Clinical trial NCT03161405
Conditions: Healthy Participants
Keywords: Drug Therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2017-06-05; Completion date: 2017-07-10
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the effect of the potent cytochrome P-450 (CYP) 3A4 inhibitor (itraconazole) on the single-dose PK of oral TAK-906 maleate.

Detailed description:
The drug being tested in this study is called TAK-906. TAK-906 is being tested in healthy participants in order to evaluate the effect of the potent CYP3A4 inhibitor itraconazole on the single-dose PK of TAK-906 maleate.

The study enrolled 12 participants. Participants received the following treatment sequence:

• TAK-906 maleate 25 mg; Itraconazole 200 mg + TAK-906 maleate 25 mg

Participants were given an oral dose of TAK-906 in the First Intervention Period which was followed by a washout period, after which participants were given Itraconazole solution along with TAK-906 orally in the Second Intervention Period.

This single center trial was conducted in the United States. The overall duration to participate in this study was 7 weeks. Participants remained confined in the clinic from Day 1 up to Day 2 (First Intervention Period) and Day 4 up Day 6 (Second Intervention Period). Participants returned for a Follow-up Visit, 10 to 14 days after last dose of study drug.

Arms: arm 1: TAK-906 maleate 25 milligram (mg), capsule, orally, once on Day 1 of First Intervention Period, followed by a minimum of 4-day washout period, further followed by Itraconazole 200 mg, solution, orally, once daily on Days 1 to 5 along with TAK-906 maleate 25 mg, capsule, orally on Day 4 of Second Intervention Period.
Interventions: intervention 1: TAK-906 Maleate intervention 2: Itraconazole
Intervention descriptions: intervention 1: TAK-906 capsule intervention 2: Itraconazole solution

Protocol documents:
Prot_000.pdf: 
This may include, but is not limited to, redaction of the following: 


•
Title: A Single-Sequence, Open-Label, 2-Period, Crossover Trial to Evaluate the Effect of the
Potent CYP3A4 Inhibitor Itraconazole on the Single-Dose Pharmacokinetics of Oral
TAK-906 in Healthy Adult Subjects.
NCT Number: NCT03161405
Protocol Approve Date: 25 May 2017
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.


TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
A Single-Sequence, Open-Label, 2-Period, Crossover Trial to Evaluate the Effect of the 
Potent CYP3A4 Inhibitor Itraconazole on the Single-Dose Pharmacokinetics of Oral 
TAK-906 in Healthy Adult Subjects.
Study Identifier:
TAK-906-1003
Compound:
TAK-906 maleate
Date:
25 May 2017
Version/Amendment 
Number:
01
Amendment History: 
Date
Amendment Number
Amendment Type (for regional 
European purposes only)
Region
21 March 2017
Initial version
Not applicable
Global
25 May 2017
01
Nonsubstantial
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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TABLE OF CONTENTS
1.0
TRIAL SUMMARY........................................................................................................6
1.1
Protocol Amendment No. 01 Summary of Changes ...................................................8
2.0
TRIAL SCHEMATIC .....................................................................................................9
3.0
SCHEDULE OF TRIAL PROCEDURES......................................................................10
4.0
INTRODUCTION.........................................................................................................13
4.1
Background .............................................................................................................13
4.2
Rationale for the Proposed Trial...............................................................................14
4.3
Benefit/Risk Profile .................................................................................................14
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................15
5.1
Objectives................................................................................................................15
5.1.1
Primary Objective............................................................................................15
5.1.2
Secondary Objective........................................................................................15
5.1.3
Exploratory Objectives ....................................................................................15
5.2
Endpoints.................................................................................................................15
5.2.1
Primary Endpoint(s).........................................................................................15
5.2.2
Safety Endpoints..............................................................................................15
5.2.3
Exploratory Endpoints .....................................................................................15
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................17
6.1
Trial Design.............................................................................................................17
6.2
Rationale for Trial Design, Dose, and Endpoints......................................................17
6.2.1
Rationale of Trial Design and Dose..................................................................17
6.2.2
Rationale for Endpoints ...................................................................................18
6.2.3
Critical Procedures Based on Trial Objectives: Timing of Procedures..............18
6.3
Trial Beginning and End/Completion.......................................................................19
6.3.1
Definition of Beginning of the Trial.................................................................19
6.3.2
Definition of End of the Trial...........................................................................19
6.3.3
Definition of Trial Discontinuation ..................................................................19
6.3.4
Criteria for Premature Termination or Suspension of the Trial .........................19
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............20
7.1
Inclusion Criteria .....................................................................................................20
7.2
Exclusion Criteria ....................................................................................................21
7.3
Excluded Medications, Supplements, Dietary Products............................................23
7.4
Diet, Fluid, Activity.................................................................................................23
7.4.1
Diet and Fluid..................................................................................................23


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7.4.2
Activity ...........................................................................................................24
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................24
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................25
7.7
Subject Replacement................................................................................................25
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................26
8.1
Clinical Trial Drug...................................................................................................26
8.1.1
Clinical Trial Drug Labeling............................................................................26
8.1.2
Clinical Trial Drug Inventory and Storage .......................................................26
8.1.3
Clinical Trial Drug Blinding ............................................................................26
8.1.4
Accountability and Destruction of Sponsor-Supplied Drugs.............................26
8.1.5
Ancillary Supplies ...........................................................................................26
9.0
TRIAL PROCEDURES.................................................................................................27
9.1
Administrative Procedures.......................................................................................27
9.1.1
Informed Consent Procedure............................................................................27
9.1.2
Assignment of Screening Numbers ..................................................................27
9.1.3
Inclusion and Exclusion Criteria ......................................................................27
9.1.4
Medical History/Demographics .......................................................................27
9.1.5
Prior and Concomitant Medication Review......................................................27
9.1.6
Physical Examinations.....................................................................................27
9.1.7
Vital Sign Measurements.................................................................................27
9.1.8
Height and Weight...........................................................................................28
9.1.9
BMI.................................................................................................................28
9.1.10
12-Lead ECG...................................................................................................28
9.1.11
AE Monitoring ................................................................................................29
9.2
Laboratory Procedures and Assessments..................................................................29
9.3
PK and PGx Samples...............................................................................................31
9.3.1
PK Evaluations ................................................................................................31
9.3.2
PGx Measurements..........................................................................................32
9.4
Trial Drug Administration........................................................................................33
9.5
Confinement ............................................................................................................33
10.0
ADVERSE EVENTS ....................................................................................................34
10.1
Definitions and Elements of AEs .............................................................................34
10.1.1
SAEs ...............................................................................................................36
10.1.2
Special Interest AEs.........................................................................................37
10.2
AE Procedures.........................................................................................................37


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10.2.1
Assigning Severity/Intensity of AEs ................................................................37
10.2.2
Assigning Causality of AEs .............................................................................37
10.2.3
Assigning Relationship to Trial Procedures......................................................38
10.2.4
Start Date.........................................................................................................38
10.2.5
Stop Date.........................................................................................................38
10.2.6
Frequency........................................................................................................38
10.2.7
Action Concerning Trial Drug .........................................................................38
10.2.8
Outcome..........................................................................................................38
10.2.9
Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs................................................................................................................39
10.2.10 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...41
11.0
STATISTICAL METHODS..........................................................................................42
11.1
Statistical and Analytical Plans ................................................................................42
11.1.1
Analysis Sets ...................................................................................................42
11.1.2
Analysis of Demographics and Other Baseline Characteristics.........................42
11.1.3
PK Analysis.....................................................................................................42
11.1.4
Safety Analysis................................................................................................43
11.2
Interim Analysis and Criteria for Early Termination ................................................44
11.3
Determination of Sample Size..................................................................................44
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................45
12.1
Trial-Site Monitoring Visits.....................................................................................45
12.2
Protocol Deviations..................................................................................................45
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................45
13.0
ETHICAL ASPECTS OF THE TRIAL .........................................................................46
13.1
IRB and/or IEC Approval ........................................................................................46
13.2
Subject Information, Informed Consent, and Subject Authorization .........................47
13.3
Subject Confidentiality ............................................................................................48
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................48
13.4.1
Publication and Disclosure...............................................................................48
13.4.2
Clinical Trial Registration................................................................................49
13.4.3
Clinical Trial Results Disclosure......................................................................49
13.5
Insurance and Compensation for Injury....................................................................49
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................50
14.1
Administrative Information......................................................................................50
14.1.1
Trial Contact Information ................................................................................50
15.0
INVESTIGATOR AGREEMENT.................................................................................51


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15.1
Trial-Related Responsibilities ..................................................................................52
15.2
List of Abbreviations ...............................................................................................53
16.0
DATA HANDLING AND RECORDKEEPING............................................................55
16.1
eCRFs......................................................................................................................55
16.2
Record Retention .....................................................................................................55
17.0
REFERENCES..............................................................................................................57
18.0
APPENDICES...............................................................................................................58
LIST OF IN-TEXT TABLES
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................23
Table 9.a
Primary Specimen Collections ...........................................................................31
Table 10.a
Takeda Medically Significant AE List................................................................37
LIST OF APPENDICES
Appendix A
Detailed Description of Amendments to Text.....................................................59
Appendix B
Responsibilities of the Investigator.....................................................................63
Appendix C
Elements of the Subject Informed Consent.........................................................65
Appendix D
Investigator Consent to Use of Personal Information..........................................68
Appendix E
Pregnancy and Contraception.............................................................................69


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1.0
TRIAL SUMMARY
Name of Sponsor:
Millennium Pharmaceuticals, Inc 
40 Landsdowne Street
Cambridge, MA 02139
Compound:
TAK-906 maleate
Study Number: 
TAK-906-1003
Phase: 1
Protocol Title: A Single-Sequence, Open-Label, 2-Period, Crossover Trial to Evaluate the Effect of the Potent 
Cytochrome P-450 3A4CYP3A4 Inhibitor Itraconazole on the Single-Dose Pharmacokinetics of Oral TAK-906 in 
Healthy Adult Subjects.
Trial Design:
This is a phase 1, single-sequence, open-label, 2-period crossover trial in approximately 12 healthy male and female 
(nonchildbearing-potential) subjects. The trial is designed to investigate the effect of a potent cytochrome P-450 
(CYP) 3A4 inhibitor (itraconazole) on the pharmacokinetics (PK) of TAK-906. 
The trial will include a Screening Visit, a Period 1 (Days 1 to 3), followed by a minimum of a 4-day washout from the 
time of TAK-906 maleate dose, a Period 2 (Days 1 to 6), and a Follow-up Visit. 
On Day 1 of Period 1, eligible subjects will be enrolled into the trial and will receive a single oral (PO) dose of 
TAK-906 maleate 25 mg. On Days 1 to 5, inclusive, of Period 2, subjects will receive itraconazole 200 mg once daily 
(QD) PO solution. Following after an overnight fast of at least 8 hours, a single PO dose of TAK-906 maleate 25 mg 
will be administered 1 hour after the itraconazole dose on Day 4 of Period 2. Both doses of TAK-906 maleate will be 
administered after an overnight fast of at least 8 hours as food reduces its bioavailability by approximately 40%.
Blood samples for assessment of TAK-906 concentrations will be collected from predose to 48 hours after each dose 
of TAK-906 maleate. 
Safety will be assessed by monitoring for adverse events, vital signs, electrocardiograms (ECGs), clinical laboratory 
results, and physical examinations throughout each dosing period.
After completion of the trial (or following subject withdrawal), all subjects will return for a Follow-up Visit 10 to 14 
days after their last dose of TAK-906 maleate.
Primary Objective:
To evaluate the effect of the potent CYP3A4 inhibitor itraconazole on the single-dose PK of PO TAK-906 maleate.
Secondary Objectives:
To evaluate the safety and tolerability of a single PO dose of TAK-906 maleate in the presence and absence of a potent 
CYP3A4 inhibitor.
Subject Population: Healthy male and female (nonchildbearing) subjects. 
Number of Subjects:
12
Number of Sites:
1 site
Dose Levels:
TAK-906 maleate 25 mg QD
Itraconazole 200 mg QD
Route of Administration:
TAK-906 maleate: PO
Itraconazole: PO
Duration of Treatment:
2 QD TAK-906 maleate doses 
5 QD itraconazole doses
Period of Evaluation:
Approximately 7 to 8 weeks


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Main Criteria for Inclusion:
Healthy male and female (nonchildbearing-potential) subjects who are aged 18 to 55 years, inclusive, with a body 
mass index (BMI) between 18 to 30 kg/m2, and a body weight >50 kg.
Main Criteria for Exclusion:
Subjects who have a history of clinically significant endocrine, gastrointestinal (GI) (including motility disorder and 
intestinal obstruction), cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or 
major neurological (including stroke and chronic seizures) abnormalities or diseases will be excluded from the trial.
Main Criteria for Evaluation and Analyses:
Plasma PK parameters (maximum observed concentration [Cmax], area under the concentration-time curve from time 0 
to time of the last quantifiable concentration [AUClast], and area under the concentration-time curve from time 0 to 
infinity, calculated using the observed value of the last quantifiable concentration [AUC∞]) for TAK-906 will be 
derived on Day 1 of Period 1 and on Day 4 of Period 2.
Safety endpoints: 
Safety and tolerability will be assessed through physical examinations, ECGs, vital signs, and clinical laboratory 
results, as well as collection of spontaneous adverse events (AEs).
Statistical Considerations:
The PK parameters of TAK-906 (and metabolites, if possible) will be summarized by regimen using descriptive 
statistics. Linear and semilogarithmic plots of the mean and individual concentration-time curves will be provided. 
Individual plasma concentration and PK parameter data will be presented in the data listing. 
For evaluation of potential effect of itraconazole on TAK-906 PK, paired t-tests and associated 90% confidence 
intervals (CIs) will be determined on the natural logarithms of Cmax and AUCs to assess the exposure between 
regimens (TAK-906 maleate alone and TAK-906 maleate with itraconazole). The geometric mean of the relative 
bioavailability of the TAK-906 maleate with itraconazole regimen relative to the TAK-906 maleate alone regimen and 
the associated 90% CIs will be determined by exponentiating the appropriate estimates for the difference between 
regimens in the log-transformed parameters.
Sample Size Justification:
Approximately 12 subjects will be enrolled in this trial. The sample size justification is based on an acceptance range 
of 50% to 200% and assumes that the intrasubject percent coefficient of variation (%CV) for AUClast and Cmax of 
TAK-906 will not exceed 25%. This sample size will provide 80% power to conclude plasma concentration of 
TAK-906 will not increase more than 2-fold in the presence of itraconazole.
Subjects who drop out for nonsafety reasons may be replaced at the discretion of the investigator in consultation with 
the sponsor. Subjects who drop out for safety reasons will not be replaced.


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1.1
Protocol Amendment No. 01 Summary of Changes
Rationale for Amendment 01
This document describes the changes in reference to the protocol incorporating Amendment 
No. 01.
The primary reason for this amendment is to add additional laboratory and screening procedures. 
Numerous clarification and administrative changes have also been made.
Minor grammatical and editorial changes are included for clarification purposes only. For specific 
descriptions of text changes and where the changes are located, see Appendix A. 
Changes in Amendment 01:
1. Added additional serum β-human chorionic gonadotropin (hCG) tests.
2. Clarified use of follicle stimulating hormone (FSH) test.
3. Extended the morning dosing time range for the TAK-906.
4. Aligned timing and procedures for collection of AE throughout document.
5. Removed data collection using digital wearable devices.
6. Clarified birth control requirements for female partners of male subjects.
7. Updated predose restriction for xanthine and/or caffeine use. 
8. Added urine cotinine as part of drug screen.
9. Corrected typographical errors, punctuation, grammar, and formatting.


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2.0
TRIAL SCHEMATIC


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3.0
SCHEDULE OF TRIAL PROCEDURES 
Screening
Period 1 (a)
Period 2
Follow-up/Early 
Termination
Procedures/Assessments
Day -28 to -2
Day
Day
10-14 days after 
last dose of 
TAK-906
-1
Predose
(Day 1)
1
2
3
1
2
3
4
5
6
Administrative Procedures
Informed consent
X
Inclusion/exclusion criteria
X
X
X
Medical history/demographics
X
Prior and concomitant medication review
------------------------------------Continuous Monitoring-----------------------------
Clinic Procedures/Assessments
Full physical examination
X
X (b)
X
Height
X
Weight
X
BMI
X
12-Lead ECG
X
X(c)
X(c)
X
X(c)
X
X
Semirecumbent vital signs (heart rate [HR], systolic 
blood pressure and diastolic blood pressure 
X
X(d)
X(d)
X
X
X(d)
X
X
Vital signs (respiratory rate, oral [at the floor of the 
mouth]/tympanic temperature) rate
X
X
X
X
X
X
X
X
TAK-906 administration
X
X
Itraconazole administration (e)
X
X
X
X
X
AE monitoring
---------Continuous Monitoring--------


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Screening
Period 1 (a)
Period 2
Follow-up/Early 
Termination
Procedures/Assessments
Day -28 to -2
Day
Day
10-14 days after 
last dose of 
TAK-906
-1
Predose
(Day 1)
1
2
3
1
2
3
4
5
6
Laboratory Procedures/Assessments
Hematology
X
X (b)
X (b)
X
X
Urinalysis
X
X (b)
X (b)
X
X
Chemistry
X
X (b)
X (b)
X
X
Serum follicle stimulating hormone (FSH)
X
β-human chorionic gonadotropin (hCG)
X
X
X
Urine drug screen
X
X
X
Urine alcohol test/alcohol breath test (f)
X
X
X
Hepatitis screen 
X
Human immunodeficiency virus (HIV)
X
Pharmacokinetics Evaluations
PGx DNA collection
X
PGx RNA collection
X
CCI
CCI


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Screening
Period 1 (a)
Period 2
Follow-up/Early 
Termination
Procedures/Assessments
Day -28 to -2
Day
Day
10-14 days after 
last dose of 
TAK-906
-1
Predose
(Day 1)
1
2
3
1
2
3
4
5
6
Other
Confinement 
X--------------X
X------------X
Meals fasting (i)
X
X
X
(a) There will be a minimum 4 day washout between Periods 1 and 2, starting from administration of TAK-906 maleate on Day 1 of Period 1.
(b) Day 1 predose assessment may be done within approximately 24 hours prior to trial drug administration.
(c) Triplicate measurements to be conducted at 0 (predose), 1, 2, 4, 8 and 48 hours postdose (times relative to TAK-906 maleate dose).
(d) Measured at 0 (predose), 1, 2, 4, 8 and 48 hours postdose (times relative to TAK-906 maleate dose).
(e) Itraconazole will be administered once daily at the same time each day and 1 hour prior to TAK-906 maleate on Day 4.
(f) An alcohol breath test may be performed at the discretion of the investigator.
(g) 
 
(h) 
 
(i) Subjects will fast overnight at least 8 hour before dose of TAK-906 maleate on Day 1 of Period 1 and at least 8 hours before itraconazole and TAK-906 maleate doses on Day 4 of 
Period 2.
CCI
CCI
CCI
CCI


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4.0
INTRODUCTION
4.1
Background
The intended indication for TAK-906 maleate is to treat patients with gastroparesis, a disorder of 
the stomach characterized by delayed gastric emptying in the absence of mechanical obstruction. 
Symptoms are chronic with episodic symptom exacerbation [1]. These symptoms may include 
nausea, vomiting, early satiety, abdominal pain, and postprandial fullness. The prevalence of 
gastroparesis in the United States is 24.2 per 100,000 [2]. In cases of chronic gastroparesis, 
diabetic (29%), postsurgical (13%), and idiopathic (36%) etiologies comprise the majority of cases 
in the tertiary referral setting [3]. Currently in the United States, there exists a large unmet medical 
need because there are no approved therapies for the chronic treatment of diabetic gastroparesis. 
Validated targets for gastroparesis are the D2 and D3 dopamine (DA) receptors. The D2 receptor 
antagonist metoclopramide is indicated for the short-term treatment of acute and recurrent diabetic 
gastroparesis and has been limited in dose and duration of treatment by well-documented 
toxicities, the most notable of which are a category of movement disorders known as 
extrapyramidal symptoms (EPS) [4]. EPS are caused by the blockade of DA D2 receptors in the 
dorsal striatum and thus are potential side effects of all centrally-penetrant drugs that share this 
mechanism of action, particularly selective DA D2 antagonists. Of greatest concern is tardive 
dyskinesia, a severe and often irreversible EPS. The risk of developing tardive dyskinesia 
increases with dose level and duration of treatment and as such, the United States package insert 
includes a black box warning regarding the chronic use of metoclopramide for longer than 
12 weeks.
Domperidone is a peripherally-acting DA D2/D3 receptor antagonist marketed for use as an 
anti-emetic and prokinetic agent in a number of countries worldwide, although not in the United 
States due to its cardiovascular safety profile which includes a risk for drug-induced long QT 
syndrome, torsades de pointes, and sudden cardiac death [5].
DA receptor antagonists are effective in the treatment of delayed gastric emptying and 
gastroparesis symptoms because of the role of D2 and D3 receptors in the upper gastrointestinal 
(GI) tract and in the area postrema which controls vomiting [6-8]. Both of these areas are outside 
of the blood brain barrier. Therefore, a peripherally-selective D2/D3 antagonist could achieve the 
desired efficacy without the undesired central nervous system (CNS) effects [9,10]. TAK-906 is a 
peripherally selective (ie, very limited penetration of the blood brain barrier) dopamine D2/D3
receptor antagonist. It demonstrated suitable pharmacokinetics (PK) and pharmacodynamic (PD) 
activity in a phase 1 trial in healthy volunteers without the CNS liabilities of metoclopramide or 
cardiac liabilities associated with domperidone. Therefore TAK-906 is expected to reduce nausea 
and vomiting, and to have prokinetic effects, without the side effects which restrict the use of other 
D2/D3 antagonist. 
TAK-906 shows rapid absorption. Half-life following a single oral (PO) dose averaged 
approximately 4 hours when administered in the fasted state. Food had a significant impact on 
reducing the exposure to TAK-906.
In conclusion, TAK-906 maleate is a promising therapeutic for the treatment of gastroparesis.


TAK-906
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Please refer to the TAK-906 Investigator’s Brochure for complete information on the 
investigational product and the most recent itraconazole product insert for the appropriate region.
4.2
Rationale for the Proposed Trial
TAK-906 has been shown to undergo oxidative metabolism in human liver microsomes and hence 
involvement of cytochrome P-450 (CYP) enzymes is possible (2C8, 3A4 and 1A2). Thus, this 
phase 1, single-sequence, open-label, 2-period crossover trial is designed to investigate the effect 
of a potent CYP3A4 inhibitor (itraconazole) on the PK of a single PO dose of TAK-906 maleate 
25 mg in healthy men and women.
4.3
Benefit/Risk Profile
As this is a trial in healthy subjects, there is no expected clinical benefit to the trial participants. 
Potential risks are based on clinical findings, the mechanism of action, and nonclinical findings. 
Also, there is minimal risk associated with study procedures including scheduled, periodic 
phlebotomy (limited to <500 mL), and noninvasive procedures including vital sign assessments 
and electrocardiograms (ECGs). The principal mitigation for these risks include appropriate 
selection of the study populations, the clinical research unit (CRU) study setting permitting close 
monitoring and rapid institution of appropriate care as needed, appropriate specified monitoring 
procedures, and utilization of experienced staff trained in study procedures. Overall, the 
risk:benefit profile is considered appropriate for this trial.


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5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective of the trial is to evaluate the effect of the potent CYP3A4 inhibitor 
itraconazole on the single-dose PK of PO TAK-906 maleate.
5.1.2
Secondary Objective
The secondary objective of the trial to evaluate the safety and tolerability of single PO dose of 
TAK-906 maleate in the presence and absence of a potent CYP3A4 inhibitor.
5.1.3
Exploratory Objectives
Exploratory endpoints of this trial include: 
5.2
Endpoints
5.2.1
Primary Endpoint(s)
The primary endpoints of the trial are the following plasma PK parameters for TAK-906 on Days 1 
and 4:

Maximum observed concentration (Cmax).

Area under the concentration-time curve from time 0 to time of the last quantifiable
concentration (AUClast).

Area under the concentration-time curve from time 0 to infinity, calculated using the observed
value of the last quantifiable concentration (AUC∞).
5.2.2
Safety Endpoints 
Safety endpoints include the following: 

Safety and tolerability will be assessed through physical examinations, ECGs, vital signs,
clinical laboratory results, and collection of spontaneous adverse events (AEs).
5.2.3
Exploratory Endpoints
Exploratory endpoints will be assessed through the following parameters: 
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6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design 
This is a phase 1, single-sequence, open-label, 2-period crossover trial in approximately 
12 healthy male and female (nonchildbearing-potential) subjects. The trial is designed to 
investigate the effect of a potent CYP3A4 inhibitor (itraconazole) on the PK of TAK-906.
The trial will include a Screening Visit, a Period 1 (Days 1 to 3), followed by a minimum of a 
4-day washout from the time of TAK-906 maleate dose, a Period 2 (Days 1 to 6), and a Follow-up 
Visit. 
On Day 1 of Period 1, eligible subjects will be enrolled into the trial and will receive a single PO 
dose of TAK-906 maleate 25 mg. On Days 1 to 5, inclusive, of Period 2, subjects will receive 
itraconazole 200 mg once daily (QD) PO solution. Following after an overnight fast of at least 8 
hours, a single PO dose of TAK-906 maleate 25 mg will be administered 1 hour after the 
itraconazole dose on Day 4 of Period 2. Both doses of TAK-906 maleate will be administered after 
an overnight fast of at least 8 hours as food reduces its bioavailability by approximately 40%.
Itraconazole will be administered to subjects under clinic supervision on an outpatient basis on the 
morning of Days 1 to 3 of Period 2 and during confinement on Days 4 to 5 of Period 2. 
Blood samples for assessment of TAK-906 concentrations will be collected from predose to 
48 hours after each dose of TAK-906 maleate. Samples may be assayed for TAK-906 metabolites 
if deemed necessary. Urine samples will be collected through 48 hours and may be assayed for 
TAK-906 concentrations and metabolites if deemed necessary for the interpretation of data.
Whole blood samples for deoxyribonucleic acid (DNA) pharmacogenomics (PGx) analysis and 
ribonucleic acid (RNA) isolation will be collected predose on Day 1 of Trial Period 1.
Safety will be assessed by monitoring for adverse events, vital signs, ECGs, clinical laboratory 
results, and physical examinations throughout each dosing period.
After completion of the trial (or following subject withdrawal), all subjects will return for a 
Follow-up Visit 10 to 14 days after their last dose of TAK-906 maleate.
6.2
Rationale for Trial Design, Dose, and Endpoints
6.2.1
Rationale of Trial Design and Dose
Itraconazole has been chosen as it is recommended by the Food and Drug Administration (FDA) 
and European Medicines Agency (EMA) as a suitable potent CYP3A4 inhibitor for use in 
drug-drug interaction (DDI) studies. CYP3A4 is the most common CYP enzyme responsible for 
oxidative metabolism, and hence the effect of itraconazole, a potent CYP3A4 inhibitor, on 
TAK-906 PK will be investigated. This type of DDI trial is typically conducted in healthy subjects. 
A single-sequence trial has been chosen to enable assessment of the PK of a single PO dose of 
TAK-906 maleate in the presence and absence of multiple doses of itraconazole.


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A single PO dose of TAK-906 maleate 25 mg has been chosen as it is expected to be clinically 
relevant, ie, 25 mg is expected to provide maximal D2 receptor occupancy at a mean Cmax of 
approximately 11 ng/mL. In addition, this dose is well below the maximum single dose (300 mg) 
that has been investigated to date that was shown to be well tolerated in healthy subjects. The 
chosen dose therefore allows for an increase in exposure due to CYP3A4 inhibition without any 
potential safety concerns. The PK of TAK-906 have also been shown to be dose proportional 
across the dose range 5 to 300 mg and apparent clearance, volume of distribution and terminal 
elimination half-life were all dose independent. The effect of itraconazole on TAK-906 PK would 
therefore be expected to be consistent across this dose range.
6.2.2
Rationale for Endpoints
6.2.2.1
PK Endpoints
The primary endpoint for this trial consists of standard PK variables (Cmax, AUClast, and AUC∞) 
that are used to determine the effect of itraconazole on the PK of TAK-906 in healthy subjects.
6.2.2.2
Safety Endpoints
Key safety endpoints will be assessed through monitoring of AEs, vital signs, ECGs, clinical 
laboratory results, and physical examinations.
6.2.2.3
Exploratory Endpoints
6.2.3
Critical Procedures Based on Trial Objectives: Timing of Procedures 
For this trial, the collection of the blood samples for TAK-906 (PK) is the critical procedure. 

At any postdose time point, the blood samples for TAK-906 (PK) need to be collected as close 
to the exact nominal time point as possible.

All other procedures should be completed as close as possible, either before or after the 
prescribed/scheduled time.

ECG and vital signs measurements should be performed before the nominal time of the 
TAK-906 PK sampling, if scheduled together.

The order of priority can be changed during the trial 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.
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6.3
Trial Beginning and End/Completion
6.3.1
Definition of Beginning of the Trial
The overall trial begins when the first subject signs the trial informed consent form.
6.3.2
Definition of End of the Trial
The overall trial ends when the last subject completes the last planned or follow-up 
visit/interaction associated with a planned visit (this can be a phone contact), discontinues from the 
trial or is lost to follow-up (ie, the investigator is unable to contact the subject).
6.3.3
Definition of Trial Discontinuation
Trial discontinuation because of nonsafety reasons, such as:

A finding (eg, PK, PD, efficacy, biologic targets) from another nonclinical or clinical trial 
using the trial treatment(s) results in the trial being stopped for a nonsafety-related reason. 

Data from comparator(s), drug(s) of the same class, or methodology(ies) used in this trial 
become available and results in the trial being stopped for a nonsafety-related reason. 

The trial is stopped because of nonscientific and nonsafety reasons, such as slow enrollment.
Trial discontinuation because of safety reasons: 

Early trial termination because of unanticipated concerns of safety to the trial subjects arising 
from clinical or preclinical trials with the trial treatment(s), comparator(s), drug(s) of the same 
class, or methodology(ies) used in this trial.
6.3.4
Criteria for Premature Termination or Suspension of the Trial
6.3.4.1
Criteria for Premature Termination or Suspension of Trial Sites
A trial site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of Good Clinical Practice (GCP), protocol, or contractual agreement, 
is unable to ensure adequate performance of the trial, or as otherwise permitted by the contractual 
agreement.
6.3.4.2
Procedures for Premature Termination or Suspension of the Trial or the Participation of 
Trial Site(s)
In the event that the sponsor, an institutional review board (IRB), 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 applicable investigational sites during the course of termination or trial suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must:
1. Understand the trial procedures and agree to participate by providing written informed 
consent.
2. Be willing and able to comply with all trial procedures and restrictions.
3. Be a man or woman (with no child bearing potential) aged 18 to 55 years, inclusive, at the 
Screening Visit. 
4. Have a body mass index (BMI) ≥18 and ≤30 kg/m2 and a body weight >50 kg at the Screening
Visit.
5. Be a nonsmoker who has not used tobacco- or nicotine-containing products (eg, nicotine 
patch) for at least 6 months before administration of the initial dose of trial drug/invasive 
procedure.
6. Be 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 before administration of the initial dose of 
trial drug.
7. Meet the following birth control requirements:
–
Is a male subject* who is sterile or agrees to use an appropriate method of contraception, 
including a condom with spermicide, from trial drug administration on the first day of the 
first dose until 5 half-lives plus 90 days after administration of the last dose of trial drug. 
No restrictions are required for a vasectomized male subject provided the subject is at least 
1 year post–bilateral vasectomy procedure before trial drug administration on the first day 
of the first dose. A male subject whose vasectomy procedure was performed less than 
1 year before trial drug administration on the first day of the first dose must follow the 
same restrictions as a nonvasectomized man. Appropriate documentation of surgical 
procedure should be provided.
–
Is a male subject who agrees to not donate sperm from trial drug administration on the first 
day of the first dose until 5 half-lives plus 90 days after administration of the last dose of 
trial drug.
–
Is a female subject* with no childbearing potential, defined by at least 1 of the following 
criteria:
a) Postmenopausal (defined as 12 months of spontaneous amenorrhea in females aged 
>45 years, 6 months of spontaneous amenorrhea in females aged >45 years with serum 
follicle stimulating hormone (FSH) levels >40 mIU/mL). A high FSH level in the 
postmenopausal range (FSH >40 IU/L) may be used to confirm a post-menopausal 
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contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient. Appropriate documentation 
of FSH levels is required.
b) Surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate 
documentation of surgical procedure.
c) Had a tubal ligation with appropriate documentation of surgical procedure.
d) Has a congenital condition resulting in no uterus.
*Details of contraception and pregnancy procedures are found in Appendix E.
7.2
Exclusion Criteria
The subject must be excluded from participating in the trial if the subject: 
1. Subjects who have a history of clinically significant endocrine, gastrointestinal (including 
motility disorder and intestinal obstruction), cardiovascular, hematological, hepatic, 
immunological, renal, respiratory, genitourinary, or major neurological (including stroke and 
chronic seizures) abnormalities or diseases will be excluded from the trial.
2. Has participated in another investigational trial within 4 weeks before the pretrial visit 
(Screening). The 4-week window will be derived from the date of the last trial procedure 
and/or AE related to the trial procedure in the previous trial to the pretrial/Screening Visit of 
the current trial. 
3. Is an employee or immediate family member (eg, spouse, parent, child, sibling) of the sponsor.
4. Has a history of cancer (malignancy).
5. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy) or 
has had an anaphylactic reaction or significant intolerability to prescription or nonprescription 
drugs or food.
6. Has a positive alcohol or drug screen.
7. Is a lactating/nursing woman.
8. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 8 weeks of
the first dose of study drug. 
9. Has a known hypersensitivity to any component of the formulation of TAK-906 or related 
compounds, or to itraconazole (see Product Insert).
10. Is unable to refrain from or anticipates the use of any medication, including prescription and 
nonprescription drugs or herbal remedies, beginning approximately 7 days before 
administration of the initial dose of trial drug, throughout the trial (including washout intervals 
between trial periods), until the Follow-up Visit. There may be certain medications that are 
permitted, see Section 7.3.


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11. Has a history of alcohol consumption exceeding 2 standard drinks per day on average (1 glass 
is approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled 
spirits [29.5 mL/1 ounce] per day).
12. Consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately 
equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated 
beverages per day.
13. Has a substance abuse disorder.


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7.3
Excluded Medications, Supplements, Dietary Products
Use of excluded agents (prescription or nonprescription) or dietary products is outline in Table 7.a.
Table 7.a
Excluded Medications, Supplements, and Dietary Products
Category
Between Screening and Enrollment 
(Days -28 to Predose [Day 1])
Randomization Post-Enrollment 
(Day 1) to Follow-up
Tobacco- and 
nicotine-containing 
products
Completely restricted
Completely restricted
Cannabis products
Completely restricted

Completely restricted 
Alcohol
Completely restricted 7 days before 
dosing

Completely restricted 7 days before 
dosing 

At all other times no more than 
3 units/day
Xanthine and/or caffeine
Completely restricted 48 hours before 
dosing
Completely restricted 48 hours before 
dosing 
At all other times no more than 
6 units/day
Medications
Completely restricted 7 days before 
dosing
Completely restricted (a)
Food substance

Grapefruit /grapefruit 
juice
Completely restricted 7 days before 
dosing
Completely restricted

Fruit
No restriction
No restriction

Fruit juice
No restriction
Dosing will occur without consumption 
of fruit juice. Fruit juice is restricted 4 
hours after dosing.

Mustard green (b)
Completely restricted 7 days before 
dosing
Completely restricted

Charbroiled meat
Completely restricted 7 days before 
dosing
Completely restricted
(a) If medications are required to treat an AE, certain medications may be allowed after discussion and agreement 
between the sponsor and principal investigator.
(b) Mustard green family includes kale, broccoli, watercress, collard greens, kohlrabi, Brussel sprouts, and mustard.
7.4
Diet, Fluid, Activity 
7.4.1
Diet and Fluid
Subjects must abstain from all food and drink (except water) at least 8 hours before any clinical 
laboratory evaluations. In addition, both doses of TAK-906 will be administered after an overnight 
fast of at least 8 hours as food reduces its bioavailability by approximately 40%. 
The bioavailability of itraconazole when administered as a PO solution is increased under fasted 
compared with fed conditions; therefore, itraconazole will be administered as fasted on Day 4 of 


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Period 2. A moderate-fat breakfast or snack may be administered on itraconazole-only days to 
alleviate gastrointestinal irritation. Itraconazole will be administered to subjects under clinic
supervision on an outpatient basis on the morning of Days 1 to 3 of Period 2.
During confinement (optional), lunch will be provided approximately 4 hours after TAK-906 
maleate dosing or 5 hours after itraconazole dosing, as applicable, on all days. Dinner will be 
provided approximately 9 or 10 hours after TAK-906 maleate or itraconazole dosing, respectively, 
on all days. An evening snack will also be permitted. The caloric content and composition of meals 
will be the same in each trial period. After the 24-hour postdose (Day 2 of Trial Period 1 and Day 
5 of Trial Period 2) procedures have been completed, subsequent meals and snacks will be 
unrestricted in caloric content, composition, and timing.
7.4.2
Activity
Subjects will avoid unaccustomed strenuous physical activity (eg, weight lifting, running, 
bicycling) from the Screening Visit until the Follow-up visit.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
1. The subject experiences an 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 AE.
2. Liver function test (LFT) abnormalities
In multidose studies, trial drug should be discontinued immediately with appropriate clinical 
follow-up (including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 10.2.9.4), if the following circumstances occur at any time 
during trial drug treatment:
–
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 times the 
upper limit of normal (ULN), or
–
ALT or AST >5×ULN and persists for more than 2 weeks, or
–
ALT or AST >3×ULN in conjunction with elevated total bilirubin >2×ULN or 
international normalized ratio >1.5, or
–
ALT or AST >3×ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).
3. Significant protocol deviation. The discovery that the subject failed to meet protocol entry 
criteria or did not adhere to protocol requirements, and continued participation poses an 
unacceptable risk to the subject’s health.
4. Lost to follow-up. The subject did not return to the clinic, and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
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5. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the trial. The reason for withdrawal, if provided, should be recorded in the 
electronic case report form (eCRF). 
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal because of 
an AE should not be recorded in the “voluntary withdrawal” category).
6. Trial termination. The sponsor, IRB, or regulatory agency terminates the trial.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s trial participation at any time during the trial 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 trial. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
Early Termination Visit. 
7.7
Subject Replacement
If a subject discontinues from the trial, a replacement subject may be enrolled, if deemed 
appropriate by the investigator and sponsor. The trial site should contact the sponsor for the 
replacement subject’s treatment assignment and allocation number. 


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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
8.1
Clinical Trial Drug 
Details regarding the composition and extemporaneous preparation of the active ingredient are 
found in the Pharmacy Manual, Compounding Instructions, and/or similar documents. Clinical 
trial drug will be packaged to support enrollment and replacement subjects as required. When a 
replacement subject is required, the sponsor needs to be contacted before dosing.
Itraconazole will be supplied by the trial site.
8.1.1
Clinical Trial Drug Labeling
Clinical trial drug packaging will be affixed with a clinical label in accordance with regulatory 
requirements.
8.1.2
Clinical Trial Drug Inventory and Storage
Clinical trial drug must be stored in a secure, limited-access location under the storage conditions 
specified on the label. Inventory (receipt and dispensing) of trial drug must be recorded by an 
authorized person at the trial site. 
8.1.3
Clinical Trial Drug Blinding
This is an open-label trial; therefore, the sponsor, investigator, and subject will know the treatment 
administered.
8.1.4
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator is responsible for keeping accurate records of the clinical trial 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 trial. For all trial sites, the local country sponsor personnel or 
designee will provide appropriate documentation that must be completed for clinical trial drug 
accountability, return, and destruction. 
8.1.5
Ancillary Supplies
All ancillary supplies will be provided by either the site or Takeda, based upon availability. If 
provided by Takeda, unused ancillary supplies will be accounted for and disposed of as directed by 
Takeda or a Takeda designee.


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9.0
TRIAL PROCEDURES
The following sections describe the trial procedures and data to be collected as indicated in the 
Schedule of Trial 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. For information regarding procedures that are scheduled concurrently, see 
Section 6.2.3.
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
Informed consent must be obtained before the subject entering into the trial and before any 
protocol-directed procedures are performed. The requirements of informed consent are described 
in Section 13.2. 
9.1.2
Assignment of Screening Numbers
All consented subjects will be given a unique screening number that will be used to identify the 
subject for all procedures that occur before 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.
9.1.3
Inclusion and Exclusion Criteria 
Each subject is assessed according to the eligibility criteria provided in Section 7.0.
9.1.4
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. 
9.1.5
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. 
9.1.6
Physical Examinations
Qualified site personnel will conduct physical examinations.
9.1.7
Vital Sign Measurements
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.


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Subjects should rest in a semirecumbent position for at least 5 minutes before having vital sign 
measurements obtained. Vital signs will include heart rate (HR), systolic blood pressure, and 
diastolic blood pressure. The same method (eg, same and appropriately sized cuff, manual or 
automated) must be used for all measurements for each individual subject and should be the same 
for all subjects. 
Subjects will continue to rest in a semirecumbent position from the time of dosing until 4 hours 
postdose except to stand for the measurement of standing vital signs (if needed) or other 
trial-related procedure. 
9.1.8
Height and Weight
Body weight and height will be obtained with the subject’s shoes off and jacket or coat removed.
9.1.9
BMI
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 round down and 0.5 to 0.9 round up.
9.1.10 12-Lead ECG
Special care must be taken for proper lead placement by qualified personnel. Skin should be clean 
and dry before lead placement. Subjects may need to be shaved to ensure proper lead placement. 
Female subjects may need to remove their bras. 
Subjects should be resting in a semirecumbent position for at least 5 minutes before each ECG 
measurement.
QT intervals with Fridericia correction method (QTcF) will be used to calculate QT intervals in 
this trial.
Before each trial period, a predose ECG will be obtained within approximately 30 minutes before 
dosing. 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.
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.


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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: HR, PR-interval, QRS-duration, QT-interval, 
QTcF-interval, and the interpretation of the ECG profile by the principal investigator. 
9.1.11 AE Monitoring
AE monitoring begins after signing of informed consent. A complete description of AE collections 
and procedures is provided in Section 10.2.9.
9.2
Laboratory Procedures and Assessments
Laboratory samples will be collected in accordance with acceptable laboratory procedures. 
Samples will be taken after a minimum 8-hour overnight fast on the days stipulated in the Schedule 
of Trial Procedures (Section 3.0).
9.2.1.1
Clinical Laboratory Tests
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)


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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.
Urine Drug Screen
A urine drug screen will include the following tests: 
Amphetamines
3,4-methylenedioxy-methamphetamine 
Barbiturates
Methadone/metabolite
Benzodiazepines
Opiates
Buprenorphine/metabolite
Oxycodone/oxymorphone
Cannabinoids
Phencyclidine
Cocaine/metabolites
Cotinine
Alcohol Screen
Subjects will undergo a urine alcohol test. An alcohol breath test may be performed at the 
discretion of the investigator.
9.2.1.2
Screening
Serum
Serum evaluations will include the following tests:
β–human chorionic gonadotropin (women only)
FSH (women only).
HIV test
Hepatitis panel, including hepatitis B surface antigen and
anti-hepatitis C virus.


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9.3
PK and PGx Samples
A portion of the DNA sample will be analyzed for the presence of allelic variants in drug 
metabolizing enzymes, drug transporters, or putative drug targets that may contribute to the 
variability in the PK of TAK-906 (Drug Metabolism Enzymes and Transporters). 
As PGx is an evolving science, many genes and their functions are not yet fully understood. Future 
data may suggest a role of these genes in drug response, which may lead to additional 
hypothesis-generating exploratory research and diagnostic development on stored samples.
Samples for PK analysis will be collected as specified in the Schedule of Trial Procedures 
(Section 3.0). Please refer to the Laboratory Manual for information on the collection, processing, 
and shipment of samples to the central laboratory. 
It is anticipated that the total blood volume drawn for the trial will be approximately 180 mL. 
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 TAK-906 PK
Plasma
PK measurements
Mandatory
Blood sample for DNA PGX
Blood
DNA
PGx measurements
Mandatory
Blood sample for RNA PGX
Blood
RNA
PGx measurements
Mandatory
9.3.1
PK Evaluations 
The PK parameters of TAK-906 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.
The following plasma PK parameters for TAK-906 will be calculated on Day 1 of Trial Period 1 
and Day 4 of Trial Period 2: 

Cmax
.

AUC∞
.

t1/2
.
Other 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 eCRF.
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9.3.2
PGx Measurements
9.3.2.1
Blood Sample for DNA and RNA PGx Measurements
When sampling of whole blood for PGx analysis occurs, every subject must sign an informed 
consent/be consented in order to participate in the trial. PGx is a component of the trial; 
participation is mandatory.
PGx is the study of variations of DNA and RNA characteristics as related to drug response. There 
is increasing evidence that an individual’s genetic background may impact the PK (absorption, 
distribution, metabolism, and excretion), pharmacodynamics (pharmacologic effects), and/or the 
clinical outcome (efficacy and/or safety).
PGx research in this trial may be conducted to understand how individual genetic variation in 
subjects impacts their trial drug treatment response. This information may be also be used, for 
example, to develop a better understanding of the safety and efficacy of TAK-906 and other trial 
drugs, to increase understanding of the disease/condition being studied and other related 
conditions, gain a better understanding of the drug pharmacology and for generating information 
needed for research, development, and regulatory approval of tests to predict response to 
TAK-906. 
Whole blood samples for DNA and RNA isolation will be collected from each consented subject in 
the trial. If necessary and feasible, a second aliquot of blood may be taken at a later time point if 
isolation of DNA from the first sample was not successful or possible.
Since PGx is an evolving science, many genes and their functions are not yet fully understood. 
Future data may suggest a role of these genes in drug response, which may lead to additional 
hypothesis-generating exploratory research and diagnostic development on stored samples.
Detailed instructions for the handling and shipping of samples are provided in the Laboratory 
Manual.
9.3.2.2
Biological Sample Retention and Destruction
In this trial, specimens for genome/gene analysis will be collected as described in the Laboratory 
Manual. The genetic material will be initially stored at the vendor, or a comparable laboratory, 
under contract to Takeda, with validated procedures in place, and then preserved and retained at 
the vendor, or a comparable laboratory with validated procedures in place, for up to but not longer 
than 15 years from the end of the trial when the trial report is signed, or if less, the maximum 
period permitted under applicable law or until consent is withdrawn.
The sponsor and vendors working with the sponsor will have access to the samples collected and 
any test results. All samples collected during the trial will be stored securely with limited access 
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and the sponsor will require anyone who works with the samples to agree to hold the research 
information and any results in confidence.
The sample will be labeled with a unique sample identifier as in the main trial but using a code that 
is different from the code attached to the health information and other clinical test results collected 
in the trial. The sample and data are linked to personal health information with code numbers; the 
samples are stripped of all personal identifying information but a key linking the samples to 
clinical analysis data exists. This link means that the subject may be identified but only indirectly. 
The sample identifier will be kept secure by or on behalf of the sponsor.
Subjects who consented and provided a pharmacogenomic sample for DNA and RNA analysis can 
withdraw their consent at any time and request disposal of a stored sample. Any remaining sample 
that can be identified as coming from the subject will be destroyed. The trial doctor and sponsor 
may continue to use and distribute any information and test results gathered before the request to 
withdraw.
9.4
Trial Drug Administration
Eligible subjects will be allocated to trial treatment by nonrandom assignment on Period 1 Day 1 to 
receive PO TAK-906 maleate 25 mg capsule QD on Period 1 Day 1 and on Period 2 Day 4 at 
approximately the same time (between 0600 and 0900). 
In Period 2, subjects will receive PO itraconazole 200 mg solution QD on Days 1 to 5 at 
approximately the same time (between 0600 and 0900). Itraconazole will be administered to 
subjects under supervision on an outpatient basis on the morning of Days 1 to 3 of Period 2. On 
Day 4, TAK-906 maleate will be administered 1 hour after itraconazole. 
9.5
Confinement
Period 1:
Subjects will report to the CRU the evening before the scheduled day of administration (Day -1) of 
the trial drug at the discretion of the investigator. Subjects will remain in the unit until after the PK 
sample collection at 48 hours after TAK-906 maleate dosing (the morning of Day 3). At the 
discretion of the investigator, subjects may be requested to remain in the CRU longer.
Period 2:
Subjects will report to the CRU the evening of Day 3 before the scheduled day of administration of 
the trial drug on Day 4 and at the discretion of the investigator. Subjects will remain in the unit 
until after the PK sample collection at 48 hours after TAK-906 maleate dosing (the morning of 
Day 6). At the discretion of the investigator, subjects may be requested to remain in the CRU 
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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 maybe 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 at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, X-ray, etc) should NOT be recorded as an AE unless 
related to a trial procedure. However, if the subject experiences a worsening or complication of 


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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 eCRF, 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 8.1.

Serious adverse events (SAEs) of overdose should be reported according to the procedure 
outlined in Section 10.2.9.

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 
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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
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.
10.1.2 Special Interest AEs
An AE of special interest (serious or nonserious) is one of scientific and medical concern specific 
to the compound or program for which ongoing monitoring and rapid communication by the 
investigator to Takeda may be appropriate. Such events may require further investigation in order 
to characterize and understand and would be described in protocols and instructions provided for 
investigators as to how and when they should be reported to Takeda.
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, 
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10.2.3 Assigning Relationship to Trial Procedures
Relationship (causality) to trial procedures should be determined for all AEs.
The relationship should be assessed as “Related” if the investigator considers that there is 
reasonable possibility that an event is due to a trial procedure. Otherwise, the relationship should 
be assessed as “Not Related”.
10.2.4 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
10.2.5 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.
10.2.6 Frequency 
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.7 Action Concerning Trial Drug 

Drug withdrawn: a trial medication is stopped because of the particular AE.

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, for 
example, the trial has been terminated, the subject died, dosing with trial medication was 
already stopped before the onset of the AE.
10.2.8 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.”


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
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 because of hospital change or residence 
change at the end of the subject’s participation in the trial.
10.2.9 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal LFTs
10.2.9.1 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 until the 
Follow-up Visit 10 to 14 days after the last dose of TAK-906. For subjects who discontinue prior 
to the administration of trial medication, AEs will be followed until the subject discontinues trial 
participation. 
10.2.9.2 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 
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).

Investigator’s opinion of the causal relationship to trial procedure(s), including the details of 
the suspected procedure.


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
Action concerning trial medication.

Outcome of event.

Seriousness.
10.2.9.3 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 
Section 14.1.1.
Any SAE spontaneously reported to the investigator after the AE collection period should be 
reported to the sponsor if considered related to trial participation.
Reporting of SAEs that begin before the first administration of investigational product will follow 
the same procedure for SAEs occurring on treatment.
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.
10.2.9.4 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, an LFT Increases eCRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms, and results of any additional diagnostic tests performed.


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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 10.2.9.3. 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 must also be 
performed. In addition, an LFT Increases eCRF must be completed and transmitted with the 
Takeda SAE form (as per Section 10.2.10). 
10.2.10 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 
independent ethics committees (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 (SAP) will be prepared and finalized before database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all trial objectives.
A targeted data review will be conducted before database lock. This review will assess the 
accuracy and completeness of the trial database, subject evaluability, or appropriateness of the 
planned statistical methods.
11.1.1
Analysis Sets
11.1.1.1 Safety Set
The safety set will consist of all subjects who are enrolled and receive at least 1 dose of trial 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 are enrolled and receive at least 1 dose of trial drug and 
have at least 1 measurable plasma TAK-906 concentration. All subjects with valid PK parameter 
estimates will be included in the summaries and analyses for that parameter.
If any subject is found to be noncompliant with the dosing schedule or has incomplete data, a 
decision will be made on a case-by-case basis as to whether that subject should be included in the 
PK analyses; however, data for all subjects will be presented in the data listings.
11.1.2
Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized for all subjects. Summary statistics 
(number of subjects, mean, SD, median, minimum, and maximum) will be presented for 
continuous variables (eg, age, weight, and BMI), and the number and percentage of subjects within 
each category will be presented for categorical variables (eg, sex, ethnicity, and race). Individual 
subject demographic and baseline characteristic data will be provided in the data listings.
11.1.3
PK Analysis
Concentrations of TAK-906 and any measured metabolites will be summarized by regimen over 
each scheduled sampling time using descriptive statistics.
The amount of TAK-906 and any measured metabolites excreted in urine will be summarized by 
regimen using descriptive statistics. 
Individual plasma and urine concentration versus time data will be presented in a data listing. 


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Plasma and urine PK parameters of TAK-906 and any measured metabolites will be summarized 
by regimen using descriptive statistics. 
For evaluation of potential effect of itraconazole on TAK-906 PK, paired t-tests and associated 
90% confidence intervals (CIs) will be determined on the natural logarithms of Cmax and AUCs to 
assess the exposure between regimens (TAK-906 maleate alone and TAK-906 maleate with 
itraconazole). The geometric mean of the relative bioavailability of the TAK-906 maleate with 
itraconazole regimen relative to the TAK-906 maleate alone regimen and the associated 90% CIs 
will be determined by exponentiating the appropriate estimates for the difference between 
regimens in the log-transformed parameters.
A more detailed analysis will be presented in the SAP. Additional analyses will be included, if 
appropriate.
11.1.4
Safety Analysis
The safety set will be used for all summaries of safety parameters. These summaries will be 
presented by regimen (TAK-906 maleate alone, itraconazole alone, and TAK-906 maleate with 
itraconazole).
11.1.4.1 AEs
All AEs will be coded by system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse events (TEAEs) 
with onset occurring within 30 days after the last dose of trial drug (onset date minus last date of 
dose +1≤30) will be included in the summary tables. All AEs will be in the listings. TEAEs will be 
summarized by SOC and PT. The following summary tables will be included in the report: 
summary of TEAEs and drug-related AEs, relationship of AEs to trial drug (related vs not related), 
severity of AEs, and SAEs. Data listings will be provided for all AEs including TEAEs, AEs 
leading to trial drug discontinuation, and SAEs.
11.1.4.2 Clinical Laboratory Evaluation
Baseline, postdose, and change from Baseline to postdose laboratory data will be summarized by 
regimen. All clinical laboratory data will be provided in the data listings.
11.1.4.3 Vital Signs
Baseline, postdose, and changes from Baseline in vital sign measurements will be summarized. All 
vital sign data will be provided in the data listings.
11.1.4.4 ECGs
Baseline, postdose, and changes from Baseline in quantitative ECG parameters will be 
summarized by regimen. Shift tables for each will be generated to show the investigator’s ECG 
interpretations at each postdose collection by the interpretation at Baseline.
All ECG data will be provided in the data listings.


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11.2
Interim Analysis and Criteria for Early Termination
No formal interim analyses will be conducted. 
11.3
Determination of Sample Size
Approximately 12 subjects will be enrolled in this trial. The sample size justification is based on an 
acceptance range of 50% to 200% and assumes that the intrasubject %CV for AUClast and Cmax of 
TAK-906 will not exceed 25%. This sample size will provide 80% power to conclude plasma 
concentration of TAK-906 will not increase more than 2-fold in presence of itraconazole.
Subjects who drop out for nonsafety reasons may be replaced at the discretion of the investigator in 
consultation with the sponsor. Subjects who drop out for safety reasons will not be replaced.


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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Trial-Site Monitoring Visits
Monitoring visits to the trial site will be made periodically during the trial 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 site guarantee access to source documents by the sponsor or its designee 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, including but not limited to the Investigator’s Binder, trial 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 site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the trial. In 
addition, there is the possibility that this trial may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
trial site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator guarantees access for quality assurance auditors to all trial
documents as described in Section 12.1.


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13.0
ETHICAL ASPECTS OF THE TRIAL
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 Harmonisation (ICH) Harmonised 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 B. 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 
because of 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 site once the sponsor has confirmed the 
adequacy of site regulatory documentation and, when applicable, the sponsor has received 
permission from competent authority to begin the trial. Until the site receives drug/notification no 
protocol activities, including screening, may occur.
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 before use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB 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 before 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 before 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 before analysis. Notify the 
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 study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for American 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 Trial Contact Information 
Contact Type/Role
Contact
SAE and pregnancy reporting
Pharmacovigilance
Takeda Development Center Americas, Inc.
Fax: 224-554-1052


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15.0
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 Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.2.10 of this protocol.

Terms outlined in the trial site agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)


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15.1
Trial-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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15.2
List of Abbreviations
%CV
percent coefficient of variation
hCG
human chorionic gonadotropin
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUClast
area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration
AUC∞
area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration
BMI
body mass index
CFR
Code of Federal Regulations
CI
confidence interval
CLR
renal clearance
Cmax
maximum observed concentration
CNS
central nervous system
CRU
clinical research unit
CYP
cytochrome P-450
DA
dopamine
DNA
deoxyribonucleic acid
DDI
drug-drug interaction
ECG
electrocardiogram
eCRF
electronic case report form
EMA
European Medicines Agency
EPS
extrapyramidal symptoms
fe
fraction of administered dose of drug excreted in urine
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
HR
heart rate
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
PD
pharmacodynamics
PGx
pharmacogenomics
PK
pharmacokinetic(s)
PO
oral(ly)
PT
preferred term


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QD
once daily
QTcF
QT interval with Fridericia correction method
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SOC
system organ class
SUSAR
suspected unexpected serious adverse reactions
t1/2
half-life
tmax
time of first occurrence of Cmax
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
WBC
white blood cell


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16.0
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.
16.1
eCRFs
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 using 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.
16.2
Record Retention
The investigator agrees to keep the records stipulated in Section 16.1 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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17.0
REFERENCES 
1. Parkman HP, Hasler WL, Fisher RS, American Gastroenterological A. American 
Gastroenterological Association technical review on the diagnosis and treatment of 
gastroparesis. Gastroenterology 2004;127(5):1592-622.
2. Camilleri M, Parkman HP, Shafi MA, Abell TL, Gerson L, American College of G. Clinical 
guideline: management of gastroparesis. Am J Gastroenterol 2013;108(1):18-37; quiz 8.
3. Hyett B, Martinez FJ, Gill BM, Mehra S, Lembo A, Kelly CP, et al. Delayed radionucleotide 
gastric emptying studies predict morbidity in diabetics with symptoms of gastroparesis. 
Gastroenterology 2009;137(2):445-52.
4. Meltzer HY. Update on typical and atypical antipsychotic drugs. Annu Rev Med 
2013;64:393-406.
5. Michaud V, Turgeon J. Domperidone and sudden cardiac death: How much longer should we 
wait? J Cardiovasc Pharmacol 2013;61(3):215-7.
6. Darmani NA, Zhao W, Ahmad B. The role of D2 and D3 dopamine receptors in the mediation 
of emesis in Cryptotis parva (the least shrew). J Neural Transm (Vienna) 
1999;106(11-12):1045-61.
7. Kashyap P, Micci MA, Pasricha S, Pasricha PJ. The D2/D3 agonist PD128907 
(R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin- 9-ol) 
inhibits stimulated pyloric relaxation and spontaneous gastric emptying. Dig Dis Sci 
2009;54(1):57-62.
8. Lee A, Kuo B. Metoclopramide in the treatment of diabetic gastroparesis. Expert Rev 
Endocrinol Metab 2010;5(5):653-62.
9. Yoshikawa T, Yoshida N, Hosoki K. Involvement of dopamine D3 receptors in the area 
postrema in R(+)-7-OH-DPAT-induced emesis in the ferret. Eur J Pharmacol 
1996;301(1-3):143-9.
10. Andrews PL, Davis CJ, Bingham S, Davidson HI, Hawthorn J, Maskell L. The abdominal 
visceral innervation and the emetic reflex: pathways, pharmacology, and plasticity. Can J 
Physiol Pharmacol 1990;68(2):325-45.


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18.0
APPENDICES


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Appendix A
Detailed Description of Amendments to Text 
Change 1: Added additional serum β-human chorionic gonadotropin (hCG) tests.
The primary change occurs in Section 3.0 Schedule of Trial Procedures:
Description 
of change:
Added hCG to table at the following visits: Screening, Day -1, End of 
Treatment/Early Termination Visit
Rationale for Change:
Addition of serum hCG for all female subjects.
Change 2: Clarified use of follicle stimulating hormone (FSH) test.
The primary change occurs in Section 7.1 Inclusion Criteria:
Initial 
wording:
a)
Postmenopausal (defined as 12 months of spontaneous amenorrhea in females 
aged >45 years, 6 months of spontaneous amenorrhea in females aged >45 years 
with serum FSH levels >40 mIU/mL). Appropriate documentation of FSH levels 
is required.
Amended 
or new 
wording:
a) Postmenopausal (defined as 12 months of spontaneous amenorrhea in females 
aged >45 years, 6 months of spontaneous amenorrhea in females aged >45 years 
with serum FSH levels >40 mIU/mL). A high FSH level in the postmenopausal 
range (FSH >40 IU/L) may be used to confirm a post-menopausal state in 
younger women (eg, those <45 year 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. Appropriate documentation of FSH levels is required.
Rationale for Change:
Provide additional guidance for performing FSH to confirm postmenopausal status of female 
subjects <45 years of age.


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Change 3: Extended the morning dosing time range for the TAK-906.
The primary change occurs in Section 9.4 Trial Drug Administration
Initial 
wording:
Eligible subjects will be allocated to trial treatment by nonrandom assignment on 
Period 1 Day 1 to receive PO TAK-906 maleate 25 mg capsule QD on Period 1 Day 1 
and on Period 2 Day 4 at approximately the same time (between 0600 and 0800). 
In Period 2, subjects will receive PO itraconazole 200 mg solution QD on Days 1 to 5 
at approximately the same time (between 0600 and 0800). Itraconazole will be 
administered to subjects under supervision on an outpatient basis on the morning of 
Days 1 to 3 of Period 2. On Day 4, TAK-906 maleate will be administered 1 hour after 
itraconazole.
Amended 
or new 
wording:
Eligible subjects will be allocated to trial treatment by nonrandom assignment on 
Period 1 Day 1 to receive PO TAK-906 maleate 25 mg capsule QD on Period 1 Day 1 
and on Period 2 Day 4 at approximately the same time (between 0600 and 0800 0900). 
In Period 2, subjects will receive PO itraconazole 200 mg solution QD on Days 1 to 5 
at approximately the same time (between 0600 and 0800 0900). Itraconazole will be 
administered to subjects under supervision on an outpatient basis on the morning of 
Days 1 to 3 of Period 2. On Day 4, TAK-906 maleate will be administered 1 hour after 
itraconazole. 
Rationale for Change:
Accommodate subject procedures performed before dosing.
Change 4: Aligned timing and procedures for collection of AE throughout document.
The primary change occurs in Section 9.1.11 AE Monitoring
Initial 
wording:
AE monitoring begins after signing of informed consent. Changes in subject health 
status from baseline assessment to trial drug administration should be captured in the 
subject’s medical history. A complete description of AE collections and procedures is 
provided in Section 10.2.9.
Amended 
or new 
wording:
AE monitoring begins after signing of informed consent. Changes in subject health 
status from baseline assessment to trial drug administration should be captured in the 
subject’s medical history. A complete description of AE collections and procedures is 
provided in Section 10.2.9.
Rationale for Change:
Removed sentence to align collection of AE data with Section 10.0 Adverse Events


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Change 5: Removed data collection using digital wearable devices.
The primary change occurs in Section 10.2.9.3 Reporting SAEs:
Deleted 
text:
Rationale for Change:
Digital wearable devices will not be used in this study.
Change 6: Clarified birth control requirements for female partners of male subjects.
The primary change occurs in Appendix E Pregnancy and Contraception.
Initial 
wording:
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the trial, and for 5 
half-lives PLUS 90 days after the last dose of trial 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. Women of 
childbearing potential who are partners of male subjects are also advised to use 
additional contraception as shown in the list containing highly effective/effective 
contraception below.
Amended 
or new 
wording:
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the trial, and for 5 
half-lives PLUS 90 days after the last dose of trial 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. Women of 
childbearing potential who are partners of male subjects are also advised to use 
additional contraception as shown in the list containing highly effective/effective 
contraception below.
Rationale for Change:
Male birth control requirements will apply to all female partners of male subjects, regardless of the 
female partner’s child-bearing potential.
CCI


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Change 7: Updated predose restriction for xanthine and/or caffeine use.
The primary change occurs in Section 7.3 Excluded Medications, Supplements, Dietary Products; 
Table 7.a Excluded Medications, Supplements, and Dietary Products
Description 
of change:
Changed length of xanthine and/or caffeine use predose from 24 to 48 hours.
Xanthine and/or caffeine
Completely restricted 2448 hours before 
dosing
Completely restricted 2448 hours before 
dosing 
At all other times no more than 
6 units/day
Rationale for Change: Lengthened restriction time for xanthine and/or caffeine use to ensure 
adequate washout before dose.
Change 8: Added urine cotinine as part of drug screen.
The primary change occurs in Section 9.2.1.1 Clinical Laboratory Tests:
Description 
of change:
Table: Urine Drug Screen
cotinine
Rationale for Change:
Added to urine drug screening because of involvement of CYP 1A2 with TAK-906’s mechanism 
of action.


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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this 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 study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, before the receipt of written 
approval from relevant governing bodies/authorities.
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 
21 Code of Federal Regulations (CFR) Part 56, 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 21 CFR Part 50, 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 
2 years after notification by the sponsor that all investigations have been discontinued or that 
the regulatory authority has approved the marketing application. The investigator should 


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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 C
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the 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 procedures that are 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 description of the possible side effects of the treatment that the subject may receive.
10. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
11. 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.
12. 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.
13. 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.
14. 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.
15. The anticipated prorated payment(s), if any, to the subject for participating in the trial.
16. The anticipated expenses, if any, to the subject for participating in the trial.
17. 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.
18. 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 
participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled.


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19. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
20. 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.
21. A statement that results of PGx analysis will not be disclosed to an individual, unless 
prevailing laws require the sponsor to do so.
22. The foreseeable circumstances or reasons under which the subject’s participation in the trial 
may be terminated.
23. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the trial. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the trial medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the trial to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that trial results are 
published.
24. Male subjects must use adequate contraception (as defined in the informed consent) from 
Screening, throughout the duration of the trial, and for 5 half-lives plus 90 days 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 treatment information. 


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25. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.


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Appendix D
Investigator Consent to Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the 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 E
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Female Subjects and Their Male Partners
Female subjects of childbearing potential are excluded from this trial; there are no requirements 
for contraception or pregnancy avoidance.
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the trial, and for 5 half-lives PLUS 
90 days after the last dose of trial drug, nonsterilized** male subjects who are sexually active with 
a female partner 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. Women who are 
partners of male subjects are also advised to use additional contraception as shown in the list 
containing highly effective/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.
1. Highly effective methods of contraception are defined as “those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this trial, where medications and devices containing hormones are included, 
females of childbearing potential who are partners of male subjects are advised to use 
additional contraception chosen from the list below: 

Nonhormonal methods: 
–
Intrauterine device.
–
Bilateral tubal occlusion. 

Hormonal methods: 
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months before the first dose of trial drug.
Oral. 
Intravaginal (eg, ring).
Transdermal. 
–
Progestogen-only hormonal contraception associated with inhibition of ovulation 
initiated at least 3 months before the first dose of trial drug.
Oral. 
Injectable.
Implantable.


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2. Since genotoxicity/teratogenicity/embryotoxicity is unlikely to be caused by the 
investigational drug, additional effective methods of contraception (there may be a higher than 
1% failure rate) that may be chosen by the female partner of a male subject are: 

Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal 
jellies or creams).

Progestogen only hormonal contraception, where inhibition of ovulation is not the primary 
mode of action. 
3. Unacceptable methods of contraception are:

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.
4. Male subjects will be provided with information on highly effective/effective methods of 
contraception as part of the subject informed consent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy and 
sperm donation during the course of the trial.
5. Male 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?


 
  
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d6805ff524
Amendmend 01 to A Single-Sequence, Open-Label, 2-Period, Crossover Trial to Evaluate the Effect of the
Potent CYP3A4 Inhibitor Itraconazole on the Single-Dose Pharmacokinetics of Oral TAK-906 in Healthy Adult
Subjects
Clinical Pharmacology Approval
25-May-2017 13:38 UTC
Statistical Approval
25-May-2017 13:45 UTC
Clinical Approval
25-May-2017 23:37 UTC
PPD

SAP_001.pdf: 
This may include, but is not limited to, redaction of the following: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Single-Sequence, Open-Label, 2-Period, Crossover Trial to Evaluate the Effect of the
Potent CYP3A4 Inhibitor Itraconazole on the Single-Dose Pharmacokinetics of Oral
TAK-906 in Healthy Adult Subjects.
NCT Number: NCT03161405
SAP Approve Date: 3 August 2017
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content 
is masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information or company confidential information. 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-906-1003
A Single-Sequence, Open-Label, 2-Period, Crossover Trial to Evaluate the Effect of the Potent 
CYP3A4 Inhibitor Itraconazole on the Single-Dose Pharmacokinetics of Oral TAK-906 in 
Healthy Adult Subjects
PHASE 1
Version: Final
Date: 03 August 2017
Prepared by:
Based on:
Protocol Version: Amendment 01
Protocol Date: 25 May 2017
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda.
PPD


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1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.


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2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
List of In-Text Figures...........................................................................................................4
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Exploratory Objectives ..............................................................................................7
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS...............................................................................................9
5.1
Primary Endpoints .....................................................................................................9
5.2
Safety Endpoints........................................................................................................9
5.3
Exploratory Endpoints ...............................................................................................9
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................10
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................11
7.1
General Principles....................................................................................................11
7.1.1
Definition of Study Days and Baseline...............................................................11
7.1.2
Missing Data......................................................................................................11
7.2
Analysis Sets ...........................................................................................................11
7.3
Disposition of Subjects ............................................................................................12
7.4
Demographic and Other Baseline Characteristics.....................................................12
7.5
Medical History and Concurrent Medical Conditions...............................................12
7.6
Medication History and Concomitant Medications...................................................13
7.7
Study Drug Exposure and Compliance.....................................................................13
7.8
Efficacy Analysis.....................................................................................................13
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................13
7.9.1
Pharmacokinetic Analysis ..................................................................................13
7.9.2
Pharmacodynamic Analysis ...............................................................................14
7.10
Other Outcomes.......................................................................................................14
7.11
Safety Analysis........................................................................................................14
7.11.1 Adverse Events ..................................................................................................14
7.11.2 Clinical Laboratory Evaluations .........................................................................15
7.11.3 Vital Signs .........................................................................................................16


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7.11.4 12-Lead ECGs ...................................................................................................16
7.11.5 Other Observations Related to Safety.................................................................17
7.12
Interim Analysis ......................................................................................................17
7.13
Changes in the Statistical Analysis Plan...................................................................17
8.0
REFERENCES..............................................................................................................18
LIST OF IN-TEXT FIGURES
Figure 4.a
Trial Schematic....................................................................................................8
LIST OF APPENDICES 
Appendix A
Schedule of Trial Procedures..............................................................................19
Appendix B
Clinical Laboratory Tests and Screening ............................................................21
Appendix C
Criteria for Identification of Markedly Abnormal Laboratory Values .................22
Appendix D
Criteria for Abnormal Changes from Baseline of Vital Signs..............................23
Appendix E
Criteria for Markedly Abnormal Values for the 12-Lead ECG Parameters..........24


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3.0
LIST OF ABBREVIATIONS
%CV
percent coefficient of variation
hCG
human chorionic gonadotropin
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUClast
area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration
AUC∞
area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration
BLQ
below the limit of quantification
BMI
body mass index
BUN
blood urea nitrogen
CPK
creatine phosphokinase
CFR
Code of Federal Regulations
CI
confidence interval
CLR
renal clearance
Cmax
maximum observed concentration
CNS
central nervous system
CRU
clinical research unit
CYP
cytochrome P-450
DA
dopamine
DNA
deoxyribonucleic acid
DDI
drug-drug interaction
ECG
electrocardiogram
eCRF
electronic case report form
EMA
European Medicines Agency
EPS
extrapyramidal symptoms
fe
fraction of administered dose of drug excreted in urine
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GI
gastrointestinal
GM
geometric mean
HIV
human immunodeficiency virus
HR
heart rate
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board


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LFT
liver function test
LLN
lower limit of normal
MAV
markedly abnormal value
MedDRA
Medical Dictionary for Regulatory Activities
PD
pharmacodynamics
PGx
pharmacogenomics
PK
pharmacokinetic(s)
PO
oral(ly)
PT
preferred term
QD
once daily
QTcF
QT interval with Fridericia correction method
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SDB
standard database
SOC
system organ class
SUSAR
suspected unexpected serious adverse reactions
t1/2
half-life
tmax
time of first occurrence of Cmax
TEAE
treatment-emergent adverse event
TLGs
tables, listings, and graphs
ULN
upper limit of normal
WBC
white blood cell
WHODrug
World Health Organization Drug Dictionary


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4.0
OBJECTIVES
4.1
Primary Objectives
The primary objective of the trial is to evaluate the effect of the potent CYP3A4 inhibitor 
itraconazole on the single-dose pharmacokinetics (PK) of PO TAK-906 maleate.
4.2
Secondary Objectives
The secondary objective of the trial to evaluate the safety and tolerability of single PO dose of 
TAK-906 maleate in the presence and absence of a potent CYP3A4 inhibitor.
4.3
Exploratory Objectives
Exploratory objectives of this trial include: 
4.4
Study Design
This is a phase 1, single-sequence, open-label, 2-period crossover trial in approximately 
12 healthy male and female (nonchildbearing-potential) subjects. The trial is designed to 
investigate the effect of a potent CYP3A4 inhibitor (itraconazole) on the PK of TAK-906.
The trial will include a Screening Visit, a Period 1 (Days 1 to 3), followed by a minimum of a 
4-day washout from the time of TAK-906 maleate dose, a Period 2 (Days 1 to 6), and a 
Follow-up Visit. 
On Day 1 of Period 1, eligible subjects will be enrolled into the trial and will receive a single PO 
dose of TAK-906 maleate 25 mg. On Days 1 to 5, inclusive, of Period 2, subjects will receive 
itraconazole 200 mg once daily (QD) PO solution. Following after an overnight fast of at least 
8 hours, a single PO dose of TAK-906 maleate 25 mg will be administered 1 hour after the 
itraconazole dose on Day 4 of Period 2. Both doses of TAK-906 maleate will be administered 
after an overnight fast of at least 8 hours as food reduces its bioavailability by approximately 
40%.
Itraconazole will be administered to subjects under clinic supervision on an outpatient basis on 
the morning of Days 1 to 3 of Period 2 and during confinement on Days 4 to 5 of Period 2. 
Blood samples for assessment of TAK-906 concentrations will be collected from predose to 
48 hours after each dose of TAK-906 maleate. Samples may be assayed for TAK-906 
metabolites if deemed necessary. Urine samples will be collected through 48 hours and may be 
assayed for TAK-906 concentrations and metabolites if deemed necessary for the interpretation 
of data.
Whole blood samples for deoxyribonucleic acid (DNA) pharmacogenomics (PGx) analysis and 
ribonucleic acid (RNA) isolation will be collected predose on Day 1 of Trial Period 1. 
CCI


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Safety will be assessed by monitoring for adverse events, vital signs, ECGs, clinical laboratory 
results, and physical examinations throughout each dosing period.
After completion of the trial (or following subject withdrawal), all subjects will return for a 
Follow-up Visit 10 to 14 days after their last dose of TAK-906 maleate.
A schematic of the study design is shown in Figure 4.a. A schedule of assessments is listed in 
Appendix A.
Figure 4.a
Trial Schematic


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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
The primary endpoints of the trial are the following plasma PK parameters for TAK-906 on 
Days 1 and 4:
!
Maximum observed concentration (Cmax).
!
Area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration (AUClast).
!
Area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration (AUC∞).
5.2
Safety Endpoints
Safety endpoints include the following: 
!
Safety and tolerability will be assessed through physical examinations, ECGs, vital signs, 
clinical laboratory results, and collection of spontaneous adverse events (AEs).
5.3
Exploratory Endpoints
Exploratory endpoints will be assessed through the following parameters: 
CCI


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6.0
DETERMINATION OF SAMPLE SIZE
Approximately 12 subjects will be enrolled in this trial. The sample size justification is based on 
an acceptance range of 50% to 200% and assumes that the intrasubject %CV for AUClast and 
Cmax of TAK-906 will not exceed 25%. This sample size will provide 80% power to conclude 
plasma concentration of TAK-906 will not increase more than 2-fold in presence of itraconazole.
Subjects who drop out for nonsafety reasons may be replaced at the discretion of the investigator 
in consultation with the sponsor. Subjects who drop out for safety reasons will not be replaced.


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
Continuous data will be summarized using descriptive statistics, including the number of 
subjects, mean, standard deviation (SD), median, minimum, and maximum. The coefficient of 
variation (%CV) and geometric mean will be included in the summary of continuous data where 
indicated. Categorical data will be summarized as the number and percentage of subjects in each 
category.
Arithmetic means, geometric means, and medians will be presented to 1 more decimal place than 
the recorded data, and SDs will be presented to 2 more decimal places than the recorded data, 
where appropriate. Where applicable, confidence intervals about a parameter estimate will be 
presented using the same number of decimal places as the parameter estimate and p-values will 
be rounded to 3 decimal places prior to assessment of statistical significance.
All study-related raw data for enrolled subjects, including derived data, will be presented in data 
listings. In addition, the actual day relative to the first dose will be presented, where applicable.
All statistical analyses will be performed using the SAS System Version 9.4.
7.1.1
Definition of Study Days and Baseline
Study Day 1 is defined as the date of the first dose of study drug, as recorded on the electronic 
case report form (eCRF) study drug administration page. Other study days are defined relative to 
Study Day 1, with Day 1 being Study Day 1 and Day -1 being the day prior to Study Day 1. 
Study days prior to the first dose of study drug will be calculated as: [date of assessment/event –
date of first dose of study drug]. Study days on or after the first dose of study drug will be 
calculated as: [date of assessment/event – date of first dose of study drug + 1].
Unless specified otherwise, baseline is defined as the last non-missing measurement prior to the 
first dose of study drug.
7.1.2
Missing Data
There will be no imputation of incomplete or missing data. 
Plasma concentrations that are below the limit of quantification (BLQ) will be treated as zero in
the summarizing concentration values and deriving of PK parameters. These values will be
flagged in the data listings.
7.2
Analysis Sets
The following analysis sets will be used for analysis and presentation of the study data:

Safety Set: The safety set will consist of all subjects who are enrolled and received at least 
1 dose of study drug. Subjects in this analysis set will be used for demographic, baseline 
characteristics, and safety summaries.


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
PK Set: The PK set will consist of all subjects who are enrolled, receive at least 1 dose of 
trial drug, and have at least 1 measurable plasma TAK-906 concentration. 
All subjects in the PK set with valid PK parameter estimates will be included in the summaries 
and analyses for that parameter. Decisions regarding inclusion or exclusion of data from PK 
analysis for subjects who are noncompliant with the dosing schedule, or who have incomplete 
data, will be made on a case-by-case basis, but the data will be presented in data listings 
regardless.
7.3
Disposition of Subjects
Study Information, including date of first subject signing Informed Consent Form (ICF), date of 
first/last study drug, date of last subject’s last visit/contact, date of last subject’s last procedure 
for collection of data for primary endpoint, Medical Dictionary for Drug Regulatory Activities 
(MedDRA) Version, World Health Organization Drug Dictionary (WHODrug) Version, and 
SAS Version, will be tabulated.
The eligibility of subjects will be summarized, along with the primary reasons of screen failure 
as recorded in eCRF.
The number and percentage of subjects who comprised each analysis set will be summarized.
Disposition of all enrolled subjects will be tabulated. Categories will include:

Subjects who were enrolled but not dosed.

Subjects who completed the study.

Subjects who prematurely discontinued study.

Primary reasons for discontinuing study, as entered on the eCRF.
7.4
Demographic and Other Baseline Characteristics
Demographic and study baseline characteristics, including age at informed consent, gender, 
ethnicity, race, height (cm), weight (kg), and body mass index (kg/m2), will be summarized.
There will be no inferential analysis of demographic and baseline characteristics.
7.5
Medical History and Concurrent Medical Conditions
Medical history is defined as significant conditions or diseases that resolved at or prior to the 
time of informed consent. Concurrent medical conditions are defined as significant conditions or 
diseases that are present at signing of informed consent.
Medical history and concurrent medical conditions will be coded using the MedDRA coding 
system, and will be presented in the data listing. There will be no summary or inferential analysis 
of medical history and concurrent medical conditions.


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7.6
Medication History and Concomitant Medications
Medication history information includes any medication stopped at or within 28 days prior to 
signing of informed consent. Medications used from signing of informed consent through the end 
of study will be considered as concomitant medications.
Medication history and concomitant medications will be coded using the WHO Drug, and will be 
presented in the data listing. There will be no summary or inferential analysis of medication 
history and concomitant medications.
7.7
Study Drug Exposure and Compliance
The date and time of each dose for each subject will be reported in the data listing for all
subjects. Summaries and listings of TAK-906 PK data will be provided. No summary statistics 
for the extent of exposure to study drug or compliance calculations will be performed for this 
study.
7.8
Efficacy Analysis
Not applicable.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
The schedule for blood and urine samples for PK analysis of TAK-906 and any measured 
metabolites is specified in Appendix A.
The plasma of TAK-906 and any measured metabolites will be summarized by regimen 
(TAK-906 maleate alone and TAK-906 maleate with itraconazole) over each scheduled sampling 
time point using descriptive statistics (N, arithmetic mean, SD, CV%, median, minimum and 
maximum). Individual plasma and urine concentration data versus time will be presented 
together with the descriptive statistics as well as in separate data listings.
In addition, the figures for mean plasma concentrations of TAK-906 versus time (linear and 
semi-log scale) will be generated.
Plasma and urine PK parameters will be calculated from the plasma and urine concentration 
values versus time profile of TAK-906 and any measured metabolites using non-compartmental 
analysis. The key PK parameters are listed below:
Plasma
CCI


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Urine
Additional plasma and/or urine PK parameters may be calculated if necessary, in accordance 
with the Clinical Pharmacology Analysis Plan (CPAP).
Plasma and urine PK parameters of TAK-906 and any measured metabolites will be summarized
by regimen using descriptive statistics. In addition, geometric mean and %CV will be computed 
for Cmax and AUCs (AUClast and AUC∞).
Box plots and scatter plots for Cmax and AUCs (AUClast and AUC∞) will be generated by
regimen.
For evaluation of potential effect of itraconazole on TAK-906 PK, paired t-tests and associated
90% confidence intervals (CIs) will be determined on the natural logarithms of Cmax and AUCs
(AUClast and AUC∞) to compare the exposure between regimens. The geometric mean of the 
relative bioavailability of the TAK-906 maleate with itraconazole regimen relative to the 
TAK-906 maleate alone regimen and the associated 90% CIs will be determined by 
exponentiating the appropriate estimates for the difference between regimens in the 
log-transformed parameters.
All PK parameters calculated will be presented in data listings.
7.9.2
Pharmacodynamic Analysis
Not applicable.
7.10
Other Outcomes
Not applicable.
7.11
Safety Analysis
Safety analyses include adverse events (AEs), clinical laboratory parameters, vital sign 
parameters, 12-lead electrocardiogram (ECG) results, and physical examination.
All summaries of safety data are based on subjects in the Safety Analysis Set.
7.11.1 Adverse Events
A treatment-emergent adverse event (TEAE) will be defined as an AE or serious adverse event 
(SAE) that started or worsened after first study drug administration and within 30 days of last 
dose of study drug (onset date – date of last dose + 1 ≤30). All AE verbatim terms will be coded 
by system organ class (SOC) and preferred term (PT) using the MedDRA dictionary.
CCI
CCI


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TEAEs will be summarized by overall and the following categories: Period 1 (onset on and after 
TAK-906 dosing on Period 1 Day 1 and before the dosing of itraconazole on Period 2 Day 1), 
Period 2 Day 1 post-dose to Day 4 pre-dose (after itraconazole dosing on Period 2 Day 1and 
before TAK-906 dosing on Period 2 Day 4), and Period 2 Day 4 post-dose and thereafter (after 
TAK-906 and itraconazole dosing on Period 2 Day 4). The tables will include the number and 
percentage (N [%]) of subjects reporting any event for that term. The following is a list of TEAE 
summary tables to be generated. 

Overview of TEAEs (at both subject and event level).

TEAEs by SOC and PT (at both subject and event level).

Subject Mappings for TEAEs.

TEAEs by PT.

Relationship of TEAEs to Study Drug by SOC and PT. 

Drug-Related TEAEs by SOC and PT.

Intensity of TEAEs by SOC and PT.

Intensity of Drug-Related TEAEs by SOC and PT. 
For each category and overall, subjects reporting more than 1 occurrence for a term (SOC or PT) 
being summarized will be counted only once using the most extreme incident (most severe for 
the intensity tables and related for the relationship to study drug tables).
Data listings will be provided for all TEAEs, PTEs, TEAEs that led to study drug 
discontinuation, TEAEs that led to abnormal liver functions, SAEs, AEs that resulted in death, 
and AEs occurring more than 30 days after the last dose of study medication.
7.11.2 Clinical Laboratory Evaluations
Clinical safety laboratory tests include chemistry, hematology, urinalysis, and diagnostic 
screening. Refer to Appendix A for scheduled clinical laboratory test measurements and to
Appendix B for the list of all clinical laboratory tests.
Descriptive statistics (N, mean, median, SD, minimum and maximum) of clinical safety
laboratory variables will be summarized for baseline, post-dosing, and change from baseline at
each visit. Only the scheduled measurements will be included in the summary. No inferential 
analysis will be performed.
Individual results for hematology and chemistry laboratory tests will be evaluated against the
Takeda predefined laboratory markedly abnormal value (MAV) criteria (Appendix C). All 
subjects that meet the MAV criteria will be presented in a data listing. If a subject has a MAV for 
a particular laboratory test, all visits for that subject for that parameter will be listed. The number 
and percentage of subjects with at least 1 post dose markedly abnormal laboratory test result will 
be summarized by regimen. The mapping of the subjects with post dose results which meet the 
MAV criteria will be listed as a table. All post dose clinical lab results within 7 days of the last 


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dose, including scheduled and unscheduled measurements will be included in the MAV 
summaries.
All clinical laboratory data will be presented in both SI and conventional units in the data 
listings. Laboratory data outside of the normal reference range will be flagged on the listing 
along with values meeting MAV criteria.
7.11.3 Vital Signs
Vital sign measurements include body temperature, pulse, respiratory rate, and blood pressure.
Refer to Appendix A for scheduled vital signs measurement visits.
Descriptive statistics (N, mean, median, SD, minimum and maximum) of these vital signs will be 
summarized by regimen for baseline, post-dosing, and change from baseline at each scheduled 
time point. For each regimen (period), baseline is defined as the last non-missing vital sign 
measurement at or prior to predose (time relative to TAK-906 dosing) in the corresponding 
period. Only the vital signs collected at the scheduled visits or time points will be included in the 
summary. No inferential analysis will be performed for the observed vital signs.
All individual vital signs that meet Takeda’s predefined criteria for markedly abnormal values 
(Appendix D) will be listed. The number and percentage of subjects with at least 1 post dose 
markedly abnormal vital sign measurement will be summarized by regimen. The mapping of the 
subjects with post dose results which meet the MAV criteria will be listed as a table. All post 
dose vital signs within 7 days of the last dose, including both scheduled and unscheduled 
measurements, will be included in the MAV summaries.
All vital sign data will be presented in the listings. Vital sign MAVs will be flagged in the 
listings.
7.11.4 12-Lead ECGs
The scheduled 12-lead ECG data will be collected according to Appendix A. The ECG 
parameters include heart rate, PR interval, QRS duration, QT interval, and QT interval with 
Fredericia’s corrections (QTcF).
Quantitative triplicate ECG measurements at each time point will be averaged. Descriptive 
statistics (N, mean, median, SD, minimum and maximum) of quantitative ECG data will be 
summarized by regimen for baseline, post-dosing, and change from baseline at each scheduled 
time point. For each regimen (period), baseline is defined as the last non-missing ECG 
measurement at or prior to predose (time relative to TAK-906 dosing) in the corresponding 
period. Only the ECGs collected at the scheduled visits or time points will be included in the 
summary. No inferential analysis will be performed for the observed ECGs.
For ECG interpretation data, shift table will be provided as the number of subjects to assess 
interpretation status change from baseline to each scheduled post-baseline measurement by 
regimen. In the ECG shift table, the best value out of triplicate ECG interpretations will be used 
to represent baseline evaluation, and the worst value will be used to represent post baseline
evaluation. 


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All individual ECGs that meet Takeda’s predefined criteria for markedly abnormal values 
(Appendix E) will be listed. The number and percentage of subjects with at least 1 markedly 
abnormal ECG measurement will be summarized by regimen. The mapping of the subjects who 
meet the MAV criteria will be listed as a table. All post dose ECGs within 7 days of the last 
dose, including both scheduled and unscheduled measurements, will be included in the MAV 
summaries.
All ECG data will be presented in the listings. ECG MAVs will be flagged in the listings.
7.11.5 Other Observations Related to Safety
Physical examination findings and all cases of overdose will be presented in data listings. No 
summary tables will be provided. 
7.12
Interim Analysis
Not applicable.
7.13
Changes in the Statistical Analysis Plan 
None.


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8.0
REFERENCES
1. A Single-Sequence, Open-Label, 2-Period, Crossover Trial to Evaluate the Effect of the 
Potent CYP3A4 Inhibitor Itraconazole on the Single-Dose Pharmacokinetics of Oral 
TAK-906 in Healthy Adult Subjects, Takeda Development Center Americas, Inc., Protocol 
No. TAK-906-1003, dated 25 May, 2017.


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Appendix A
Schedule of Trial Procedures
Screening
Period 1 (a)
Period 2
Follow-
up/Early 
Termina-
tion
Procedures/Assessments
Day -28 to
-2
Day
Day
10-14 days 
after last 
dose of 
TAK-906
-1
Pre-
dose
(Day 
1)
1
2
3
1
2
3
4
5
6
Administrative Procedures
Informed consent
X
Inclusion/exclusion criteria
X
X
X
Medical history/demographics
X
Prior and concomitant medication 
review
----------------------------------Continuous Monitoring-------------------------
Clinic Procedures/Assessments
Full physical examination
X
X 
(b)
X
Height
X
Weight
X
BMI
X
12-Lead ECG
X
X(c)
X(c)
X
X(c)
X
X
Semirecumbent vital signs (heart 
rate [HR], systolic blood pressure 
and diastolic blood pressure 
X
X(d)
X(d)
X
X
X(d)
X
X
Vital signs (respiratory rate, oral 
[at the floor of the 
mouth]/tympanic temperature) rate
X
X
X
X
X
X
X
X
TAK-906 administration
X
X
Itraconazole administration (e)
X
X
X
X
X
AE monitoring
---------Continuous Monitoring--------
Laboratory Procedures/Assessments
Hematology
X
X 
(b)
X 
(b)
X
X
Urinalysis
X
X 
(b)
X 
(b)
X
X
Chemistry
X
X 
(b)
X 
(b)
X
X
Serum follicle stimulating 
hormone (FSH)
X
β-human chorionic gonadotropin 
(hCG)
X
X
X


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Screening
Period 1 (a)
Period 2
Follow-
up/Early 
Termina-
tion
Procedures/Assessments
Day -28 to
-2
Day
Day
10-14 days 
after last 
dose of 
TAK-906
-1
Pre-
dose
(Day 
1)
1
2
3
1
2
3
4
5
6
Urine drug screen
X
X
X
Urine alcohol test/alcohol breath 
test (f)
X
X
X
Hepatitis screen 
X
Human immunodeficiency virus 
(HIV) 
X
Pharmacokinetics Evaluations
Pharmacogenomic (PGx) Evaluations
PGx DNA collection
X
PGx RNA collection
X
Other
Confinement 
X--------------X
X------------X
Meals fasting (i)
X
X
X
(a) There will be a minimum 4 day washout between Periods 1 and 2, starting from administration of TAK-906 maleate on Day 1 
of Period 1.
(b) Day 1 predose assessment may be done within approximately 24 hours prior to trial drug administration.
(c) Triplicate measurements to be conducted at 0 (predose), 1, 2, 4, 8 and 48 hours postdose (times relative to TAK-906 maleate 
dose).
(d) Measured at 0 (predose), 1, 2, 4, 8 and 48 hours postdose (times relative to TAK-906 maleate dose).
(e) Itraconazole will be administered once daily at the same time each day and 1 hour prior to TAK-906 maleate on Day 4.
(f) An alcohol breath test may be performed at the discretion of the investigator.
(g) 
 
 
(h) 
 
(i) Subjects will fast overnight at least 8 hour before dose of TAK-906 maleate on Day 1 of Period 1 and at least 8 hours before 
itraconazole and TAK-906 maleate doses on Day 4 of Period 2.
CCI
CCI
CCI
CCI
CCI
CCI


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Appendix B
Clinical Laboratory Tests and Screening
Chemistry 
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)
Hematology
Erythrocytes (red blood cells [RBCs])
Hemoglobin
Hematocrit
Platelets
Leukocytes (white blood cells [WBCs]) with absolute 
differential
Urinalysis
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.
Urine Drug Screen
Amphetamines
3,4-methylenedioxy-methamphetamine 
Barbiturates
Methadone/metabolite
Benzodiazepines
Opiates
Buprenorphine/metabolite
Oxycodone/oxymorphone
Cannabinoids
Phencyclidine
Cocaine/metabolites
Cotinine
Alcohol Screen
Subjects will undergo a urine alcohol test. An alcohol breath test may be performed at the discretion of the 
investigator.
Screening - Serum
β–human chorionic gonadotropin (women only)
FSH (women only).
HIV test
Hepatitis panel, including hepatitis B surface antigen 
and anti-hepatitis C virus.


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Appendix C
Criteria for Identification of Markedly Abnormal Laboratory Values
Hematology—Criteria for Markedly Abnormal Values
Parameter
Unit
Low Abnormal
High Abnormal
Hemoglobin
Both 
<0.8 × LLN
>1.2 × ULN
Hematocrit
Both
<0.8 × LLN
>1.2 × ULN
RBC count 
Both
<0.8 × LLN 
>1.2 × ULN
WBC count 
Both 
<0.5 x LLN
>1.5 x ULN
Platelet count
Conventional
<75 x 103/L
>600 x 103/L
SI
<75 x 109/L
>600 x 109/L
LLN=lower limit of normal, RBC=red blood cell, ULN=upper limit of normal, WBC=white blood cell. 
Serum Chemistry—Criteria for Markedly Abnormal Values
Parameter
Unit 
Low Abnormal
High Abnormal
ALT
Both
--
>3x ULN
AST
Both
--
>3x ULN
GGT
Both
--
>3x ULN
Alkaline phosphatase
Both
--
>3x ULN
Total bilirubin
Conventional
--
>2.0 mg/dL
SI
--
>34.2 mol/L
Albumin
Conventional 
<2.5 g/dL
--
SI 
<25 g/L
--
Total protein
Both
<0.8x LLN
>1.2x ULN
Creatinine
Conventional 
--
>2.0 mg/dL
SI
>177 mol/L
Blood urea nitrogen
Conventional 
>30 mg/dL
SI
>10.7 mmol/L
Sodium
Conventional
<130 mEq/L
>150 mEq/L
SI
<130 mmol/L
>150 mmol/L
Potassium
Conventional
<3.0 mEq/L
>6.0 mEq/L
SI
<3.0 mmol/L
>6.0 mmol/L
Glucose
Conventional
<50 mg/dL
>350 mg/dL
SI
<2.8 mmol/L
>19.4 mmol/L
Chloride
Conventional
<75 mEq/L
>126 mEq/L
SI
<75 mmol/L
>126 mmol/L
Calcium
Conventional 
<7.0 mg/dL
>11.5 mg/dL
SI
<1.75 mmol/L
>2.88 mmol/L
Carbon dioxide
Conventional 
<8.0 mEq/L
SI 
<8.0 mmol/L
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=-glutamyl transferase, LLN=lower limit of 
normal, ULN=upper limit of normal.


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Appendix D
Criteria for Abnormal Changes from Baseline of Vital Signs
Parameter
Unit
Lower Criteria
Upper Criteria
Pulse
bpm
<50 
>120
Systolic blood pressure
mm Hg
<85
>180 
Diastolic blood pressure
mm Hg
<50
>110
Body temperature
oC
<35.6
>37.7


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Appendix E
Criteria for Markedly Abnormal Values for the 12-Lead ECG Parameters
Parameter
Lower Criteria
Upper Criteria
Heart rate
<50 beats per minute
>120 beats per minute
PR
≤120 milliseconds
≥200 milliseconds
QT Interval
≤300 milliseconds
≥460 milliseconds
QTcF Interval
≤300 milliseconds
≥500 milliseconds OR
≥30 milliseconds change from baseline and
≥450 milliseconds
QRS
≤60 milliseconds
≥120 milliseconds


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