 
 
 
 
 
Blood will be drawn for 
 on Day 1 of each Treatment Period at the following times relative to 
the TAK-041 or placebo dose: 0 (within 30 min prior to TAK-041/placebo dosing), 1, 2, 5, and 6 hours postdose. In 
addition, single time point PK will be collected in both Periods at the Second Testing Visit (Day 14), end of period 1 
washout visit (Day 35 + 7 days), Follow-up Visit (Day 49 ±4 days for Period 2), Final Visit (Day 77 ±7 days), and at 
early termination if it occurs before Day 49 (for Period 2).
 
Typical treatment, testing, and washout periods are illustrated below. Testing day scheduled times are estimates of 
time in minutes required to complete the procedures.
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Primary Objectives:
!
To determine whether motivation/reward deficits observed in schizophrenia are attenuated by add-on TAK-041 
administration to antipsychotics in subjects with stable schizophrenia.
!
To determine whether cognitive impairment associated with schizophrenia is improved by add-on TAK-041 
administration to antipsychotics in subjects with stable schizophrenia.
Primary Hypotheses:
!
TAK-041 demonstrates greater increase compared with placebo in BOLD signal in the average of left and right 
ventral striatum (VS) activation in the MID Reward Task (high posterior probability of [a difference between 
TAK-041 and placebo >0.09] is expected).
!
TAK-041 demonstrates greater increase than placebo in the BACS composite score (high posterior probability of 
[a difference between TAK-041 and placebo > 2.0] is expected).
Secondary Objectives:
To determine safety and tolerability of TAK-041 as add-on therapy to antipsychotics in subjects with stable 
schizophrenia.
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Primary Objectives:
!
To determine whether motivation/reward deficits observed in schizophrenia are attenuated by add-on TAK-041 
administration to antipsychotics in subjects with stable schizophrenia.
!
To determine whether cognitive impairment associated with schizophrenia is improved by add-on TAK-041 
administration to antipsychotics in subjects with stable schizophrenia.
Primary Hypotheses:
!
TAK-041 demonstrates greater increase compared with placebo in BOLD signal in the average of left and right 
ventral striatum (VS) activation in the MID Reward Task (high posterior probability of [a difference between 
TAK-041 and placebo >0.09] is expected).
!
TAK-041 demonstrates greater increase than placebo in the BACS composite score (high posterior probability of 
[a difference between TAK-041 and placebo >2.0] is expected).
Secondary Objectives:
!
To determine safety and tolerability of TAK-041 as add-on therapy to antipsychotics in subjects with stable 
schizophrenia.
Subject Population: Male and female subjects with schizophrenia who are on a stable dose of an antipsychotic for at 
least 2 months prior to screening.
Number of Subjects:
Up to 32 subjects enrolled to ensure 24 subjects 
complete postdose PD assessments on Day 1 in both 
Treatment Periods
Number of Sites:
Approximately 4 sites 
Dose Levels:
TAK-041)/matching placebo: initially 40 mg followed 
by a potentially higher dose if supported by emerging 
safety, tolerability and PK data
Route of Administration:
Oral
Duration of Treatment:
Single oral dose on Day 1 of each Treatment Period
Period of Evaluation:
126 to 154 days
Main Criteria for Inclusion:
In order to be eligible for participation, subjects must:
1.
Be on a stable dose of an antipsychotic for at least 2 months as documented by medical history and assessed by 
site staff (other than those on the excluded medication list).
2.
Meet schizophrenia criteria as defined by the DSM-5 by the Mini International Neuropsychiatric Interview.
3.
Have PANSS total score ≤90 and PANSS 
 
5.
Have had a structural brain MRI within the preceding year or during screening indicating no concerning structural 
brain abnormalities or other abnormalities that would interfere with interpretation of functional brain imaging 
results.
Main Criteria for Exclusion:
The subject must be excluded from participating in the trial if the subject:
1.
Has a history of claustrophobia or inability to tolerate mock scanner environment if used during 
habituation/screening session.
2.
Fulfills any of the MRI contraindications on the standard radiography screening questionnaire at a participating 
site’s imaging facility (eg, history of surgery involving metal implants, metal body piercing, dentures, dental 
plates or bridges, any implanted device that is electrically, magnetically, and mechanically activated).
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3.
Has a history in the last year or is currently receiving treatment with clozapine.
4.
Has a current diagnosis of a significant psychiatric illness other than schizophrenia, per DSM-5, and is in an acute 
phase/episode.
Main Criteria for Evaluation and Analyses:
The primary endpoints of the trial are:
!
Change from placebo in BOLD signal in the average of left and right VS activation in the MID Reward Task at 
first testing after TAK-041 administration (Day 1).
!
Change from placebo in the BACS composite score at second testing after TAK-041 administration (Day 14).
The secondary endpoints will be assessed through evaluation of the following parameters:
!
Percentage of subjects who experience at least 1 treatment-emergent adverse event.
!
Percentage of subjects who meet the markedly abnormal criteria for safety laboratory tests at least once postdose.
!
Percentage of subjects who meet the markedly abnormal criteria for vital sign measurements at least once 
postdose.
!
Percentage of subjects who meet the markedly abnormal criteria for safety ECG parameters at least once 
postdose.
!
Columbia-Suicide Severity Rating Scale at all time points assessed.
Statistical Considerations:
Measures and Bayesian GO/NO-GO Decision-Making Approach at the End of the Study
Both primary endpoints will be used for the evaluation of the effect of TAK-041 for the treatment of schizophrenia.
A Bayesian GO/NO-GO decision-making approach will be implemented for the evaluation of the effect of TAK-041 
on schizophrenia. Using the observed mean (SD) difference in the 2 primary endpoints between the 2 groups 
(TAK-041 and placebo), the posterior probability that TAK-041 increases the BACS composite score by 2 points over 
placebo, and the posterior probability that TAK-041 increases the VS activity by at least 0.09 compared to placebo, 
will be calculated. Noninformative prior distribution will be used. The criteria for declaring GO and NO-GO is defined 
in the SAP.
In addition to estimating the probability of TAK-041 meeting the effect thresholds, summary statistics on the primary, 
secondary, 
 endpoints on the original scale and/or natural log scale will be provided for TAK-041 and 
placebo. Analysis of covariance models for crossover design will be implemented where appropriate.
Safety
Safety analyses including adverse events, changes in clinical laboratory values, vital signs, ECGs, and other safety 
observations will be summarized by placebo and TAK-041.
Pharmacokinetic Measures
Descriptive statistics will be used to summarize plasma concentrations over collection time points and PK parameters 
of TAK-041. Individual plasma concentration and PK parameter data will be presented in data listings.
Interim Analysis:
A small group from the sponsor will remain unblinded to treatment assignment during the study for the purpose of 
conducting interim analyses of PD effects. In order to minimize any potential unblinding of investigators, these staff 
will not regularly interact with the investigators or their staff.
A planned, unblinded IA of various PD endpoints will be conducted when approximately 12 subjects have completed 
the Day 14 procedures in both periods including the primary endpoints. The purpose of the interim PD analysis will be 
to determine whether to change the dose of TAK-041. Any alternative dose will be supported by emerging safety, 
tolerability and PK data. The Bayesian decision rule will be specified in the SAP before the data are unblinded for the 
IA. In addition, a decision to switch to a lower dose may be made based on safety, tolerability and PK data of a higher 
dose.
Property of Takeda: For non-commercial use only and s
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Study No. TAK-041-2001
Page 12 of 101
Protocol Incorporating Amendment No. 04
10 August 2018
Sample Size Justification:
Up to 32 subjects are planned to be randomized equally to 2 treatment sequences to ensure 24 subjects complete the 
trial. 
Both primary endpoints will be used at the IA and the end of the study for decision making. A Bayesian method will be 
used to calculate the posterior probability of the endpoints meeting the predefined criteria. The probability of making 
a “GO” decision based on the predefined “GO” criteria with 24 subjects is at least 70% when the true TAK-041 effect 
on either endpoint is clinically meaningful. This sample size will also keep the type 1 error rate no more than 30% 
when the true drug effect is minimal or the same as placebo. The SD for the BACS composite score is assumed to be 
9.30 points. The SD for the VS activation is assumed to be 0.360. Independence between these 2 endpoints was 
assumed in the sample-size calculation.
Noninformative prior distribution was used in the above probability calculation. Allowing for 8 dropouts (due to long 
washout interval), up to 32 subjects are planned to be enrolled in order to have 24 completed this trial.
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TAK-041
Study No. TAK-041-2001
Page 13 of 101
Protocol Incorporating Amendment No. 04
10 August 2018
1.1
Protocol Amendment 04 
Rationale for Amendment 04 
This document describes the changes in reference to the protocol incorporating Amendment 
No. 04.
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 E.
Changes in Amendment 04:
1. Modified rationale and potential range for study drug dose level.
2. Detailed potential study drug dose level change following the interim analysis.
3. Clarified Period 2 baseline serum pregnancy test collection day.
4. Revised exclusion criteria for abnormal laboratory values to clarify collection times for 
screening and baseline laboratory tests.
5. Revised exclusion criterion for magnetic resonance imaging contraindication before imaging 
assessments.
6. Detailed follow-up laboratory tests required for drug-induced liver injury (DILI). 
7. Updated and further clarified excluded medications, supplements, and dietary products
8. Modified potential number of sites to approximately 4.
9. Introduced randomization stratification by site.
10. Extended screening period to 35 days prior to dosing.
11. Updated schedule of study procedures.
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TAK-041
Study No. TAK-041-2001
Page 14 of 101
Protocol Incorporating Amendment No. 04
10 August 2018
2.0
STUDY SCHEMATIC
Typical treatment, testing, and washout periods are illustrated in Figure 2.a. Testing day scheduled 
times are estimates of time required in minutes to complete the procedures.
Figure 2.a
TAK-041-2001 Study Schematic
 BACS=Brief Assessment of Cognition in Schizophrenia, 
 
, 
 MID=Monetary Incentive Delay, PK=pharmacokinetic, 
 
.
Property of T
For non-com
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For non-com
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Study No. TAK-041-2001
Page 15 of 101
Protocol Incorporating Amendment No. 04
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3.0
SCHEDULE OF STUDY PROCEDURES
Table 3.a
Schedule of Study Procedures
Schedule for Period 1(a)
End of Period 1 
Washout Visit (c)
ET
Day -1 
Baseline 
assessments 
(b)
Treatment Assessments
Follow-
up Visit
Study Days
Days
-35 to -2
Dosing and PD Testing Day 1
Day 14 
35 +7 days 
postdose
Hours
Predose
1
2
3.5
5
6
Administrative procedures
Informed consent 
 
X
Inclusion/exclusion criteria
X
X
X
Medical history/demographics
X
Prior and concomitant 
medication review
--------------------------------------------------Continuous Review----------------------------------------------------------------
Clinical Procedures/Assessments
Full physical examination
X
X (d)
Psychiatric examination
X
Height
X
Weight
X
BMI
X
Semirecumbent vital signs (HR, 
SBP, and DBP) 
X
X (e)
X
X
X
Footnotes are on last table page.
Property of Takeda: For non-commercial 
al us
use only and subject to the applicable Terms of Use
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Day 1
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Study No. TAK-041-2001
Page 16 of 101
Protocol Incorporating Amendment No. 04
10 August 2018
Table 3.a 
Schedule of Study Procedures (continued)
Schedule for Period 1 (a)
End of Period 
1 Washout 
Visit (c)
ET
Day -1 
Baseline 
assessments 
(b)
Treatment Assessments
Follow-
up Visit
Study Days
Days
-35 to -2
Dosing and PD Testing Day 1
Day 14
35 +7 days 
postdose
Hours
Predose
1
2
3.5
5
6
Vital signs (respiratory rate, oral 
[floor of the mouth]/ tympanic 
temperature)
X
X (e)
X
X
X
Standard 12-lead ECG
X
X (e)
X
X
X
TAK-041/placebo 
administration (f)
X
(0 hour)
MINI
X
PANSS
X
X
Structural MRI (h)
X
AE monitoring
--------------------------------------------------Continuous Monitoring----------------------------------------------------
X
Laboratory Procedures/Assessments
Hematology
X (i)
X (i)
X
X
Urinalysis
X (i)
X (i)
X
X
Serum chemistry
X (i)
X (i)
X
X
Serum FSH
X
Footnotes are on last table page.
Property of Takeda: For non-comm
---------
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Study No. TAK-041-2001
Page 17 of 101
Protocol Incorporating Amendment No. 04
10 August 2018
Table 3.a 
Schedule of Study Procedures (continued)
Schedule for Period 1 (a)
End of 
Period 1 
Washout 
Visit (c)
ET
Day -1 
Baseline 
assessments 
(b)
Treatment Assessments
Follow-
up 
Visits
Study Days
Days
-35 to 
-2
Dosing and PD Testing Day 1
Day 14 
35 +7 days 
postdose
Hours
Predose
1
2
3.5
5
6
Urine drug screen (j)
X (i)
X (i)
X
X
Alcohol breath test (j)
X
X
X
Serum pregnancy test (c)
X
X
X
X
X
Hepatitis panel (including 
HBsAg and anti-HCV), HIV, 
TSH
X
5'-nucleotidase
X
X
X
X (k)
PK Evaluations
Plasma sample for PK (k)
X
X
X
X
X
X
X
X (k)
PD Evaluations
BACS
X(l)
X
X
Imaging Battery
X (m)
X
X
Footnotes are on last table page.
Property of Takeda: F
commercial use only and subject to the applicable Terms of Use
le
lic
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Study No. TAK-041-2001
Page 18 of 101
Protocol Incorporating Amendment No. 04
10 August 2018
Table 3.a 
Schedule of Study Procedures (continued)
Schedule for Period 1 (a)
End of 
Period 1 
Washout 
Visit (c)
ET
Day -1 
Baseline 
assessments 
(b)
Treatment Assessments
Follow-
up Visits
Study Days
Days
-35 to -2
Dosing and PD Testing Day 1
Day 14 
35 +7 days 
postdose
Hours
Predose
1
2
3.5
5
6
PGx Evaluations
Other
Tobacco and caffeine 
consumption (o)
X
X
X
X
Footnotes are on last table page.
Property of Takeda: For non-commerci
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 subject to the applicable Terms of Use
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Study No. TAK-041-2001
Page 19 of 101
Protocol Incorporating Amendment No. 04
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Table 3.a
Schedule of Study Procedures (continued)
Study Days 
Schedule for Period 2 (a)
End of 
Period 2 
Study Exit 
ET
Day -1 
Period 2 
Baseline 
assessments 
(b)
Treatment Assessments
Period 2
Follow-up Visits
Dosing and PD Testing Day 1
Day 14 
Day 49±4 
days post 
dose
77 ±7 days 
post dose
Hours
Predose
1
2
3.5
5
6
Administrative procedures
Informed consent (retained samples, 
Inclusion/exclusion criteria
X
Medical history/demographics 
Prior and concomitant medication 
review
--------------------------------------------------Continuous 
Review-----------------------------------------------------------------
Clinical Procedures/Assessments
Full physical examination
X (d)
Psychiatric examination
Height 
Weight 
BMI 
Semirecumbent vital signs (HR, SBP, 
and DBP) 
X (e)
X
X
X
X
Footnotes are on last table page.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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Peri
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Study No. TAK-041-2001
Page 20 of 101
Protocol Incorporating Amendment No. 04
10 August 2018
Table 3.a 
Schedule of Study Procedures (continued)
Study Days 
Schedule for Period 2 (a)
End of 
Period 2 
Study Exit 
(c)
ET
Period 2 
Day-1 
Baseline 
assessmen
ts (b)
Treatment Assessments
Follow-up Visits
Dosing and PD Testing Day 1
Day 14 
Day 49±4 
days 
postdose
77 ± 7 days 
postdose
Hours
Predose
1
2
3.5
5
6
Vital signs (respiratory rate, oral [floor 
of the mouth]/ tympanic temperature) 
X (e)
X
X
X
X
Standard 12-lead ECG 
X (e)
X
X
X
X
TAK-041/placebo administration (f)
X
(0 hour)
MINI 
C-SSRS (g) 
X
X
X
X
Structural MRI (h)
AE monitoring
--------------------------------------------------Continuous Monitoring--------------------------------
X
Laboratory Procedures/Assessments
Hematology
X (i)
X
X
X
Urinalysis
X (i)
X
X
X
Serum chemistry
X (i)
X
X
X
Footnotes are on last table page.
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 only and subject to the applicable Terms of Use
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Study No. TAK-041-2001
Page 21 of 101
Protocol Incorporating Amendment No. 04
10 August 2018
Table 3.a 
Schedule of Study Procedures (continued)
Schedule for Period 2 (a)
End of 
Period 2 
Study Exit 
(c)
ET
Day -1 Period 
2 Baseline 
assessments 
(b)
Treatment Assessments
Follow-up Visits
Study Days 
Dosing and PD Testing Day 1
Day 14 
Day 49±4 
days 
postdose
77 ±7 days 
postdose
Hours
Predose
1
2
3.5
5
6
Urine drug screen (j)
X (i)
X
X
Alcohol breath test (j)
X
X
Serum pregnancy test (c)
X
X
X
X
X
Hepatitis panel (including 
HBsAg and anti-HCV), HIV, 
TSH
5'-nucleotidase
X
X
X
X (k)
PK Evaluations
Plasma sample for PK (k)
X
X
X
X
X
X
X
X
X (k)
PD Evaluations
BACS
X(l)
X
X
Motivation/Reward Battery
X (l)
Imaging Battery
X (m)
X
X
Footnotes are on last table page.
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ommercial use only and subject to the applicable Terms of Use
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6
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TAK-041
Study No. TAK-041-2001
Page 22 of 101
Protocol Incorporating Amendment No. 04
10 August 2018
Table 3.a 
Schedule of Study Procedures (continued)
Schedule for Period 2 (a)
End of 
Period 2 
Study Exit 
(c)
ET
Day -1
Period 2 
Baseline 
assessments 
(b)
Treatment Assessments
Follow-up Visits
Study Days 
Dosing and PD Testing Day 1
Day 14 
(Period 2)
Day 49±4 
days 
postdose
77 ± 7 
days 
postdose
Hours
Predose
1
2
3.5 
5
6
PGx Evaluations
Other
Tobacco and caffeine consumption (o)
X
X
X
X
AE=adverse event, BACS=Brief Assessment of Cognition in Schizophrenia, BMI=body mass index, 
, 
 
, C-SSRS=Columbia-Suicide Severity Rating Scale, DBP=diastolic blood 
pressure, ECG=electrocardiogram, ET=Early Termination, FSH=follicle-stimulating hormone, HBsAg=hepatitis B surface antigen, HCV=hepatitis C virus, 
HIV=human immunodeficiency virus, HR=heart rate, MINI=Mini International Neuropsychiatric Interview, MRI=magnetic resonance imaging, 
 
, PD=pharmacodynamic, PGx=pharmacogenomics, PK=pharmacokinetics, SBP=systolic blood pressure, TSH=thyrotropin.
(a) The schedule for Periods 1 and 2 is identical from Day -1 to Day 14. 
(b) Baseline PD assessments must be completed within 24 hours before Day 1 dosing and PD testing in both Periods. PD assessments and testing take priority over 
all other procedures. If P1 Day 35 and P2 Day-1 are the same day, assessments required for both visits only need to be completed once. PD testing will be performed 
in 3 blocks, separated by two breaks, Figure 2.a.
(c) The sites will schedule a visit for subjects at the end of the Period 1 Washout. Subjects may return to the sites for this visit any day between Day 35 and 42. This 
Visit will serve to conduct end of Period 1 procedures and may also be the same calendar day as Day -1 Baseline assessments for Period 2. If P1 Day 35 and P2 Day 
1 are the same day, assessments required for both visits only need to be completed once. Subjects will return to the clinic the next day for Period 2 dosing and PD 
testing.
(d) Predose physical may be done within approximately 24 hours predose.
(e) Vital signs and a 12-lead ECG will be performed within approximately 1 hour predose on Day 1 in both Periods.
(f) Subjects will be administered study drug at the clinic on Day 1 of Periods 1 and 2.
Property of Takeda: For non-comm
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d subject to the applicable Terms of Use
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Study No. TAK-041-2001
Page 23 of 101
Protocol Incorporating Amendment No. 04
10 August 2018
(g) Two versions of the C-SSRS will be used in this trial: the Screening/Baseline C-SSRS Lifetime Version 14Jan2009 and the Since-Last-Visit C-SSRS Version 
14Jan2009. C-SSRS only needs to be captured once if P1 Day 35 and P2 D-1 are the same day.
(h) If not conducted within the preceding year, a structural MRI may be performed during screening to ensure the absence of structural brain abnormalities that 
might interfere with interpretation of functional brain imaging results.
(i) Must be reviewed by the investigator before dosing on Day 1 in both Periods.
(j) May be repeated within 28 days of screening per investigator’s discretion.
(k) Collect a blood sample if subject early terminates before Day 49.
(l) Subjects will complete practice sessions as well as baseline measurements in Period 1 only. 
(m) Familiarization with tasks ONLY in Period 1. No imaging data collected here.
(n) 
(o) Subjects will be questioned if they have used tobacco- or caffeine-containing products on the day prior to baseline assessments and testing.
(p) 
 
 
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Study No. TAK-041-2001
Page 24 of 101
Protocol Incorporating Amendment No. 04
10 August 2018
4.0
INTRODUCTION
4.1
Background
G protein-coupled receptor 139 (GPR139) is an orphan G protein-coupled receptor identified as a 
target mainly expressed in the dorsal medial habenula. The habenula is part of the diencephalon, 
which along with the pineal gland makes up the “epithalamus.” The pineal gland is attached to the 
diencephalon by a stalk, with 2 (bilateral) small nuclei at the base that are the habenulae. This is a 
highly conserved and crucial brain region that facilitates functional interactions among the limbic 
system, basal ganglia, ventral tegmental area, and midbrain raphe nuclei. The habenula has been 
shown to be involved in appropriate social interactions, learning behavior, and cognition [1,2]. In 
monozygotic twins discordant for schizophrenia, copy number variants of GPR139 have been 
reported in the affected twin [3]. In GPR139 -/- knockout mice, impairments in tasks associated 
with motivation and social behavior are observed. Taken together, these results suggest that 
GPR139 plays an integral part in regulating medial habenular function and thereby may be 
important in the regulation of social and other behaviors that are impaired in people with 
schizophrenia.
TAK-041 is a highly selective and potent agonist of GPR139. In numerous preclinical studies, 
TAK-041 has demonstrated potential efficacy in animal models of amotivation, anhedonia, and 
asociality, which are behaviors classified as “negative symptoms of schizophrenia.” Negative 
symptoms include difficulties with expressive behaviors (blunted affect, poverty of speech) as 
well as impairments in emotional behaviors (amotivation, asociality, anhedonia). Impairments in 
social behavior are common, with shared characteristics across a host of other psychiatric 
conditions, including autism spectrum disorders, attention-deficit/hyperactivity disorder, and 
major depressive disorder.
4.2
Rationale for the Proposed Study
To date there are no approved drugs addressing negative symptoms or cognitive impairment 
associated with schizophrenia. Since motivational deficits and anhedonia are core components of 
negative symptoms, recent research has focused on developing translational tasks in these domains 
in order to support development of new pharmacological interventions for negative symptoms.
Based on the unique target expression profile of GPR139 in the habenula, data obtained from 
GPR139 -/- knockout mice, as well as efficacy of TAK-041 in multiple preclinical models of 
anhedonia, the current trial is designed to evaluate the effects of TAK-041 on motivational 
anhedonia and cognitive function using motivation/reward battery tests, 
 
in subjects with stable schizophrenia, as an add-on to 
stable antipsychotic treatment.
Property
 Takeda: For non-commercial use only and subject to the applicable Terms of Use
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Study No. TAK-041-2001
Page 25 of 101
Protocol Incorporating Amendment No. 04
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4.3
Benefit/Risk Profile
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 blinded results from the TAK-041-1001 study indicate that single doses of 5, 10, 20, 
40, 80, 120 and 160 mg and multiple dose cohorts 1 (40mg/20mg) and 2 (80 mg/40 mg) consisting 
of 4 weekly doses, 1 loading dose followed by weekly maintenance doses for 3 weeks are well 
tolerated. In the TAK-041-1001 study, 31 AEs were observed that were all mild and resolved 
without medication treatment. Thirty of the AEs were deemed not related to study drug, and 
resolved without treatment. For the 66 subjects in the above cohorts there were no serious AEs, no 
clinically meaningful abnormalities in safety laboratory results (including ALP, AST, ALT, GGT, 
and TBILI) and no clinically significant abnormalities in physical examination, vital signs, or ECG 
results reported.
The potential risks can be monitored clinically and/or with laboratory tests and were considered in 
setting up the stopping rules for this clinical trial. Appropriate eligibility criteria that exclude 
individuals with past history or concurrent conditions that increase the risk have been applied.
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TAK-041
Study No. TAK-041-2001
Page 26 of 101
Protocol Incorporating Amendment No. 04
10 August 2018
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
!
To determine whether motivation/reward deficits observed in schizophrenia are attenuated by 
add-on TAK-041 administration to antipsychotics in subjects with stable schizophrenia.
!
To determine whether cognitive impairment associated with schizophrenia is improved by 
add-on TAK-041 administration to antipsychotics in subjects with stable schizophrenia.
Primary Hypotheses:
!
TAK-041 demonstrates greater increase compared with placebo in BOLD signal in the average 
of left and right ventral striatum (VS) activation in the Monetary Incentive Delay (MID) 
Reward Task (high posterior probability of [a difference between TAK-041 and placebo 
>0.09] is expected).
!
TAK-041 demonstrates greater increase than placebo in the BACS composite score (high 
posterior probability of [a difference between TAK-041 and placebo >2.0] is expected).
5.1.2
Secondary Objectives
!
To determine safety and tolerability of TAK-041 as add-on therapy to antipsychotics in 
subjects with stable schizophrenia.
5.1.3
Exploratory Objectives
5.2
Endpoints
5.2.1
Primary Endpoints
!
Change from placebo in BOLD signal in the average of left and right VS activation in the MID 
Reward Task at first testing after TAK-041 administration (Day 1).
!
Change from placebo in the BACS composite score at second testing after TAK-041 
administration (Day 14).
Property of T
5.2
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5.2.2
Secondary Endpoints
!
Percentage of subjects who experience at least 1 treatment-emergent adverse event (TEAE).
!
Percentage of subjects who meet the markedly abnormal criteria for safety laboratory tests at 
least once postdose.
!
Percentage of subjects who meet the markedly abnormal criteria for vital sign measurements at 
least once postdose.
!
Percentage of subjects who meet the markedly abnormal criteria for safety ECG parameters at 
least once postdose.
!
Columbia-Suicide Severity Rating Scale (C-SSRS) at all time points assessed.
5.3
Exploratory Endpoints
Prope
 to the applicable Terms of Use
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This study is a randomized, double-blind, placebo-controlled, 2-period, crossover phase 2 study to 
evaluate the pharmacodynamic (PD) effects, safety, tolerability, and PK of single doses of oral 
TAK-041 in adult subjects with schizophrenia, particularly negative symptoms characterized by 
reduced motivation. Effects of at least 1 dose level and placebo will be assessed. The study is 
designed to evaluate the effect of TAK-041, a GPR139 orphan receptor agonist, as an add-on to 
antipsychotics in attenuating the impairment in motivational anhedonia as well as cognitive 
function using motivation/reward battery tests as well as brain imaging 
 
in subjects with stable schizophrenia. Subjects should be stable on their existing 
medicine (ie, second-generation antipsychotics [SGAs]) for at least 2 months prior to screening. 
The initial dose level selected will be 40 mg but may be adjusted based on emerging safety, 
tolerability and PK data. A planned unblinded interim analysis (IA) for efficacy may be conducted 
when approximately 12 subjects have completed the Day 14 procedures in both periods. The IA 
objective is to determine whether to continue the current TAK-041 dose after the IA, or revise to a 
different dose.
The study will consist of 2 treatment periods, with a single dose of study drug administered in each 
period. There will be a 35 day (+ 7 days) washout interval between the 2 doses to reduce the 
potential for residual TAK-041 to impact the PD endpoints. Treatment Period 2 begins at the end 
of the Treatment Period 1 washout. Because subjects are not confined in this study, they will come 
to the clinic for the following visits:
!
Screening Visit (between Days -35 to -2) covering full medical and psychiatric examinations.
!
Baseline Assessments Visit (Day -1 in each Treatment Period), covering motivation/reward 
and cognitive testing baseline, except fMRI.
!
Dosing and First Testing Visit (Day 1 in each Treatment Period).
!
Second Testing Visit (Day 14 in each Treatment Period).
!
Follow-up Visit (Day 49 [±4 days] post dose for Treatment Period 2 only).
!
End of Period 1 Visit (Day 35 [+7 days] postdose in Period 1). This Visit will serve to conduct 
end of Period 1 procedures and the Day -1 Baseline assessments for Period 2.
!
Study Exit occurs at the Final Visit 77 ±7 days post–Period 2 dose.
The trial population will include subjects with stable schizophrenia aged 18-60 years, inclusive, 
considered eligible on the basis of the trial inclusion and exclusion criteria. The trial will
randomize up to 32 subjects to ensure 24 subjects complete. On Day 1 of Period 1, eligible 
subjects will be randomized in a ratio of 1:1 to 1 of the 2 treatment sequences (Table 6.a) and will 
receive each study drug according to the randomized sequence group. The randomization will be 
stratified by the sites. The initial dose of TAK-041 will be 40 mg and may be adjusted prior to the 
IA depending on available PK and safety data from emerging first-in-human cohorts. The dose for 
Property of Takeda: For non-commercial use only and subject to th
plicable Terms of Use
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TAK-041 may also be changed for subjects enrolled after the IA. The decision criteria will be 
predefined in the SAP before unblinding.
Table 6.a
Sequence Groups
Sequence
Period 1
Period 2
1
TAK-041 + 
antipsychotic
Placebo + 
antipsychotic
2
Placebo + 
antipsychotic
TAK-041 + 
antipsychotic
During the Screening Visit (Days -35 to -2), subjects meeting Diagnostic and Statistical Manual of 
Mental Disorders fifth edition (DSM-5) criteria for schizophrenia [4] and on stable antipsychotic 
therapy for at least 2 months will complete medical and psychiatric examinations, 
electrocardiogram (ECG), and laboratory safety tests. At the Baseline Assessments Visit (Day -1)
for Period 1, subjects will complete practice sessions of the motivation/reward and cognitive 
battery in order to minimize potential practice effects at subsequent treatment visits, and be 
familiarized to the magnetic resonance imaging (MRI) tasks. At both study periods, subjects will
also be tested for Day -1 baseline assessments (except fMRI). Practice sessions will be carried out 
prior to the baseline assessments in Period 1 only. Subjects meeting all inclusion criteria and no 
exclusion criteria will be administered study medication or placebo in the clinic based on the 
randomization schedule on Day 1 of Treatment Periods 1 and 2.
On Day 1 of each Treatment Period, following study drug administration, and commencing at 
approximately 2 hours postdose, subjects will undergo PD tests for a total of approximately 
4 hours. Blood samples will be collected at defined times after dosing to assess the PK of 
TAK-041. After the last PK collection at 6 hours postdose, subjects will leave the clinic. On Day 
14 of each Treatment Period, subjects will take the second set of PD tests along with a single time 
point PK collection. Samples for PK will also be collected on Day 49 and Final Visit of second 
Treatment Period. There will be a washout period of 35 days (+ 7 days) between doses in each
Treatment Period to reduce the potential for residual TAK-041 to impact the PD endpoints.
PD testing will be performed in 3 blocks, separated by two breaks. The test schedule is detailed in 
the Schedule of Study Procedures, Table 3.a. The first block will comprise the 
 
and BACS. After a break, subjects will take the second block that 
comprises a battery of imaging tests;
 
 
 
 
 
 
 
 
 
Property of
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For non-commercial use only and subject to the applicable Terms of Use
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These tasks will only be included if the feasibility and validity of data generated by the tasks are 
confirmed. If included in the study procedures, these tasks will be conducted only in participants 
randomized to study treatment after the feasibility of the task (or tasks) and devices have been 
demonstrated.
Blood will be drawn for PK analysis at defined days and times during the treatment period, 
follow-up and final visit or at early termination if it occurs, as detailed in the Schedule of Study 
Procedures, Table 3.a.
Typical treatment, testing, and washout periods are illustrated in Figure 2.a.
6.2
Rationale for Study Design, Dose, and Endpoints
6.2.1
Rationale of Study Design and Regimen
Based on the target expression profile and preclinical data obtained from GPR139 -/- knockout 
mice as well as from preclinical data for TAK-041, the current trial is designed to evaluate the 
effect of TAK-041 in attenuating impairment in motivational anhedonia, cognitive function using 
motivation/reward battery tests, as well as task-based fMRI brain imaging using BOLD in subjects 
with stable schizophrenia.
To date there are no approved compounds addressing negative symptoms as well as cognitive 
impairment associated with schizophrenia. Since motivational deficits and anhedonia are core 
components of negative symptoms, recent research has focused on developing translational tasks
in these domains in order to support development of new pharmacological interventions for 
negative symptoms in subjects with schizophrenia.
The crossover design has been selected in order to reduce sample size (N = 24), as well as 
minimize variability in the endpoints. TAK-041 has been evaluated in a single-rising dose (SRD) 
and multiple rising dose (MRD) trial in healthy volunteers with single doses up to 160 mg and 
multiple doses regimen 40/20 mg (loading dose on week 1/followed by 3 weekly maintenances 
doses) of a crystalline suspension. During the SRD trial, PK blood samples were collected for 
43 days following a single TAK-041 dose. Preliminary PK data indicated that TAK-041 has a 
mean terminal elimination half-life (t1/2) of approximately 11 days. Therefore, 35 + 7 days 
between the 2 treatment periods is sufficient to ensure that there is no drug carryover effect. At the 
end of 35 +7 days, the probability of exceeding the “effect” cut-off is less than 2%, with 
17 subjects out of 1000 expected to have plasma concentrations of TAK-041 above 132.5 ng/mL.
6.2.2
Rationale for Dose
The initial dose examined in this study will be a single 40 mg dose of TAK-041 crystalline 
suspension (or matching placebo) administered on Day 1 of each treatment period according to the 
sequence group assigned. A 40 mg dose of TAK-041 has been administered to healthy volunteers 
Property of Takeda: For non-commercial use only and subject to t
able Terms of Use
od, 
d, 
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2 a
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in the first in human study, TAK-041-1001, and was found to be safe and well-tolerated. During 
the study, 6 AEs were observed that were mild in nature, were deemed not related to study drug, 
and resolved without treatment. No SAEs and no clinically meaningful changes in safety 
laboratory results, physical examinations, vital signs, or ECGs were reported for the 16 subjects 
who received a single dose of TAK-041 crystalline suspension up to 40 mg or matching placebo.
Dose adjustment will be allowed based on emerging safety, tolerability, and PK data from this 
study and study TAK-041-1001. Overall, the proposed dose range of TAK-041 is anticipated to 
achieve sufficient range of plasma exposures with a margin above and beyond the predicted 
pharmacologically active exposures/concentrations established in preclinical models. Based on the 
IA results, adjustment to higher doses may be performed to allow for the exploration of the 
dose-response. 
The clinical exposure achieved at the 40 mg dose is aligned with predicted human exposure of the 
highest efficacious dose (1 mg/kg) tested in nonclinical in vivo models of anhedonia and 
asociality. The maximum efficacious dose preclinically observed was 3 mg/kg in the ASST 
[(attention set shifting task) which measures executive function, applicable to cognitive 
impairment associated with schizophrenia (CIAS) and negative symptoms of schizophrenia], and 
5 mg/kg on the Nicotine and Amphetamine dopamine release on the nucleus accumbens. 
TAK-041 continues to be evaluated in the ongoing SRD/MRD study (Study TAK-041-1001), and 
the safety and exposure data for additional single and multiple doses will be evaluated. 
Preliminary blinded results from the TAK-041-1001 study indicate that single doses of 5, 10, 20, 
40, 80,120, and 160 mg and multiple dose cohorts 1 (40 mg/20 mg) and 2 (80 mg/40 mg)
consisting of 4 weekly doses, 1 loading dose followed by weekly maintenance doses for 3 weeks 
are well tolerated. In the TAK-041-1001 study, 31 AEs were observed that were all mild and 
resolved without treatment. For the 66 subjects in the above cohorts, there were no serious AEs, no 
clinically meaningful abnormalities in safety laboratory results (including ALP, AST, ALT, GGT, 
and TBILI) and no clinically significant abnormalities in physical examination, vital signs, or ECG 
results reported.
The highest planned dose will not exceed the highest dose (target range 40-160 mg) deemed safe, 
and well tolerated in healthy subjects. Dose escalation documents may be provided separately to 
the principal investigator and ethics as appropriate to support any dose change and will not exceed 
160 mg.
6.2.3
Rationale for Endpoints
6.2.3.1
PK Endpoints
The PK endpoints selected for this study, AUCs and Cmax of TAK-041, are commonly used PK 
parameters to measure the exposure to the study drug following a single-dose administration in 
clinical studies.
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6.2.3.2
PD Endpoints
Based on the fact that patients with schizophrenia often have difficulty with anticipatory pleasure 
and recruiting efforts to pursue rewards, a number of functional tasks have been developed 
recently to study avolition and anhedonia as PD endpoints in this patient population [5-9]. Using 
these tasks, it has been reported that patients with schizophrenia demonstrate reduced effort 
allocation or impaired effort-cost computations compared to healthy controls [5-9]. In order to
assess motivation/reward in patients with schizophrenia, a specific test battery containing both 
performance tests and task-induced fMRI BOLD assessments has been chosen [5-9]. Patients with 
schizophrenia also show impairments in executive functions including cognitive flexibility [10]
and this will be assessed using the set-shifting task [11].
Primary Endpoints
MID Task-induced fMRI BOLD signal: the MID task is a well-established reward anticipation 
paradigm that is known for robustly engaging the VS, a key area associated with coding incentive 
reward. Dysfunctional processing of reward information has been associated with motivational 
impairments in schizophrenia. Motivational impairment is a key aspect of negative symptoms, and 
has been associated with reduced activity in the VS. 
The MID Reward Task-induced fMRI BOLD signal also has fair to good test-retest reliability (ie, 
ICC value 0.62) as well as moderate effect size (ie, d value 0.56) [9].
BACS: This is a reliable and sensitive measure of cognitive function in schizophrenia [12]. The 
BACS version in this study will assesses 4 domains of cognitive function found to be consistently 
impaired in schizophrenia: verbal and visual memory, verbal fluency, and processing speed. The 
set of tests is of approximately 25 minutes duration and may be conducted using either paper and 
pencil or a comparable version delivered electronically [13].
Secondary Endpoints
During the SRD trial, in order to fully assess the safety and PK profile of TAK-041 in subjects 
receiving up to 40 mg TAK-041 doses, follow-up PK blood draws were performed until TAK-041 
plasma concentrations were below the limit of quantitation (<1 ng/mL). Six AEs were observed 
that were mild in nature, were deemed not related to study drug, and resolved without treatment. 
No SAEs and no clinically meaningful changes in safety laboratory results, physical examinations, 
vital signs, or ECGs were reported for the 16 subjects who received a single dose of TAK-041 
crystalline suspension up to 40 mg or matching placebo. Therefore, standard safety endpoints and 
monitoring have been included in the current trial.
Exploratory Endpoints
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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Prope
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6.2.3.3
6.2.3.4
Optional Wearable Devices
6.2.4
Critical Procedures Based on Study Objectives: Timing of Procedures
For this trial, the MID Task-induced fMRI BOLD, BACS, and Grip Effort Task are the critical 
procedures.
!
At any postdose time point, these procedures should occur as close as possible to the 
prescribed/scheduled time.
Property
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!
All other procedures should be completed as close as possible, either before or after the 
prescribed/scheduled time.
!
The order of priority can be changed during the study with joint agreement of the investigator 
and the sponsor.
!
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
6.3
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This trial is a proof-of-activity assessment of TAK-041.
!
The washout period between the doses in the 2 Treatment Periods may be lengthened (not to 
exceed 42 days total).
!
!
Up to an additional 50 mL of blood may be drawn for PK and/or PD analyses. This may 
include repeat samples or modified PK/PD time points based on emerging data. The total blood 
volume withdrawn from any single subject will not exceed the maximum allowable volume 
during his/her participation in the entire trial.
!
The timing of planned procedures for assessment of safety procedures (eg, vital signs, ECG, 
safety laboratory tests) currently outlined in the protocol may be modified during the study
based on newly available safety, tolerability, PK, or PD data (eg, to obtain data closer to the 
time of peak plasma concentrations). These changes will not increase the number of trial 
procedures for a given subject during his/her participation in the entire trial.
!
Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information (eg, adding creatinine kinase to serum chemistry panel that was 
already drawn).
!
It is understood that the current trial may employ some or none of the alterations described above. 
Any alteration made to this protocol to meet the trial objectives must be detailed by the Sponsor in 
a letter to the Master File and forwarded to the investigator for retention. The letter may be 
Property o
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forwarded to the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) at the 
discretion of the investigator.
6.4
Study Beginning and End/Completion
6.4.1
Definition of Beginning of the Study
The trial begins when the first subject signs the trial informed consent form.
6.4.2
Definition of End of the Study
The overall trial ends when the last subject completes the last planned or follow-up 
visit/interaction associated with a planned visit, discontinues from the trial or is lost to follow-up 
(ie, the investigator is unable to contact the subject).
6.4.3
Definition of Study Completion
The primary objective of this trial is to estimate the likelihood of attenuating motivation/reward 
deficits observed in schizophrenia by add-on TAK-041 administration to antipsychotics in 
subjects with stable schizophrenia. It is possible that study subjects may not receive all dose levels 
specified in the protocol, or that the study may be stopped before all planned subjects are enrolled 
if this objective is achieved early in this study. This is not considered an early termination of the 
trial, but rather an earlier than anticipated achievement of the trial objective or trial completion.
6.4.4
Definition of Study Discontinuation
Study discontinuation due to non-safety reasons, such as:

A finding (eg, PK, PD, biologic targets) from another preclinical or clinical trial using the same 
treatment results in the trial being stopped for a non-safety-related reason.

Data from comparator, drug of the same class, or methodology used in this trial become 
available and result in the trial being stopped for a non-safety-related reason. 

The trial is stopped due to non-scientific and non-safety reasons, such as slow enrollment.
Study discontinuation due to safety reasons:
Early trial termination due to unanticipated concerns of safety to the trial subjects arising from 
clinical or preclinical studies with the same treatment, drug of the same class, or methodology used 
in this trial.
6.4.5
Criteria for Premature Termination or Suspension of the Study
The trial will be completed as planned unless one or more of the following criteria are satisfied that 
require temporary suspension or early termination of the trial.

New information or other evaluation regarding the safety or efficacy of the trial medication 
that indicates a change in the known risk/benefit profile for the compound, such that the 
risk/benefit is no longer acceptable for subjects participating in the trial.
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
Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary trial objectives or compromises subject safety.
6.4.5.1
Criteria for Premature Termination or Suspension of Study Sites
A trial 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 trial, or as otherwise permitted by the contractual agreement.
6.4.5.2
Procedures for Premature Termination or Suspension of the Study or the Participation of 
Study Site
In the event that the sponsor, an IRB/IEC, or regulatory authority elects to terminate or suspend the 
trial or the participation of an investigational site, a trial-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 trial suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to randomization.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the trial:
1. The subject understands the trial procedures and agrees to participate by providing written 
informed consent.
2. The subject is willing and able to comply with all trial procedures and restrictions.
3. The subject is judged to be in good health by the investigator, based on clinical evaluations 
including laboratory safety tests, medical history, physical examination, 12-lead ECG, and 
vital sign measurements performed at the Screening Visit and prior to administration of the 
initial dose of study drug/invasive procedure.
4. The subject is male or female and 18 to 60 years of age, inclusive, at the Screening Visit.
5. A female subject of childbearing potential who is sexually active with a nonsterilized male 
partner must agree to use 2 highly effective methods of contraception from signing of informed 
consent throughout the duration of the trial and for 85 days after the last dose or she is 
postmenopausal or of non-childbearing potential.
6. A male subject who is nonsterilized and sexually active with a female partner of childbearing 
potential must agree to use adequate contraception from signing of informed consent 
throughout the duration of the trial and for 145 days after last dose. The female partner of a 
male subject should also be advised to use a highly effective method of contraception.
7. The subject is on a stable dose of an antipsychotic for at least 2 months as documented by 
medical history and assessed by site staff (other than those excluded in Table 7.a).
8. The subject meets schizophrenia criteria as defined by the DSM-5 by the Mini International 
Neuropsychiatric Interview (MINI).
9. The subject has PANSS total score ≤90 and PANSS negative symptom factor score (NSFS; 
Sum of PANSS N1, N2, N3, N4, N6, G7, and G16) ≥15 at screening and baseline (Day -1).
10. The subject has stable screening and baseline (Day -1) PANSS and NSFS total scores (<20% 
change).
11. The subject has had a structural brain MRI within the preceding year or during screening 
indicating no concerning structural brain abnormalities or other abnormalities that would 
interfere with interpretation of functional brain imaging results.
7.2
Exclusion Criteria
The subject must be excluded from participating in the trial if the subject: 
1. Has participated in another investigational trial within 4 weeks prior to the pretrial/screening 
visit. The 4-week window will be derived from the date of the last trial procedure and/or AE 
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related to the trial procedure in the previous trial to the pretrial/Screening Visit of the current 
trial.
2. Is an employee or immediate family member (eg, spouse, parent, child, sibling) of the Clinical 
Site or the Sponsor.
3. Has a history of cancer (malignancy).
4. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex) or has had an 
anaphylactic reaction or significant intolerability to prescription or nonprescription drugs or 
food.
5. Has a positive alcohol and/or positive drug screen at Screening or Day -1.
6. Has a positive pregnancy test. (Female only).
7. Is a lactating/nursing female.
8. Is positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or 
human immunodeficiency virus (HIV) antibody/antigen (confirmatory testing is allowed; most 
sensitive test should take precedence).
9. The subject has abnormal Screening or baseline laboratory values (>ULN for the respective 
serum chemistries) of ALT, AST, TBILI, ALP, GGT, confirmed upon repeat testing, 
5’nucleotidase (Screening only) and/or abnormal urine osmolality, confirmed upon repeat 
testing.
10. Had major surgery, or donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks 
prior to the pretrial/Screening Visit.
11. Is unable to refrain from or anticipates the use of any medication (except those prescribed) as 
described in Section 7.3.
12. Meets DSM-5 criteria for substance use disorder or history of alcohol abuse within 1 month 
prior to Screening Visit.
13. Has a history of claustrophobia or inability to tolerate mock scanner environment during 
habituation/screening session.
14. Fulfills any of the MRI contraindications on the site standard radiography screening document. 
15. Has a history in the last year from the randomization visit or is currently receiving treatment 
with clozapine.
16. Has a current diagnosis of a significant psychiatric illness other than schizophrenia, per 
DSM-5 and is in an acute phase/episode.
17. Has a risk of suicide according to the investigator’s clinical judgment (eg, per C-SSRS positive 
answers on questions 4 or 5 for the last 6 months or has made a suicide attempt within 
6 months prior to screening visit).
18. Is unsuitable for inclusion in the trial in the opinion of the investigator or sponsor.
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7.3
Excluded Medications, Supplements, and Dietary Products
Use of the agents in Table 7.a the (prescription or nonprescription) is prohibited at the time points 
specified.
Table 7.a
Excluded Medications, Supplements, and Dietary Products
Disallowed (X) During the Study
(sections without [X] indicate no restrictions) (a)
Drug Class 
Chronic Use
Episodic use
Comments or Exceptions
Any investigational drug
X
X
<60 days before Screening or 
5 half-lives – whichever is longer
Narcotic analgesics
X
X
Alcohol
Not restricted, except for 72 hours prior 
to and during baseline assessments and 
during PD testing on Day -1, Day 1, 
and Day 14 in Periods 1 and 2.
Anorexiants (eg, phentermine, 
benzphetamine, phendimetrazine, 
methamphetamine, amphetamine, 
stimulants, sibutramine, Belviq (lorcaserin), 
Qsymia (phentermine/topiramate)
X
X
Must be discontinued for ≥30 days 
prior to Screening
Antiarrhythmics of 1C class, quinidine
X
X
Antibiotics
X
Anticholinergics
X
X
Maximum dose of chronic 
anticholinergic treatment is 2 mg/day 
of benztropine or equivalent.
Antithrombic agents and anticoagulants 
(excluding warfarin, which is excluded)
X
Anticonvulsants 
X
X
Exception: gabapentin and pregabalin 
are permitted if they are prescribed at a 
stable dose for ≥2 months prior to 
Screening and throughout study 
treatment. Subjects taking other 
anticonvulsants should not be 
considered for participation in the 
study, as their discontinuation could 
lead to symptom instability.
Antidepressants (excluding tricyclic 
antidepressants, MAOIs, and RIMAs)
X
Tricyclic antidepressants, MAOIs, and 
RIMAs are excluded, and subjects 
taking them should not be considered 
for participation in the study, as their 
discontinuation could lead to symptom 
instability.
Footnotes are on last table page.
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Table 7.a
Excluded Medications, Supplements, and Dietary Products (continued)
Disallowed (X) During the Study
(sections without [X] indicate no restrictions) (a)
Drug Class 
Chronic Use
Episodic use
Comments or Exceptions
Antihistamines
X
X
Except loratadine, desloratadine, 
cetirizine, levocetirizine, mizolastine, 
and fexofenadine.
Antihypertensives
Clonidine NOT allowed.
Antipsoriatic agents
X
X
Topical agents are allowed.
Antipsychotics
X
Phenothiazines (chlorpromazine, 
perphenazine, prochlorperazine, 
thioridazine), haloperidol, and 
clozapine are excluded and must be 
discontinued 60 days prior to 
screening; all other treatments must 
adhere to requirements outlined in the 
study entry criteria.
As an exception, occasional use of an 
additional dose of the background 
antipsychotic may be permitted with 
sponsor or designee approval.
Fruit juice
Not restricted, except that dosing will 
occur without consumption of fruit 
juice. Fruit juice is restricted until 4 
hours after dosing.
Herbal remedies, which are psychoactive 
(eg, St John’s Wort, kava, valerian, ginkgo 
biloba,)
X
X
Must be discontinued ≥7 days prior to 
Screening.
Melatonin
X
X
Must be discontinued ≥7 days prior to 
Screening.
Sedative hypnotics 
Barbiturates are excluded. Chronic 
treatment with BZs is allowed up to 3 
mg/day lorazepam or equivalent (BZ 
equivalence standards will be provided 
in a site reference document).
Insulin
X
X
Mood stabilizers
X
X
Lithium, valproic acid, and lamotrigine 
Footnotes are on last table page.
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Table 7.a
Excluded Medications, Supplements, and Dietary Products (continued)
Disallowed (X) During the Study
(sections without [X] indicate no restrictions) (a)
Drug Class 
Chronic Use
Episodic use
Comments or Exceptions
Medications that may interfere with 
cognitive function
Such as cold medicines containing 
antihistamine or dextromethorphan as a 
cough suppressant are not restricted 
except for 7 days prior to and during 
baseline assessments and during PD 
testing on Day -1 and Day 1; and 7 days 
prior to and during the Day 14 
assessments in Periods 1 and 2.
Medicines in the statin class
X
X
Atorvastatin, fluvastatin, lovastatin, 
pitavastatin, pravastatin, rosuvastatin,
and simvastatin.
Psychotropic agents known to affect 
cognition
X
X
Such as long-acting sleep aids, 
amphetamines, barbiturates, lithium, 
methylphenidate, anticholinergics, 
antidepressants (eg, tricyclic 
antidepressants and MAOIs). Note: the 
definitive guidelines for each 
medication/class entry in this row is the 
primary table row for each 
medication/class.
Steroids
Systemic oral or 
injectable
X
X
As an exception, treatment with local 
steroid injections for orthopedic 
conditions may be permitted with 
sponsor or designee approval.
Topical
Inhalant
Stimulants
X
X
Must be discontinued for ≥30 days 
prior to Screening. This category does 
not include substances containing 
caffeine or nicotine.
Tobacco- and nicotine-containing products
Not restricted, except for 2 hours prior 
to and during baseline assessments and 
during PD testing on Day -1, Day 1, 
and Day 14 in Periods 1 and 2 (unless 
the subject exhibits nicotine 
withdrawal symptoms that pose a risk 
to the study PD assessments in the 
judgment of the investigator).
UGT enzyme inhibitors (probenecid and 
valproic acid)
Not within 14 days of dosing.
Footnotes are on last table page.
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Table 7.a
Excluded Medications, Supplements, and Dietary Products (continued)
Disallowed (X) During the Study
(sections without [X] indicate no restrictions) (a)
Drug Class 
Chronic Use
Episodic use
Comments or Exceptions
Xanthine and/or caffeine
Not restricted, except for 4 hours prior 
to and during baseline assessments and 
during PD testing on Day -1, Day 1, 
and Day 14 in Periods 1 and 2.
BZ=benzodiazepine, MAOI=monoamine oxidase inhibitor, RIMA=reversible inhibitor of monoamine oxidase type 
A, UGT=uridine 5'-diphosphate-glucuronosyltransferase.
(a) If medications are required to treat an AE, this will be done based on medical need. However, continuation in the 
trial may be allowed for certain medications after discussion and agreement between the sponsor and principal 
investigator.
Occasional use of acetaminophen/paracetamol (≤1 g/day) or other medication as approved by 
Takeda on a case-by-case basis is allowed.
Concomitant medications to treat concurrent diseases or co-morbidities should be maintained at a 
stable dose and regimen from the Screening Visit throughout the trial; however, medication 
adjustments may be made by the investigator based on the subject’s condition and standard of care.
Subjects must be instructed not to take any medications, including OTC products without first 
consulting with the investigator. However, if a medication is taken, it is the responsibility of the 
investigator to ensure that the details regarding the medication are recorded in full in the electronic 
case report form (eCRF).
7.4
Diet, Fluid, Activity
7.4.1
Diet and Fluid
There are no restrictions on diet or intake of fluids, except as specifically noted.
7.4.2
Activity
There are no restrictions on activity, except to avoid strenuous activity 24 hours before a clinic 
visit.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the trial should be 
recorded in the eCRF using the following categories. 
1. Pretreatment event or AE. The subject has experienced a pretreatment event 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 pretreatment event or AE.
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
Liver Function Test Abnormalities
Based on local country criteria, subjects in a clinical trial who experience ALT >3× ULN 
and TBILI >2×ULN and satisfy the following 2 criteria: (1) the liver injury is 
hepatocellular in nature and there is not a prominent cholestatic component; (2) there is no 
more likely alternative cause than drug induced liver injury, such as acute viral hepatitis A 
or B, or other acute liver disease. 
If ALT or AST is >3×ULN, laboratory tests should be repeated within a maximum of 7 
days, and preferably within 48 to 72 hours. If the ALT or AST remains elevated >3×ULN 
on these 2 consecutive occasions, and this observation cannot be explained by concomitant 
disease or another alternative etiology, the abnormality should be recorded as an AE. The 
investigator must contact the Medical Monitor for consideration of immediate 
discontinuation of trial medication, discussion of the relevant subject details and possible 
alternative etiologies.
In addition, trial medication should be discontinued immediately with appropriate clinical 
follow-up, including repeat laboratory tests, until a subject’s laboratory profile has 
returned to normal, if the following circumstances occur at any time during trial 
medication treatment:
–
ALT or AST >8×ULN, or
–
ALT or AST >5×ULN and persists for more than 2 weeks, or
–
ALT or AST >3×ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio >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 elevations >1.5×ULN in conjunction with elevated total bilirubin >1.5×ULN or 
elevated 5'-nucleotidase >2×ULN or elevated GGT >5×ULN or elevated AST/ALT 
>3×ULN or elevated ALP >2×ULN, persisting for longer than 3 days.
–
ALP >3×ULN.

Psychiatric Emergencies 
Subjects with the following conditions will be discontinued from the trial with appropriate 
follow-up (which may include immediate contact with the subject’s mental health 
practitioner; and/or possible referral to the emergency room; and/or admission to an 
in-patient unit): 
–
Subjects who experience acute psychotic episode during the study, requiring 
hospitalization or a change in the current treatment regimen.
–
Subjects who experience suicidal ideation with intent to act or with a specific plan 
(C-SSRS level 4 and 5) or any suicidal behavior.
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2. Protocol deviation. The discovery post-randomization that the subject failed to meet protocol 
entry criteria or did not adhere to protocol requirements, and continued participation poses an 
unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented.
4. Withdrawal by subject. The subject wishes to withdraw from the trial. 
5. Withdrawal by parent/guardian. The subject’s legally acceptable representative wishes to 
withdraw the subject from the trial.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE should not be recorded in the “voluntary withdrawal” category).
6. Study terminated by sponsor. The sponsor, IRB, IEC, or regulatory agency terminates the trial.
7. Pregnancy. The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 7.6.
8. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
Note: Skin reactions (cutaneous hypersensitivity) to a wearable digital device will lead to
removal of that device for the remainder of the trial. The subject would not be required to
discontinue the trial as a whole.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may terminate a subject’s trial participation at any time during the study when the 
subject meets the trial termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded. In 
addition, efforts should be made to perform all procedures scheduled for the Early Termination 
Visit.
7.7
Subject Replacement
Discontinued or withdrawn subjects may be replaced at the discretion of the study team. Up to 32 
subjects will be randomized to ensure 24 subjects complete postdose PD assessments on Day 1 of 
both Treatment Periods.
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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug
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 in a blinded fashion for third party dispensing. An unblinded pharmacist will manage and 
prepare doses as needed throughout the study. The oral suspensions will contain 5 to 160 mg of 
TAK-041 per dose.
8.1.1
Investigational Drug
The oral suspension containing crystalline TAK-041 (milled) will be prepared at a pharmacy 
laboratory 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 vehicle (Tween/MC vehicle). 
The bottle is wrapped with aluminum foil to cover the appearance of the suspension for blinding 
purposes. 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.
A placebo will be prepared by adding 70 mL of 0.5% Tween/MC vehicle into a unit dosing bottle 
and wrapped with aluminum foil to cover the appearance of the suspension for blinding purposes.
8.1.2
Storage
Investigational drug must be kept in an appropriate, limited-access, secure place until it is used or 
returned to the sponsor or designee for destruction. Investigational drug must be stored under the 
conditions specified on the label, and remain in the original container until dispensed.
TAK-041 crystalline drug substance (milled) is stored at controlled room temperature (20°C-25°C 
with excursions allowed from 15°C-30°C).
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8.1.3
Dose and Regimen
The planned initial dose of TAK-041 is 40 mg or matching placebo. The dose level is subject to 
change and will be determined based on the available safety, tolerability, and PK data from an 
equivalent dose cohort in healthy volunteers in Study TAK-041-1001. The doses will be 
administered to the subjects by the investigator or the investigator’s designee. Subjects will 
receive the 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.
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study subject, at a dose above that which is assigned to that individual subject according 
to the study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on AE CRF(s) according to Section 10.0, Pretreatment 
Events and Adverse Events.
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.8, Collection and Reporting of SAEs.
In the event of drug overdose, the subject should be treated symptomatically.
8.1.5
Clinical Study Drug Labeling
Clinical study drug packaging will be affixed with a clinical label in accordance with regulatory 
requirements.
8.1.6
Clinical Study Drug Inventory
Inventory (receipt and dispensing) of study drug must be recorded by an authorized unblinded 
person at the trial site.
8.1.7
Clinical Study Drug Blinding
This is a double-blind trial. The study drug blind is maintained through a randomization schedule 
held by the randomization personnel. Investigational drug doses will be manufactured in a manner 
so as to minimize the possibility of identification of different doses through appearance. Further 
details will be provided in the Pharmacy Manual.
8.1.8
Randomization Code Creation and Storage
Takeda Biostatistics Department or designee will generate the randomization schedule and a copy 
will be provided to the randomization personnel prior to the start of this study. The randomization 
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will be stratified by site. All randomization information will be stored in a secured area, accessible 
only by authorized personnel.
8.1.9
Clinical Study Blind Maintenance/Unblinding Procedure
The investigational drug blind is maintained through a randomization schedule held by the 
randomization personnel.
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. All trial 
assessments and causality should be performed, if possible, prior to unblinding. In the event of a 
medical emergency, if possible, the medical monitor or designee should be contacted before the 
investigational drug blind is broken to discuss the need for unblinding. The sponsor must be 
notified as soon as possible if the investigational drug blind is broken.
8.1.10
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator is responsible for keeping accurate records of the clinical study drug received 
from the sponsor or designee, the amount dispensed to and returned by the subjects, and the 
amount remaining at the conclusion of the study. For all study sites, the local country sponsor 
personnel or designee will provide appropriate documentation that must be completed for clinical 
study drug accountability, return, and destruction.
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9.0
STUDY PROCEDURES
The following sections describe the trial procedures and data to be collected as indicated in the 
Schedule of Study Procedures (Section 3.0). For each procedure, subjects are to be assessed by the 
same investigator or site personnel whenever possible. Please note that it may become necessary to 
perform the following procedures at unscheduled time periods, per the discretion of the 
investigator.
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
The requirements of informed consent are described in Section 13.2. Informed consent must be 
obtained prior to the subject entering into the trial and before any protocol-directed procedures are 
performed, including requesting that a subject fast for laboratory evaluations. Pharmacogenomics 
informed consent is a component of the overall trial informed consent. A separate optional 
informed consent is required for the digital device component of the trial. Subject participation in 
the wearable device component of the trial is optional.
When subjects have performed screening assessments prior to trial, the data from screening using a 
generic screening consent form can be used in this trial for those who were subsequently enrolled, 
as long as the procedure was performed within the protocol screening to enrollment window.
9.1.1.1
Assignment of Screening and Randomization Numbers
All consented subjects will be given a unique screening number that will be used to identify the 
subject for all procedures that occur prior to randomization or allocation. Each subject will be 
assigned only 1 screening number. Screening numbers must not be re-used for different subjects. 
Any subject who is screened multiple times will be assigned a new screening number for each 
screening event.
All eligible subjects will be randomized and will receive a randomization number. The 
randomization number identifies the subject for all procedures occurring after randomization. A 
single subject cannot be assigned more than 1 randomization number.
9.1.1.2
Clinical Study Drug Assignment
On Day 1 of Period 1, eligible subjects will be randomized 1:1 to 1 of 2 sequence groups. See 
Table 6.a for a description of the drug assignments in Periods 1 and 2 for each sequence group. 
Each sequence group will consist of 12-16 subjects. Each participant will be dispensed blinded 
trial treatment, labeled with his/her unique randomization number, throughout the trial.
9.1.2
Inclusion and Exclusion Criteria
Each subject is assessed through randomization, according to the eligibility criteria provided in 
Section 7.0.
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9.1.3
Medical History/Demographics
Qualified site personnel are to collect subject significant medical history (past and ongoing) per 
the site’s standard of care and appropriate clinical judgment as well as subject demographics.
9.1.4
Prior and Concomitant Medication Review
Medications are defined as prescription and over-the-counter drugs, vitamin supplements, 
nutraceuticals, and oral herbal preparations. Qualified site personnel are to review subject 
medication use.
9.2
Clinical Procedures and Assessments
9.2.1
Full Physical Exam
Qualified site personnel will conduct full physical examinations.
9.2.2
Height and Weight
Body weight and height will be obtained with the subject’s shoes off, and jacket or coat removed.
9.2.3
Body Mass Index
BMI equals a person’s weight in kilograms divided by height in meters squared (BMI=kg/m2). 
BMI will be rounded to the nearest whole number according to the standard convention of 
0.1 to 0.4 rounds down and 0.5 to 0.9 rounds up.
9.2.4
Vitals (Body Temperature, Heart Rate, Blood Pressure)
Body temperature will be measured with an oral (temperature taken at floor of the mouth) or 
tympanic thermometer. The same method (eg, oral or tympanic) must be used for all subsequent 
measurements for each individual subject and should be the same for all subjects.
Subjects should rest in a semirecumbent position for at least 5 minutes prior to having vital sign 
measurements obtained. Vital signs will include heart rate, systolic blood pressure, and diastolic 
blood pressure. The same method (eg, same size cuff, manual or automated) must be used for all
measurements for each individual subject and should be the same for all subjects.
9.2.5
12-Lead ECG
Special care must be taken for proper lead placement by qualified personnel. Skin should be clean 
and dry prior to lead placement. Subjects may need to be shaved to ensure proper lead placement. 
Female subjects may need to remove their bra.
Subjects should be resting in a semirecumbent position for at least 5 minutes prior to each ECG 
measurement.
QT intervals with Fridericia correction method (QTcF) will be used to calculate QT intervals in 
this trial.
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Prior to each Treatment Period, a predose ECG will be obtained within approximately 1 hour prior 
to dosing TAK-041. This measurement will be used as the Baseline. The principal investigator 
should arrange to have a trial cardiologist available as needed to review ECG tracings with 
abnormalities.
During each Treatment Period, if a subject demonstrates an increase in QTcF interval ≥40 msec 
compared with a predose baseline measurement, the ECG will be repeated within 5 minutes. The 
average value of the QTcF interval from the 2 ECGs will represent the value at that time point. If 
the average QTcF interval increase from Baseline for any postdose time point is ≥40 msec, the 
subject will continue to be monitored by repeat 12-lead ECGs every 60 minutes for at least 4 hours 
or until the QTcF is within 40 msec of the baseline value. If prolongation of the QTcF interval 
≥40 msec persists, a consultation with a trial cardiologist may be appropriate and the Sponsor 
should be notified.
If the QTcF interval is ∀500 msec, the Sponsor should be notified and the ECGs should be 
reviewed by a cardiologist. The subject should be telemetry-monitored (until the QTcF is 
<500 msec) or should be considered for transfer to a location where closer monitoring is available.
If the subject has unstable hemodynamics, or has any clinically significant dysrhythmias noted on 
telemetry, the subject should be immediately transferred to an acute care setting for definitive 
therapy. 
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in place or 
mark the position of the electrodes for subsequent ECGs. To mark the position of the electrodes, 
12-lead electrode sites will be marked on the skin of each subject with an ECG skin marker pen to 
ensure reproducible electrode placement.
The following ECG parameters will be recorded: heart rate, PR-interval, QRS-duration, QT 
interval, QTcF interval, and the interpretation of the ECG profile by the principal investigator.
9.2.6
Study Drug Administration
The dose of study drug (TAK-041 or placebo) will be administered to the subjects by the 
investigator or the investigator’s designee. Subjects will receive the 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.
9.2.7
Cognitive Assessments
The first block of PD tests will include the 
 
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A trial manual describing the procedures to be used with these assessments will be supplied to the 
sites. The assessments will be performed at the times and flexibility stipulated in the Schedule of 
Study Procedures, Table 3.a. PD assessments and testing take priority over all other procedures.
9.2.8
AE Monitoring
AE monitoring begins following signing of informed consent. Changes in subject health status 
from baseline assessment to study drug administration should be captured. A complete description 
of AE collections and procedures is provided in Section 10.0.
9.2.9
9.2.10
Laboratory Procedures and Assessments
Laboratory samples will be collected in accordance with acceptable laboratory procedures. 
Samples will be taken on the days stipulated in the Schedule of Study Procedures (Section 3.0).
9.2.10.1 Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Erythrocytes (red blood cells [RBCs])
Hemoglobin
Hematocrit
Platelets
Leukocytes (white blood cells [WBCs]) with absolute differential
Urinalysis
Urinalysis will consist of the following tests:
Protein
Glucose
Blood
Nitrite
Urine microscopy will be performed if urinalysis is abnormal. Microscopy consists of RBC/high-power field, 
WBC/high-power field, and casts.
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Chemistry
Chemistry evaluations will consist of the following standard chemistry panel:
Albumin
Alkaline phosphatase
ALT
AST
Blood urea nitrogen
Calcium
Carbon dioxide
Chloride
Creatinine
Glucose
Gamma-glutamyl transferase
Sodium
Potassium
Bilirubin (total), if above ULN, will be fractionated
Protein (total)
5'-nucleotidase
9.2.10.2 DILI follow-up testing:
5’nucleotidase, GGT, ALT, AST, INR, and any other laboratory tests deemed necessary after 
discussion with the medical monitor
9.2.10.3 Diagnostic Screening
Chemistry (Serum)
Serum diagnostic evaluations will include the following tests:
β–human chorionic gonadotropin (females only)
Follicle-stimulating hormone 
(FSH) (females only)
Hepatitis panel (including HBsAg and anti-HCV), HIV, and TSH
Alcohol Screen
Subjects will undergo an alcohol breath test. A urine alcohol test may be performed at the 
discretion of the investigator.
Drug Screen (Urine)
A urine drug screen will include the following tests: 
Amphetamines
3,4-methylenedioxy-methamphetamine (MDMA)
Barbiturates
Methadone/metabolite
Benzodiazepines
Opiates
Buprenorphine/metabolite
Oxycodone/oxymorphone
Cannabinoids
Phencyclidine
Cocaine/metabolites
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9.2.11
C-SSRS
Suicidal ideation will be assessed using the C-SSRS at the times stipulated in the Schedule of 
Study Procedures (Section 3.0). Two versions of the C-SSRS will be used in this trial: the 
Screening C-SSRS Lifetime Version 14Jan2009 and the Since-Last-Visit C-SSRS Version 
14Jan2009.
9.3
Biomarker, PK, PD, 
Samples for PK analysis will be collected as specified in the Schedule of Study Procedures 
(Section 3.0). If a PK collection time point overlaps with PD assessment or test, the PD assessment 
should be prioritized. Please refer to the Laboratory Manual for information on the collection 
including sample windows, processing, and shipment of samples to the Central Laboratory. Some 
analyses will be exploratory in nature and may be used to identify or validate biomarkers.
The decision as to which plasma collected will be assayed for evaluation of PK will be determined 
by the Sponsor (eg, samples at lower doses may not be assayed if samples at higher doses reveal 
undetectable drug concentrations). If indicated, these samples may also be assayed and/or pooled 
for assay in an exploratory manner for metabolites and/or additional biomarkers.
Primary specimen collection parameters are provided in Table 9.a.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of 
Intended Use
Sample Collection
Plasma sample for PK
Plasma
N/A
Plasma sample for PK 
analysis
Mandatory
9.3.1
PK Measurements
Samples for PK analysis will be collected as specified in the Schedule of Study Procedures 
(Section 3.0). Please refer to the Laboratory Manual for information on the collection, including 
sample windows, processing, and shipment of samples to the Central Laboratory.
It is anticipated that the total blood volume drawn for an individual subject during this trial will be 
approximately 130.5 mL.
The PK parameters of TAK-041 will be derived using noncompartmental analysis methods and 
will be determined from the concentration-time data for all evaluable subjects. Actual sampling 
times, rather than scheduled sampling times, will be used in all PK computations involving 
sampling times. A more detailed description will be given in the clinical pharmacology analysis 
plan (CPAP).
Property of Takeda: For non
ercial use only and subject to the applicable Terms of Use
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The following plasma PK parameters for TAK-041 will be calculated:
!
Area under the plasma concentration-time curve from time 0 to time t (AUCt).
!
Area under the plasma concentration-time curve from time 0 to infinity (AUC∞).
!
Cmax.
!
Time of first occurrence of Cmax (tmax).
!
t1/2z.
Additional PK parameters may be calculated if deemed necessary for the interpretation of the data. 
All efforts will be made to obtain the PK samples at the exact nominal time relative to dosing. 
However, samples obtained within 10% of the nominal time from dosing will not be captured as a 
protocol deviation, as long as the exact time of the sample collection is noted on the eCRF.
9.3.2
Biomarker Measurements
9.3.3
9.3.3.1
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9.3.3.2
Biological Sample Retention and Destruction
9.3.4
Confinement
There is no confinement in this trial.
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10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a trial; it does not necessarily have to have a causal 
relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of trial medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters may be considered to be AEs if they are 
judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory re-test and/or continued monitoring of an abnormal value are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, evaluation 
or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present before signing of the informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (laboratory test, ECG, X-ray, etc) present before signing of the informed consent 
should NOT be recorded as an AE. However, if the subject experiences a worsening or 
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complication of such a concurrent medical history condition, the worsening or complication 
should be recorded appropriately as an AE (worsening or complication occurs after informed 
consent is signed). 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 an 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 from Baseline in the condition (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an 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 AEs:

If the subject experiences a worsening or complication of an AE after the first administration of 
trial medication or after any change in trial 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:

If the subject experiences a change in the severity of an AE that is not associated with a change 
in trial medication, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered 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 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 AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a trial subject, at a dose above that which is assigned to that individual subject 
according to the trial protocol. It is up to the investigator or the reporting physician to decide 
whether a dose is to be considered an overdose, in consultation with the Sponsor.

All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the (e)CRF, in order to capture this important safety information consistently in the 
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database. AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 10.0.

SAEs of overdose should be reported according to the procedure outlined in Section 10.2.8.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1
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).
Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory 
distress syndrome
Hepatic necrosis
Acute liver failure
Torsade de pointes/ventricular fibrillation/ 
ventricular tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by a 
medicinal product
Toxic epidermal necrolysis/
Stevens-Johnson syndrome
Neuroleptic malignant syndrome/malignant hyperthermia
Spontaneous abortion/stillbirth and fetal death
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AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Section 10.2.8.3).
10.2
AE Procedures
10.2.1
Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
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.
10.2.2
Assigning Causality of AEs
The relationship of each AE to trial 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 can be argued, 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.
10.2.3
Start Date
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
10.2.4
Stop Date
The stop date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.2.5
Frequency
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.6
Action Concerning Study Drug

Drug withdrawn – a trial medication is stopped due to the particular AE.
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
Dose not changed – the particular AE did not require stopping a trial medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a trial medication was stopped for a reason other than the particular AE 
eg, the trial has been terminated, the subject died, dosing with trial medication was already 
stopped before the onset of the AE.
10.2.7
Outcome

Recovered/resolved – subject returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the subject died from a cause other 
than the particular AE 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 
trial period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved.”

Resolved/resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – an AE that is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the trial.
10.2.8
Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal LFTs
10.2.8.1 Collection Period
Collection of AEs (ie, AEs, SAEs, Special Interest AEs, and Abnormal LFTs) will commence at 
the time the subject signs the informed consent. Routine collection of AEs will continue 
throughout the duration of the trial. For subjects who discontinue prior to the administration of trial 
medication, AEs will be followed until the subject discontinues trial participation.
10.2.8.2 Reporting AEs
At each trial 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 trial. Subjects experiencing an SAE prior to the 
first exposure to investigational product 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 AEs that begin prior to the first exposure to investigational 
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product, related or unrelated to the trial procedure, need not be followed-up for the purposes of the 
protocol.
All subjects experiencing AEs, whether considered associated with the use of the trial 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 AEs will be documented in the 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:

Event term.

Start and stop date and time.

Severity.

Investigator’s opinion of the causal relationship between the event and administration of trial 
medication(s) (related or not related).

Action concerning trial medication.

Outcome of event.

Seriousness.
10.2.8.3 Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the
procedure outlined below:
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 trial medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Appendix 14.1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the Sponsor if considered related to trial participation.
Reporting of SAEs that begin before first administration of investigational product will follow the 
same procedure for SAEs occurring on treatment.
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SAE Follow-Up
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.
10.2.8.4 Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, a drug-induced liver injury (DILI) eCRF 
must be completed providing additional information on relevant recent history, risk factors, 
clinical signs and symptoms and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.8.3. 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. Follow-up laboratory tests as described in Section 9.2.10 must also be 
performed. In addition, a DILI eCRF must be completed and transmitted with the Takeda SAE 
form (as per Section 9.2.10.2).
10.2.9
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The Sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the trial 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 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
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
A statistical analysis plan will be prepared and finalized prior to unblinding of subject’s treatment 
sequence assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives.
11.1.1
Analysis Sets
11.1.1.1 Safety Set
The safety analysis set will consist of all subjects who are enrolled and received 1 dose of study 
drug. Subjects in this analysis set will be used for demographic, baseline characteristics, and safety 
summaries.
11.1.1.2 PK Set
The PK set will consist of all subjects who receive at least 1 dose of study drug and have at least 1 
measurable plasma concentration.
11.1.1.3 PD Set
The PD set will consist of all subjects who receive at least 1 dose of study drug and have at least 1 
evaluable primary or secondary endpoint.
11.1.2
Analysis of Demographics and Other Baseline Characteristics
For all randomized subjects, descriptive statistics (N, mean, SD, median, minimum, and 
maximum) will be generated for continuous demographic variables and baseline characteristics 
variables (age, height, weight, BMI, etc.) by sequence groups and overall. The number and 
percentage of subjects in each class of the categorical demographic variables and baseline 
characteristics variables (sex, ethnicity, race, etc.) will be tabulated by sequence groups and 
overall. If more than 1 dose is studied, the summary will be by dose, sequence groups and overall.
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 trial. Individual 
demographic characteristics, date of informed consent, and reason for screen failure will be listed.
11.1.3
PK Analysis
11.1.3.1 Concentrations in Plasma
For each dose of TAK-041, plasma concentrations will be tabulated and descriptive statistics 
(mean, median, SD, percent coefficient of variation [%CV], minimum and maximum) computed. 
Individual subject plasma concentration data will be listed.
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11.1.3.2 Plasma PK Parameters
For each dose of TAK-041, plasma PK parameter estimates will be tabulated and descriptive 
statistics (mean, median, SD, %CV, minimum and maximum) computed. In addition, geometric 
means will be calculated for Cmax and AUCs. Individual subject plasma PK parameter data will be 
listed.
Additional statistical analyses of the plasma PK parameters will be performed if appropriate. A 
more detailed analysis will be presented in the SAP.
11.1.4
PD Analysis
Observed values along with change from Baseline of PD parameters (primary, secondary 
 
endpoints) will be summarized by TAK-041 and placebo. Difference from placebo in 
the observed values and baseline-adjusted values will also be summarized by TAK-041 doses and 
TAK-041 overall.
A Bayesian GO/NO-GO decision-making approach will be implemented for the evaluation of the 
effect of TAK-041 for schizophrenia at the interim analysis (after approximately 12 subjects have 
completed the dosing and Day 1 procedures for both periods including the primary endpoints) and 
after all subjects complete the study. Using the observed mean (SD) difference in the 2 primary 
endpoints between the 2 groups (TAK-041 and placebo), the posterior probability that TAK-041 
increases the BACS composite score by 2 points over placebo, and the posterior probability that 
TAK-041 increases the VS activity by at least 0.09 compared to placebo, will be calculated. 
Noninformative prior distribution will be used. The criteria for declaring GO and NO-GO will be 
defined in the SAP.
In addition to estimating the probability of TAK-041 meeting the effect thresholds, analysis of 
covariance models for repeated measures will be implemented on observed PD endpoints and 
baseline-adjusted PD endpoints. Baseline PD endpoints will be used as covariate in the model, 
period, treatment (TAK-041 dose[s], placebo) and sequence will be included as fixed factors in the 
model. Subject within sequence will be the repeated factor.
Additional analyses will be performed if deemed appropriate.
11.1.5
Safety Analysis
Safety data will be presented by TAK-041 dose(s), TAK-041 overall, and placebo.
All AEs will be coded using Medical Dictionary of Regulatory Activities (MedDRA). Data will be 
summarized using preferred term and primary system organ class. TEAEs will be summarized by 
placebo, each TAK-041 dose level, and TAK-041 overall.
Clinical laboratory variables, vital signs, and ECG parameters will be summarized with 
descriptive statistics for baseline, postdose, and change from baseline to postdose values by 
TAK-041 dose(s), TAK-041 overall, and placebo.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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The number and percentage of subjects with postdose values meeting Takeda’s criteria for 
markedly abnormal values for clinical laboratory variables, vital signs, and ECG parameters will 
be presented by dose.
All summaries will be performed by TAK-041 doses, TAK-041 overall, and placebo. Physical 
examination findings will be presented in data listings.
11.2
Interim Analysis and Criteria for Early Termination
A small group from the sponsor will remain unblinded to treatment assignment during the study 
for the purpose of conducting interim analyses of PD effects. In order to minimize any potential 
unblinding of investigators, these staff will not regularly interact with the investigators or their 
staff.
A planned unblinded IA of various PD endpoints will be conducted after approximately 
12 subjects have completed the Day 14 procedures for both periods including the primary 
endpoints. The purpose of the interim PD analysis will be to determine whether to change the dose 
of TAK-041 for the rest of the subjects, or continue with their current TAK-041 dose. The 
Bayesian decision rule will be specified in the SAP before the data are unblinded for the IA. In 
addition, a decision to switch to the low dose may be made based on safety, tolerability and PK 
data of the high dose.
11.3
Determination of Sample Size
Up to 32 subjects are planned to be randomized equally to 2 treatment sequences (Table 6.a) to 
ensure 24 subjects complete the trial. 
Both primary endpoints will be used at the IA and the end of the study for decision making. A 
Bayesian method will be used to calculate the posterior probability of the endpoints meeting the 
predefined criteria (see the SAP) using data from TAK-041 and placebo. The probability of 
making a ‘GO’ decision based on the predefined ‘GO’ criteria with 24 subjects is at least 70% 
when the true TAK-041 effect on either endpoint is clinically meaningful (see the SAP). This 
sample size will also keep the type 1 error rate no more than 30% when the true drug effect is 
minimal or the same as placebo. The SD for the BACS composite score is assumed to be 
9.30 points. The SD for the VS activation is assumed to be 0.360. Independence between these 
2 endpoints was assumed in the sample size calculation.
Noninformative prior distribution was used in the above probability calculation. Allowing for 
8 dropouts (due to the long washout interval), up to 32 subjects are planned to be enrolled in order 
to have 24 completers for this trial.
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QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the trial sites 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 trial sites guarantee access to source documents by the Sponsor or its 
designee (contract research organization [CRO]) and by the IRB or IEC.
All aspects of the trial and its documentation will be subject to review by the Sponsor or the 
Sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, study drug, subject medical records, informed consent documentation, and 
review of eCRFs and associated source documents. It is important that the investigator and other 
trial personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
12.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to trial 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.
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 trial assessment.
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The trial sites also may be subject to quality assurance audits by the Sponsor or designees. In this 
circumstance, the Sponsor-designated auditor will contact the sites 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 trial may be inspected by regulatory agencies, including 
those of foreign governments (eg, the Food and Drug Administration [FDA], the United Kingdom 
Medicines and Healthcare Products Regulatory Agency, the Pharmaceuticals and Medical Devices 
Agency of Japan). If any of the trial sites are contacted for an inspection by a regulatory body, the 
Sponsor should be notified immediately. The investigator guarantees access for quality assurance 
auditors to all trial documents as described in Section 12.1.
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ETHICAL ASPECTS OF THE STUDY
This trial 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 International Conference on Harmonization (ICH) Harmonized Tripartite 
Guideline for GCP. Each investigator will conduct the trial 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 A. The principles of Helsinki are 
addressed through the protocol and through appendices containing requirements for informed 
consent and investigator responsibilities.
13.1
IRB and/or IEC Approval
IRBs and 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 trial, written notification regarding his or her abstinence from voting 
must also be obtained. Those Americas sites unwilling to provide names and titles of all members 
due to privacy and conflict of interest concerns should instead provide a Federal Wide Assurance 
Number or comparable number assigned by the Department of Health and Human Services.
The Sponsor or designee will supply relevant documents for submission to the respective IRB 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 trial (ie, before shipment of the Sponsor-supplied drug or trial-specific 
screening activity). The IRB or IEC approval must refer to the trial by exact protocol title, number, 
and version date; identify versions of other documents (eg, informed consent form) reviewed; and 
state the approval date. The Sponsor will ship drug/notify sites 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 trial.
Sites must adhere to all requirements stipulated by their respective 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 trial at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and 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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13.2
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 trial. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the trial, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and, if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the Sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the trial, and (2) decide whether or not to participate in the trial. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the trial, 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 trial. 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 trial; however, the Sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
Subjects who consented and provided a PGx sample for DNA and RNA analysis can withdraw 
their consent and request disposal of a stored sample at any time prior to analysis. Notify Sponsor 
of consent withdrawal.
13.3
Subject Confidentiality
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this trial, a subject’s source data will only be linked to the 
Sponsor’s clinical trial database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the Sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the Sponsor’s designated auditors, and the 
appropriate IRBs and IECs 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 trial 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 13.2).
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).
13.4
Publication, Disclosure, and Clinical Trial Registration Policy
13.4.1
Publication and Disclosure
The investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the investigator from the trial. During and after the trial, only the Sponsor may make trial 
information available to other trial investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical trial site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or trial results, other 
than trial recruitment materials and/or advertisements, is the sole responsibility of the Sponsor.
The Sponsor may publish any data and information from the trial (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.
13.4.2
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum, register all 
interventional clinical trials it Sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of trial, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing.
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the Sponsor.
Any investigator who objects to the Sponsor providing this information to callers must provide the 
Sponsor with a written notice requesting that their information not be listed on the registry site.
13.4.3
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.
13.5
Insurance and Compensation for Injury
Each subject in the trial 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 trial insurance against the risk of injury to trial subjects. Refer to the 
trial 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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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1
Study Contact Information
Contact Type / Role
Contact
Serious adverse event and pregnancy reporting
Pharmacovigilance
Takeda Development Centre Europe Ltd.
Email: eupv@tgrd.com
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14.1.2
Investigator Agreement
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert and any other product information provided by the Sponsor. I agree to conduct this trial in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of trial subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonization, 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 10.2.9 of this 
protocol.

Terms outlined in the trial site agreement.

Responsibilities of the Investigator (Appendix A).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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14.1.3 Study-Related Responsibilities 
The Sponsor will perform all trial-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific trial-related activities 
will perform these activities in full or in partnership with the Sponsor.
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14.1.4 List of Abbreviations
Term
Definition
%CV
percent coefficient of variation
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
BACS
Brief Assessment of Cognition in Schizophrenia
BMI
body mass index
BOLD
blood-oxygen-level-dependent
Cmax
maximum observed plasma concentration
CPAP
clinical pharmacology analysis plan
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
DILI
drug-induced liver injury
DSM-5
Diagnostic and Statistical Manual of Mental Disorders-fifth edition
ECG
electrocardiogram
eCRF
electronic case report form 
FDA
Food and Drug Administration
fMRI
functional magnetic resonance imaging
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
γ-glutamyl transferase
GPR139
G protein-coupled receptor 139
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IA
interim analysis
ICC
intra-class correlation
ICH
International Conference of Harmonisation
IEC
independent ethics committee
IRB
institutional review board
IRT
interactive response technology
Property of Takeda: For non-c
ercial use only and subject to the applicable Terms of Use
entration
ration
s plan
plan
tion
erity Rati
rity R
injury
injury
Statistica
tatisti
ogram
gram
ic case re
se r
Food and D
od a
functio
func
fol
fo
g
V
HIV
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IA
IA
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Term
Definition
LFT
liver function tests
MedDRA
Medical Dictionary of Regulatory Activities
MID
Monetary Incentive Delay
MINI
Mini International Neuropsychiatric Interview
MRD
multiple-rising dose
MRI
magnetic resonance imaging
NSFS
negative symptom factor score
OTC
over-the-counter
PANSS
Positive and Negative Syndrome Scale
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
QTcF
QT interval with Fridericia correction method
rs-fMRI
resting state functional magnetic resonance imaging
SAE
serious adverse event
SAP
statistical analysis plan
SRD
single-rising dose
SUSAR
suspected unexpected serious adverse reaction
t-fMRI
2-task functional magnetic resonance imaging
t1/2z
terminal disposition phase half-life 
TBILI
total bilirubin
TEAE
treatment-emergent adverse event
Tween/MC vehicle
0.5% Tween 80 in 0.5% methylcellulose vehicle
ULN
upper limit of normal
VS
ventral striatum
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
imaging
maging
s adverse 
advers
c resonan
sona
hase half
ase ha
rgent adv
gent ad
en 80 in 0
80 in 
imit of no
mit of n
ral striatu
al stria
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15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent conditions will be coded using the MedDRA. Drugs will be 
coded using the World Health Organization Drug Dictionary.
15.1
CRFs (Electronic and Paper)
Completed eCRFs are required for each subject who signs an informed consent.
The Sponsor or its designee will supply investigative sites with access to eCRFs. The Sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this trial to the Sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
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 principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
After the lock of the clinical trial database, any change of, modification of, or addition to the data 
on the eCRFs should be made by the investigator with use of change and modification records of 
the eCRFs. The principal investigator must review the data change for completeness and accuracy, 
and must sign and date. 
eCRFs will be reviewed for completeness and acceptability at the trial site during periodic visits by 
trial monitors. The Sponsor or its designee will be permitted to review the subject’s medical and 
hospital records pertinent to the trial 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.
15.2
Record Retention
The investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the trial-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the Sponsor or its designees. Any source 
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documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, ICH 
E6 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 trial records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the Clinical Study Site Agreement 
between the investigator and Sponsor.
Refer to the Clinical Study Site Agreement for the Sponsor’s requirements on record retention. 
The investigator and the head of the institution should contact and receive written approval from 
the Sponsor before disposing of any such documents.
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REFERENCES
1. van Kerkhof LW, Damsteegt R, Trezza V, Voorn P, Vanderschuren LJ. Functional integrity of 
the habenula is necessary for social play behaviour in rats. Eur J Neurosci 
2013;38(10):3465-75.
2. Lecourtier L, Neijt HC, Kelly PH. Habenula lesions cause impaired cognitive performance in 
rats: implications for schizophrenia. Eur J Neurosci 2004;19(9):2551-60.
3. Castellani CA, Awamleh Z, Melka MG, O'Reilly RL, Singh SM. Copy number variation 
distribution in six monozygotic twin pairs discordant for schizophrenia. Twin Res Hum Genet 
2014;17(2):108-20.
4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 
(DSM-5). 5th ed. Arlington, VA: American Psychiatric Association; 2013.
5. Reddy LF, Horan WP, Barch DM, Buchanan RW, Dunayevich E, Gold JM, et al. Effort-Based 
Decision-Making Paradigms for Clinical Trials in Schizophrenia: Part 1-Psychometric 
Characteristics of 5 Paradigms. Schizophr Bull 2015;41(5):1045-54.
6. Horan WP, Reddy LF, Barch DM, Buchanan RW, Dunayevich E, Gold JM, et al. Effort-Based 
Decision-Making Paradigms for Clinical Trials in Schizophrenia: Part 2-External Validity and 
Correlates. Schizophr Bull 2015;41(5):1055-65.
7. Strauss GP, Whearty KM, Morra LF, Sullivan SK, Ossenfort KL, Frost KH. Avolition in 
schizophrenia is associated with reduced willingness to expend effort for reward on a 
Progressive Ratio task. Schizophr Res 2016;170(1):198-204.
8. Barch DM, Treadway MT, Schoen N. Effort, anhedonia, and function in schizophrenia: 
reduced effort allocation predicts amotivation and functional impairment. J Abnorm Psychol 
2014;123(2):387-97.
9. Plichta MM, Schwarz AJ, Grimm O, Morgen K, Mier D, Haddad L, et al. Test-retest reliability 
of evoked BOLD signals from a cognitive-emotive fMRI test battery. Neuroimage 
2012;60(3):1746-58.
10. Ceaser AE, Goldberg TE, Egan MF, McMahon RP, Weinberger DR, Gold JM. Set-shifting 
ability and schizophrenia: a marker of clinical illness or an intermediate phenotype? Biol 
Psychiatry 2008;64(9):782-8.
11. Hampshire A, Owen AM. Fractionating attentional control using event-related fMRI. Cereb 
Cortex 2006;16(12):1679-89.
12. Keefe RS, Goldberg TE, Harvey PD, Gold JM, Poe MP, Coughenour L. The Brief Assessment 
of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a standard 
neurocognitive battery. Schizophr Res 2004;68(2-3):283-97.
13. Atkins AS, Tseng T, Vaughan A, Twamley EW, Harvey P, Patterson T, et al. Validation of the 
tablet-administered Brief Assessment of Cognition (BAC App). Schizophr Res 
2017;181:100-6.
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14.
 
15. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophr Bull 1987;13(2):261-76.
16. Kay SR, Opler LA, Lindenmayer JP. Reliability and validity of the positive and negative 
syndrome scale for schizophrenics. Psychiatry Res 1988;23(1):99-110.
17.
 
18.
 
 
19.
 
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17.0
APPENDICES
Appendix A
Responsibilities of the Investigator
Clinical research studies sponsored by the Sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this trial.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the trial in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that trial-related procedures, including trial-specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the trial are informed of 
these obligations.
6. Secure prior approval of the trial and any changes by an appropriate IRB/IEC that conform to 
ICH and local regulatory requirements.
7. 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 trial to the 
IRB/IEC, and issue a final report within 3 months of trial completion.
8. Ensure that requirements for informed consent as outlined in ICH and local regulations are 
met.
9. Obtain valid informed consent from each subject who participates in the trial, 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 
trial. 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.
10. Prepare and maintain adequate case histories of all persons entered into the trial, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
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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.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of Sponsor-supplied 
drugs, and return all unused Sponsor-supplied drugs to the Sponsor. 
13. Report adverse reactions to the Sponsor promptly. In the event of an SAE, notify the Sponsor 
within 24 hours.
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Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the trial 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 procedure that is experimental.
6. The estimated number of subjects involved in the trial.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the trial.
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 trial.
17. The anticipated expenses, if any, to the subject for participating in the trial.
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 trial.
22. A statement that results of PGx analysis will not be disclosed to an individual, unless 
prevailing laws require the Sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the trial 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the trial. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
–
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.
–
that 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.
–
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 trial medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies.
–
that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the trial to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research.
–
that the subject’s identity will remain confidential in the event that trial results are 
published.
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25. Male subjects must use adequate contraception and female subjects must use 2 highly effective 
methods of contraception (as defined in the informed consent) from signing of the informed 
consent form, throughout the duration of the study, and for either 145 days (males) or 85 days 
(females) after last dose of trial medication. If the partner or wife of the subject is found to be 
pregnant during the trial, the investigator will offer the subject the choice to receive unblinded 
treatment information.
26. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.
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Appendix C
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 trial and/or other clinical studies.

Management, monitoring, inspection, and audit of the trial.

Analysis, review, and verification of the trial results.

Safety reporting and pharmacovigilance relating to the trial.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the trial.

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 trial medication.

Inspections and investigations by regulatory authorities relating to the trial.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of trial records.

Posting investigator site contact information, trial 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 D
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Female Subjects and their Male Partners
From signing of informed consent, throughout the duration of the trial, and for 85 days after last 
dose of study drug, female subjects of childbearing potential who are sexually active with a 
nonsterilized male partner must use 2 highly effective methods of contraception (from the list 
below).
In addition they must be advised not to donate ova during this period.
A woman is considered a woman of childbearing potential, ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses 
for 12 months without an alternative medical cause. A high FSH level in the postmenopausal range 
(FSH >40 IU/L) may be used to confirm a postmenopausal state in younger women (eg, those <45 
years old) or women who are not using hormonal contraception or hormonal replacement therapy. 
However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and for 145 days after the 
last dose of study drug, nonsterilized** male subjects who are sexually active with a female 
partner of childbearing potential must use barrier contraception (eg, condom with or without 
spermicidal cream or jelly). In addition, they must be advised not to donate sperm during this 
period. Females of childbearing potential who are partners of male subjects are also advised to use 
additional contraception as shown in the list containing highly effective contraception below.
Sterilized males should be at least 1 year post–bilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
The following procedures apply for contraception and pregnancy avoidance:
1. Highly effective methods of contraception are defined as “those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly)”:

Nonhormonal methods:
–
Intrauterine device (IUD).
–
Bilateral tubal occlusion.
–
Vasectomized partner (provided that partner is the sole sexual partner of the trial 
participant and that the vasectomized partner has received medical assessment of the 
surgical success).
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–
True sexual abstinence, only if this is in line with the preferred and usual lifestyle of the 
subject. True abstinence is defined as refraining from heterosexual intercourse during the 
entire period of the trial, from 1 month prior to the first dose until 167 days after last dose.
2. Unacceptable methods of contraception are:

Hormonal methods.

Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.
3. Subjects will be provided with information on highly effective methods of contraception as 
part of the subject informed consent process and will be asked to sign a consent form stating 
that they understand the requirements for avoidance of pregnancy, and sperm donation during 
the course of the trial.
4. Subjects will receive continued guidance with respect to the avoidance of pregnancy and 
sperm donation as part of the trial procedures. Such guidance should include a reminder of the 
following:

Contraceptive requirements of the trial.

Reasons for use of barrier methods (ie, condom) in males with pregnant partners.

Assessment of subject compliance through questions such as:
–
Have you used the contraception consistently and correctly since the last visit?
–
Have you forgotten to use contraception since the last visit?
–
Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)?
–
Is there a chance you could be pregnant?
5. In addition to a negative serum pregnancy test at Screening, female subjects of childbearing 
potential must also have confirmed menses in the month before first dosing (no delayed 
menses), a negative urine pregnancy test at time points specified in the Schedule of 
Procedures, Table 3.a.
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Appendix E
Detailed Description of Amendments to Text
The primary section(s) of the protocol affected by the changes in Amendment No. 04 are indicated. 
The corresponding text has been revised throughout the protocol.
Change 1: Modified rationale and potential range for study drug dose level..
The primary change occurs in Section 6.2 Rationale for Study Design, Dose, and Endpoints.
Initial 
wording:
The crossover design has been selected in order to reduce sample size (N = 24), as 
well as minimize variability in the endpoints. TAK-041 has been evaluated in a 
single-rising dose (SRD) trial in healthy volunteers at doses up to 40 mg crystalline
suspension. During the SRD trial, PK blood samples were collected for 146 days 
following the 40 mg TAK-041 dose. Preliminary PK data indicated that TAK-041 
has a mean terminal elimination half-life (t1/2) of approximately 11 days. Therefore, 
35 + 7 days between the 2 treatment periods is sufficient to ensure that there is no 
drug carryover effect. At the end of 35 +7 days, the probability of exceeding the 
“effect” cut-off is less than 2%, with 17 subjects out of 1000 expected to have plasma 
concentrations of TAK-041 above 132.5 ng/mL.
Section 6.2 Rationale for Dose
Up to 2 doses of TAK-041 will be used in this study. The first dose examined in this 
study will be a single 40 mg dose of TAK-041 crystalline suspension (or matching
placebo) administered on Day 1 of each treatment period according to the sequence 
group assigned through the IA. This dose is the highest dose that has been studied 
thus far in the ongoing TAK-041-1001 first-in-human Phase 1 study. The clinical 
exposure achieved at this dose is aligned with predicted human exposure of the 
highest efficacious dose (1 mg/kg) tested in nonclinical in vivo models of anhedonia 
and asociality. As discussed in Section 4.3, this dose was found to be well tolerated 
and safe in the ongoing TAK-041-1001 study. TAK-041 continues to be evaluated in 
the ongoing SRD/multiple-rising dose study (Study TAK-041-1001), and the safety 
and exposure data for additional single and multiple doses will be evaluated before 
the IA for this study is conducted. Pending the results of the IA, which will be 
conducted after an appropriate number of subjects have completed the study at the 40 
mg dose level (as outlined in the SAP), a second dose level of 20 mg (or an 
alternative higher dose such as 80 mg if supported by emerging compound clinical 
safety data) will be examined in subjects randomized after the IA to explore 
dose/exposure relationships on the PD endpoints.
Amended or 
new 
wording:
The crossover design has been selected in order to reduce sample size (N = 24), as 
well as minimize variability in the endpoints. TAK-041 has been evaluated in a 
single-rising dose (SRD) and multiple rising dose (MRD) trial in healthy 
volunteers at with single doses up to 120 and multiple doses regimen 40/20 mg 
(loading dose on week 1 followed by 3 weekly maintenances doses) of a 
crystalline suspension. During the SRD trial, PK blood samples were collected for 
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14643 days following the 40 mga single TAK-041 dose. Preliminary PK data 
indicated that TAK-041 has a mean terminal elimination half-life (t1/2) of 
approximately 11 days. Therefore, 35 + 7 days between the 2 treatment periods is 
sufficient to ensure that there is no drug carryover effect. At the end of 35 +7 days, 
the probability of exceeding the “effect” cut-off is less than 2%, with 17 subjects out 
of 1000 expected to have plasma concentrations of TAK-041 above 132.5 ng/mL.
6.2.2 Rationale for Dose
Up to 2 doses of TAK-041 will be used in this study. The firstThe initial dose 
examined in this study will be a single 40 mg dose of TAK-041 crystalline 
suspension (or matching placebo) administered on Day 1 of each treatment period 
according to the sequence group assignedthrough the IA. This dose is the highest 
dose that has been studied thus far in the ongoing TAK-041-1001 first-in-human 
Phase 1 study. The clinical exposure achieved at this. A 40 mg dose of TAK-041 has 
been administered to healthy volunteers in the first in human study, 
TAK-041-1001, and was found to be safe and well-tolerated. During the trial, 6 
AEs were observed that were mild in nature, were deemed not related to trial 
drug, and resolved without treatment. No SAEs and no clinically meaningful 
changes in safety laboratory results, physical examinations, vital signs, or ECGs 
were reported for the 16 subjects who received a single dose of TAK-041 
crystalline suspension up to 40 mg or matching placebo Dose adjustment will be 
allowed based on emerging safety, tolerability, and PK data from this study and 
study TAK-041-1001. Overall, the proposed dose range of TAK-041 is 
anticipated to achieve sufficient range of plasma exposures with a margin above 
and beyond the predicted pharmacologically active exposures/concentrations 
established in preclinical models. Based on the IA results, adjustment to higher 
doses may be performed to allow for the exploration of the dose-response. 
The clinical exposure achieved at the 40 mg dose is aligned with predicted human 
exposure of the highest efficacious dose (1 mg/kg) tested in nonclinical in vivo 
models of anhedonia and asociality. As discussed in Section 4.3, this dose was found
to be well toleratedcognitive impairment associated with schizophrenia (CIAS) 
and negative symptoms of schizophrenia], and 5 mg/kg on the Nicotine and 
Amphetamine dopamine release on the nucleus accumbens. TAK-041 continues 
to be evaluated in the ongoing SRD/multiple-rising doseMRD study (Study 
TAK-041-1001), and the safety and exposure data for additional single and multiple 
doses will be evaluatedbefore the IA for this study is conducted. Pending the results 
of the IA, which will be conducted after an appropriate number of subjects have 
completed the study at the 40 mg dose level (as outlined in the SAP), a second dose 
level of 20 mg (or an alternative higher dose such as 80 mg if supported by emerging 
compound clinical safety data) will be examined in subjects randomized after the IA 
to explore dose/exposure relationships on the PD endpoints. 
Preliminary blinded results from the first-in-human trial TAK-041-1001 study
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indicate that single doses of TAK-041 at 5, 10, 20, 40, 80, and 40120 and 160 mg 
and multiple dose cohorts 1 (40mg/20mg) and 2 (80 mg/40 mg) consisting of 4 
weekly doses, 1 loading dose followed by weekly maintenance doses for 3 weeks 
are well tolerated. To fully assess the safety and pharmacokinetic (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 belowIn the lower 
level of quantitation of the assay (<1 ng/ mL). Six adverse events (TAK-041-1001 
study, 31 29AEs) were observed that were all mild and resolved without 
medication treatment. Twenty seven Thirty of the AEs were deemed not related 
to trialstudy drug, and resolved without treatment. For the 66 subjects in the above 
cohorts there were no serious adverse events (SAEs),AEs, no clinically meaningful 
abnormalities in safety laboratory results (including 5'-nucleotidase, sorbitol 
dehydrogenase, and urine osmolality),ALP, AST, ALT, GGT, and TBILI) and no 
clinically significant abnormalities in physical examination, vital signs, or 
electrocardiogram (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 single-rising-dose Cohorts 1 and 2. The potential risks can be 
monitored clinically and/or with laboratory tests and arewere considered in setting up 
the stopping rules for this clinical trial. Appropriate eligibility criteria that exclude 
individuals with past history or concurrent conditions that increase the risk will 
behave been applied
Rationale for Change: To provide rationale for the potential change in dose level.
The following sections also contain this change:
!
Section 1.0 STUDY SUMMARY
!
Section 4.3 Benefit/Risk Profile
!
Section 8.1.3 Dose and Regimen
Change 2: Detailed potential study drug dose level change following the interim analysis.
Initial 
wording:
Section 6.1 Study Design
…
Effects of up to 2 dose levels and placebo will be assessed. The study is designed to 
evaluate the effect of TAK-041, a GPR139 orphan receptor agonist, as an add-on to 
antipsychotics in attenuating the impairment in motivational anhedonia as well as 
cognitive function using motivation/reward battery tests as well as brain imaging 
 
in subjects with stable schizophrenia. Subjects 
should be stable on their existing medicine (ie, second-generation antipsychotics 
[SGAs]) for at least 2 months prior to screening. A planned unblinded interim analysis 
(IA) for efficacy will be conducted when 12 subjects at the 40 mg dose level have 
completed the Day 14 procedures in both periods. The IA objective is to determine 
Property of Takeda: For
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whether to continue using 40 mg as the dose for TAK-041 after the IA, or revise to a 
different dose; based on the results of the IA, a second dose level of 20 mg (or an 
alternative higher dose if supported by emerging compound clinical safety data) will 
be examined to explore dose/exposure relationships on the PD endpoints.
The study will consist of 2 treatment periods, with a single dose of study drug 
administered in each period. There will be a35 day (+ 7 days) washout interval 
between the 2 doses to reduce the potential for residual TAK-041 to impact the PD 
endpoints. Treatment Period 2 begins at the end of the Treatment Period 1 washout. 
Because subjects are not confined in this study, they will come to the clinic for the 
following visits:
Screening Visit (between Days -28 to -2) covering full medical and psychiatric 
examinations. …
The initial dose of TAK-041 will be 40 mg. After the IA, the dose for TAK-041 might 
be changed for subjects enrolled after the IA, or the initial dose will be continued
based on the IA results. The decision criteria will be predefined in the SAP before 
unblinding.
…
During the Screening Visit (Days -28 to -2), subjects meeting Diagnostic and 
Statistical Manual of Mental Disorders fifth edition (DSM-5) criteria for 
schizophrenia [4] and on stable antipsychotic therapy for at least 2 months will 
complete medical and psychiatric examinations, electrocardiogram (ECG), and 
laboratory safety tests. At the Baseline Assessments Visit (Day -1), subjects will 
complete practice sessions of the motivation/reward and cognitive battery in order to 
minimize potential practice effects at subsequent treatment visits, be familiarized to 
the magnetic resonance imaging (MRI) environment, and further will be tested for 
baseline assessments (except fMRI). Practice sessions will only be conducted in 
Period 1. Subjects meeting all inclusion criteria and no exclusion criteria will be 
administered study medication or placebo in the clinic based on the randomization 
schedule on Day 1 of Treatment Periods 1 and 2.
On Day 1 of each Treatment Period, following study drug administration, subjects 
will undergo commencing at 2 hours postdose PD tests for a total of 3 hours 45 
minutes and blood samples will be collected at various times after dosing to assess the 
PK of TAK-041. After the last PK collection at 6 hours postdose, subjects will leave 
the clinic. On Day 14 of each Treatment Period, subjects will take the second set of 
PD tests along with a single time point PK collection. Samples for PK will also be 
collected on Day 49 and Final Visit of second Treatment Period. There will be a 
washout period of 35 days (+ 7 days) between doses in each Treatment Period to 
reduce the potential for residual TAK-041 to impact the PD endpoints.
PD testing will be performed in 3 blocks, separated by two 30-minute breaks. The first 
block will comprise the Grip Effort Task (15 minutes), Progressive Ratio Test (20 
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minutes), and BACS (25 minutes). After a 30-minute break, subjects will take the 
second block that comprises a battery of imaging tests;
 
 
 
. 
…
 
 
 
Amended 
or new 
wording:
Section 6.1 Study Design
…
Effects of up to 2at least 1 dose levelslevel and placebo will be assessed. The study is 
designed to evaluate the effect of TAK-041, a GPR139 orphan receptor agonist, as an 
add-on to antipsychotics in attenuating the impairment in motivational anhedonia as 
well as cognitive function using motivation/reward battery tests as well as brain 
imaging 
) in subjects with stable 
schizophrenia. Subjects should be stable on their existing medicine (ie, 
second-generation antipsychotics [SGAs]) for at least 2 months prior to screening. 
The initial dose level selected will be 40 mg but may be adjusted based on 
emerging safety, tolerability and PK data. A planned unblinded interim analysis 
(IA) for efficacy willmay be conducted when 12approximately12 subjectsat the 40 
mg dose level have completed the Day 14 procedures in both periods. The IA 
objective is to determine whether to continue using 40 mg as the doseforcurrent
TAK-041 dose after the IA, or revise to a different dose; based on the results of the IA, 
a second dose level of 20 mg (either lower or an alternative higherdose if supported by 
emerging compound clinical safety data) will be examined to explore dose/exposure 
relationships on the PD endpoints.
On Day 1 of Period 1, eligible subjects will be randomized in a ratio of 1:1 to 1 of the 
2 treatment sequences (Table 6.a) and will receive each trial drug according to the 
randomized sequence group. The randomization will be stratified by the sites. The 
initial dose of TAK-041 will be 40 mg. After and may be adjusted prior to the IA, 
thedepending on available PK and safety data from emerging first-in-human 
cohorts. The dose for TAK-041 mightmay also be changed for subjects enrolled after 
the IA, or the initial dose will be continued based on the IA results. The decision 
Property of Takeda: For non-comm
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TAK-041
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criteria will be predefined in the SAP before unblinding.
…
During the Screening Visit (Days -2835 to -2), subjects meeting Diagnostic and 
Statistical Manual of Mental Disorders fifth edition (DSM-5) criteria for 
schizophrenia [4] and on stable antipsychotic therapy for at least 2 months will 
complete medical and psychiatric examinations, electrocardiogram (ECG), and 
laboratory safety tests. At the Baseline Assessments Visit (Day -1) for Period 1,
subjects will complete practice sessions of the motivation/reward and cognitive 
battery in order to minimize potential practice effects at subsequent treatment visits, 
and be familiarized to the magnetic resonance imaging (MRI) environment, and 
furthertasks. At both study periods, subjects will also be tested for Day -1 baseline 
assessments (except fMRI). Practice sessions will only be conductedcarried out 
prior to the baseline assessments in Period 1 only. Subjects meeting all inclusion 
criteria and no exclusion criteria will be administered study medication or placebo in 
the clinic based on the randomization schedule on Day 1 of Treatment Periods 1 and 2.
On Day 1 of each Treatment Period, following study drug administration, subjects 
will undergo and commencing at approximately 2 hours postdose subjects will 
undergo PD tests for a total of 3approximately 4 hours minutesand blood. Blood
samples will be collected at variousdefined times after dosing to assess the PK of 
TAK-041. After the last PK collection at 6 hours postdose, subjects will leave the 
clinic. On Day 14 of each Treatment Period, subjects will take the second set of PD 
tests along with a single time point PK collection. Samples for PK will also be 
collected on Day 49 visit and Final Visit of second Treatment Period. There will be a 
washout period of 35 days (+ 7 days) between doses in each Treatment Period to 
reduce the potential for residual TAK-041 to impact the PD endpoints.
PD testing will be performed in 3 blocks, separated by two 30-minute breaks. The test 
schedule is detailed in the Schedule of Study Procedures, Table 3.a. The first 
block will comprise the 
and BACS (25 minutes). After a 30-minute break, subjects will take the 
second block that comprises a battery of imaging tests; namely, brain perfusion using 
non-contrast 
scans which monitor changes in BOLD signal. The 
fMRI will be run in resting state without a task (rs-fMRI) and with 2-task functional 
magnetic resonance imaging (t-fMRI) using the MID Reward Task and a Set-Shifting 
Task. The imaging block will last for approximately 60 minutes. After a 30-minute
break,
…
 
Property of Takeda: F
on-commercial use only and subject to the applicable Terms of Use
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TAK-041
Study No. TAK-041-2001
Page 96 of 101
Protocol Incorporating Amendment No. 04
10 August 2018
 
 
Rationale for Change: To base increase in dose based on safety, tolerability and PK data from 
emerging TAK-041-1001 study, and interim analysis.
The following sections also contain this change:
!
Section 1.0 STUDY SUMMARY
!
Section 11.2 Interim Analysis and Criteria for Early Termination
Change 3: Clarified Period 2 baseline serum pregnancy test collection day.
The primary change occurs in Footnote (c) of Section 3.0 SCHEDULE OF STUDY 
PROCEDURES.
Initial 
wording:
c) The sites will schedule a visit for subjects at the end of the Period 1 Washout. 
Subjects may return to the sites for this visit any day between Day 35 and 42. This 
Visit will serve to conduct end of Period 1 procedures and the Day -1 Baseline 
assessments for Period 2. Subjects will return to the clinic the next day for Period 2 
dosing and PD testing.
Amended 
or new 
wording:
(c) The sites will schedule a visit for subjects at the end of the Period 1 Washout. 
Subjects may return to the sites for this visit any day between Day 35 and 42. This 
Visit will serve to conduct end of Period 1 procedures and themay also be the same 
calendar day as Day -1 Baseline assessments for Period 2. If P1 Day 35 and P2 Day 
1 are the same day, assessments required for both visits only need to be 
completed once. Subjects will return to the clinic the next day for Period 2 dosing and 
PD testing.
Note: In addition, the Table has been expanded to display Period 1 and Period 2 
separately.
Rationale for Change: The serum pregnancy test was required at the Day 35 visit and the Day-1 
visit of each period. Due to the reduction of the washout period from 77 days to 35 days in 
Amendment 3, P2 Day-1 and P1 Day 35 are equivalent. It has been agreed that this unique sample 
is called P2 Day 1 and is now consistent with the eCRF.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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CCI

TAK-041
Study No. TAK-041-2001
Page 97 of 101
Protocol Incorporating Amendment No. 04
10 August 2018
Change 4: Revised exclusion criteria for abnormal laboratory values to clarify collection times for 
screening and baseline laboratory tests.
The primary change occurs in Section 7.2 Exclusion Criteria.
Initial 
wording:
Exclusion criterion 9
Has abnormal Screening or Day -1 laboratory values (>upper limit of normal [ULN]
for the respective serum chemistries) of alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), total bilirubin (TBILI), alkaline phosphatase (ALP), 
γ-glutamyl transferase (GGT), 5'-nucleotidase, and/or abnormal urine osmolality, 
confirmed upon repeat testing.
Amended 
or new 
wording:
Exclusion criterion 9
HasThe subject has abnormal Screening or Day -1baseline laboratory values 
(>upper limit of normal [ULN for the respective serum chemistries) of alanine 
aminotransferase (ALT), aspartate aminotransferase, AST), total bilirubin 
(TBILIalkaline phosphatase (ALP), γ-glutamyl transferase (GGT), 5'-nucleotidase,
confirmed upon repeat testing, 5’nucleotidase (Screening only) and/or abnormal 
urine osmolality, confirmed upon repeat testing.
Rationale for Change: To state collection days consistent with Section 3.0 Schedule of Study 
Procedures. In addition, the 5’ nucleotidase assay is not a standard laboratory assessment and 
requires several days to obtain results. Eligibility determinations based on 5’ nucleotidase results 
are obtained from Screening only. 
Change 5: Revised exclusion criterion for magnetic resonance imaging contraindication before 
imaging assessments.
The primary change occurs in Section 7.2 Exclusion Criteria.
Initial 
wording:
Exclusion Criterion 14
Fulfills any of the MRI contraindications on the standard radiography screening 
questionnaire at the Centre for Neuroimaging Sciences, Institute of Psychiatry, 
Psychology & Neuroscience, King’s College London (ie, history of surgery involving 
metal implants, metal body piercing, dentures, dental plates or bridges, any implanted 
device that is electrically, magnetically, and mechanically activated).
Amended 
or new 
wording:
Exclusion Criterion 14
Fulfills any of the MRI contraindications on the site standard radiography screening 
questionnaire at the Centre for Neuroimaging Sciences, Institute of Psychiatry, 
Psychology & Neuroscience, King’s College London (ie, history of surgery involving 
metal implants, metal body piercing, dentures, dental plates or bridges, any implanted 
device that is electrically, magnetically, and mechanically activated).document. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

TAK-041
Study No. TAK-041-2001
Page 98 of 101
Protocol Incorporating Amendment No. 04
10 August 2018
Rationale for Change: To allow new sites, as TAK-041 2001 has now become a multi-site study, 
to follow their own process and use their own standard radiography screening questionnaire.
Change 6: Detailed follow-up laboratory tests required for drug-induced liver injury (DILI).
The primary change occurs in Section 10.2.8.4.
Initial 
wording:
Section 10.2.8.4 Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive 
occasions, the abnormality should be recorded as an AE. In addition, a drug-induced 
liver injury (DILI) eCRF must be completed providing additional information on 
relevant recent history, risk factors, clinical signs and symptoms and results of any 
additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for 
which an alternative etiology has not been identified, the event should be recorded as 
an SAE and reported as per Section 10.2.8.3 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. Follow-up 
laboratory tests as described in Section 9.2.9 must also be performed. In addition, a 
DILI eCRF must be completed and transmitted with the Takeda SAE form (as per 
Section 10.2.9).
Amended 
or new 
wording:
Section 10.2.8.4 Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive 
occasions, the abnormality should be recorded as an AE. In addition, a drug-induced 
liver injury (DILI) eCRF must be completed providing additional information on 
relevant recent history, risk factors, clinical signs and symptoms and results of any 
additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for 
which an alternative etiology has not been identified, the event should be recorded as 
an SAE and reported as per Section 10.2.8.3. 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. Follow-up 
laboratory tests as described in Section 9.2.9 9.2.10 must also be performed. In 
addition, a DILI eCRF must be completed and transmitted with the Takeda SAE form 
(as per Section 10.2.9 9.2.10.2).
Rationale for Change: To correct typographical errors and provide clarity on required follow-up 
DILI tests.
The following sections also contain this change:

Section 9.2.10.2 DILI follow-up testing:.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

TAK-041
Study No. TAK-041-2001
Page 99 of 101
Protocol Incorporating Amendment No. 04
10 August 2018
Change 7: Updated and further clarified excluded medications, supplements, and dietary products
The primary change occurs in Section 7.3 Excluded Medications, Supplements, and Dietary 
Products.
Amended 
or new 
wording:

Melatonin changed from herbal to its own class.

Mood stabilizers examples given as Lithium, valproic acid and lamotrigine.

Medications that may interfere with cognitive function: Such as cold medicines 
containing antihistamine or dextromethorphan as a cough suppressant are not 
restricted except for 7 days prior to and during baseline assessments and during 
PD testing on Day -1, Day 1, and Day 1; and 7 days prior to and during the 
Day 14 assessments in Periods 1 and 2.

Psychotropic agents known to affect cognition: Such as long-acting sleep aids, 
amphetamines, barbiturates, lithium, monoamine inhibitors, methylphenidate, 
anticholinergics, antidepressants (eg, fluoxetinefluvoxamine).tricyclic 
antidepressants and MAOIs). Note: the definitive guidelines for each 
medication/class entry in this row is the primary table row for each 
medication/class.
Rationale for Change: To correct, update and/or clarify entries and examples in Table 7.3 
Excluded Medications, Supplements and Dietary Products. 
Change 8: Modified potential number of sites to approximately 4.
The primary change occurs in Section 1.0 STUDY SUMMARY.
Initial 
wording:
Number of Sites:
Up to 4 sites
Amended 
or new 
wording:
Number of Sites:
Up to 4Approximately 4 sites
Rationale for Change: to provide the opportunity to add additional sites if needed to reach the 
required enrollment. 
Change 9: Introduced randomization stratification by site
The primary change occurs in Section 6.1 Study Design.
Initial 
wording:
…
The initial dose of TAK-041 will be 40 mg. After the IA, the dose for TAK-041 might 
be changed for subjects enrolled after the IA, or the initial dose will be continued 
based on the IA results. The decision criteria will be predefined in the SAP before 
unblinding
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

TAK-041
Study No. TAK-041-2001
Page 100 of 101
Protocol Incorporating Amendment No. 04
10 August 2018
Amended 
or new 
wording:
The trial population will include subjects with stable schizophrenia aged 18-60 years, 
inclusive, considered eligible on the basis of the trial inclusion and exclusion criteria. 
The trial will randomize up to 32 subjects to ensure 24 subjects complete. On Day 1 
of Period 1, eligible subjects will be randomized in a ratio of 1:1 to 1 of the 2 
treatment sequences (Table 6.a) and will receive each trial drug according to the 
randomized sequence group. The randomization will be stratified by the sites. The 
initial dose of TAK-041 will be 40 mg. After and may be adjusted prior to the IA, 
thedepending on available PK and safety data from emerging first-in-human 
cohorts. The dose for TAK-041 mightmay also be changed for subjects enrolled 
after the IA, or the initial dose will be continued based on the IA results. The decision 
criteria will be predefined in the SAP before unblinding.
Rationale for Change: To maintain the balance between the sequence groups at each site.
The following sections also contain this change:

Section 8.1.8 Randomization Code Creation and Storage.
Change 10: Extended screening period to 35 days prior to dosing.
The primary change occurs in Section 6.1 Study Design.
Initial 
wording:
…

Screening Visit (between Days -28 to -2) covering full medical and psychiatric 
examinations.
Amended 
or new 
wording:
…

Screening Visit (between Days -2835 to -2) covering full medical and psychiatric 
examinations.
Rationale for Change: To improve the opportunity for enrollment in this population.
The following sections also contain this change:

Section 1.0 STUDY SUMMARY

Section 3.0 SCHEDULE OF STUDY PROCEDURES
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

TAK-041
Study No. TAK-041-2001
Page 101 of 101
Protocol Incorporating Amendment No. 04
10 August 2018
Change 11: Updated schedule of study procedures.
The primary change occurs in Section 3.0 SCHEDULE OF STUDY PROCEDURES.
Amended 
or new 
wording:
Table 3.a Schedule of Assessments was reformatted for clarity:

Table was split into 2 separate tables by period.

PK and PD assessments were updated. 
Rationale for Change: To improve operational use of the table and update, correct and clarify 
assessment information.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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